Acute Pulmonary Embolism (PE)


Epidemiology

Incidence

  • The Incidence of Pulmonary Embolism Has Increased with the Increased Use of Computed Tomography (CT) Pulmonary Artery Angiogram for the Diagnosis of Pulmonary Embolism (see Computed Tomography Pulmonary Artery Angiogram)
    • Increasing Incidence of Acute Pulmonary Embolism (Arch Intern Med, 2011) [MEDLINE]
      • 1993-1998: 62 cases per 100k
      • 1998-2005: 112 cases per 100k
    • Autopsy Incidence of Acute Pulmonary Embolism: evidence of old PE is found in 25-30% of all autopsies


Risk Factors for Venous Thromboembolism

General Comments

  • Risk Factors are the Same for Both Deep Venous Thrombosis (DVT) and Acute Pulmonary Embolism (PE) (see Deep Venous Thrombosis and Acute Pulmonary Embolism)
    • Risk Factor Can Be Identified in >80% of Patients with Deep Venous Thrombosis
      • More than One Factor May Often Be Present
      • 50% of Thrombotic Events in Patients with Inherited Hypercoagulable States are Associated with an Additional Risk Factor (Pregnancy, Surgery, Prolonged Immobilization, Oral Contraceptives)

Inherited Hypercoagulable States (see Hypercoagulable States)

  • General Comments
    • Factor V Leiden Gene Mutation and Prothrombin Gene Mutation Account for 50-60% of Inherited (Primary) Hypercoagulable States
  • Antithrombin Deficiency (see Antithrombin Deficiency)
  • Dysfibrinogenemia (see Dysfibrinogenemia)
    • Epidemiology
      • Rare
  • Factor V Leiden (see Factor V Leiden)
    • Epidemiology
      • Factor V Leiden is the Most Common Inherited Hypercoagulable State in Caucasian Populations
    • Diagnosis
      • Abnormal Activated Protein C (APC) Resistance Assay
  • Factor XII Deficiency (see Factor XII Deficiency)
    • Epidemiology
      • Rare
  • Family History of Venous Thromboembolism
    • Epidemiology
      • Strong Risk Factor
  • Heparin Cofactor II Deficiency
    • Epidemiology
      • Unclear Risk Factor for Venous Thromboembolism
      • Rare
  • Hereditary Hemorrhagic Telangiectasia (HHT) (Osler-Weber-Rendu Syndrome) (see Hereditary Hemorrhagic Telangiectasia)
    • Epidemiology
      • Associated with Decreased Serum Iron Levels and Increased Plasma Factor VIII Levels (Thorax, 2012) [MEDLINE]
    • Physiology
      • Associated with Decreased Serum Iron Levels (Due to Inadequate Replacement of Hemorrhagic Iron Loss) and Increased Plasma Factor VIII Levels (Thorax, 2012) [MEDLINE]
  • Homocystinuria
    • Clinical
      • May Result in Both Venous and Arterial Thromboses
  • Increased Factor VIII Coagulant Activity
    • Epidemiology
      • Rare
  • Plasminogen Deficiency
    • Epidemiology
      • Unclear Risk Factor for Venous Thromboembolism
  • Protein C Deficiency (see Protein C Deficiency)
  • Protein S Deficiency (see Protein S Deficiency)
  • Prothrombin G20210A Gene Mutation (see Prothrombin G20210A Gene Mutation)
    • Epidemiology
      • Second Most Common Inherited Hypercoagulable State (After Factor V Leiden)
    • Diagnosis
      • Abnormal Activated Protein C (APC) Resistance Assay
  • Race/Ethnicity
    • Epidemiology
      • Data from the California Patient Discharge Dataset Indicate that Race/Ethnicity are Associated with the Risk of Venous Thromboembolism (Thromb Res, 2009) [MEDLINE]
        • Asians/Pacific Islanders and Hispanics Have a Lower Incidence of Venous Thromboembolism, as Compared to Non-Hispanic Whites
        • Blacks/African Americans Have a Higher Incidence of Venous Thromboembolism of Venous Thromboembolism, as Compared to Non-Hispanic Whites
      • Multivariable Cox Proportional Hazards Regression Model Study of the Relationship Between Race/Ethnicity and Risk of Cancer-Associated Thrombosis (Data from the California Cancer Registry) (Blood Adv, 2022) [MEDLINE]: n = 942, 109 (with the 13 Most Common, First Primary Malignancies)
        • Blacks/African Americans Had a Higher Incidence of Cancer-Associated Thrombosis for All Tumor Types (Except Multiple Myeloma), as Compared with Non-Hispanic Whites, After Adjusting for Potential Confounders
        • Asians/Pacific Islanders Had a Lower Incidence of Cancer-Associated Thrombosis, as Compared with Non-Hispanic Whites, After Adjusting for Potential Confounders
        • The Main Driver for the Racial/Ethnic Differences was the Incidence of Acute Pulmonary Embolism
        • Authors Speculated the Association of Race/Ethnicity with Incidence of Cancer-Associated Thrombosis May Be Partially Because of Underlying Thrombotic Predisposition Which Varies by Ancestry, But They Also Considered the Potential Impact of Social Determinants of Health Which Might Impact the Findings

Acquired Hypercoagulable States (see Hypercoagulable States)

Cardiovascular Disease

  • Acute Myocardial Infarction (Within Prior 3 Months) (see Coronary Artery Disease)
    • Epidemiology
      • Myocardial Infarction (in Prior 3 Months) is a Strong Risk Factor for Venous Thromboembolism (with Odds Ratio >10) (Eur Heart J, 2020) [MEDLINE]
  • Atrial Fibrillation/Flutter (see Atrial Fibrillation and Atrial Flutter)
    • Epidemiology
      • Hospitalization for Atrial Fibrillation/Flutter (within Prior 3 Months) is a Strong Risk Factor for Venous Thromboembolism (with Odds Ratio >10) (Eur Heart J, 2020) [MEDLINE]
  • Congestive Heart Failure (CHF) (see Congestive Heart Failure)
    • Epidemiology
      • Congestive Heart Failure Itself is a Moderate Risk Factor for Venous Thromboembolism (with Odds Ratio >2-9) (Eur Heart J, 2020) [MEDLINE]
      • Hospitalization for Congestive Heart Failure (within Prior 3 Months) is a Strong Risk Factor for Venous Thromboembolism (with Odds Ratio >10) (Eur Heart J, 2020) [MEDLINE]
  • Hypertension (see Hypertension)
    • Epidemiology
      • Longitudinal Investigation of Thromboembolism Etiology (LITE) Study Indicated that Alcohol Use, Hypertension, Hyperlipidemia, Physical Inactivity, and Tobacco Abuse were Not Associated with an Increased Risk of Venous Thromboembolism (Arch Intern Med, 2002) [MEDLINE]
      • Meta-Analysis Indicated that Obesity (Risk 2.33), Hypertension (Risk 1.51), Diabetes Mellitus (Risk 1.42), Smoking (Risk 1.15), and Hypercholesterolemia (Risk 1.16) Increased the Risk of Venous Thromboembolism (Circulation, 2008) [MEDLINE]
      • Hypertension is a Weak Risk Factor for Venous Thromboembolism (with Odds Ratio <2) (Eur Heart J, 2020) [MEDLINE]

Central Venous Catheter/Lead/Device

  • Central Venous Catheter (CVC) (see Central Venous Catheter)
    • Epidemiology
      • Central Venous Catheters/Leads are a Moderate Risk for Venous Thromboembolism (Odds Ratio 2-9) (Eur Heart J, 2020) [MEDLINE]
  • Peripherally Inserted Central Catheter (PICC) (see Peripherally Inserted Central Catheter)
    • Epidemiology
      • Meta-Analysis Comparing PICC Line with Central Venous Catheter (Lancet, 2013) [MEDLINE]
        • PICC Lines Had a Higher Risk of Venous Thrombosis than Central Venous Catheters, Especially in Patients Who are Critically Ill or in Those with Cancer
        • PICC Lines Had No Increased Risk of Acute Pulmonary Embolism

Chronic Myeloproliferative Disease (see Chronic Myeloproliferative Diseases)

  • Essential Thrombocythemia (see Essential Thrombocythemia)
    • Diagnosis
      • Some Cases Manifest Abnormal Activated Protein C (APC) Resistance Assay
    • Clinical
      • May Result in Both Venous and Arterial Thromboses
  • Polycythemia Vera (see Polycythemia Vera)
    • Epidemiology
      • Venous Thrombosis Occurs in 7% of Polycythemia Vera Cases (Leukemia, 2013) [MEDLINE]
    • Physiology
      • Hyperviscosity and Qualitative Platelet Defects
    • Diagnosis
      • Some Cases Manifest Abnormal Activated Protein C (APC) Resistance Assay
    • Clinical
      • May Result in Both Venous and Arterial Thromboses

Endocrinologic Therapy/Disease

  • Diabetes Mellitus (DM) (see Diabetes Mellitus)
    • Epidemiology
      • Longitudinal Investigation of Thromboembolism Etiology (LITE) Study Demonstrated that Diabetes Mellitus Increased the Risk of Venous Thromboembolism (Adjusted Hazard Ratio 1.5) (Arch Intern Med, 2002) [MEDLINE]
      • Meta-Analysis Indicated that Obesity (Risk 2.33), Hypertension (Risk 1.51), Diabetes Mellitus (Risk 1.42), Smoking (Risk 1.15), and Hypercholesterolemia (Risk 1.16) Increased the Risk of Venous Thromboembolism (Circulation, 2008) [MEDLINE]
      • Diabetes Mellitus is a Weak Risk Factor for Venous Thromboembolism (with Odds Ratio <2) (Eur Heart J, 2020) [MEDLINE]
  • Hormonal Therapy: see Drug/Toxin below
  • In Vitro Fertilization
    • Epidemiology
      • In Vitro Fertilization is a Moderate Risk Factor for Venous Thromboembolism (with Odds Ratio >2-9) (Eur Heart J, 2020) [MEDLINE]
  • Ovarian Hyperstimulation Syndrome (see Ovarian Hyperstimulation Syndrome)
    • Physiology
      • Due to Capillary Leak Syndrome with Hemoconcentration
  • Polycystic Ovary Syndrome (see Polycystic Ovary Syndrome)
  • Pregnancy (see Pregnancy)
    • Epidemiology
      • Pregnancy Itself is a Weak Risk Factor for Venous Thromboembolism (with Odds Ratio <2) (Eur Heart J, 2020) [MEDLINE]
      • Postpartum Period is a Moderate Risk Factor for Venous Thromboembolism (with Odds Ratio >2-9) (Eur Heart J, 2020) [MEDLINE]
      • Incidence of Deep Venous Thrombosis is Roughly Equal Throughout Pregnancy
        • First Trimester: 22%
        • Second Trimester: 41%
        • Third Trimester: 37%
      • Incidence of Acute Pulmonary Embolism During Pregnancy
        • Prepartum: 34%
        • Postpartum: 66% (with 82% of these occurring following C-section)
      • Physiology
        • Increased Risk of Deep Venous Thrombosis in Left Leg During Pregnancy (Possibly Due to Left Common Iliac Vein Compression by the Overlying Right Iliac Artery)
    • Diagnosis
      • Some Cases Manifest Abnormal Activated Protein C (APC) Resistance Assay
    • Treatment
      • Aspirin Does Not Affect the Risk of Deep Venous Thrombosis in Pregnancy (Even in the Presence of Antiphospholipid Antibody Syndrome)

Gastrointestinal/Hepatic Disease

  • Inflammatory Bowel Disease (see Inflammatory Bowel Disease)
    • General Comments
      • Inflammatory Bowel Disease is a Moderate Risk Factor for Venous Thromboembolism (with Odds Ratio >2-9) (Eur Heart J, 2020) [MEDLINE]
    • Crohn’s Disease (see Crohn’s Disease)
    • Ulcerative Colitis (UC) (see Ulcerative Colitis)
  • Liver Disease (see Cirrhosis)
    • Epidemiology
      • There is a High (6.3%) Risk of Venous Thromboembolism in Hospitalized Liver Disease Patients, Despite Abnormal Coagulation Parameters (Chest, 2010) [MEDLINE]

Hyperviscosity Syndrome

Immobilization

  • Bedrest
    • Epidemiology
      • Bedrest >3 Days is a Weak Risk Factor for Venous Thromboembolism (with Odds Ratio <2) (Eur Heart J, 2020) [MEDLINE]
  • Critical Illness (Especially with Mechanical Ventilation)
    • Epidemiology
      • Risk of Deep Venous Thrombosis in Mechanically-Ventilated Patients is 5-10%, Despite Adequate DVT Prophylaxis (J Intensive Care Med, 2006) [MEDLINE] (Crit Care MED, 2005) [MEDLINE] (NEJM, 2011) [MEDLINE]
  • Extended Travel (“Travelers’ Thrombosis”)
    • Epidemiology
      • Travel (Air, Train, Auto) for >4 hrs is Associated with Increased Risk of Deep Venous Thrombosis (Aviat Space Environ Med, 2014) [MEDLINE]
      • Incidence of Pulmonary Embolism Following Air Travel is Correlated with the Distance Traveled (NEJM, 2001) [MEDLINE]
      • Extended Travel is a Weak Risk Factor for Venous Thromboembolism (with Odds Ratio <2) (Eur Heart J, 2020) [MEDLINE]
  • Lower Extremity Fracture/Injury
    • Epidemiology
      • Lower Extremity Fracture is a Strong Risk Factor for Venous Thromboembolism (with Odds Ratio >10) (Eur Heart J, 2020) [MEDLINE]

Infection

  • General Comments
    • Infection (Particularly Pneumonia, Urinary Tract Infection, and Human Immunodeficiency Virus Infection) is a Moderate Risk Factor for Venous Thromboembolism (with Odds Ratio >2-9) (Eur Heart J, 2020) [MEDLINE]
  • Human Immunodeficiency Virus (HIV) (see Human Immunodeficiency Virus)
  • Sepsis (see Sepsis)
    • Epidemiology
      • Multicenter Prospective Study of Risk Factors for and Incidence of Venous Thromboembolism in Severe Sepsis/Septic Shock (Chest, 2015) [MEDLINE]
        • Despite Guideline-Recommended DVT Prophylaxis, the Incidence of Venous Thromboembolism was 37.2% in Patients with Severe Sepsis/Septic Shock
        • Most Venous Thromboembolism Events were Clinically Significant (Defined as Pulmonary Embolism, Proximal DVT, and/or Symptomatic Distal DVT) and were Associated with an Increased Length of Stay (18.2 ± 9.9 days vs 13.4 ± 11.5 days, P < 0.05)
        • Mortality was Higher in Patients with Acute Venous Thromboembolism, But this Did Not Reach Statistical Significance
        • Insertion of a CVC and Longer Mechanical Ventilation Duration were Significant Venous Thromboembolism Risk Factors
        • There was No Difference in the Incidence of Venous Thromboembolism Incidence Between Patients Receiving Pharmacologic Prophylaxis vs Sequential Compression Devices (37.3% vs 36.3%)
        • There was No Difference in the Incidence of Venous Thromboembolism Incidence Between Patients Receiving Low Molecular Weight Heparin Prophylaxis vs Unfractionated Heparin Prophylaxis (33.3% vs 41.3%)
  • Severe Acute Respiratory Syndrome Coronavirus-2 (SARS CoV-2) (see Severe Acute Respiratory Syndrome Coronavirus-2)
    • Epidemiology
      • In a Multicenter Prospective Cohort Study of Patients with Acute Respiratory Distress Syndrome (ARDS), Patients with SARS CoV-2-Associated ARDS Had a Significantly Higher Incidence of Acute Pulmonary Embolism, as Compared to Non-SARS CoV-2-Associated ARDS (11.7% vs 2.1%, p < 0.008) (Intensive Care Med, 2020) [MEDLINE]
      • High Relative Incidence of Vascular Thrombotic Events Soon After SARS CoV-2 Diagnosis Declines More Rapidly for Arterial Thromboses than for Venous Thromboembolism (Circulation, 2022) [MEDLINE]
        • However, Incidence of Vascular Thrombotic Events Remains Elevated Up to 49 wks After SARS CoV-2 Diagnosis
  • Tuberculosis (Active) (see Tuberculosis)
    • Epidemiology
      • There May Be an Association Between Tuberculosis and Venous Thromboembolism (Asian Cardiovasc Thorac Ann, 2014) [MEDLINE]
  • Varicella-Zoster Virus (VZV) (see Varicella-Zoster Virus)
    • Epidemiology
      • Varicella-Zoster Virus Infection-Associated Stroke and Deep Venous Thrombosis Have Been Rarely Reported in Children (Pediatr Infect Dis J, 2015) [MEDLINE]

Malignancy

  • General Comments
    • Malignancy Imparts a 4 to 7-Fold Increased Risk of Developing Venous Thromboembolism, as Compared to the General Population (Med Insights Oncol, 2014) [MEDLINE]
    • Cancer (Particularly Metastatic Cancer) is a Moderate Risk Factor for Venous Thromboembolism (with Odds Ratio >2-9) (Eur Heart J, 2020) [MEDLINE]
    • Incidence of Cancer-Associated Thrombosis Varies by Tumor Type, Stage at Diagnosis, Type of Therapy, and Patient Comorbidities (Blood Adv, 2022) [MEDLINE]
    • Risk of Venous Thrombembolism in Course of Cancer is Highest During the Initial Hospitalization, at the Onset of Chemotherapy, and at the Time of Disease Progression
    • Presence of a Central Venous Catheter Further Compounds the Risk of Malignancy-Associated Venous Thromboembolism
    • Most Cancers (78%) are Diagnosed Before the Diagnosis of the Deep Venous Thrombosis
  • Common Sites of Malignancies at Time of Venous Thromboembolism Diagnosis
    • Lung Cancer (see Lung Cancer): 17% of cases develop venous thromboembolism
    • Pancreatic Cancer (see Pancreatic Cancer): 10% of cases develop venous thromboembolism
    • Colorectal Cancer (see Colorectal Cancer): 8% of cases develop venous thromboembolism
    • Renal Cancer (Renal Cancer): 8% of cases develop venous thromboembolism
    • Prostate Cancer (Prostate Cancer): 7% of cases develop venous thromboembolism

Neurologic Disease

  • Ischemic Cerebrovascular Accident (CVA) (Within Prior 3 Months) (see Ischemic Cerebrovascular Accident)
    • Epidemiology
      • Stroke with Paralysis is a Moderate Risk Factor for Venous Thromboembolism (with Odds Ratio >2-9) (Eur Heart J, 2020) [MEDLINE]

Obesity (see Obesity)

  • Epidemiology
    • Longitudinal Investigation of Thromboembolism Etiology (LITE) Study Demonstrated that Obesity Increased the Risk of Venous Thromboembolism Using Age/Race/Sex-Adjusted Hazard Ratios for BMI (BMI <25 = 1.0, BMI 25-30 = 1.5, BMI 30-35 = 2.2, BMI 35-40 = 1.5, and BMI ≥40 = 2.7) (Arch Intern Med, 2002) [MEDLINE]
    • Meta-Analysis Indicated that Obesity (Risk 2.33), Hypertension (Risk 1.51), Diabetes Mellitus (Risk 1.42), Smoking (Risk 1.15), and Hypercholesterolemia (Risk 1.16) Increased the Risk of Venous Thromboembolism (Circulation, 2008) [MEDLINE]
    • Obesity Increased the Risk of Pulmonary Embolism (Relative Risk 2.03), But Decreased the Mortality of Pulmonary Embolism in Hospitalized Patients (Thromb Res, 2011) [MEDLINE]
    • Obesity is a Weak Risk Factor for Venous Thromboembolism (with Odds Ratio <2) (Eur Heart J, 2020) [MEDLINE]

Renal Disease

Rheumatologic Disease/Autoimmune Disease/Vasculitis (see Vasculitis)

  • General Comments
    • Autoimmune Disease is a Moderate Risk for Venous Thromboembolism (Odds Ratio 2-9) (Eur Heart J, 2020) [MEDLINE]
  • Behcet’s Disease (see Behcet’s Disease)
    • Clinical
      • Arterial/Venous Thrombosis May Occur in Behcet’s Disease (Clin Exp Rheumatol, 2018) [MEDLINE]
  • Eosinophilic Granulomatosis with Polyangiitis (EGPA) (Churg-Strauss Syndrome) (see Eosinophilic Granulomatosis with Polyangiitis)
  • Giant Cell Arteritis (Temporal Arteritis, Horton Disease, Cranial Arteritis) (see Giant Cell Arteritis)
    • Epidemiology
      • Incidence of Venous Thromboembolism (DVT or PE) was 13.3 per 1000 Person-Years with Incidence Rate Ratio of 3.58 (2.33-5.34, CI 95%) (Ann Rheum Dis, 2016) [MEDLINE]
  • Granulomatosis with Polyangiitis (GPA) (Wegener’s Granulomatosis) (see Granulomatosis with Polyangiitis)
  • Microscopic Polyangiitis (see Microscopic Polyangiitis)
  • Psoriasis (Chronic) (see Psoriasis)
  • Rheumatoid Arthritis (RA) (see Rheumatoid Arthritis)
  • Scleroderma (see Scleroderma)
    • Epidemiology
      • Scleroderma Increases the Risk of Venous Thromboembolism (Rheumatology-Oxford, 2014) [MEDLINE] (Arthritis Care Res-Hoboken, 2016) [MEDLINE]
      • Increased Risk Appears to Be the Highest in the First Year After the Diagnosis of Scleroderma
  • Systemic Lupus Erythematosus (SLE) (see Systemic Lupus Erythematosus)
    • Physiology
      • Hypercoagulability is Believed to Be Related to Impaired Fibrinolysis (Semin Thromb Hemost, 2013) [MEDLINE]

Surgery

  • Cancer Surgery
  • Laparoscopic Surgery
    • Epidemiology
      • Laparoscopic Surgery is a Weak Risk Factor for Venous Thromboembolism (with Odds Ratio <2) (Eur Heart J, 2020) [MEDLINE]
  • Major Vascular Surgery
  • Neurosurgery
  • Orthopedic Surgery
    • Arthroscopic Knee Surgery
      • Arthroscopic Knee Surgery is a Moderate Risk for Venous Thromboembolism (Odds Ratio 2-9) (Eur Heart J, 2020) [MEDLINE]
    • Total Hip Arthroplasty (see Total Hip Arthroplasty)
      • 30-day Risk of Symptomatic Non-Fatal Venous Thromboembolism is 2.5% (NEJM, 2000) [MEDLINE] (Lancet, 2001) [MEDLINE]
      • Total Hip Replacement is a Strong Risk Factor for Venous Thromboembolism (with Odds Ratio >10) (Eur Heart J, 2020) [MEDLINE]
    • Total Knee Arthroplasty (see Total Knee Arthroplasty)
      • 30-Day Risk of Symptomatic Non-Fatal Venous Thromboembolism is 1.4% (NEJM, 2000) [MEDLINE] (Lancet, 20001) [MEDLINE]
      • Total Knee Replacement is a Strong Risk Factor for Venous Thromboembolism (with Odds Ratio >10) (Eur Heart J, 2020) [MEDLINE]

Trauma

  • Spinal Cord Injury (SCI) (see Spinal Cord Injury)
    • Epidemiology
      • Spinal Cord Injury is a Strong Risk Factor for Venous Thromboembolism (with Odds Ratio >10) (Eur Heart J, 2020) [MEDLINE]
  • Trauma of Any Etiology
    • Epidemiology
      • Major Trauma is a Strong Risk Factor for Venous Thromboembolism (with Odds Ratio >10) (Eur Heart J, 2020) [MEDLINE]
    • Physiology
      • Decreased Lower Extremity Venous Blood Flow, Decreased Fibrinolysis, and Immobilization

Vascular Disease

  • Congenital Venous Malformation of the Inferior Vena Cava
  • Lower Extremity Venous Insufficiency (see Lower Extremity Chronic Venous Disease)
  • May-Thurner Syndrome (May-Thurner Syndrome)
    • Physiology
      • Compression of the Left Common Iliac Vein Between the Overlying Right Common Iliac Artery and Underlying Vertebral Body
  • Paget-Schroetter Syndrome (see Paget-Schroetter Syndrome)
    • Physiology
      • Underlying Venous Compression at the Thoracic Outlet
  • Superficial Thrombophlebitis/Superficial Venous Thrombosis (SVT) (see Superficial Venous Thrombosis)
    • Epidemiology
      • Superficial Venous Thrombosis May Occur in Patients with Inherited/Acquired Hypercoagulable States
      • Superficial Venous Thrombosis a Moderate Risk Factor for Venous Thromboembolism (with Odds Ratio >2-9) (Eur Heart J, 2020) [MEDLINE]
    • Clinical
      • Occult Deep Venous Thrombosis: occult deep venous thrombosis is present in 7-32% of superficial thrombophlebitis cases (suggests that screening of these patients with lower extremity dopplers may be warranted)
      • Recurrence of Superficial Venous Thrombosis: 24% of cases have recurrent superficial venous thrombosis (Thromb Haemost, 1999) [MEDLINE]
      • Later Development of Deep Venous Thrombosis: 32% of superficial venous thrombosis cases develop deep venous thrombosis at median interval of 4 years (Thromb Haemost, 1999) [MEDLINE]
  • Varicose Veins (see Varicose Veins)
    • Epidemiology
      • Varicose Veins are a Weak Risk Factor for Venous Thromboembolism (with Odds Ratio <2) (Eur Heart J, 2020) [MEDLINE]

Drug/Toxin

  • Bevacizumab (Avastin) (see Bevacizumab)
    • Epidemiology
      • Two-Fold Increased Risk of Thromboembolic Disease
    • Physiology
      • MayBe Due to Vascular Injury
    • Clinical
      • May Result in Both Venous and Arterial Events
  • Blood Transfusion
    • Epidemiology
      • Blood Transfusion is a Moderate Risk for Venous Thromboembolism (Odds Ratio 2-9) (Eur Heart J, 2020) [MEDLINE]
  • Chemotherapy
    • Epidemiology
      • Chemotherapy is a Moderate Risk for Venous Thromboembolism (Odds Ratio 2-9) (Eur Heart J, 2020) [MEDLINE]
  • Corticosteroids (see Corticosteroids)
    • Epidemiology
      • Dutch Population-Based Case-Control Study of Danish Adults (Over 7 Year Period) [MEDLINE]: n= 38,765 Danish adults who developed venous thromboembolism (with n = 387,650 controls)
        • Systemic vs Non-Systemic Steroids: risk of venous thromboembolism was highest with use of systemic glucocorticoids, as compared to a relatively lower risk with inhaled or gastrointestinal glucocorticoids
        • Time of Onset-Related Effect: risk of venous thromboembolism was highest with new use of glucocorticoids (incidence ratio 3.06), as compared to continuing or past use
        • Dose-Effect: risk of venous thromboembolism increased with increasing cumulative doses of the glucocorticoids
        • Possible Study Flaws Include that the Study Did Not Fully Account for All of the Confounding Risks of Venous Thromboembolism Related to the Underlying Disease Itself (For Which the Glucocorticoids were Prescribed): consequently, the underlying disease may have increased the risk of venous thromboembolism or the increased risk of immobility (which could indirectly increase the risk of venous thromboembolism)
      • United States Population-Based Retrospective Cohort Study of the Risks of Short-Term Corticosteroid Use in Adults (BMJ, 2017) [MEDLINE]
        • One in Five American Adults in a Commercially-Insured Plan were Given at Least One Outpatient Short-Term Corticosteroid Course During the Three Year Study (2012-2014): mostly for upper respiratory tract infections, spinal conditions, and allergies
        • Within 30 Days of Initiation, Short-Term Use of Corticosteroids Increased the Risk of Sepsis (Incidence Rate Ratio 5.30, 95% CI: 3.80-7.41), Venous Thromboembolism (Incidence Rate Ratio 3.33, 95% CI: 2.78-3.99), and Fractures (Incidence Rate Ratio 1.87, 95% CI: 1.69-2.07): increased risk persisted at prednisone equivalent doses of <20 mg/day (incidence rate ratio 4.02 for sepsis, 3.61 for venous thromboembolism, and 1.83 for fracture)
  • Erythropoiesis-Stimulating Agents
    • Epidemiology
      • Erythropoiesis-Stimulating Agents are a Moderate Risk Factor for Venous Thromboembolism (with Odds Ratio >2-9) (Eur Heart J, 2020) [MEDLINE]
    • Agents
  • Heparin-Induced Thrombocytopenia (HIT) (see Heparin)
    • Clinical
      • May Result in Both Venous and Arterial Thromboses
  • Hormone Replacement Therapy (see Estrogen)
    • Epidemiology
      • Hormone Replacement Therapy is a Moderate Risk Factor for Venous Thromboembolism (with Odds Ratio >2-9) (Eur Heart J, 2020) [MEDLINE]
    • Diagnosis
      • Some Cases Manifest Abnormal Activated Protein C (APC) Resistance Assay
    • Clinical
      • May Result in Both Venous and Arterial Thromboses
  • Injection Drug Abuse (see Injection Drug Abuse)
    • Physiology
      • Due to Femoral Injection of Drugs
  • Lenalidomide (Revlimid) (see Lenalidomide)
    • Epidemiology
      • Risk of Venous Thromboembolism is Higher in Multiple Myeloma Patients Who Receive Thalidomide or Lenalidomide (Especially in Combination with Dexamethasone or Chemotherapy) (Leukemia, 2008) [MEDLINE]
  • Nonsteroidal Anti-Inflammatory Drugs (NSAID’s) (see Nonsteroidal Anti-Inflammatory Drug)
    • Epidemiology
      • In a Systematic Review and Meta-Analysis, NSAID’s Increased the Risk of Venous Thromboembolism with Relative Risk of 1.80 (95% CI: 1.28-2.52) (Rheumatology, 2015) [MEDLINE]
  • Oral Contraceptives (OCP) (see Oral Contraceptives)
    • Epidemiology
      • Oral Contraceptives are a Moderate Risk Factor for Venous Thromboembolism (with Odds Ratio >2-9) (Eur Heart J, 2020) [MEDLINE]
    • Diagnosis
      • Some Cases Manifest Abnormal Activated Protein C (APC) Resistance Assay
    • Clinical
      • May Result in Both Venous and Arterial Thromboses
  • Prothrombin Complex Concentrate-3 Factor (Profilnine SD) (see Prothrombin Complex Concentrate-3 Factor)
  • Prothrombin Complex Concentrate-4 Factor (Kcentra, Beriplex, Confidex) (see Prothrombin Complex Concentrate-4 Factor)
  • Tamoxifen (see Tamoxifen)
    • Clinical
      • May Result in Both Venous and Arterial Thromboses
  • Testosterone (see Testosterone)
  • Thalidomide (see Thalidomide)
  • Tobacco Abuse (see Tobacco)
    • Epidemiology
      • Longitudinal Investigation of Thromboembolism Etiology (LITE) Study Indicated that Alcohol Use, Hypertension, Hyperlipidemia, Physical Inactivity, and Tobacco Abuse were Not Associated with an Increased Risk of Venous Thromboembolism (Arch Intern Med, 2002) [MEDLINE]
      • Meta-Analysis Indicated that Obesity (Risk 2.33), Hypertension (Risk 1.51), Diabetes Mellitus (Risk 1.42), Smoking (Risk 1.15), and Hypercholesterolemia (Risk 1.16) Increased the Risk of Venous Thromboembolism (Circulation, 2008) [MEDLINE]
  • Tofacitinib (Xeljanz) (see Tofacitinib)
    • Epidemiology
      • Increased Risk of Pulmonary Embolism Has Been Reported with Higher Tofacitinib Doses (10 mg BID) (JAMA, 2019) [MEDLINE]
        • The High Dose 10 mg BID Regimen is FDA-Approved Only for Ulcerative Colitis (see Ulcerative Colitis)

Other

  • Acquired Thrombotic Thrombocytopenic Purpura (TTP) (see Thrombotic Thrombocytopenic Purpura-Acquired)
    • Clinical
      • May Result in Both Venous and Arterial Thromboses
  • Activated Protein C (APC) Resistance (Non-Genetic)
  • Age
    • Epidemiology
      • Hazard Ratio of 1.7 (95% Confidence Interval: 1.5 to 2.0) for Every Decade of Life After Age 55 (Arch Intern Med, 2002) [MEDLINE]
      • Increased Age is a Weak Risk Factor for Venous Thromboembolism (with Odds Ratio <2) (Eur Heart J, 2020) [MEDLINE]
  • Antiphospholipid Antibody Syndrome (see Antiphospholipid Antibody Syndrome)
    • Diagnosis
      • Some Cases Manifest Abnormal Activated Protein C (APC) Resistance Assay
    • Clinical
      • May Result in Both Venous and Arterial Thromboses
  • Asthma (see Asthma)
  • Disseminated Intravascular Coagulation (DIC) (see Disseminated Intravascular Coagulation)
    • Clinical
      • May Result in Both Venous and Arterial Thromboses
  • Hyperhomocysteinemia (see Hyperhomocysteinemia)
  • Hyperlipidemia (see Hyperlipidemia)
    • Epidemiology
      • Longitudinal Investigation of Thromboembolism Etiology (LITE) Study Indicated that Alcohol Use, Hypertension, Hyperlipidemia, Physical Inactivity, and Tobacco Abuse were Not Associated with an Increased Risk of Venous Thromboembolism (Arch Intern Med, 2002) [MEDLINE]
      • Meta-Analysis Indicated that Obesity (Risk 2.33), Hypertension (Risk 1.51), Diabetes Mellitus (Risk 1.42), Smoking (Risk 1.15), and Hypercholesterolemia (Risk 1.16) Increased the Risk of Venous Thromboembolism (Circulation, 2008) [MEDLINE]
  • Obstructive Sleep Apnea (OSA) (see Obstructive Sleep Apnea)
  • Paroxysmal Nocturnal Hemoglobinuria (PNH) (see Paroxysmal Nocturnal Hemoglobinuria)
    • Clinical
      • May Result in Both Venous and Arterial Thromboses
  • Prior Thrombotic Event
    • Epidemiology
      • Prior Venous Thromboembolism is a Strong Risk Factor for Venous Thromboembolism (with Odds Ratio >10) (Eur Heart J, 2020) [MEDLINE]
  • Respiratory Failure (see Respiratory Failure)
    • Epidemiology
      • Respiratory Failure is a Moderate Risk Factor for Venous Thromboembolism (with Odds Ratio >2-9) (Eur Heart J, 2020) [MEDLINE]


Physiology

Virchow’s Triad: Contributors to the Development of Venous Thromboembolism

  • Alteration in Blood Flow
    • Stasis
  • Vascular Endothelial Injury
  • Alteration in Constituents of Blood

Lower Extremity Venous Anatomy

Superficial Veins

  • Greater Saphenous Vein Above or Below the Knee
  • Non-Saphenous Veins
  • Small Saphenous Vein
  • Telangiectasias/Reticular Veins

Deep Veins

  • Proximal
    • Inferior Vena Cava (IVC)
    • Iliac Veins
      • Common Iliac Vein
      • External Iliac Vein
      • Internal Iliac Vein
    • Pelvic Veins
      • Broad Ligament Vein
      • Gonadal Vein
      • Other Pelvic Vein
    • Femoral Veins
      • Common Femoral Vein
      • Deep Femoral Vein
    • Popliteal Vein
  • Distal
    • Crural Calf Veins
      • Anterior Tibial Vein: less common site of distal deep venous thrombosis
      • Posterior Tibial Vein: more common site of distal deep venous thrombosis
      • Peroneal Vein: more common site of distal deep venous thrombosis
    • Muscular Calf Veins: less common site of distal deep venous thrombosis
      • Gastrocnemius Vein
      • Soleal Vein
      • Other Muscular Calf Vein

Perforator Veins

  • Thigh Perforator Vein
  • Calf Perforator Vein

Upper Extremity Venous Anatomy

Superficial Veins

  • Basilic Vein
  • Cephalic Vein
  • Median Antebrachial Vein
  • Median Antecubital Vein
  • Accessory Cephalic Vein

Deep Veins

  • Radial Vein
  • Ulnar Vein
  • Interosseous Vein (In the Forearm)
  • Brachial Vein
  • Axillary Vein
  • Subclavian Vein
  • Internal Jugular Vein
    • Most Common Site for Central Venous Catheter (CVC)-Related Deep Venous Thrombosis

Lower Extremity Deep Venous Thrombosis

Calf Vein (Distal) Deep Venous Thrombosis

  • Progression
    • Left Untreated, Distal Deep Venous Thrombosis Will Progress to Proximal Deep Venous Thrombosis in Approximately 33% of Cases
      • If it Does Progress, Distal Deep Venous Thrombosis Usually Progresses within the First 2 wks After Diagnosis
        • If Extension Does Not Occur in the First 2 wks, it is Unlikely to Occur
      • Limited Muscular Calf Vein Distal Deep Venous Thrombosis Has a Low Risk of Extension without Treatment (Risk of Extension: 3%), as Compared to Extensive Thrombosis of Multiple Calf Veins (Risk of Extension: 15%)
    • Risk of Pulmonary Embolism with Distal Deep Venous Thrombosis is Approximately 50% the Risk of Proximal Deep Venous Thrombosis Embolization (BMJ, 2011) [MEDLINE]

Proximal Deep Venous Thrombosis

  • Thrombi in Lower Extremities Develop within Minutes, Then Organize, and Fibrinolyse (Stabilizing within 7-10 Days)
    • Risk of (Symptomatic or Asymptomatic) Pulmonary Embolism with Proximal Deep Venous Thrombosis is Approximately 50%
    • Highest Risk Period for Embolization of Proximal Deep Venous Thrombosis is within the First Few Days After Deep Venous Thrombosis Formation

Upper Extremity Deep Venous Thrombosis

  • Risk of Pulmonary Embolism with Upper Extremity DVT: 10-25% of cases (BMJ, 2004) [MEDLINE] (Exp Oncol, 2006) [MEDLINE] (J Thromb Haemost, 2008) [MEDLINE]

Source of Pulmonary Embolism

  • In Situ Pulmonary Artery Thrombosis
    • Rare
  • Lower Extremity Deep Venous Thrombosis
    • Accounts for >95% of Pulmonary Embolism Cases
    • Larger Lower Extremity Veins (Iliac, Femoral, Popliteal) are the Source of Most Clinically Significant Pulmonary Emboli
  • Pelvic Vein Deep Venous Thrombosis
  • Arteriovenous Hemodialysis Fistula (see Arteriovenous Hemodialysis Fistula)
    • Thrombectomy (Including Cases with Paradoxical Arterial Embolism) May Lead to Pulmonary Embolism
  • Upper Extremity Deep Venous Thrombosis (Usually Near Venous Valves)

Clinical Consequences of Acute Pulmonary Embolism

Pulmonary Infarction

  • Epidemiology
    • Pulmonary Infarction Occurs in 10% of Acute Pulmonary Embolism Cases (Since Bronchial Artery Collateral Vessels Usually Supply Blood)
  • Physiology
    • Inflammatory Response in the Lung and Adjacent Visceral/Parietal Pleura Results in Pleuritic Chest Pain and Hemoptysis

Abnormal Gas Exchange

  • Mechanisms
    • Mechanical Obstruction of Pulmonary Vascular Bed, Resulting in Alteration of V/Q Ratio
    • Surfactant Dysfunction and Atelectasis, Resulting in Functional Intrapulmonary Shunting
    • Inflammation Resulting in Respiratory Drive Stimulation

Increased Pulmonary Vascular Resistance Due to Mechanical Obstruction of Pulmonary Vascular Bed and Hypoxic Pulmonary Vasoconstriction

  • Obstruction of Only 33% of Pulmonary Vasculature Produces Pulmonary Hypertension (Due to Pulmonary Arterial Vasoconstriction Induced by Serotonin and Thromboxane (Cardiovasc Res, 2000) [MEDLINE] – In Addition, When Obstruction of the Pulmonary Vascular Bed Approaches 75%, the Right Ventricle Must Generate a Systolic Pressure >50 mmHg to Preserve Adequate Pulmonary Artery Blood Flow
  • Cardiovascular Consequences – Right Ventricular Dilation/Flattening of the Interventricular Septum
    • Decreased Flow from the Right Ventricle and Right Ventricular Dilation, Resulting in Decreased Left Ventricular Preload
    • Decreased Left Ventricular Stroke Volume and Decreased Cardiac Output, Resulting in Hypotension

Increased Alveolar Dead Space Fraction

  • Physiology
    • Due to Occluded Vasculature with Remaining Ventilation
  • Clinical
    • Most Patients with Acute Pulmonary Embolism Have Alveolar Dead Space Fraction >20% and Positive D-Dimer
    • Most Patients with Normal Alveolar Dead Space (<20%) and Negative D-Dimer Do No Have Acute Pulmonary Embolism

Resolution of Acute Pulmonary Embolism

  • Embolus in the Pulmonary Vasculature Lyses over Hours-Days


Diagnosis

Plasma D-Dimer (see Plasma D-Dimer)

Assay

  • Rationale
    • D-Dimer is the Degradation Product of Cross-Linked Fibrin
    • D-Dimer is Easy to Obtain
    • However, D-Dimer May Be Elevated in Conditions Other Than Venous Thromboembolism
  • “Sensitive” D-Dimer Assays: quantitative or semiquantitative newer generation assays
    • Rapid Enzyme-Linked Immunosorbent Assay (ELISA)
    • Immunoturbidimetric Assay
    • Latex Agglutination Assay

Interpretation

  • Normal D-Dimer Level: <500 ng/mL (<0.5 μg/mL or <500 μg/L) Fibrinogen Equivalent (FE) Units
    • Age-Adjusted D-Dimer Thresholds Have Also Been Suggested to Decrease Unnecessary Imaging, But Have Not Widely Adopted in Clinical Practice (Ann Intern Med, 2016) [MEDLINE]

Clinical Efficacy

  • ANTELOPE Study (Am J Respir Crit Care Med, 2002) [MEDLINE]
    • The Sensitivity of D-Dimer was Lower in Subsegmental Pulmonary Embolism (53%), as Compared to Large Main, Lobar, and Segmental Pulmonary Embolism (93%)
  • Systematic Review of D-Dimer in the Diagnosis of Venous Thromboembolism (Ann Intern Med, 2004) [MEDLINE]
    • For the Diagnosis of Deep Venous Thrombosis (DVT)
      • Enzyme-linked Immunosorbent Assay (ELISA) D-Dimer Assay Had a 96% Sensitivity (95% CI: 0.91-1.00) and Negative Likelihood Ratio of 12% (95% CI: 0.04-0.33)
      • Quantitative Rapid Enzyme-linked Immunosorbent Assay (ELISA) D-Dimer Assay Had a 96% Sensitivity (95% CI: 0.90-1.00) and Negative Likelihood Ratio of 9% (95% CI: 0.02-0.41)
    • For the Diagnosis of Pulmonary Embolism (PE)
      • Enzyme-linked Immunosorbent Assay (ELISA) D-Dimer Assay Had a 95% Sensitivity (95% CI: 0.85-1.00) and Negative Likelihood Ratio of 13% (95% CI: 0.03-0.58)
      • Quantitative Rapid Enzyme-linked Immunosorbent Assay (ELISA) D-Dimer Assay Had a 95% Sensitivity (95% CI: 0.83-1.00), and Negative Likelihood Ratio of 13% (95% CI: 0.02-0.84)
  • Emergency Department Study of the Use of Age-Adjusted D-Dimer Thresholds (Chest, 2014) [MEDLINE]
    • Use of Age-Adjusted D-Dimer Threshold Decreased Imaging Among Patients >50 y/o with a Revised Geneva Score ≤10
    • Although the Adoption of an Age-Adjusted D-Dimer Threshold is Probably Safe, the Confidence Intervals Surrounding the Additional 1.5% of Pulmonary Emboli Missed Necessitate Prospective Study Before this Practice Can Be Adopted into Routine Clinical Practice
  • European ADJUST-PE Study of Age-Adjusted D-Dimer Levels in the Diagnosis of Pulmonary Embolism (JAMA, 2014) [MEDLINE]
    • Age-Adjusted D-Dimer (Only for Patients ≥50 y/o): defined as 10 x age
    • Compared with a Fixed D-Dimer Cutoff of 500 μg/L (500 ng/mL), the Combination of a Pre-Test Clinical Probability Assessment and Age-Adjusted D-Dimer Cutoff was Associated with a Larger Number of Patients in Whom Pulmonary Embolism Could Be Considered Ruled Out with a Low Likelihood of Subsequent Clinical Venous Thromboembolism
  • Retrospective Study of the Use of Age-Adjusted D-Dimer Thresholds in the Emergency Department (Ann Emerg Med, 2016) [MEDLINE]
    • An Age-Adjusted D-Dimer Limit Has the Potential to Reduce Chest Imaging Among Older Emergency Department Patients and is More Accurate than a Standard Threshold of 500 ng/dL
  • Systematic Review of D-Dimer in the Diagnosis of Pulmonary Embolism (Cochrane Database Syst Rev, 2016) [MEDLINE]: n = 1585 (total of 4 studies)
    • Sensitivity: 80-100%
    • Specificity: 23-63%
    • High Levels of False-Positive Results were Observed, Especially Among Patients >65 y/o
    • A Negative D-Dimer is Valuable in Ruling Out Pulmonary Embolism in Patients Who Present to the Ambulatory/Emergency Setting with a Low Pre-Test Probability for Pulmonary Embolism
    • Evidence from One Study Suggests that D-Dimer May Have Less Utility in Older Patient Populations, But No Empirical Evidence was Available to Support an Increase in the Diagnostic Threshold of Interpretation of D-Dimer Results for those >65 y/o
  • Systematic Review and Meta-Analysis of Wells Criteria and D-Dimer Testing in the Diagnosis of Pulmonary Embolism (Ann Intern Med, 2016) [MEDLINE]
    • In Patients with an “Unlikely” Pre-Test Probability of Pulmonary Embolism, Age-Adjusted D-Dimer Testing is Associated with a 5% Increase in the Proportion of Patients with Suspected Pulmonary Embolism in Whom Imaging Can Be Safely Withheld, as Compared to Fixed D-Dimer Testing
  • Systematic Review and Meta-Analysis of 6 Prospective Studies of Age-Adjusted D-Dimer Thresholds (Ann Intern Med, 2016) [MEDLINE]
    • Age-Adjusted D-Dimer Testing is Associated with a 5% Absolute Increase in the Proportion of Patients with Suspected Pulmonary Embolism in Whom Imaging Can Be Safely Withheld Compared with Fixed D-Dimer Testing
    • This Strategy Seems Safe Across Different High-Risk Subgroups, But its Efficiency Varies
  • Interval Likelihood Ratios for Plasma D-Dimer (Acad Emerg Med, 2017) [MEDLINE]
    • If the Pre-D-Dimer Probability of PE is 15% (Intermediate Pre-Test Probability), Only a D-DImer <500 ng/mL Will Result in a Post-Test Probability <3%
    • Consequently, Given a Pre-Test Probability of 15% (Intermediate Pre-Test Probability) and a CT Pulmonary Artery Angiogram Threshold of 3%, a Strategy to Obtain CT Pulmonary Artery Angiogram for D-Dimer ≥500 ng/ mL is Consistent with the Interval Likelihood Ratios Reported
  • Study of Age-Adjusted D-Dimer Threshold to YEARS Algorithm in the Diagnosis of Pulmonary Embolism ( J Thromb Haemost, 2017) [MEDLINE]
    • There was No Added Value of Age-Adjusted D-Dimer Cut-Off to the YEARS Algorithm in Patients with Suspected Pulmonary Embolism
  • Prospective PEGeD Trial of Probability-Adjusted D-Dimer (NEJM, 2019) [MEDLINE]: n = 2017
    • Acute Pulmonary Embolism was Considered Ruled Out Without Further Testing in Outpatients with a Low Clinical Pretest Probability and a D-Dimer <1000 ng/mL or with a Moderate Clinical Pretest Probability and a D-Dimer <500 ng/mL
    • Overall, 7.4% of Patients Had Acute Pulmonary Embolism on Initial Diagnostic Testing
    • A Combination of a Low Clinical Pretest Probability and D-Dimer <1000 ng/mL Identified a Group of Patients at Low Risk for Pulmonary Embolism During Follow-Up

Recommendations (American Thoracic Society/Society of Thoracic Radiology Clinical Practice Guidelines for the Evaluation of Suspected Pulmonary Embolism in Pregnancy) (Am J Respir Crit Care Med, 2011) [MEDLINE]

  • In Pregnant Women with Suspected Acute Pulmonary Embolism, D-Dimer Should Not Be Used to Exclude Acute Pulmonary Embolism (Weak Recommendation, Very Low Quality Evidence)

Recommendations (European Society of Cardiology and European Respiratory Society Guidelines for the Diagnosis and Management of Acute Pulmonary Embolism, 2019) (Eur Heart J, 2020) [MEDLINE]

  • Plasma D-dimer Measurement (Preferably Using a High Sensitivity Assay, is Recommended in Outpatients/Emergency Department Patients with Low-Intermediate Clinical Probability, or those that are Acute Pulmonary Embolism-Unlikely, to Decrease the Need for Unnecessary Imaging and Irradiation (Class I, Level A)
  • As an Alternative to the Fixed D-Dimer Cutoff, a Negative D-Dimer Test Using an Age-Adjusted Cutoff (age x 10 mg/L, in Patients >50 y/o) Should Be Considered for Excluding Acute Pulmonary Embolism in Patients with Low-Intermediate Clinical Probability, or Those Who are Acute Pulmonary Embolism-Unlikely (Class IIa, Level B)
  • As an Alternative to the Fixed or Age-Adjusted D-Dimer Cutoff, D-Dimer Levels Adapted to Clinical Probability Should Be Considered to Exclude Acute Pulmonary Embolism (Class IIa, Level B)
  • D-Dimer Measurement is Not Recommended in Patients with High Clinical Probability, as a Normal Result Does Not Safely Exclude Acute Pulmonary Embolism, Even When Using a High Sensitivity Assay (Class III, Level A)

Lower Extremity Venogram (see Lower Extremity Venogram)

  • Indications
    • Gold Standard for the of Lower Extremity Deep Venous Thrombosis (Although Rarely Used in the Modern Era)

Lower Extremity Compression Venous Doppler Ultrasound (see Lower Extremity Compression Venous Doppler Ultrasound)

  • Advantages
    • Allows for Evaluation of Superficial and Deep Venous Systems
    • Easily Repeated
    • Non-Invasive
  • Accuracy
    • Sensitivity: xxx
    • Specificity: xxx

Clinical Efficacy-Occlusiveness of Deep Venous Thrombosis

  • Study of Occlusiveness of Lower Extremity DVT in Patients After Hip Surgery (Thromb Haemost, 1996) [MEDLINE]
    • Most DVT’s Diagnosed in Asymptomatic Patients After Hip Surgery (59.1%-67.1%, Depending on the Vessel) are Non-Occlusive: for this reason, diagnostic methods based on venous flow measurements would be expected to be less sensitive

Clinical Efficacy-Other

  • Trial of Clinical Pretest Probability Scoring Combined with Lower Extremity Venous Ultrasound in the Diagnosis of Outpatient DVT (Lancet, 1997) [MEDLINE]
    • Using Pretest Probability Scoring with Lower Extremity Venous Ultrasound was Safe and Feasible
  • Prospective Study of Lower Extremity Venous Ultrasound in the Diagnosis of DVT (Ann Intern Med, 2004) [MEDLINE]
    • It is Safe to Withhold Anticoagulation After Negative Lower Extremity Doppler Studies in Nonpregnant Patients with a First Suspected Episode of Symptomatic Lower Extremity DVT
  • Systematic Review and Meta-Analysis of Risk Stratification of Patients with Acute PE Based on Presence/Absence of Lower Extremity DVT (Chest, 2016) [MEDLINE]
    • In Patients Diagnosed with Acute Symptomatic PE, Concomitant DVT was Significantly Associated with an Increased Risk of Death within 30 days of the PE Diagnosis, as Compared to Those without a Concomitant Lower Extremity DVT (6.2% vs 3.8%)

Recommendations (American Thoracic Society/Society of Thoracic Radiology Clinical Practice Guidelines for the Evaluation of Suspected Pulmonary Embolism in Pregnancy) (Am J Respir Crit Care Med, 2011) [MEDLINE]

  • In Pregnant Women with Suspected Acute Pulmonary Embolism and Symptoms/Signs of Deep Venous Thrombosis, Bilateral Venous Compression Ultrasound of Lower Extremities is Recommended (Weak Recommendation, Very Low Quality Evidence)
    • If Positive, Anticoagulation Treatment is Recommended (Weak Recommendation, Very Low Quality Evidence)
    • If Negative, Further Testing is Recommended (Weak Recommendation, Very Low Quality Evidence)
  • In Pregnant Women with Suspected Acute Pulmonary Embolism and No Symptoms/Signs of Deep Venous Thrombosis, Studies of the Pulmonary Vasculature are Recommended Rather than Venous Compression Ultrasound of the Lower Extremities (Weak Recommendation, Very Low Quality Evidence)

Recommendations (European Society of Cardiology and European Respiratory Society Guidelines for the Diagnosis and Management of Acute Pulmonary Embolism, 2019) (Eur Heart J, 2020) [MEDLINE]

  • If a Compression Ultrasound Study Demonstrates a Proximal Deep Venous Thrombosis in a Patient with Clinical Suspicion of Acute Pulmonary Embolism, it is Recommended to Accept the Diagnosis of Venous Thromboembolism (and Acute Pulmonary Embolism) (Class I, Level A)
  • If Compression Ultrasound Study Demonstrates Only Distal Deep Venous Thrombosis, Further Testing Should Be Considered to Confirm Acute Pulmonary Embolism (Class IIa, Level B)
  • If a Positive Proximal Compression Ultrasound Study is Used to Confirm Acute Pulmonary Embolism, Assessment of Acute Pulmonary Embolism Severity Should Be Considered to Permit Risk-Adjusted Management (Class IIa, Level C)

Upper Extremity Compression Venous Doppler Ultrasound (see Upper Extremity Compression Venous Doppler Ultrasound)

  • Advantages
    • Allows for Evaluation of Superficial and Deep Venous Systems
    • Easily Repeated
    • Non-Invasive
  • Accuracy
    • Sensitivity: 91% (with large confidence intervals)
    • Specificity: 93% (with large confidence intervals)

Recommendations

  • See Below

Computed Tomography (CT) Lower Extremity Venogram (see Computed Tomography Lower Extremity Venogram)

Recommendations (Chest Antithrombotic Therapy and Prevention of Thrombosis 2012 Guidelines) [MEDLINE]

  • CT Venogram is an Alternative to Compression Lower Extremity Venous Doppler Ultrasound for the Diagnosis of Lower Extremity Deep Venous Thrombosis When Ultrasound is Impractical (Patients with Lower Extremity Casting, Significant Lower Extremity Edema or Wounds, etc)

Recommendations (European Society of Cardiology and European Respiratory Society Guidelines for the Diagnosis and Management of Acute Pulmonary Embolism, 2019) (Eur Heart J, 2020) [MEDLINE]

  • CT Venography is Not Recommended as an Adjunct to CT Pulmonary Artery Angiogram for the Diagnosis of Acute Pulmonary Embolism (Class III, Level B)

Computed Tomography (CT) Upper Extremity Venogram (see Computed Tomography Upper Extremity Venogram)

  • Recommendations for Diagnostic Testing Suspected Upper Extremity Deep Venous Thrombosis (Chest Antithrombotic Therapy and Prevention of Thrombosis 2012 Guidelines) [MEDLINE]
    • Upper Extremity Compression Venous Doppler Ultrasound is Recommended (Grade 2C Recommendation)
    • If Upper Extremity Compression Venous Doppler Ultrasound is Negative with High Clinical Suspicion, Moderate/High-Sensitivity D-Dimer, Serial Ultrasound, CT Upper Extremity Venogram, or Gadolinium-Enhanced Magnetic Resonance Upper Extremity MRI Venogram is Recommended (Grade 2C Recommendation)

Gadolinium-Enhanced Magnetic Resonance Venogram and Pulmonary Artery Angiogram (MRA) (see Magnetic Resonance Imaging)

Advantages

  • No Exposure to Iodinated Radiographic Contrast
  • No Radiation Exposure

Disadvantages

  • Magnetic Resonance Venogram and Pulmonary Artery Angiogram Have High Rates of Technically Inadequate Studies [MEDLINE]: technically inadequate studies were found in 25% (range: 11-52%) of studies performed in the PIOPED III Study (2010), depending on the center
    • Due to the large number of technically inadequate studies in PIOPED III, magnetic resonance venography and pulmonary angiogram only identified 57% of patients with pulmonary embolism
    • Vascular opacification and motion artifact are the principal factors which influence interpretability of MRA [MEDLINE]: some centers appear to obtain better images (for unclear reasons)
  • Technically Adequate Magnetic Resonance Pulmonary Angiogram
    • Sensitivity: 78%
    • Specificity: 99%
  • Technically Adequate Magnetic Resonance Pulmonary Angiogram + Magnetic Resonance Venogram: combination has significantly higher sensitivity than magnetic resonance pulmonary angiogram alone (however, only 52% of patients had technically inadequate results)
    • Sensitivity: 92%
    • Specificity: 96%

Recommendations

  • Magnetic Resonance Pulmonary Artery Angiogram and Venogram Studies Should Only be Performed in Centers with Local Expertise

Recommendations (European Society of Cardiology and European Respiratory Society Guidelines for the Diagnosis and Management of Acute Pulmonary Embolism, 2019) (Eur Heart J, 2020) [MEDLINE]

  • Magnetic Resonance Pulmonary Artery Angiogram is Not Recommended to Rule Out Acute Pulmonary Embolism (Class III, Level A)

Gadolinium-Enhanced Magnetic Resonance Upper Extremity Venogram (see Magnetic Resonance Upper Extremity Venogram)

  • Recommendations for Diagnostic Testing Suspected Upper Extremity Deep Venous Thrombosis (Chest Antithrombotic Therapy and Prevention of Thrombosis 2012 Guidelines) [MEDLINE]
    • Upper Extremity Compression Venous Doppler Ultrasound is Recommended (Grade 2C Recommendation)
    • If Upper Extremity Compression Venous Doppler Ultrasound is Negative with High Clinical Suspicion, Moderate/High-Sensitivity D-Dimer, Serial Ultrasound, CT Upper Extremity Venogram, or Gadolinium-Enhanced Magnetic Resonance Upper Extremity MRI Venogram is Recommended (Grade 2C Recommendation)

Lower Extremity Impedance Plethysmography (IPG)

  • Indications
    • Sensitive for Above the Knee Deep Venous Thrombosis

Lower Extremity Radiofibrinogen Study

  • Indications
    • Sensitive for Calf/Lower Thigh Deep Venous Thrombosis

Electrocardiogram (EKG) (see Electrocardiogram)

  • See Below

Arterial Blood Gas (ABG) (see Arterial Blood Gas)

Arterial Blood Gas Patterns in the Setting of Acute Pulmonary Embolism (PE)

  • Hypocapnia with Respiratory Alkalosis
    • Physiology
      • Due to Hyperventilation Associated with Pulmonary Hypertension
  • Hypoxemia with Elevated A-a Gradient
    • Epidemiology
      • Hypoxemia (pO2 <80 mm Hg) Occurs in Approximately 74% of Acute Pulmonary Embolism Cases (Chest, 1991) [MEDLINE]
      • Alveolar-Arterial (A-a) Gradient >20 mm Hg Occurs in Approximately 86% of Acute Pulmonary Embolism Cases (Chest, 1991) [MEDLINE]
    • Physiology
      • Due to V/Q Mismatch/Intrapulmonary Shunt/Decreased Cardiac Output with Low SvO2
    • Clinical
      • Presence of SaO2 <95% at Time of Acute Pulmonary Embolism Diagnosis Confers an Increased Risk of In-Hospital Complications (Such as Respiratory Failure, Cardiogenic Shock, and Death)

Pleural Fluid (see Thoracentesis)

Pleural Fluid Findings in the Setting of Acute Pulmonary Embolism (PE)

  • Exudative Pleural Fluid (see Pleural Effusion-Exudate)
    • Occurs in 75% of Cases
  • Transudative Pleural Fluid (see Pleural Effusion-Transudate)
    • Occurs in 25% of Cases
  • Hemorrhagic Pleural Fluid
    • May Occur in Some Cases
    • Hemorrhagic Pleural Fluid is Not a Considered a Contraindication to Anticoagulants or Thrombolytics
  • Pleural Fluid Eosinophilia (see Pleural Effusion-Cell Count Patterns)
    • May Be Seen in Cases Where Pleural Effusion is Bloody

Pulmonary Function Tests (PFT’s) (see Pulmonary Function Tests)

  • Findings in the Setting of Acute Pulmonary Embolism (PE)
    • Decreased DLCO (Due to Loss of Capillary Blood Volume)
      • May Be the Only Pulmonary Function Test Abnormality

Chest X-Ray (CXR)/Chest Computed Tomography (Chest CT) (see Chest X-Ray and Chest Computed Tomography)

  • General Comments
    • Chest X-Ray is Abnormal in Approximately 84% of Acute Pulmonary Embolism (PE) Cases (Chest, 1991) [MEDLINE]
      • The Most Commonly Observed Findings are Atelectasis or Pulmonary Parenchymal Abnormalities
  • Findings in the Setting of Acute Pulmonary Embolism (PE)
    • Atelectasis (see Atelectasis)
    • Alveolar Infiltrate (see Pneumonia)
      • May Cavitate in Some Cases
    • Cardiomegaly
      • Seen in 50% of Cases
    • Enlarged Pulmonary Arteries and Enlarged Right Ventricle
      • Seen with Large Pulmonary Embolism Only
    • “Hampton’s Hump”
      • Wedge-Shaped Infiltrate in the Area of the Pulmonary Embolism (Appears Approximately 12-36 hrs Later) (NEJM, 2021) [MEDLINE]
      • May Cavitate
    • “Westermark Sign”
      • Wedge-Shaped Area of Vascular Clearing (Oligemia) in the Area of the Pulmonary Embolism
    • Pleural Effusion
      • Pleural Effusion is Seen in 47% of Acute Pulmonary Embolism (PE) Cases
      • Pleural Effusion is Usually Unilateral and Small: 86% are only blunted costophrenic angle
      • Pleural Effusion May Precede the Development of Pulmonary Infiltrates
        • 50% of Acute Acute Pulmonary Emboli with Effusion Have Associated Lung Parenchymal Infiltrates
      • Pleural Effusion Usually Reaches the Maximum Size withiin the First 3 Days
        • Enlargement of the Pleural Effusion After that Suggests Recurrent Pulmonary Embolism or Other Complication
    • Normal Chest X-Ray
      • Most Common Pattern in Acute Pulmonary Embolism (PE)

Ventilation/Perfusion (V/Q) Scan (see Ventilation-Perfusion Scan)

General Comments Rehgarding V/Q Scan in the Setting of Acute Pulmonary Embolism

  • Overall Diagnostic Accuracy of V/Q is Poor (Ranges from 15-86%) in 72% of All Patients, Insufficient to Diagnose Acute Pulmonary Embolism or Exclude the Diagnosis of Acute Pulmonary Embolism
  • Normal Scan
    • Normal V/S SCan Virtually Excludes the Diagnosis of Acute Pulmonary Embolism
  • Low Probability Scan
    • Low Clinical Probability + Low Probability V/Q Svcan = 4% Probability of Acute Pulmonary Embolism
    • Note: if clinical probability is high, low probability V/Q has 40% probability of Acute Pulmonary Embolism
  • Intermediate Probability Scan = Ranges from 15-66% Probability of Acute Pulmonary Embolism (Depending on the Clinical Probability)
  • High Probability Scan
    • High Clinical Probability + High Probability V/Q Scan = 95% Probability of Acute Pulmonary Embolism (These Patients Can Be Treated with Heparin, Thrombolytics without Pulmonary Angiogram)
    • Note: if clinical probability is low, high prob V/Q has 56% probability of Acute Pulmonary Embolism

Recommendations (European Society of Cardiology and European Respiratory Society Guidelines for the Diagnosis and Management of Acute Pulmonary Embolism, 2019) (Eur Heart J, 2020) [MEDLINE]

  • If the Perfusion Lung Scan is Normal, Acute Pulmonary Embolism Can Be Excluded without Further Testing (Class I, Level A)
  • If the V/Q Scan is High Probability for Acute Pulmonary Embolism, it Should Be Considered to Accept that the Diagnosis of Acute Pulmonary Embolism (without Further Testing) (Class IIa, Level B)
  • A Non-Diagnostic V/Q Scan Should Be Considered as Exclusion of Acute Pulmonary Embolism when Combined with a Negative Lower Extremity Proximal Compression Ultrasound Study in Patients with Low Clinical Probability or Who are Acute Pulmonary Embolism-Unlikely (Class IIa, Level B)

Ventilation-Perfusion SPECT Study

Recommendations (European Society of Cardiology and European Respiratory Society Guidelines for the Diagnosis and Management of Acute Pulmonary Embolism, 2019) (Eur Heart J, 2020) [MEDLINE]

  • V/Q SPECT Study May Be Considered for the Diagnosis of Acute Pulmonary Embolism (Class IIb, Level B)

Pulmonary Artery Angiogram (see Pulmonary Artery Angiogram)

  • Indications for Pulmonary Artery Angiogram in the Diagnosis of Acute Pulmonary Embolism
    • Gold Standard Diagnostic Test: negative pulmonary angiogram excludes clinically relevant acute pulmonary embolism
  • Adverse Effects: generally safe in patients without acute, severe pulmonary hypertension
    • Procedure-Related Mortality: <2%
    • Procedure-Related Morbidity: 5% (due mainly to catheter insertion-related complications, contrast reactions, arrhythmias, respiratory failure)
    • Radiation Exposure: greater than that from CT pulmonary angiogram
  • Pulmonary Angiographic Patterns
    • “Rat Tail Configuration”: vessel tapers to a point
    • “Filling Defects”: may be seen in most cases
    • “Abrupt Cut-Off”: may be seen in complete occlusion

Computed Tomography Pulmonary Artery Angiogram (CTPA) (see Computed Tomography Pulmonary Artery Angiogram)

  • Sensitivity: 86% in large (main/lobar/segmental) vessels (75% in all vessels)
  • Specificity: 91% in large (main/lobar/segmental) vessels (89% in all vessels)
  • CT Pulmonary Angiogram Has Traditionally Been Considered Most Accurate for Large/Main/Lobar/Segmental PE’s and Less Accurate for Smaller/Peripheral Subsegmental PE’s: however, there is improved detection of PE by multi-detector CT pulmonary angiogram (9.4%) vs single-detector CT pulmonary angiogram (4.7%)
  • Low Risk of PE Following a Negative CT Pulmonary Angiogram: <2% risk of PE in 3-month F/U in patients with negative CT angio + low-intermediate clinical probability + negative LE dopplers
    • This risk increases to 5% if clinical probability is high

Clinical Efficacy

  • Grading of CT Signs of Right Ventricular Dysfunction in Acute PE (AJR Am J Roentgenol, 2010) [MEDLINE]
    • Volumetric Determination of the Right Ventricular Volume/Left Ventricular Volume Ratio: most reproducible/least user-dependent of the CT measurements (as compared to septal bowing or IVC reflux) -> ratio >1.2 is suggestive of RV strain
  • Grading of Intermediate-Risk Pulmonary Embolism Patients (Eur Respir J, 2014) [MEDLINE]
    • SBP 90-100 mm Hg: 2 pts
    • Elevated Troponin: 2 pts
    • RV Dysfunction (by Echocardiogram or CT): 2 pts
    • HR ≥100 BPM: 1 pt
    • Scoring: range 0-7
      • Stage I (0-2 points)
        • 3.6% risk for in-hospital PE-related complications
        • 4.2% risk for 30-day PE-related complications
        • 1.7% 30-day PE-related mortality
      • Stage II (3-4 points)
        • 9.7% risk for in-hospital PE-related complications
        • 10.8% risk for 30-day PE-related complications
        • 5.0% 30-day PE-related mortality
      • Stage III (>4 points)
        • 28.0% risk for in-hospital PE-related complications
        • 29.2% risk for 30-day PE-related complications
        • 15.5% 30-day PE-related mortality
  • Retrospective Review of CT Pulmonary Artery Angiograms in Tertiary Care Hospital (AJR Am J Roentgenol, 2015) [MEDLINE]: n = 937 CT pulmonary artery angiogram studies
    • Acute PE was Diagnosed in 18.6% of CT Pulmonary Artery Angiograms
    • There was Discordance Between the Chest Radiologist and the Original Radiologist in 25.9% of Cases
      • Discordance Occurred More Commonly When the Original Reported PE was Solitary (46.2% of Solitary PE’s were Considered Negative on Retrospective Review) and Located in a Segmental/Subsegmental Pulmonary Artery (26.8% of Segmental and 59.4% of Subsegmental PE’s were Considered Negative on Retrospective Review)

Recommendations (European Society of Cardiology and European Respiratory Society Guidelines for the Diagnosis and Management of Acute Pulmonary Embolism, 2019) (Eur Heart J, 2020) [MEDLINE]

  • In Suspected High-Risk Acute Pulmonary Embolism (Presence of Hemodynamic Instability), Bedside Echocardiogram or Emergency CT Pulmonary Artery Angiogram (Depending on Availability and Clinical Circumstances) is Recommended for Diagnosis (Class I, Level C)
  • If the CT Pulmonary Artery Angiogram is Normal in a Patient with Low-Intermediate Clinical Probability, or Who is Acute Pulmonary Embolism-Unlikely, it is Recommended to Reject the Diagnosis of Acute Pulmonary Embolism (without Further Testing) (Class I, Level A)
  • If the CT Pulmonary Artery Angiogram Demonstrates a Segmental or More Proximal Filling Defect in a Patient with Intermediate-High Clinical Probability, it is Recommended to Accept the Diagnosis of Acute Pulmonary Embolism (without Further Testing) (Class I, Level B)
  • If the CT Pulmonary Artery Angiogram is Normal in a Patient with High Clinical Probability or Who is Acute Pulmonary Embolism-Likely , It Should Be Considered to Reject the Diagnosis of Acute Pulmonary Embolism (without Further Testing) (Class IIa, Level B)
  • Further Imaging Tests to Confirm Acute Pulmonary Embolism May Be Considered in Cases of Isolated Subsegmental Filling Defects (Class IIb, Level C)
  • CT Venography is Not Recommended as an Adjunct to CT Pulmonary Artery Angiogram (Class III, Level B)

Serum Lactate (see Serum Lactate)

General Comments

  • Serum Lactate May Be Used to Risk Stratify Patients in Acute Pulmonary Embolism

Clinical Efficacy

  • Prospective Study of Plasma Lactate in Acute Symptomatic Pulmonary Embolism (with Normotension) (Thorax, 2015) [MEDLINE]: n = 496 (between 2012-2014)
    • Pulmonary Embolism-Related Complications Occurred in 4.0% of Patients (95% CI: 2.5-6.2%)
    • Patients with Pulmonary Embolism-Related Complications Had Higher Baseline Lactate Levels (Median 2.66 mmol/L; Interquartile Range 1.56-5.96 mmol/L) than Patients without Complications (Median 1.20 mmol/L; Interquartile Range 1.20-2.00 mmol/L) (p<0.001)
    • Patients with Elevated Plasma Lactate Had an Increased Rate of Pulmonary Embolism-Related Complications (Adjusted Odds Ratio 5.3; 95% CI: 1.9-14.4; p = 0.001), as Compared to Those with Low Plasma Lactate
    • Combination of Elevated Plasma Lactate with Markers of Right Ventricular Dysfunction (by Echocardiogram) and Myocardial Injury (by Cardiac Troponin) was a Particularly Useful Prognostic Indicator (Positive Predictive Value 17.9%; 95% CI 6.1-36.9%)
  • Study of Serum Venous Lactate in the Prediction of In-Hospital Adverse Outcomes in Normotensive Acute Pulmonary Embolism (Eur J Intern Med, 2021) [MEDLINE]
    • An Optimized Venous Lactate Cutoff Value of 3.3 mmol/L Predicted Both In-Hospital Adverse Outcome (Odds Ratio 11.0; 95% CI 4.6-26.3) and All-Cause Mortality (Odds Ratio 3.8; 95%CI 1.3-11.3)
    • The Established Cutoff Value for Arterial Lactate (2.0 mmol/L) and the Upper Limit of Normal for Venous Lactate (2.3 mmol/l) Had Lower Prognostic Value for Adverse Outcomes (Odds Ratio 3.6; 95% CI 1.5-8.7 and Odds Ratio 5.7; 95% CI 2.4-13.6, Respectively) and Did Not Predict Mortality
    • If Added to the 2019 European Society of Cardiology Algorithm, Venous Lactate <2.3 mmol/L was Associated with a High Negative Predictive Value (0.99 [95% CI 0.97-1.00]) for Adverse Outcomes in Intermediate-Low Risk Patients, Whereas Lactate Levels ≥3.3 mmol/L Predicted Adverse Outcomes in the Intermediate-High Risk Group (Odds Ratio 5.2; 95% CI 1.8-15.0)

    Serum Brain Natriuretic Peptide (BNP) (see Serum Brain Natriuretic Peptide)

    General Comments

    • Serum Brain Natriuretic Peptide May Be Elevated in Acute Pulmonary Embolism
      • Magnitude of Increase in Brain Natriuretic Peptide Correlates with the Risk of Subsequent Complications and Prolonged Hospitalization
      • BNP >90 pg/ml (within 4 hrs of Presentation): associated with adverse outcomes (death, cardioplumonary resuscitation, mechanical ventilation, pressor therapy, thrombolysis, and embolectomy)
      • BNP <50 pg/ml (within 4 hrs of Presentation): benign clinical course in 95% of cases
    • Sensitivity: 60%
    • Specificity: 62%

    Clinical Data

    • Grading of Factors Associated with 30-Day Frequency of Adverse Events in Prep Study (Am J Respir Crit Care Med, 2010) [MEDLINE]
      • Altered Mental Status: OR 6.8 (95% CI: 2.0-23.3)
      • Shock on Admission: OR 2.8 (95% CI: 1.1-7.5)
      • Cancer: OR 2.9 (95% CI: 1.2-6.9)
      • Elevated BNP: OR 1.3 for an increase of 250 ng/L (95% CI: 1.1-1.6)
      • Echocardiographic Right Ventricular Volume/Left Ventricular Volume Ratio: OR 1.2 for an increase of 0.1 (95% CI: 1.1-1.4)
    • Combination of Troponin-T >0.07 µg/L + NT-proBNP >600 ng/L is Associated with 33% 40-Day Mortality Rate (as Compared to 0% Mortality with NT-proBNP level <600 ng/L)

    Serum Troponin (see Serum Troponin)

    General Comments

    • Serum Troponin May Be Elevated in Acute Pulmonary Embolism: due to acute right heart overload
      • Not Useful for the Diagnosis of Acute Pulmonary Embolism, But Offers Prognostic Information
        • Elevated Serum Troponin is Associated with Increased Incidence of Prolonged Hypotension and Increased 30-Day Mortality
      • Troponin I: elevated in 30% of moderate-large PE
      • Troponin T: elevated in 50% of moderate-large PE

    Clinical Efficacy

    • Grading of Pulmonary Embolism Using Right Ventricular Dysfunction and Troponin Levels (Chest, 2013) [MEDLINE]
      • Right Ventricular Dysfunction and Elevated Troponin Level: these criteria have an incremental prognostic value for risk stratification in hemodynamically-stable patients with acute pulmonary embolism
    • Grading of Intermediate-Risk Pulmonary Embolism Patients (Eur Respir J, 2014) [MEDLINE]
      • SBP 90-100 mm Hg: 2 pts
      • Elevated Troponin: 2 pts
      • RV Dysfunction (by Echocardiogram or CT): 2 pts
      • HR ≥100 BPM: 1 pt
      • Scoring: range 0-7
        • Stage I (0-2 points)
          • 3.6% risk for in-hospital PE-related complications
          • 4.2% risk for 30-day PE-related complications
          • 1.7% 30-day PE-related mortality
        • Stage II (3-4 points)
          • 9.7% risk for in-hospital PE-related complications
          • 10.8% risk for 30-day PE-related complications
          • 5.0% 30-day PE-related mortality
        • Stage III (>4 points)
          • 28.0% risk for in-hospital PE-related complications
          • 29.2% risk for 30-day PE-related complications
          • 15.5% 30-day PE-related mortality
    • Combination of Troponin-T >0.07 µg/L + NT-proBNP >600 ng/L is Associated with 33% 40-Day Mortality Rate (as Compared to 0% Mortality with NT-proBNP level <600 ng/L)

    Echocardiogram (see Echocardiogram)

    • General Comments
      • Only 30-40% of Acute Pulmonary Emboli Have Positive Echocardiographic Evidence of Acute Pulmonary Embolism
        • This Percentage is Higher in Cases of Massive Acute Pulmonary Embolism
    • Features
      • Features of RV Strain/Overload: present in 30-40% of patients with acute PE (higher percentage in patients with massive acute pulmonary embolism)
        • Decreased Right Ventricular Ejection Fraction
        • Right Ventricular Enlargement (RVE)
        • Tricuspid Regurgitation (TR): Doppler of tricuspid regurgitation jet allows estimation of the pulmonary artery pressure
      • Pulmonic Regurgitation
      • RV Thrombus: >35% patients with right ventricular thrombus develop acute pulmonary embolism, but only 4% of acute pulmonary embolism patients have an right ventricular thrombus
      • McConnell’s Sign (77% sensitivity for diagnosis of acute acute pulmonary embolism): regional wall motion abnormalities that spare the right ventricular apex
      • Normal LV Ejection Fraction: usually seen

    Clinical Data

    • Grading of Factors Associated with 30-Day Frequency of Adverse Events in Prep Study (Am J Respir Crit Care Med, 2010) [MEDLINE]
      • Altered Mental Status: OR 6.8 (95% CI: 2.0-23.3)
      • Shock on Admission: OR 2.8 (95% CI: 1.1-7.5)
      • Cancer: OR 2.9 (95% CI: 1.2-6.9)
      • Elevated BNP: OR 1.3 for an increase of 250 ng/L (95% CI: 1.1-1.6)
      • Echocardiographic Right Ventricular Volume/Left Ventricular Volume Ratio: OR 1.2 for an increase of 0.1 (95% CI: 1.1-1.4)
    • Grading of Pulmonary Embolism Using Right Ventricular Dysfunction and Troponin Levels (Chest, 2013) [MEDLINE]
      • Right Ventricular Dysfunction and Elevated Troponin Level: these criteria have an incremental prognostic value for risk stratification in hemodynamically-stable patients with acute pulmonary embolism
    • Grading of Intermediate-Risk Pulmonary Embolism Patients (Eur Respir J, 2014) [MEDLINE]
      • SBP 90-100 mm Hg: 2 pts
      • Elevated Troponin: 2 pts
      • RV Dysfunction (by Echocardiogram or CT): 2 pts
      • HR ≥100 BPM: 1 pt
      • Scoring: range 0-7
        • Stage I (0-2 points)
          • 3.6% risk for in-hospital PE-related complications
          • 4.2% risk for 30-day PE-related complications
          • 1.7% 30-day PE-related mortality
        • Stage II (3-4 points)
          • 9.7% risk for in-hospital PE-related complications
          • 10.8% risk for 30-day PE-related complications
          • 5.0% 30-day PE-related mortality
        • Stage III (>4 points)
          • 28.0% risk for in-hospital PE-related complications
          • 29.2% risk for 30-day PE-related complications
          • 15.5% 30-day PE-related mortality

    Recommendations (European Society of Cardiology and European Respiratory Society Guidelines for the Diagnosis and Management of Acute Pulmonary Embolism, 2019) (Eur Heart J, 2020) [MEDLINE]

    • In Suspected High-Risk Acute Pulmonary Embolism (Presence of Hemodynamic Instability), Bedside Echocardiogram or Emergency CT Pulmonary Artery Angiogram (Depending on Availability and Clinical Circumstances) is Recommended for Diagnosis (Class I, Level C)

    Swan-Ganz Catheter (Pulmonary Artery Catheter) (see Swan-Ganz Catheter)

    • Right Atrial Pressure (RA): normal (at rest)
    • Right Ventricular Systolic Pressure (RV-SYS): moderately elevated (with normal RV-EDP)
    • Pulmonary Artery Systolic Pressure (PA-SYS) and Pulmonary Artery Diastolic Pressure (PA-DIA): moderately elevated (severe elevations suggest CTEPH, since vascular remodeling is required to raise pressures this high/acute severe elevations will also produce rapid RV failure)
    • Pulmonary Artery Oxygen Saturation (PA-SaO2): lack of “step-up” excludes intracardiac shunt
    • Pulmonary Capillary Wedge Pressure (PCWP): normal (reflects normal LA and LV-EDP)
    • Cardiac Output (CO): normal-decreased (at rest)
    • Pulmonary Vascular Resistance (PVR): may be elevated

    Point-of-Care Ultrasound (POCUS) (see Point-of-Care Ultrasound)

    Clinical Efficacy

    • Prospective Trial of the Diagnostic Accuracy of Multiorgan Point-of Care (POCUS) Ultrasound, as Compared to Computed Tomography Pulmonary Artery Angiogram in the Diagnosis of Acute Pulmonary Embolism in Critically Ill Patients with Suspected Pulmonary Embolism (PLoS One, 2022) [MEDLINE]: n = 88
      • 42% of Patients Had Acute Pulmonary Embolism
      • Multivariate Analysis Demonstrated a Relative Risk of Acute Pulmonary Embolism of 2.79 (95% CI: 1.61-4.84) for the Presence of Right Ventricular Dysfunction, of 2.54 (95% CI: 0.89-7.20) for D-Dimer Level >1000 ng/mL, and of 1.69 (95% CI: 1.12-2.63) for the Absence of an Alternative dDiagnosis to Acute Pulmonary Embolism on Lung POCUS or Chest X-Ray
      • The Combination with the Highest Diagnostic Accuracy for Acute Pulmonary Embolism Included the Following Variables
        • POCUS Transthoracic Echocardiography with Evidence of Right Ventricular Dysfunction
        • Lung POCUS or Chest X-Ray without an Alternative Diagnosis to Acute Pulmonary Embolism
        • Plasma D-Dimer Level >1000 ng/mL
      • Combining These Three Findings Resulted in an Area Under the Curve of 0.85 (95% CI: 0.77-0.94)
        • 50% Sensitivity and 96% Specificity

    Clinical Evaluation for Suspected Pulmonary Embolism in Pregnancy (see Pregnancy)

    Clinical Efficacy

    • Markov Decision Model Study of Six International Societal Guidelines for the Evaluation of Suspected Pulmonary Embolism in Pregnancy (Chest, 2022) [MEDLINE]
      • Base-Case Analysis Demonstrated that the American Thoracic Society/Society of Thoracic Radiology (ATS-STR) Guidelines Yielded the Highest Health Benefits (22.90 QALYs) and was Cost-Effective (ICER of $7,808) Over the Australian Society of Thrombosis and Haemostasis Guidelines and the Society of Obstetric Medicine of Australia and New Zealand (ASTH-SOMANZ) Guidelines

    Recommendations (American Thoracic Society/Society of Thoracic Radiology Clinical Practice Guidelines for the Evaluation of Suspected Pulmonary Embolism in Pregnancy) (Am J Respir Crit Care Med, 2011) [MEDLINE]

    • In Pregnant Women with Suspected Acute Pulmonary Embolism, D-Dimer Should Not Be Used to Exclude Acute Pulmonary Embolism (Weak Recommendation, Very Low Quality Evidence)
    • In Pregnant Women with Suspected Acute Pulmonary Embolism and Symptoms/Signs of Deep Venous Thrombosis, Bilateral Venous Compression Ultrasound of Lower Extremities is Recommended (Weak Recommendation, Very Low Quality Evidence)
      • If Positive, Anticoagulation Treatment is Recommended (Weak Recommendation, Very Low Quality Evidence)
      • If Negative, Further Testing is Recommended (Weak Recommendation, Very Low Quality Evidence)
    • In Pregnant Women with Suspected Acute Pulmonary Embolism and No Symptoms/Signs of Deep Venous Thrombosis, Studies of the Pulmonary Vasculature are Recommended Rather than Venous Compression Ultrasound of the Lower Extremities (Weak Recommendation, Very Low Quality Evidence)
    • In Pregnant Women with Suspected Acute Pulmonary Embolism, Chest X-Ray is Recommended as the First Radiation-Associated Procedure in the Imaging Work-Up (Strong Recommendation, Low Quality Evidence)
    • In Pregnant Women with Suspected Acute Pulmonary Embolism and a Normal Chest X-Ray, V/Q Scan is Recommended as the Next Imaging Test Rather than CT Pulmonary Artery Angiogram (Strong Recommendation, Low Quality Evidence)
    • In Pregnant Women with Suspected Acute Pulmonary Embolism and a Non-Diagnostic V/Q Scan, Further Diagnostic Testing is Recommended Over Clinical Management Alone (Weak Recommendation, Low Quality Evidence)
      • In Patients with a Non-Diagnostic V/Q Scan in Whom a Decision is Made to Further Investigate, CT Pulmonary Artery Angiogram is Recommended Over Digital Subtraction Angiography (Strong Recommendation, Very Low Quality Evidence)
    • In Pregnant Women with Suspected Acute Pulmonary Embolism and an Abnormal Chest X-Ray, CT Pulmonary Artery Angiogram is Suggested as the Next Imaging Test Rather than V/Q Scan (Weak Recommendation, Very Low Quality Evidence)

    Clinical Decision Rules for the Diagnosis of Acute Pulmonary Embolism

    Clinical Decision Rules

    Wells Criteria/Modified (Dichotomized) Wells Criteria (BMJ, 2015) [MEDLINE]

    • Criteria
      • Clinical Symptoms of DVT (Leg Swelling, Pain with Palpation): 3.0 pts
      • Other Diagnosis Less Likely than Pulmonary Embolism: 3.0 pts
      • Heart Rate >100 bpm: 1.5 pts
      • History of DVT/PE: 1.5 pts
      • Immobilization (≥3 Days) or Surgery in Previous 4 Weeks: 1.5 pts
      • Hemoptysis: 1.0 pt
      • Malignancy: 1.0 pt
    • Wells Criteria Scoring
      • Low Probability of Pulmonary Embolism: <2 pts
      • Intermediate/Moderate Probability of Pulmonary Embolism: 2-6 pts
      • High Probability of Pulmonary Embolism: >6 pts
    • Modified (Dichotomized) Wells Criteria Scoring
      • Pulmonary Embolism Unlikely: ≤4 pts
      • Pulmonary Embolism Likely: >4 pts

    Simplified Wells Criteria

    • Criteria
      • Clinical Symptoms of DVT (Leg Swelling, Pain with Palpation): 1 pt
      • Other Diagnosis Less Likely than Pulmonary Embolism: 1 pt
      • Heart Rate >100 bpm: 1 pt
      • History of DVT/PE: 1 pt
      • Immobilization (≥3 Days) or Surgery in Previous 4 Weeks: 1 pt
      • Hemoptysis: 1 pt
      • Malignancy: 1 pt
    • Simplified Wells Criteria Scoring
      • Pulmonary Embolism Unlikely: ≤1 pt
      • Pulmonary Embolism Likely: >1 pt

    Revised Geneva Score

    • Criteria
      • Age > 65 y/o: 1 pt
      • Previous Deep Venous Thrombosis/Pulmonary Embolism: 3 pts
      • Surgery (Under General Anesthesia) or Fracture of Lower Extremity in Last Month: 2 pts
      • Cancer (Solid or Hematologic; Currently Active or Considered Cured for <1 Year): 2 pts
      • Unilateral Lower Extremity Pain: 3 pts
      • Hemoptysis: 2 pts
      • Heart Rate 75-94: 3 pts
      • Heart Rate ≥95: 5 pts
      • Pain on Lower Extremity Deep Venous Palpation and Unilateral Edema: 4 pts
    • Revised Geneva Scoring
      • Low Probability of Pulmonary Embolism: <4 pts
      • Intermediate/Moderate Probability of Pulmonary Embolism: 4-10 pts
      • High Probability of Pulmonary Embolism: >10 pts

    Simplified Revised Geneva Score

    • Criteria
      • Age >65 y/o: 1 pt
      • Previous Deep Venous Thrombosis/Pulmonary Embolism: 1 pt
      • Surgery (Under General Anesthesia) or Fracture of Lower Extremity in Last Month: 1 pt
      • Cancer (Solid or Hematologic; Currently Active or Considered Cured for <1 Year): 1 pt
      • Unilateral Lower Extremity Pain: 1 pt
      • Hemoptysis: 1 pt
      • Heart Rate 75-94: 1 pt
      • Heart Rate ≥95: 2 pts
      • Pain on Lower Extremity Deep Venous Palpation and Unilateral Edema: 1 pt
    • Simplified Revised Geneva Scoring
      • Pulmonary Embolism Unlikely: ≤2 pts
      • Pulmonary Embolism Likely: >2 pts

    Kline Rule (Ann Emerg Med, 2002) [MEDLINE]

    • Algorithmic Approach Which May Also Be Used

    Pisa Model (Am J Respir Crit Care Med, 2008) [MEDLINE]

    • Age
      • Age 57–67: coefficient 0.80 (Odds Ratio = 2.23)
      • Age 68–74: coefficient 0.87 (Odds Ratio = 2.38)
      • Age ≥75: coefficient 1.14 (Odds Ratio = 3.11)
    • Male Sex: coefficient 0.60 (Odds Ratio = 1.82)
    • Risk Factors
      • Immobilization: coefficient 0.42 (Odds Ratio = 1.53)
      • Deep Venous Thrombosis (Ever): coefficient 0.64 (Odds Ratio = 1.90)
    • Preexisting Diseases
      • Cardiovascular coefficient –0.51 (Odds Ratio = 0.60)
      • Pulmonary: coefficient –0.89 (Odds Ratio = 0.41)
    • Symptoms
      • Dyspnea (Sudden Onset): coefficient 2.00 (Odds Ratio = 7.38)
      • Orthopnea: coefficient –1.51 (Odds Ratio = 0.22)
      • Chest Pain: coefficient 1.01 (Odds Ratio = 2.74)
      • Fainting/Syncope: coefficient 0.66 (Odds Ratio = 1.93)
      • Hemoptysis: coefficient 0.93 (Odds Ratio = 2.52)
    • Signs
      • Unilateral Leg Swelling: coefficient 0.80 (Odds Ratio = 2.23)
      • Fever >38°C ( >100.4°F): coefficient –1.47 (Odds Ratio = 0.23)
      • Wheezes: coefficient –1.20 (Odds Ratio = 0.30)
      • Crackles: coefficient –0.61 (Odds Ratio = 0.54)
    • Electrocardiogram
      • Acute Cor Pulmonale (Includes ≥1 of the Following EKG Abnormalities: S1Q3T3, S1S2S3, Negative T-Waves in Right Precordial Leads, Transient Right Bundle Branch Block, or Pseudoinfarction Pattern): coefficient 1.96 (Odds Ratio = 7.11)
    • Constant: coefficient –3.43
    • Calculation
      • Add All of the Coefficients + Constant –3.43 to Obtain a Sum Score
      • Probability of Pulmonary Embolism = [1 + exp(–sum)]–1

    Pulmonary Embolism Rule Out Criteria (PERC)

    • Rationale: pulmonary embolism rule out criteria (PERC) were first developed to identify patients with a low probability of pulmonary embolism in whom the risk of unnecessary diagnostic testing would outweigh the risk of pulmonary embolism (Ann Emerg Med, 2004) [MEDLINE]
    • Criteria
      • Age <50 y/o: 0 = meets criterion, 1 = does not meet criterion
      • Initial Heart Rate <100 bpm: 0 = meets criterion, 1 = does not meet criterion
      • Initial Room Air SaO2 >94%: 0 = meets criterion, 1 = does not meet criterion
      • Absence of Unilateral Leg Swelling: 0 = meets criterion, 1 = does not meet criterion
      • Absence of Hemoptysis: 0 = meets criterion, 1 = does not meet criterion
      • Absence of Surgery/Trauma within 4 wks: 0 = meets criterion, 1 = does not meet criterion
      • Absence of History of Venous Thromboembolism: 0 = meets criterion, 1 = does not meet criterion
      • Absence of Estrogen Use: 0 = meets criterion, 1 = does not meet criterion
    • Scoring: pre-test probability with score = 0 is <1%

    Clinical Utility of Diagnostic Algorithms for the Diagnosis of Acute Pulmonary Embolism

    Clinical Efficacy

    • Single-Center Study of the Use of Pulmonary Embolism Rule Out Criteria (PERC) in an Emergency Department (Ann Emerg Med, 2004) [MEDLINE]
      • Point of Care Pulmonary Embolism Rule Out Criteria (PERC) Doubled the Rate of Screening for Pulmonary Embolism in the Emergency Department
      • Point of Care Pulmonary Embolism Rule Out Criteria (PERC) Had a False-Negative Rate of <1%, Did Not Increase the Pulmonary Vascular Imaging Rate, and Decreased the Length of Stay
    • Prospective Observational Study of the Accuracy of Clinical Gestalt in the Diagnosis of Acute Pulmonary Embolism (Chest, 2005) [MEDLINE]
      • Accurate Determination of the Pretest Probability of Acute Pulmonary Embolism Appears to Increase with Clinical Experience
      • However, the Difference in Accuracy Between Inexperienced and Experienced Physicians is Not Sufficiently Large to Distinguish Between the Two When Determining Whether Clinical Gestalt or a Clinical Prediction Rule Should Be Used to Determine the Pretest Probability of Acute Pulmonary Embolism
    • Dutch Prospective Cohort Christopher Study Using Algorithm Combining Clinical Probability, D-Dimer, and Computed Tomography in the Diagnosis of Pulmonary Embolism (JAMA, 2006) [MEDLINE]: patients were followed for 3 mos
      • Initial Modified Wells Criteria Scoring: patients were categorized into “pulmonary embolism unlikely” vs “pulmonary embolism likely” groups
        • “Unlikely Group”: underwent D-dimer testing -> if D-dimer was normal, pulmonary embolism was considered excluded
        • All Others (“Likely” Group” or Those with Positive D-Dimer): underwent CT pulmonary angiogram to diagnose or exclude pulmonary embolism
      • Diagnostic Strategy Using Modified Wells Criteria, D-Dimer Testing, and CT Pulmonary Angiogram was Safe and Effective in the Diagnosis of Pulmonary Embolism
    • Prospective Multicenter Trial Examining the Effectiveness of Pulmonary Embolism Rule Out Criteria (PERC) in Patients at Low-Risk of Pulmonary Embolism ( J Thromb Haemost, 2008) [MEDLINE]: n = 8131 (85% of patients had a chief complaint of either dyspnea or chest pain), providers reported a low suspicion of pulmonary embolism in 20% of the patients
      • Low Pre-Test Probability for Pulmonary Embolism + PERC-Negative Had a Sensitivity of 97.4% and Specificity of 21.9%
      • The Combination of Gestalt Estimate of Low Pre-Test Probability for Pulmonary Embolism and PERC-Negative Decreases the Probability of Pulmonary Embolism to <2% in About 20% of Outpatients with Suspected Pulmonary Embolism
    • Secondary Analysis of a Prospective Database Examining the Effectiveness of Pulmonary Embolism Rule Out Criteria (PERC) in the Emergency Deopartment (Am J Emerg Med, 2008) [MEDLINE]
      • Pulmonary Embolism Rule Out Criteria (PERC) Had 100% Sensitivity and 16% Specificity
      • Pulmonary Embolism Rule Out Criteria (PERC) Had 14% Positive Predictive Value and 100% Negative Predictive Value
    • Dutch (Prometheus Study Group) Prospective Cohort Study of Clinical Decision Rules in the Diagnosis of Pulmonary Embolism (Ann Intern Med, 2011) [MEDLINE]
      • All 4 Clinical Decision Rules (Wells Rule, Revised Geneva Score, Simplified Wells Rule, and Simplified Revised Geneva Score) Had Similar Performance for the Exclusion of Acute Pulmonary Embolism in Combination with a Normal D-Dimer Result
    • Retrospective Study of the Effectiveness of Pulmonary Embolism Rule Out Criteria (PERC) in the Emergency Department (J Thromb Haemost, 2011) [MEDLINE]
      • Pulmonary Embolism Rule Out Criteria (PERC) is Only Valid in Patients with a Low Pre-Test Probability of Pulmonary Embolism (<15%): the predictive value is significantly lower in patients with intermediate/high pre-test probability for pulmonary embolism and should not be used in these populations
    • Systematic Review and Meta-Analysis of Pulmonary Embolism Rule Out Criteria (PERC) in Acute Pulmonary Embolism (Emerg Med J, 2013) [MEDLINE]
      • Overall Proportion of Missed Pulmonary Emboli by Using PERC was Only 0.3%
      • PERC Had 97% Sensitivity and 22% Specificity: indicates that 22% of D-dimer tests could have been safely avoided had the PERC been universally applied
    • Dutch Study of the Accuracy of Clinical Decision Rules in the Diagnosis of Acute Pulmonary Embolism in Patients with a Delayed Clinical Presentation (Am J Respir Crit Care Med, 2013) [MEDLINE]
      • Pulmonary Embolism Can Be Safely Excluded Based on Clinical Decision Rules and D-Dimer Testing in Patients with a Delayed Clinical Presentation
      • Patients with a Delayed Clinical Presentation More Frequently Had a Centrally-Located Pulmonary Embolism
      • Cumulative Rates of Recurrent Venous Thromboembolism and Mortality Were Not Different for Patients with and without a Delayed Clinical Presentation
    • European ADJUST-PE Study of Age-Adjusted D-Dimer Levels in the Diagnosis of Pulmonary Embolism (JAMA, 2014) [MEDLINE]
      • Age-Adjusted D-Dimer (Only for Patients ≥50 y/o): defined as 10 x age
      • Compared with a Fixed D-Dimer Cutoff of 500 μg/L (500 ng/mL), the Combination of a Pre-Test Clinical Probability Assessment and Age-Adjusted D-Dimer Cutoff was Associated with a Larger Number of Patients in Whom Pulmonary Embolism Could Be Considered Ruled Out with a Low Likelihood of Subsequent Clinical Venous Thromboembolism
    • Systematic Review and Meta-Analysis of Wells Criteria and D-Dimer Testing in the Diagnosis of Pulmonary Embolism (Ann Intern Med, 2016) [MEDLINE]
      • In Patients with an “Unlikely” Pre-Test Probability of Pulmonary Embolism, Age-Adjusted D-Dimer Testing is Associated with a 5% Increase in the Proportion of Patients with Suspected Pulmonary Embolism in Whom Imaging Can Be Safely Withheld, as Compared to Fixed D-Dimer Testing
    • Study of the Yield of CT Pulmonary Artery Angiogram When Providers Used Well Criteria-Based Clinical Decision Support in the ED (Radiology, 2016) [MEDLINE]
      • Odds of Diagnosis of Acute Pulmonary Embolism was 2x Higher (Yield: 11.2% of Studies) When Providers Adhered to Wells Criteria-Based Clinical Decision Support, as Compared to Providers who Overrode the Clinical Decision Support (Yield: 4.2% of Studies)
        • Wells Criteria ≤4: providers were recommended to initially use D-dimer testing (since the probability of acute PE is low in this population, if D-dimer level is normal)
        • Providers Who Overrode the Clinical Decision Support Ordered a CT Pulmonary Angiogram in Patients with Wells Criteria ≤4 and Negative D-Dimer (or Did Not Perform D-Dimer Testing)
    • Interval Likelihood Ratios for Plasma D-Dimer (Acad Emerg Med, 2017) [MEDLINE]
      • If the Pre-D-Dimer Probability of PE is 15% (Intermediate Pre-Test Probability), Only a D-DImer <500 ng/mL Will Result in a Post-Test Probability <3%
      • Consequently, Given a Pre-Test Probability of 15% (Intermediate Pre-Test Probability) and a CT Pulmonary Artery Angiogram Threshold of 3%, a Strategy to Obtain CT Pulmonary Artery Angiogram for D-Dimer ≥500 ng/ mL is Consistent with the Interval Likelihood Ratios Reported
    • Dutch Multicenter Prospective Cohort YEARS Study (Lancet, 2017) [MEDLINE]: n= 3616
      • D-Dimer and Three Years Items were Assessed (Clinical Signs of Deep Venous Thrombosis, Hemoptysis, Pulmonary Embolism as the Most Likely Diagnosis
        • 0 YEARS Items + D-Dimer <1000 ng/mL -> Pulmonary Embolism Excluded
        • 0 YEARS Items + D-Dimer ≥1000 ng/mL -> CT Pulmonary Artery Angiogram
        • ≥ 1 YEARS Items + D-Dimer ≤500 ng/mL -> Pulmonary Embolism Excluded
        • ≥ 1 YEARS Items + D-Dimer ≥500 ng/mL -> CT Pulmonary Artery Angiogram
      • YEARS Diagnostic Algorithm Safely Excluded the Diagnosis of Pulmonary Embolism
      • Years Algorithm Resulted in an Absolute 14% Decrease of CT Pulmonary Artery Angiogram Studies in All Ages and Across Several Relevant Subgroups
    • French Randomized PROPER Trial Using Pulmonary Embolism Rule-Out Criteria (PERC) in Low-Risk Emergency Department Patients (JAMA, 2018) [MEDLINE]: crossover cluster-randomized clinical noninferiority trial in 14 emergency departments in France
      • In Patients at Very Low-Risk with Suspected Pulmonary Embolism, PERC Strategy vs Conventional Strategy Had Similar Rates of Thromboembolic Events Over 3 mo
      • PERC Strategy is Safe for Use in Very Low-Risk Patients Presenting to the Emergency Department

    Recommendations (American College of Physicians Guidelines for the Evaluation of Patients with Suspected Pulmonary Embolism, 2015) (Ann Intern Med, 2015) [MEDLINE]

    • Use Validated Clinical Prediction Rules (or Clinical Gestalt) to Estimate the Pretest Probability of Pulmonary Embolism
      • Clinical Gestalt: the overall accuracy of an experienced clinician’s gestalt appears to be similar to that of clinical decision rules (however, clinical decision rules allow standardization for evaluation of suspected acute pulmonary embolism by clinician’s who less frequently evaluate patient’s with suspected acute pulmonary embolism)
      • Clinical Decision Rules
        • Wells Criteria or Modified (Dichotomized) Wells Criteria
        • Revised Geneva Score or Revised Simplified Geneva Score
        • Kline Rule
        • Pisa Model
    • Low Pre-Test Probability of Pulmonary Embolism + Meets All Pulmonary Embolism Rule Out Criteria (PERC)
      • D-Dimer and Imaging Studies are Not Recommended
    • Intermediate Pre-Test Probability of Pulmonary Embolism + Does Not Meet All Pulmonary Embolism Rule Out Criteria (PERC)
      • Initial High-Sensitivity D-Dimer (But Not Imaging Study) is Recommended as the Initial Diagnostic Test
        • Use Age-Adjusted D-Dimer Thresholds (Age x 10) Rather than Generic 500 ng/mL Threshold in Patients >50 y/o
        • If D-Dimer is Below the Age-Adjusted Cutoff, Do Not Use Imaging Study
    • High Pre-Test Probability of Pulmonary Embolism
      • CT Pulmonary Artery Angiogram (But Not D-Dimer) is Recommended
      • Ventilation/Perfusion (V/Q) Scan Should Be Reserved for Patients with Contraindication to CT Pulmonary Artery Angiography (or When CT Pulmonary Artery Angiography is Not Available)

    Recommendations (European Society of Cardiology and European Respiratory Society Guidelines for the Diagnosis and Management of Acute Pulmonary Embolism, 2019) (Eur Heart J, 2020) [MEDLINE]

    • For Suspected Acute Pulmonary Embolism without Hemodynamic Instability, Use of Validated Criteria for Diagnosing Acute Pulmonary Embolism is Recommended (Class I, Level B)
    • It is Recommended that the Diagnostic Strategy Be Based on Clinical Probability (Assessed Either by Clinical Judgement or By a Validated Prediction Rule (Class I, Level A)

    Clinical Grading/Risk Stratification of Pulmonary Embolism Severity

    Pulmonary Embolism Severity Index (PESI) (Am J Respir Crit Care Med, 2005) [MEDLINE]

    • Criteria
      • Age (in Years)
      • Altered Mental Status: +60 pts
      • Cancer: +30 pts
      • Chronic Heart Failure: +10 pts
      • Chronic Pulmonary Disease: +10 pts
      • Heart Rate ≥110 bpm: +20 pts
      • Hypoxemia (SpO2 <90%): +20 pts
      • Male Sex: +10 pts
      • Respiratory Rate >30 bpm: +20 pts
      • Systolic Blood Pressure <100 mm Hg: +30 pts
      • Temperature <36 °C: +20 pts
    • Scoring (with 30-Day Mortality Rates)
      • Class I (≤65 pts): 0-1.6%
      • Class II (66-85 pts): 1.7-3.5%
      • Class III (86-105 pts): 3.2-7.1%
      • Class IV (106-125 pts): 4-11.4%
      • Class V (>125 pts): 10-24.5%

    Simplified Pulmonary Embolism Severity Index (sPESI) (Arch Intern Med, 2010) [MEDLINE]

    • General Comments
      • Simplified Pulmonary Embolism Severity Index (sPESI): has similar prognostic accuracy and clinical utility and greater ease of use, as compared with the original PESI
    • Criteria
      • Age >80 y/o: 1 pt
      • Cancer: 1 pt
      • Chronic Heart Failure or Chronic Pulmonary Disease: 1 pt
      • Heart Rate ≥110 bpm: +1 pt
      • Hypoxemia (SpO2 <90%): +1 pt
      • Systolic Blood Pressure <100 mm Hg: +1 pt
    • Scoring (with 30-Day Mortality Rates)
      • 0 Points: 1% (95% CI: 0-2.1%)
      • ≥1 Points: 10.9% (95% CI: 8.5-13.2%)

    Other Clinical Grading/Risk Stratification Criteria

    Clinical Data

    • Grading of CT Signs of Right Ventricular Dysfunction in Acute Pulmonary Embolism (AJR Am J Roentgenol, 2010) [MEDLINE]
      • Volumetric Determination of the Right Ventricular Volume/Left Ventricular Volume Ratio
        • Ratio >1.2 is Suggestive of Right Ventricular Strain
        • Most Reproducible/Least User-Dependent of the CT Measurements (as Compared to Septal Bowing or IVC Reflux)
    • Grading of Factors Associated with 30-Day Frequency of Adverse Events in Prep Study (Am J Respir Crit Care Med, 2010) [MEDLINE]
      • Altered Mental Status: OR 6.8 (95% CI: 2.0-23.3)
      • Shock on Admission: OR 2.8 (95% CI: 1.1-7.5)
      • Cancer: OR 2.9 (95% CI: 1.2-6.9)
      • Elevated BNP: OR 1.3 for an increase of 250 ng/L (95% CI: 1.1-1.6)
      • Echocardiographic Right Ventricular Volume/Left Ventricular Volume Ratio: OR 1.2 for an increase of 0.1 (95% CI: 1.1-1.4)
    • Grading of Pulmonary Embolism Using Right Ventricular Dysfunction and Troponin Levels (Chest, 2013) [MEDLINE]
      • Right Ventricular Dysfunction and Elevated Troponin Level: these criteria have an incremental prognostic value for risk stratification in hemodynamically-stable patients with acute pulmonary embolism
    • Grading of Intermediate-Risk Pulmonary Embolism Patients (Eur Respir J, 2014) [MEDLINE]
      • SBP 90-100 mm Hg: 2 pts
      • Elevated Troponin: 2 pts
      • Right Ventricular Dysfunction (by Echocardiogram or CT): 2 pts
      • HR ≥100 BPM: 1 pt
      • Scoring: range 0-7
        • Stage I (0-2 points)
          • 3.6% risk for in-hospital PE-related complications
          • 4.2% risk for 30-day PE-related complications
          • 1.7% 30-day PE-related mortality
        • Stage II (3-4 points)
          • 9.7% risk for in-hospital PE-related complications
          • 10.8% risk for 30-day PE-related complications
          • 5.0% 30-day PE-related mortality
        • Stage III (>4 points)
          • 28.0% risk for in-hospital PE-related complications
          • 29.2% risk for 30-day PE-related complications
          • 15.5% 30-day PE-related mortality

    Recommendations (European Society of Cardiology and European Respiratory Society Guidelines for the Diagnosis and Management of Acute Pulmonary Embolism, 2019) (Eur Heart J, 2020) [MEDLINE]

    • Initial Risk Stratification of Suspected/Confirmed Acute Pulmonary Embolism (Based on the Presence of Hemodynamic Instability) is Recommended to Identify Patients at High Risk of Early Mortality (Class I, Level B)
      • Low-Risk Acute Pulmonary Embolism
        • Defined as Acute Pulmonary Embolism with Hemodynamic Stability and Absence of Right Ventricular Dilation/Dysfunction and/or Positive Biomarkers Suggestive of Myocardial Injury/Myocardial Distention
      • Intermediate-Risk (“Submassive”) Acute Pulmonary Embolism
        • Defined as Acute Pulmonary Embolism with Class III-V PESI ≥86 pts (or sPESI ≥1 pt) or Right Ventricular Dilation/Dysfunction (by CT PA Angiogram or Echocardiography), or Elevated Serum Troponin
          • Note: Elevation of Other Laboratory Biomarkers (Such as NT-ProBNP ≥600 ng/L, H-FABP ≥6 ng/mL, or Copeptin ≥24 pmol/L) May Provide Additional Prognostic Information (However, These Biomarkers Have Been Validated in Cohort Studies, But They Have Not Been Used to Guide Treatment Decisions in Randomized Controlled Trials)
        • Subclassification Per the European Society of Cardiology and European Respiratory Society Guidelines (Eur Heart J, 2020) [MEDLINE]
          • Intermediate-Low Risk: presence of either right ventricular dysfunction or troponin elevation
          • Intermediate-High Risk: presence of both right ventricular dysfunction and troponin elevation (with any PESI/sPESI score)
      • High-Risk (“Massive”) Acute Pulmonary Embolism
        • Defined as Acute Pulmonary Embolism with Hemodynamic Instability Characterized by Any of the Following
          • Cardiac Arrest
          • Obstructive Shock (Systolic Blood Pressure <90 mm Hg or Vasopressors Required to Achieve a Blood Pressure ≥90 mmHg Despite Adequate Filling Status, in Combination with End-Organ Hypoperfusion)
          • Persistent Hypotension (Systolic Blood Pressure <90 mm Hg or a Systolic Blood Pressure Decrease ≥40 mm Hg for >15 min, Not Caused by New-Onset Arrhythmia, Hypovolemia, or Sepsis)
          • The Presence of Remaining Variables (PESI Score ≥86 pts/sPESI ≥1/Elevated Troponin/etc) are Not Required to Define a Patient as High-Risk
    • In Patients without Hemodynamic Instability, Further Stratification of Patients with Acute Pulmonary Embolism into Low and Intermediate Risk Categories is Recommended (Class I, Level B)
    • In Patients without Hemodynamic Instability, Use of Clinical Prediction Rules Integrating Acute Pulmonary Embolism Severity and Comorbidity (Preferably the PESI or sPESI) Should Be Considered for Risk Assessment in the Acute Phase of Pulmonary Embolism (Class IIa, Level B)
    • Assessment of the Right Ventricle by Imaging Methods or Laboratory Biomarkers (Troponin or Brain Natriuretic Peptide) Should Be Considered, Even in the Presence of a Low PESI or a Negative sPESI (Class IIa, Level B)
    • In Patients without Hemodynamic Instability, Use of Validated Scores Combining Clinical, Imaging, and Laboratory Acute Pulmonary Embolism-Related Prognostic Factors May Be Considered to Further Stratify the Severity of the Acute Pulmonary Embolism Episode (Class IbI, Level C)

    Recommendations (Consensus Practice from the PERT Consortium, 2019) (Clin Appl Thromb Hemost, 2019) [MEDLINE]

    • Once Acute Pulmonary Embolism is Diagnosed, Risk Stratification is Recommended Using a Composite of Clinical Appearance, Systolic Blood Pressure, Heart Rate, Respiratory Rate, Oxygen Requirement, PESI or sPESI, Imaging for Right Ventricular Dysfunction (by CT PA Angiogram or Echocardiography) and/or Biomarkers (Troponin, BNP, or NT-pro-BNP)

    Clinical Manifestations

    Cardiovascular Manifestations

    Atrial Fibrillation (AF) (see Atrial Fibrillation)

    • Epidemiology
      • Large Prospective Registry of Acute Pulmonary Embolism Patients (Eur Respir J, 2005) [MEDLINE]
        • Atrial Arrhythmias, Complete Right Bundle Branch Block, Peripheral Low Voltage, Pseudoinfarction Pattern (Q Waves in III and aVF), ST Segment Changes (Elevation or Depression) in Left Precordial Leads are Associated with Increased Risk of Mortality in Acute PE: 29% of patients with at least one of these findings on hospital admission did not survive to hospital discharge
      • Norwegian Tromso Study of the Association Between Venous Thromboembolism and Atrial Fibrillation (J Am Heart Assoc, 2014) [MEDLINE]
        • Venous Thromboembolism was Associated with an Increased Future Risk of Atrial Fibrillation: 9.3% of patients with venous thromboembolism developed subsequent atrial fibrillation
        • Risk of Atrial Fibrillation was Particularly High in the First 6 Months After the Venous Thomboembolism Event (Hazard Ratio 4.00, 95% CI: 2.21-7.25) and in Those with Pulmonary Embolism (Hazard Ratio 1.78, 95% CI: 1.13-2.8)
      • Systematic Review and Meta-Analysis of EKG Findings Which Predict Circulatory Shock in Acute Pulmonary Embolism (Acad Emerg Med, 2015) [MEDLINE]
        • Findings Consistent with RV Strain (Heart Rate >100 bpm, S1Q3T3 Pattern, Complete RBBB, Inverted T-Waves in V1-V4, ST Elevation in aVR, and Atrial Fibrillation) are Associated with Increased Risk of Circulatory Shock and Death
      • Systematic Review and Meta-Analysis of Prognostic Value of EKG Findings in Acute Pulmonary Embolism (Clin Cardiol, 2017) [MEDLINE]
        • Presence of S1Q3T3 Predicted Increased In-Hospital Mortality in Acute PE (OR: 3.38, 95% CI: 2.46-4.66, P <0.001)
        • Presence of Complete RBBB (But Not Incomplete RBBB) Predicted Increased In-Hospital Mortality in Acute PE (OR: 3.90, 95% CI: 2.46-6.20, P <0.001)
        • Presence of T-Wave Inversion in Precordial/Inferior Leads Predicted Increased In-Hospital Mortality in Acute PE (OR: 1.62, 95% CI: 1.19-2.21, P = 0.002)
        • Presence of Right Axis Deviation Predicted Increased In-Hospital Mortality in Acute PE (OR: 3.24, 95% CI: 1.86-5.64, P <0.001)
        • Presence of Atrial Fibrillation Predicted Increased In-Hospital Mortality in Acute PE (OR: 1.96, 95% CI: 1.45-2.67, P <0.001)
      • Pooled Analysis of the Prevalence and Prognostic Significance of Atrial Fibrillation in Patients with Acute Pulmonary Embolism (Respir Med, 2022) [MEDLINE]: n = 819,380 (from 27 studies)
        • Prevalence of Pre-Existing Atrial Fibrillation was 11.3%
        • Prevalence of New Atrial Fibrillation was 4.7%
        • Prevalence of Any Atrial Fibrillation 13.2%
        • Predictors for Newly-Diagnosed Atrial Fibrillation
          • Congestive Heart Failure (Adjusted Odds Ratio 3.33; 95% CI: 1.81-6.12)
          • Ischemic Heart Disease (Adjusted Odds Ratio 3.25; 95% CI: 1.65-6.39)
          • Massive Pulmonary Embolism (Adjusted Odds Ratio 2.67; 95% CI: 1.19-5.99)
        • Atrial Fibrillation was Associated with Increased Risk of Short-Term Mortality (Adjusted Odds Ratio 1.54; 95% CI: 1.44-1.64) and Long-Term Mortality (Adjusted Odds Ratio 1.58; 95% CI: 1.26-1.97)
        • In Subgroup Analysis, All Types of Atrial Fibrillation were Associated with Increased Risk of Short-Term Mortality
          • Pre-Existing Atrial Fibrillation (Adjusted Odds Ratio 1.90; 95% CI: 1.59-2.27)
          • Newly diagnosed Atrial Fibrillation (Adjusted Odds Ratio 1.51; 95% CI: 1.18-1.93)
          • Any Atrial Fibrillation (Adjusted Odds Ratio 1.50; 95% CI: 1.42-1.60)
        • Pre-existing AF (Adjusted Odds Ratio 2.08; 95% CI: 1.27-3.42) and Any Atril Fibrillation (Adjusted Odds Ratio 1.29; 95% CI: 1.02-1.63) were Also Associated with Higher Long-Term Mortality

    Cardiac Physical Exam Findings

    • Accentuated P2 Component of the Second Heart Sound (S2) (see Increased Intensity of P2)
      • Epidemiology
        • Accentuated P2 Occurs in 23% of Pulmonary Embolism Cases (Chest, 1991) [MEDLINE]
      • Physiology
        • Due to Pulmonary Hypertension (Pulmonary Hypertension of Any Etiology is the Most Common Etiology of Increased Intensity of P2)
      • Clinical
        • P2 (the Pulmonic Valve Closure Sound) is Heard Over the Right Second Intercostal Space and Along the Left Sternal Border
    • Fourth Heart Sound (S4) (see Fourth Heart Sound)
      • Epidemiology
        • S4 Occurs in 24% of Pulmonary Embolism Cases (Chest, 1991) [MEDLINE]
    • Jugular Venous Distention
      • Physiology
        • Due to Acute Pulmonary Hypertension
    • Right Ventricular (Parasternal) Heave/Lift (see Parasternal Heave)
      • Epidemiology
        • Right Ventricular Heave Occurs in 4% of Pulmonary Embolism Cases (Chest, 1991) [MEDLINE]
    • Pulsatile Liver
      • Physiology
        • Due to Acute Pulmonary Hypertension
    • Third Heart Sound (S3) (see Third Heart Sound)
      • Epidemiology
        • Occurs in 3% of Pulmonary Embolism Cases (Chest, 1991) [MEDLINE]

    Chest Pain (see Chest Pain)

    • Epidemiology
      • Chest Pain is Common in Pulmonary Embolism
    • Clinical
      • Pleuritic Chest Pain Occurs in 66% of Pulmonary Embolism Cases (Chest, 1991) [MEDLINE]
      • Angina-Like Chest Pain Occurs in 4% of Pulmonary Embolism Cases (Chest, 1991) [MEDLINE]
        • Located in the Anterior Chest and Does Not Radiate

    Electrocardiographic (EKG) Abnormalities (see Electrocardiogram)

    • General Comments
      • Normal EKG is Present in Many Cases of Acute PE
      • While EKG Abnormalities are Common in Acute PE, They are Usually Non-Specific and Non-Diagnostic (Am J Cardiol, 2000) [MEDLINE]
      • Retrospective Review of EKG Changes in Acute Pulmonary Embolism ( J Emerg Med, 2017) [MEDLINE]
        • No Change in EKG was Observed in 25% of Acute PE Cases
    • Peripheral Low Voltage
      • Epidemiology
        • Large Prospective Registry of Acute Pulmonary Embolism Patients (Eur Respir J, 2005) [MEDLINE]
          • Atrial Arrhythmias, Complete Right Bundle Branch Block, Peripheral Low Voltage, Pseudoinfarction Pattern (Q Waves in III and aVF), ST Segment Changes (Elevation or Depression) in Left Precordial Leads are Associated with Increased Risk of Mortality in Acute PE: 29% of patients with at least one of these findings on hospital admission did not survive to hospital discharge
        • Systematic Review and Meta-Analysis of Prognostic Value of EKG Findings in Acute Pulmonary Embolism (Clin Cardiol, 2017) [MEDLINE]
          • Low-Voltage in Limb/Precordial Leads Did Not Predict Increased In-Hospital Mortality
    • P-Pulmonale
      • Epidemiology
        • Systematic Review and Meta-Analysis of Prognostic Value of EKG Findings in Acute Pulmonary Embolism (Clin Cardiol, 2017) [MEDLINE]
          • Presence of P-Pulmonale Did Not Predict Increased In-Hospital Mortality in Acute PE
    • Pseudoinfarction Pattern (Q Waves in III and aVF)
      • Epidemiology
        • Large Prospective Registry of Acute Pulmonary Embolism Patients (Eur Respir J, 2005) [MEDLINE]
          • Atrial Arrhythmias, Complete Right Bundle Branch Block, Peripheral Low Voltage, Pseudoinfarction Pattern (Q Waves in III and aVF), ST Segment Changes (Elevation or Depression) in Left Precordial Leads are Associated with Increased Risk of Mortality in Acute PE: 29% of patients with at least one of these findings on hospital admission did not survive to hospital discharge
    • Right Axis Deviation (RAD)
      • Epidemiology
        • Systematic Review and Meta-Analysis of Prognostic Value of EKG Findings in Acute Pulmonary Embolism (Clin Cardiol, 2017) [MEDLINE]
          • Presence of S1Q3T3 Predicted Increased In-Hospital Mortality in Acute PE (OR: 3.38, 95% CI: 2.46-4.66, P <0.001)
          • Presence of Complete RBBB (But Not Incomplete RBBB) Predicted Increased In-Hospital Mortality in Acute PE (OR: 3.90, 95% CI: 2.46-6.20, P <0.001)
          • Presence of T-Wave Inversion in Precordial/Inferior Leads Predicted Increased In-Hospital Mortality in Acute PE (OR: 1.62, 95% CI: 1.19-2.21, P = 0.002)
          • Presence of Right Axis Deviation Predicted Increased In-Hospital Mortality in Acute PE (OR: 3.24, 95% CI: 1.86-5.64, P <0.001)
          • Presence of Atrial Fibrillation Predicted Increased In-Hospital Mortality in Acute PE (OR: 1.96, 95% CI: 1.45-2.67, P <0.001)
    • Right Bundle Branch Block (see Right Bundle Branch Block)
      • Epidemiology
        • Large Prospective Registry of Acute Pulmonary Embolism Patients (Eur Respir J, 2005) [MEDLINE]
          • Atrial Arrhythmias, Complete Right Bundle Branch Block, Peripheral Low Voltage, Pseudoinfarction Pattern (Q Waves in III and aVF), ST Segment Changes (Elevation or Depression) in Left Precordial Leads are Associated with Increased Risk of Mortality in Acute PE: 29% of patients with at least one of these findings on hospital admission did not survive to hospital discharge
        • Systematic Review and Meta-Analysis of EKG Findings Which Predict Circulatory Shock in Acute Pulmonary Embolism (Acad Emerg Med. 2015) [MEDLINE]
          • Findings Consistent with RV Strain (Heart Rate >100 bpm, S1Q3T3 Pattern, Complete RBBB, Inverted T-Waves in V1-V4, ST Elevation in aVR, and Atrial Fibrillation) are Associated with Increased Risk of Circulatory Shock and Death
        • Systematic Review and Meta-Analysis of Prognostic Value of EKG Findings in Acute Pulmonary Embolism (Clin Cardiol, 2017) [MEDLINE]
          • Presence of S1Q3T3 Predicted Increased In-Hospital Mortality in Acute PE (OR: 3.38, 95% CI: 2.46-4.66, P <0.001)
          • Presence of Complete RBBB (But Not Incomplete RBBB) Predicted Increased In-Hospital Mortality in Acute PE (OR: 3.90, 95% CI: 2.46-6.20, P <0.001)
          • Presence of T-Wave Inversion in Precordial/Inferior Leads Predicted Increased In-Hospital Mortality in Acute PE (OR: 1.62, 95% CI: 1.19-2.21, P = 0.002)
          • Presence of Right Axis Deviation Predicted Increased In-Hospital Mortality in Acute PE (OR: 3.24, 95% CI: 1.86-5.64, P <0.001)
          • Presence of Atrial Fibrillation Predicted Increased In-Hospital Mortality in Acute PE (OR: 1.96, 95% CI: 1.45-2.67, P <0.001)
    • “RV Strain” Findings
      • Physiology
        • EKG Findings Indicating “RV Strain” (Due to RV Hypertrophy or Dilatation)
          • ST Depression and T-Wave Inversion in the Right Precordial Leads, V1-V3 (and Sometimes V4)
          • ST Depression and T-Wave Inversion in Inferior Leads, II, III, and AVF: III is the most rightward facing lead
      • Epidemiology
        • Systematic Review and Meta-Analysis of EKG Findings Which Predict Circulatory Shock in Acute Pulmonary Embolism (Acad Emerg Med. 2015) [MEDLINE]
          • Findings Consistent with RV Strain (Heart Rate >100 bpm, S1Q3T3 Pattern, Complete RBBB, Inverted T-Waves in V1-V4, ST Elevation in aVR, and Atrial Fibrillation) are Associated with Increased Risk of Circulatory Shock and Death
        • Systematic Review and Meta-Analysis of Prognostic Value of EKG Findings in Acute Pulmonary Embolism (Clin Cardiol, 2017) [MEDLINE]
          • Presence of S1Q3T3 Predicted Increased In-Hospital Mortality in Acute PE (OR: 3.38, 95% CI: 2.46-4.66, P <0.001)
          • Presence of Complete RBBB (But Not Incomplete RBBB) Predicted Increased In-Hospital Mortality in Acute PE (OR: 3.90, 95% CI: 2.46-6.20, P <0.001)
          • Presence of T-Wave Inversion in Precordial/Inferior Leads Predicted Increased In-Hospital Mortality in Acute PE (OR: 1.62, 95% CI: 1.19-2.21, P = 0.002)
          • Presence of Right Axis Deviation Predicted Increased In-Hospital Mortality in Acute PE (OR: 3.24, 95% CI: 1.86-5.64, P <0.001)
          • Presence of Atrial Fibrillation Predicted Increased In-Hospital Mortality in Acute PE (OR: 1.96, 95% CI: 1.45-2.67, P <0.001)
        • Study of the Incidence of RV Strain-Related Electrocardiographic Changes from the Italian Pulmonary Embolism Registry (Thromb Res, 2018) [MEDLINE]: RV strain/ischemia findings examined in the study included complete or incomplete right bundle branch block, S1Q3 pattern, T-wave inversion in leads V1- V3 (V4), inferior (II/III/AVF) ST-segment elevation, and Qr pattern in lead V1
          • At Least One of the RV Strain/Ischemia Findings was Present in 53.1% of Acute PE Cases (high risk patients: at least one finding was present in 74.8% of cases, intermediate-risk (BP 90-100) patients: at least one finding was present in 73.5% of cases, intermediate-risk (BP >100) patients: at least one finding was present in 56.5% of cases, and low-risk patients: at least one finding was present in 28.2% of cases)
          • Right Bundle Branch Block Occurred in 22.4% of Acute PE Cases
          • S1Q3 Occurred in 24.4% of Acute PE Cases
          • T-Wave Inversion in V1-V3 (V4) Occurred in 28.4% of Acute PE Cases
          • Inferior ST Elevation Occurred in 6.2% of Acute PE Cases
          • V1 Qr Pattern Occurred in 6.8% of Acute PE Cases
    • S1Q3T3 Pattern
      • Epidemiology
        • S1Q3T3 Pattern Occurs Infrequently in Acute PE: occurs in <10% of cases
        • Systematic Review and Meta-Analysis of EKG Findings Which Predict Circulatory Shock in Acute Pulmonary Embolism (Acad Emerg Med. 2015) [MEDLINE]
          • Findings Consistent with RV Strain (Heart Rate >100 bpm, S1Q3T3 Pattern, Complete RBBB, Inverted T-Waves in V1-V4, ST Elevation in aVR, and Atrial Fibrillation) are Associated with Increased Risk of Circulatory Shock and Death
        • Systematic Review and Meta-Analysis of Prognostic Value of EKG Findings in Acute Pulmonary Embolism (Clin Cardiol, 2017) [MEDLINE]
          • Presence of S1Q3T3 Predicted Increased In-Hospital Mortality in Acute PE (OR: 3.38, 95% CI: 2.46-4.66, P <0.001)
          • Presence of Complete RBBB (But Not Incomplete RBBB) Predicted Increased In-Hospital Mortality in Acute PE (OR: 3.90, 95% CI: 2.46-6.20, P <0.001)
          • Presence of T-Wave Inversion in Precordial/Inferior Leads Predicted Increased In-Hospital Mortality in Acute PE (OR: 1.62, 95% CI: 1.19-2.21, P = 0.002)
          • Presence of Right Axis Deviation Predicted Increased In-Hospital Mortality in Acute PE (OR: 3.24, 95% CI: 1.86-5.64, P <0.001)
          • Presence of Atrial Fibrillation Predicted Increased In-Hospital Mortality in Acute PE (OR: 1.96, 95% CI: 1.45-2.67, P <0.001)
    • ST-Segment Changes (Elevation or Depression)
      • Epidemiology
        • Large Prospective Registry of Acute Pulmonary Embolism Patients (Eur Respir J, 2005) [MEDLINE]
          • Atrial Arrhythmias, Complete Right Bundle Branch Block, Peripheral Low Voltage, Pseudoinfarction Pattern (Q Waves in III and aVF), ST Segment Changes (Elevation or Depression) in Left Precordial Leads are Associated with Increased Risk of Mortality in Acute PE: 29% of patients with at least one of these findings on hospital admission did not survive to hospital discharge
        • Systematic Review and Meta-Analysis of EKG Findings Which Predict Circulatory Shock in Acute Pulmonary Embolism (Acad Emerg Med. 2015) [MEDLINE]
          • ST Elevation in aVR was Present in 36% of Acute PE Cases
          • Findings Consistent with RV Strain (Heart Rate >100 bpm, S1Q3T3 Pattern, Complete RBBB, Inverted T-Waves in V1-V4, ST Elevation in aVR, and Atrial Fibrillation) are Associated with Increased Risk of Circulatory Shock and Death
        • Systematic Review and Meta-Analysis of Prognostic Value of EKG Findings in Acute Pulmonary Embolism (Clin Cardiol, 2017) [MEDLINE]
          • Presence of ST Elevation in V1 Predicted Increased Adjusted In-Hospital Mortality in Acute PE
    • T-Wave Inversion/Flattening
      • Epidemiology
        • Systematic Review and Meta-Analysis of EKG Findings Which Predict Circulatory Shock in Acute Pulmonary Embolism (Acad Emerg Med. 2015) [MEDLINE]
          • T-Wave Inversion in Lead V1 was Present in 38% of Acute PE Cases
          • Findings Consistent with RV Strain (Heart Rate >100 bpm, S1Q3T3 Pattern, Complete RBBB, Inverted T-Waves in V1-V4, ST Elevation in aVR, and Atrial Fibrillation) are Associated with Increased Risk of Circulatory Shock and Death
        • Retrospective Review of EKG Changes in Acute Pulmonary Embolism ( J Emerg Med, 2017) [MEDLINE]
          • T-Wave Inversion/Flattening (Most Commonly in the Inferior Leads) is the Most Common EKG Finding in Acute PE: occurs in 33% of cases
        • Systematic Review and Meta-Analysis of Prognostic Value of EKG Findings in Acute Pulmonary Embolism (Clin Cardiol, 2017) [MEDLINE]
          • Presence of S1Q3T3 Predicted Increased In-Hospital Mortality in Acute PE (OR: 3.38, 95% CI: 2.46-4.66, P <0.001)
          • Presence of Complete RBBB (But Not Incomplete RBBB) Predicted Increased In-Hospital Mortality in Acute PE (OR: 3.90, 95% CI: 2.46-6.20, P <0.001)
          • Presence of T-Wave Inversion in Precordial/Inferior Leads Predicted Increased In-Hospital Mortality in Acute PE (OR: 1.62, 95% CI: 1.19-2.21, P = 0.002)
          • Presence of Right Axis Deviation Predicted Increased In-Hospital Mortality in Acute PE (OR: 3.24, 95% CI: 1.86-5.64, P <0.001)
          • Presence of Atrial Fibrillation Predicted Increased In-Hospital Mortality in Acute PE (OR: 1.96, 95% CI: 1.45-2.67, P <0.001)

    Elevated Serum Brain Natriuretic Peptide (BNP) (see Serum Brain Natriuretic Peptide)

    • General Comments
      • Serum Brain Natriuretic Peptide (BNP) May Be Elevated
        • Magnitude of Increase in Brain Natriuretic Peptide Correlates with the Risk of Subsequent Complications and Prolonged Hospitalization
        • BNP >90 pg/ml (within 4 hrs of Presentation): associated with adverse outcomes (death, cardioplumonary resuscitation, mechanical ventilation, pressor therapy, thrombolysis, and embolectomy)
        • BNP <50 pg/ml (within 4 hrs of Presentation): benign clinical course in 95% of cases
      • Sensitivity: 60%
      • Specificity: 62%
    • Clinical Data
      • Grading of Factors Associated with 30-Day Frequency of Adverse Events in Prep Study (Am J Respir Crit Care Med, 2010) [MEDLINE]
        • Altered Mental Status: OR 6.8 (95% CI: 2.0-23.3)
        • Shock on Admission: OR 2.8 (95% CI: 1.1-7.5)
        • Cancer: OR 2.9 (95% CI: 1.2-6.9)
        • Elevated BNP: OR 1.3 for an increase of 250 ng/L (95% CI: 1.1-1.6)
        • Echocardiographic Right Ventricular Volume/Left Ventricular Volume Ratio: OR 1.2 for an increase of 0.1 (95% CI: 1.1-1.4)

      Elevated Serum Troponin (see Elevated Serum Troponin)

      • General Comments
        • Serum Troponin May Be Elevated (Due to Acute Right Heart Overload
          • Serum Troponin is Not Useful for the Diagnosis of Acute Pulmonary Embolism, But Offers Prognostic Information
            • Elevated Serum Troponin is Associated with Increased Incidence of Prolonged Hypotension and Increased 30-Day Mortality
          • Troponin I: elevated in 30% of moderate-large PE’s
          • Troponin T: elevated in 50% of moderate-large PE’s
      • Clinical Efficacy
        • Grading of Pulmonary Embolism Using Right Ventricular Dysfunction and Troponin Levels (Chest, 2013) [MEDLINE]
          • Right Ventricular Dysfunction and Elevated Troponin Level: these criteria have an incremental prognostic value for risk stratification in hemodynamically-stable patients with acute pulmonary embolism
        • Grading of Intermediate-Risk Pulmonary Embolism Patients (Eur Respir J, 2014) [MEDLINE]
          • SBP 90-100 mm Hg: 2 pts
          • Elevated Troponin: 2 pts
          • RV Dysfunction (by Echocardiogram or CT): 2 pts
          • HR ≥100 BPM: 1 pt
          • Scoring Range: 0-7
            • Stage I (0-2 Points): 3.6% risk for in-hospital PE-related complications, 4.2% risk for 30-day PE-related complications, 1.7% 30-day PE-related mortality
            • Stage II (3-4 Points): 9.7% risk for in-hospital PE-related complications, 10.8% risk for 30-day PE-related complications, 5.0% 30-day PE-related mortality
            • Stage III (>4 Points): 28.0% risk for in-hospital PE-related complications, 29.2% risk for 30-day PE-related complications, 15.5% 30-day PE-related mortality

      Hypotension/Shock (see Hypotension)

      • Epidemiology
        • Hypotension Occurs in Approximately 8% of Pulmonary Embolism Cases
      • Clinical
        • Criteria for Hemodynamic Instability (Eur Heart J, 2020) [MEDLINE]
          • Need for Cardiopulmonary Resuscitation
          • Obstructive Shock Characterized by Systolic BP <90 mm Hg or Vasopressors Required to Achieve a Blood Pressure ≥90 mm Hg Despite Adequate Filling Status and End-Organ Hypoperfusion (Altered Mental Status, Cold Clammy Skin, Oliguria/Anuria, Increased Serum Lactate)
          • Systolic Blood Pressure <90 mm Hg or Systolic Blood Pressure Drop ≥40 mm Hg, Lasting Longer than 15 min and Not Caused by New-Onset Arrhythmia, Hypovolemia, or Sepsis

      Palpitations (see Palpitations)

      • Epidemiology
        • Palpitations Occur in 10% of Pulmonary Embolism Cases (Chest, 1991) [MEDLINE]

      Sinus Bradycardia (see Sinus Bradycardia)

      • Epidemiology
        • Sinus Bradycardia is Associated with a Poor Prognosis in Acute Pulmonary Embolism

      Sinus Tachycardia (see Sinus Tachycardia)

      • Epidemiology
        • Sinus Tachycardia Occurs in Approximately 30% of Pulmonary Embolism Cases (Chest, 1991) [MEDLINE]
        • Systematic Review and Meta-Analysis of EKG Findings Which Predict Circulatory Shock in Acute Pulmonary Embolism (Acad Emerg Med, 2015) [MEDLINE]
          • Sinus Tachycardia was Present in 38% of Acute PE Cases
          • Findings Consistent with RV Strain (Heart Rate >100 bpm, S1Q3T3 Pattern, Complete RBBB, Inverted T-Waves in V1-V4, ST Elevation in aVR, and Atrial Fibrillation) are Associated with Increased Risk of Circulatory Shock and Death
        • Retrospective Review of EKG Changes in Acute Pulmonary Embolism ( J Emerg Med, 2017) [MEDLINE]
          • Sinus Tachycardia Occurs in 25% of Acute PE Cases
        • Systematic Review and Meta-Analysis of Prognostic Value of EKG Findings in Acute Pulmonary Embolism (Clin Cardiol, 2017) [MEDLINE]
          • Presence of Sinus Tachycardia Predicted Increased Adjusted 30-Day Mortality in Acute PE
        • Study of Heart Rate and Mortality in Patients with Symptomatic Pulmonary Embolism (Chest, 2022) ([MEDLINE]: n = 44,331 (nonhypotensive patients with symptomatic pulmonary embolism from the Registro Informatizado de la Enfermedad TromboEmbólica registry between 2001-2021)
          • Considering a Heart Rate of 80-99 beats/min as a Reference, Patients in the Higher Heart Rate Strata Manifested Higher 30-Day All-Cause Mortality Rates
            • Adjusted Odds Ratio 1.5 for Heart Rate of 100-109 beats/min
            • Adjusted Odds Ratio 1.7 for Heart Rate of 110-119 beats/min
            • Adjusted Odds Ratio 1.9 for Heart Rate of 120-139 beats/min
            • Adjusted Odds Ratio 2.4 for Heart Rate of ≥140 beats/min
          • Patients in the Lower Heart Rate Strata Manifested Significantly Lower 30-Day All-Cause Mortality Rates, as Compared to the Same Reference Group
            • Adjusted Odds Ratio 0.6 for Heart Rate of 60-79 beats/min
            • Adjusted Odds Ratio 0.5 for HR of <60 beats/min
          • For Identification of Low-Risk Patients, a Cutoff Value of 80 beats/min (vs 110 beats/min) Increased the Sensitivity of the Simplified Pulmonary Embolism Severity Index (sPESI) from 93.4% to 98.8%
          • For Identification of Intermediate to High-Risk Patients, a Cutoff Value of 140 beats/min (vs 110 beats/min) Increased the Specificity of the Bova Score from 93.2% to 98.0%

        Supraventricular Tachycardia (SVT) (see Supraventricular Tachycardia)

        • Epidemiology
          • May Occur in Some Cases

        Syncope (see Syncope)

        • Epidemiology
          • Systematic Review and Meta-Analysis of Incidence of Acute Pulmonary Embolism in Patients with Syncope (Am J Emerg Med, 2017) [MEDLINE]: n = 12 studies
            • Pooled Estimate of Incidence of Acute Pulmonary Embolism in Patients with Syncope Presenting to the ED: 0.8%
            • Pooled Estimate of Incidence of Acute Pulmonary Embolism in Hospitalized Patients with Syncope: 1%

        Hematologic Manifestions

        Association of Isolated Pulmonary Embolism with Arterial Thrombotic Events

        • As Compared to Deep Venous Thrombosis-Associated Pulmonary Embolism, Isolated Pulmonary Embolism (without Deep Venous Thrombosis) is Believed to Represent a Distinct Clinical Entity
          • VTEval Study of Isolated Pulmonary Embolism (Chest, 2020) [MEDLINE]: n = 510 (63 with isolated pulmonary embolism + 447 with other venous thromboembolism phenotypes)
            • As Compared to Patients with Deep Venous Thrombosis-Associated Pulmonary Embolism, Patients with Isolated Pulmonary Embolism Had Significantly Higher Prevalence of COPD, Peripheral Artery Disease (PAD), Atrial Fibrillation (AF), and Coronary Artery Disease (CAD)
            • Isolated Pulmonary Embolism Patients had Significantly Higher Risk (Incidence Rate Ratio vs DVT-Associated Pulmonary Embolism, 3.7 (95% CI, 1.3-10.8, P 1⁄4 .009) vs Isolated Deep Venous Thrombosis DVT, 4.8 (1.7- 14.3, P 1⁄4 .001) of Arterial Thrombotic Events (Myocardial Infarction, Stroke/Transient Ischemic Attack)
            • After Adjustment for Clinical Profile and Medication Intake, the RISK of Arterial Thrombotic Events for Patients with Isolated Pulmonary Embolism Remained Quadruple that of Other Venous Thromboembolism Phenotypes (Hazard Ratio 3.8 [1.3-10.9], P = 0.01)

        Pulmonary Manifestations

        • Bronchospasm (see Obstructive Lung Disease)
          • Epidemiology
            • Bronchospasm/Wheezing May Occur in Association with Pulmonary Embolism (Am Rev Respir Dis, 1975) [MEDLINE] and (Clin Nucl Med, 1985) [MEDLINE]
          • Physiology
            • Likely Due to Platelet Release of Serotonin
          • Clinical
            • Wheezing (see Wheezing): occurs in 9% of pulmonary embolism cases (Chest, 1991) [MEDLINE]
        • Chest Pain (see Chest Pain)
          • Epidemiology
            • Chest Pain is Common in Pulmonary Embolism
          • Clinical
            • Pleuritic Chest Pain: occurs in 66% of pulmonary embolism cases (Chest, 1991) [MEDLINE]
            • Angina-Like Chest Pain: occurs in 4% of pulmonary embolism cases (Chest, 1991) [MEDLINE]
              • Located in the Anterior Chest and Does Not Radiate
        • Cough (see Cough)
          • Epidemiology
            • Cough Occurs in Approximately 37% of Pulmonary Embolism Cases (Chest, 1991) [MEDLINE]
          • Clinical
            • Dry Cough (Chest, 1991) [MEDLINE]
            • Clear, Bloody, or Purulent Sputum (Chest, 1991) [MEDLINE]
        • Crackles
          • Epidemiology
            • Crackles Occur in 51% of Pulmonary Embolism Cases (Chest, 1991) [MEDLINE]
            • Most Patients with Pulmonary Embolism with Rales (88%) Had Parenchymal Abnormalities, Atelectasis, or Pleural Effusion on CXR (Chest, 1991) [MEDLINE]
        • Dyspnea (see Dyspnea)
          • Epidemiology
            • Dyspnea Occurs in Approximately 73% of Pulmonary Embolism Cases (Chest, 1991) [MEDLINE]
        • Hemoptysis (see Hemoptysis)
          • Epidemiology -Hemoptysis Occurs in Approximately 13% of Pulmonary Embolism Cases (Chest, 1991) [MEDLINE]
          • Physiology
            • Due to Pulmonary Infarction
          • Clinical
            • Blood-Streaked, Blood-Tinged, or Pure Blood (Chest, 1991) [MEDLINE]
        • Hypocapnia with Respiratory Alkalosis (see Respiratory Alkalosis)
          • Physiology
            • XXXXXXXXXXXX
        • Hypoxemia (see Hypoxemia)
          • Epidemiology
            • pO2 <80 mm Hg Occurs in Approximately 74% of Pulmonary Embolism Cases (Chest, 1991) [MEDLINE]
            • Alveolar-Arterial (A-a) Gradient >20 mm Hg Occurs in Approximately 86% of Pulmonary Embolism Cases (Chest, 1991) [MEDLINE]
        • Pleural Rub (see Pleural Rub)
          • Epidemiology
            • Pleural Rub Occurs in 3% of Pulmonary Embolism Cases (Chest, 1991) [MEDLINE]
          • Physiology
            • Due to Pulmonary Infarction
        • Pulmonary Hypertension/Acute Cor Pulmonale (see Pulmonary Hypertension)
          • Physiology -Due to Acute Pulmonary Hypertension with Resulting Right Ventricular Failure
        • Systolic/Continuous Murmur Over Lung
          • Physiology
            • Due to Shunt of Blood Around Pulmonary Embolism
        • Tachypnea (see Tachypnea)
          • Epidemiology
            • Tachypnea Occurs in Approximately 70% of Pulmonary Embolism Cases (Chest, 1991) [MEDLINE]

        Renal Manifestations

        Lactic Acidosis (see Lactic Acidosis)

        • General Comments
          • Serum Lactate May Be Used to Risk Stratify Patients in Acute Pulmonary Embolism
        • Clinical Efficacy
          • Prospective Study of Plasma Lactate in Acute Symptomatic Pulmonary Embolism (with Normotension) (Thorax, 2015) [MEDLINE]: n = 496 (between 2012-2014)
            • Pulmonary Embolism-Related Complications Occurred in 4.0% of Patients (95% CI: 2.5-6.2%)
            • Patients with Pulmonary Embolism-Related Complications Had Higher Baseline Lactate Levels (Median 2.66 mmol/L; Interquartile Range 1.56-5.96 mmol/L) than Patients without Complications (Median 1.20 mmol/L; Interquartile Range 1.20-2.00 mmol/L) (p<0.001)
            • Patients with Elevated Plasma Lactate Had an Increased Rate of Pulmonary Embolism-Related Complications (Adjusted Odds Ratio 5.3; 95% CI: 1.9-14.4; p = 0.001), as Compared to Those with Low Plasma Lactate
            • Combination of Elevated Plasma Lactate with Markers of Right Ventricular Dysfunction (by Echocardiogram) and Myocardial Injury (by Cardiac Troponin) was a Particularly Useful Prognostic Indicator (Positive Predictive Value 17.9%; 95% CI 6.1-36.9%)
          • Study of Serum Venous Lactate in the Prediction of In-Hospital Adverse Outcomes in Normotensive Acute Pulmonary Embolism (Eur J Intern Med, 2021) [MEDLINE]
            • An Optimized Venous Lactate Cutoff Value of 3.3 mmol/L Predicted Both In-Hospital Adverse Outcome (Odds Ratio 11.0; 95% CI 4.6-26.3) and All-Cause Mortality (Odds Ratio 3.8; 95%CI 1.3-11.3)
            • The Established Cutoff Value for Arterial Lactate (2.0 mmol/L) and the Upper Limit of Normal for Venous Lactate (2.3 mmol/l) Had Lower Prognostic Value for Adverse Outcomes (Odds Ratio 3.6; 95% CI 1.5-8.7 and Odds Ratio 5.7; 95% CI 2.4-13.6, Respectively) and Did Not Predict Mortality
            • If Added to the 2019 European Society of Cardiology Algorithm, Venous Lactate <2.3 mmol/L was Associated with a High Negative Predictive Value (0.99 [95% CI 0.97-1.00]) for Adverse Outcomes in Intermediate-Low Risk Patients, Whereas Lactate Levels ≥3.3 mmol/L Predicted Adverse Outcomes in the Intermediate-High Risk Group (Odds Ratio 5.2; 95% CI 1.8-15.0)

        Other Manifestations

        Diaphoresis (see Diaphoresis)

        • Epidemiology
          • Diaphoresis Occurs in 11% of Pulmonary Embolism Cases (Chest, 1991) [MEDLINE]

        Fever (see Fever)

        • Epidemiology
          • Temperature >38.5°C Occurs in 7% of Pulmonary Embolism Cases (Chest, 1991) [MEDLINE]
        • Physiology
          • Due to Pulmonary Infarction

        Leg Pain (see Leg Pain)

        • Epidemiology
          • Leg Pain Occurs in 26% of Pulmonary Embolism Cases (Chest, 1991) [MEDLINE]

        Leg Swelling/Peripheral Edema (see Peripheral Edema)

        • Epidemiology
          • Leg Swelling Occurs in 28% of Pulmonary Embolism Cases (Chest, 1991) [MEDLINE]

        Treatment

        Pulmonary Embolism Response Team (PERT)

        General Comments

        • Pulmonary Embolism Response Teams (PERT) Have Been Put into Practice in Many Centers to Facilitate the More Eficient Management of Patients with Acute Pulmonary Embolism (Particularly with Regard to Rapid Identification and Deployment of Systemic Thrombolytics, Catheter-Directed Thrombolysis, and Surgical Embolectomy)

        Recommendations (European Society of Cardiology and European Respiratory Society Guidelines for the Diagnosis and Management of Acute Pulmonary Embolism, 2019) (Eur Heart J, 2020) [MEDLINE]

        • Set-Up of a Multidisciplinary Team and Program for the Management of High-Risk (and in Selected Cases, Intermediate-Risk Acute Pulmonary Embolism) Should Be Considered, Depending on the Resources and Expertise Available in Each Hospital (Class IIa, Level C)

        Recommendations (Consensus Practice from the PERT Consortium, 2019) (Clin Appl Thromb Hemost, 2019) [MEDLINE]

        • Utilize a Multidisciplinary Pulmonary Embolism Response Team (PERT) in Patients with Intermediate or High-Risk Acute Pulmonary Embolism, as Well as for Acute Pulmonary Embolism Patients in Whom There is Uncertainty Regarding Treatment

        General Goals of Anticoagulation in Venous Thromboembolism

        Prevention of Early Complications of Venous Thromboembolism

        • General Comments
          • The Benefits of Anticoagulation are the Greatest During the Initial Period of Anticoagulation
        • Prevention of Acute Pulmonary Embolism (PE) (see Acute Pulmonary Embolism)
        • Prevention of Clot Extension
          • Anticoagulation Inhibits Clot Extension
        • Prevention of Death
          • Anticoagulation Decreases Risk of Deep Venous Thrombosis Recurrence and the Decreases the Mortality Rate (Lancet, 1960) [MEDLINE]
          • In Patients Admitted for Acute Pulmonary Embolism Through the Emergency Department, Early Anticoagulation was Associated with Decreased Mortality Rate (Chest, 2010) [MEDLINE]: n = 400 emergency department patients with acute pulmonary embolism (treated with unfractionated heparin from 2002-2005)
            • Overall, the In-Hospital Mortality Rate was 3.0% and 30-Day Mortality Rate was 7.7% in the Study
            • Patients Who Received Heparin in the Emergency Department Had Decreased In-Hospital Mortality Rate (1.4% vs 6.7%; P = 0.009) and Decreased 30-Day Mortality Rate (4.4% vs 15.3%; P < 0.001), as Compared to Patients Who Received Heparin After Asmission
            • Patients Who Achieved a Therapeutic PTT within 24 hrs Had Decreased In-Hospital Mortality Rate (1.5% vs 5.6%; P = 0.093) and Decreased 30-Day Mortality Rate (5.6% vs 14.8%; P = .037), as Compared to Patients Who Achieved a Therapeutic PTT After 24 hrs
            • In Multiple Logistic Regression Models, Receiving Heparin in the Emergency Department Remained Predictive of Decreased Mortality Rate, and Intensive Care Unit Admission Remained Predictive of Increased Mortality Rate
          • Large Prospective Cohort Study of the Effects of Anticoagulation on Major Cardiovascular Events in Patients with Venous Thromboembolism (Chest, 2022) [MEDLINE]: n = 3,790
            • Treatment of Venous Thromboembolism for >3 Months was Associated with a Decreased Risk of Major Cardiovascular Events (Non-Fatal Acute Coronary Syndrome, Non-Fatal Stroke, and All-Cause Mortality)
            • Treatment of Venous Thromboembolism with Direct Oral Anticoagulant (DOAC) vs Coumadin was Associated with Decreased Risk of Major Cardiovascular Events

        Prevention of Late Complications of Venous Thromboembolism

        • Prevention of Chronic Thromboembolic Pulmonary Hypertension (CTEPH) (see Chronic Thromboembolic Pulmonary Hypertension)
        • Prevention of Recurrent Deep Venous Thrombosis (DVT)
          • Anticoagulation Decreased Risk of DVT Recurrence and Mortality Rate (Lancet, 1960) [MEDLINE]
          • Anticoagulation Decreased the Risk of Recurrent Venous Thromboembolism to 3.4% and Risk of Fatal Venous Thromboembolism to 0.4% (Ann Intern Med, 2010) [MEDLINE]
          • Systematic Review and Meta-Analysis of Anticoagulation Regimens for Venous Thromboembolism (JAMA, 2014) [MEDLINE]: n = 45 trials (44,989 patients)
            • No Statistically Significant Differences (in Terms of Safety/Efficacy) Between Anticoagulation Regimens (Low Molecular Weight Heparin/Coumadin, Unfractionated Heparin/Coumadin, Fondaparinux/Coumadin, Low Molecular Weight Heparin with Dabigatran/Edoxaban, Apixaban, Rivaroxaban, or Low Molecular Weight Heparin Alone)
            • Combination of Unfractionated Heparin/Coumadin Appeared to Have the Highest Risk of Venous Thromboembolism Recurrence (Hazard Ratio 1.42)
            • Apixaban/Rivaroxaban Regimens were Associated with the Lowest Risk of Hemorrhage
        • Prevention of Post-Thrombotic (Post-Phlebitic) Syndrome (see Post-Thrombotic Syndrome)

        Recommendations (European Society of Cardiology and European Respiratory Society Guidelines for the Diagnosis and Management of Acute Pulmonary Embolism, 2019) (Eur Heart J, 2020) [MEDLINE]

        • Intermediate/Low-Risk Pulmonary Embolism
          • In Patient without Hemodynamic Instability and with Intermediate/High Clinical Probability of Acute Pulmonary Embolism, Initiation of Anticoagulation is Recommended without Delay While Diagnostic Work-Up is in Progress (Class I, Level C)
          • If Anticoagulation is Initiated Parenterally, Low Molecular Weight Heparin or Fondaparinux is Recommended Over Unfractionated Heparin for Most Patients (Class I, Level A)
          • When Oral Anticoagulation is Started in a Patient with Acute Pulmonary Embolism Who is Eligible for a Direct Oral Anticoagulant (Apixaban, Dabigatran, Edoxaban, Rivaroxaban), a Direct Oral Anticoagulant is Recommended in Preference to Coumadin (Class I, Level A)
          • When Patients are Treated with Coumadin, Overlapping with Parenteral Anticoagulation is Recommended Until an INR of 2.5 (Range 2-3) is Reached (Class I, Level A)
          • Direct Oral Anticoagulant are Not Recommended in Patients with Severe Renal Impairment, During Pregnancy and Lactation, and in Patients with Antiphospholipid Antibody Syndrome (Class III, Level C)
          • Routine Use of Primary Systemic Thrombolysis is Not Recommended in Patients with Low-Intermediate Risk Acute Pulmonary Embolism (Class III, Level B)

        Risk Stratification for Anticoagulation-Associated Hemorrhage (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) (Chest, 2016) [MEDLINE]

        Risk Factors for Anticoagulation-Associated Hemorrhage

        Absolute Risk of Major Hemorrhage

        • Anticoagulation Duration 0-3 Months
          • Low Risk (0 Risk Factors)
            • Baseline Risk of Hemorrhage = 0.6%
            • Increased Risk of Hemorrhage = 1.0%
            • Total Risk of Hemorrhage = 1.6%
          • Moderate Risk (1 Risk Factors)
            • Baseline Risk of Hemorrhage = 1.2%
            • Increased Risk of Hemorrhage = 2.0%
            • Total Risk of Hemorrhage = 3.2%
          • High Risk (At Least 2 Risk Factors)
            • Baseline Risk of Hemorrhage = 4.8%
            • Increased Risk of Hemorrhage = 8.0%
            • Total Risk of Hemorrhage = 12.8%
        • Anticoagulation Duration >3 Months
          • Low Risk (0 Risk Factors)
            • Baseline Risk of Hemorrhage = 0.3%/year
            • Increased Risk of Hemorrhage = 0.5%/year
            • Total Risk of Hemorrhage = 0.8%/year
          • Moderate Risk (1 Risk Factors)
            • Baseline Risk of Hemorrhage = 0.6%/year
            • Increased Risk of Hemorrhage = 1.0%/year
            • Total Risk of Hemorrhage = 1.6%/year
          • High Risk (At Least 2 Risk Factors)
            • Baseline Risk of Hemorrhage = at least 2.5%/year
            • Increased Risk of Hemorrhage = at least 4.0%/year
            • Total Risk of Hemorrhage = at least 6.5%/year

        Clinical Features Which May Influence the Choice of Specific Initial/Long-Term Anticoagulants (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) (Chest, 2016) [MEDLINE] (Chest Antithrombotic Therapy for VTE Disease 2021 Guidelines) (Chest, 2021) [MEDLINE]

        • Cancer
        • Chronic Kidney Disease (CrCl <30 mL/min) (see Chronic Kidney Disease)
          • Preferred Agent
          • Direct Oral Anticoagulants and Low Molecular Weight Heparins are Contraindicated with Severe Renal Insufficiency
          • Dosing of Direct Oral Anticoagulants are Variable, Dependent on the Agent
          • Systematic Review/Meta-Analysis Comparing Rates of Hemorrhage of Novel Oral Anticoagulants vs Coumadin When Used in the Setting of Renal Insufficiency (Chest, 2016) [MEDLINE]
            • CrCl 50-80 mL/min: direct oral anticoagulants had a significantly decreased risk of major bleeding, as compared to coumadin
            • CrCl <50 mL/min: direct oral anticoagulants had a non-significantly decreased risk of major bleeding, as compared to coumadin
            • Apixaban Had the Lowest Rate of Major Bleeding in this Subgroup
        • Coronary Artery Disease (CAD) (see Coronary Artery Disease)
          • Preferred Agents
          • Coronary Artery Events Occur More Frequently with Dabigatran than with Coumadin: this is not seen with other direct oral anticoagulants
          • If Possible, Antiplatelet Therapy (for Coronary Artery Disease) Should Be Avoided in Patients on Anticoagulants Because of Increased Risk of Bleeding
        • Gastrointestinal Hemorrhage/Dyspepsia (see Gastrointestinal Hemorrhage)
          • Preferred Agents
          • Dabigatran Increases Dyspepsia
          • Dabigatran, Rivaroxaban, and Edoxaban May Be Associated with Higher Risk of Gastrointestinal Hemorrhage than Coumadin
            • Data Supporting This is from Atrial Fibrillation Trials (But Venous Thromboembolism Trials DO Not Support This)
        • Liver Disease with Coagulopathy (see Cirrhosis)
          • Preferred Agent
          • Direct Oral Anticoagulants are Contraindicated if INR is Elevated Due to Liver Disease
          • Coumadin is Difficult to Control and INR May Not Reflect Anti-Thrombotic Effect in Liver Disease
        • Once Daily Oral Therapy is Preferred
        • Parenteral Therapy Not Desired
          • Preferred Agents
          • Coumadin, Dabigatran, and Edoxaban Require Initial Parenteral Anticoagulant Therapy Prior to Their Use
        • Poor Patient Compliance
          • Preferred Agent
          • INR Monitoring Can Help to Detect Poor Patient Compliance
        • Pregnancy (see Pregnancy)
          • Preferred Agent
          • There is a Potential for Other Agents to Cross the Placenta in Pregnancy
            • Coumadin is Teratogenic
        • Reversal Agent Required
        • Suspected Heparin-Induced Thrombocytopenia (HIT) (see Heparin-Induced Thrombocytopenia)
        • Thrombolytic Therapy Use (see Thrombolytics)
          • Preferred Agents
            • Unfractionated Heparin Drip (see Heparin)
          • There is a More Extensive Clinical Experience with Unfractionated Heparin Use in Patients Treated with Thrombolytic Therapy
        • Cost/Coverage Issues
          • Preferred Agents
            • Variable
          • Clinical Data
            • Cost-Effectiveness of Rivaroxaban Compared to Enoxaparin/Coumadin in Treatment of Venous Thrombembolism (J Med Econ, 2014) [MEDLINE]
              • Rivaroxaban Cost $2,448 Per-Patient Less and was Associated with 0.0058 More QALY’s, as Compared with Enoxaparin + Coumadin
            • Cost-Effectiveness of Novel Oral Anticoagulants, Compared to Coumadin, in Non-Valvular Atrial Fibrillation and Venous Thromboembolism (J Med Econ, 2015) [MEDLINE]
              • Medical Costs are Reduced When Direct Oral Anticoagulants are Used Instead of Coumadin for the Treatment of Non-Valvular Atrial Fibrillation/Venous Thromboembolism, with Apixaban Being Associated with the Greatest Reduction in Medical Costs
            • UK Study of Cost-Effectiveness of Rivaroxaban Compared to Enoxaparin/Coumadin in Treatment of Venous Thrombembolism (Thromb J, 2015) [MEDLINE]
            • Rivaroxaban was a Cost-Effective Choice for Acute Treatment of Venous Thromboembolism and Secondary Prevention of Venous Thromboembolism, as Compared with Low Molecular Weight Heparin/Coumadin Treatment, Regardless of the Treatment Duration

        Initial Treatment of Venous Thromboembolism

        Parenteral Anticoagulation

        • Parenteral Anticoagulants
        • Requirements for Initial Parenteral Anticoagulation with Specific Long-Term Anticoagulants
          • Parenteral Anticoagulation is Indicated Prior to Coumadin (see Coumadin)
            • Conversion from Parenteral Anticoagulation to Coumadin
              • Coumadin Should Be Started Concurrently with Parenteral Anticoagulation, Rather Than Waiting (Grade 2C Recommendation) (Chest Antithrombotic Therapy and Prevention of Thrombosis 2012 Guidelines) [MEDLINE]: start coumadin 5 mg qday (with a lower dose used in elderly or those with a high risk of bleeding, malnutrition, debility, congestive heart failure, or liver disease)
              • Coumadin Should Be Overlapped with Parenteral Anticoagulation for at Least 4-5 Days
              • Parenteral Anticoagulation Can Be Discontinued When INR Remains >2 for at Least 2 Consecutive Days
          • Parenteral Anticoagulation is Indicated Prior to Dabigatran (Pradaxa) (see Dabigatran)
            • Conversion from Unfractionated Heparin Drip/Argatroban Drip to Dabigatran: start dabigatran as soon as heparin drip is stopped
            • Conversion from Low Molecular Weight Heparin (Enoxaparin, Dalteparin, Tinzaparin) or Fondaparinux to Dabigatran: start dabigatran approximately 2 hrs prior to next scheduled dose of subcutaneous anticoagulant
          • Parenteral Anticoagulation is Indicated Prior to Edoxaban (Savaysa, Lixiana) (see Edoxaban)
            • Conversion from Unfractionated Heparin/Argatroban Drip to Edoxaban (Savaysa, Lixiana): discontinue heparin/argatroban drip and initiate edoxaban 4 hrs later
            • Conversion from Low Molecular Weight Heparin (Enoxaparin, Dalteparin, Tinzaparin) to Edoxaban: discontinue low molecular weight heparin and initiate edoxaban at the time of the next scheduled administration of low molecular weight heparin
          • Parenteral Anticoagulation is Not Indicated Prior to Apixaban (Eliquis)/Rivaroxaban (Xarelto) (see Apixaban and Rivaroxaban): monotherapy with these agents is considered safe and effective when administered as monotherapy (without heparin pre-treatment) to outpatients
            • EINSTEIN Trial Demonstrated that in Acute Symptomatic Deep Venous Thrombosis, Rivaroxaban “Monotherapy” was Non-Inferior to Enoxaparin (SQ) Followed by Coumadin (NEJM, 2010) [MEDLINE]
            • AMPLIFY Trial Demonstrated that in Acute Symptomatic Venous Thromboembolism, Apixaban “Monotherapy” was Non-Inferior to Enoxaparin (SQ) Followed by Coumadin and was Associated with Significantly Lower Risk of Bleeding (NEJM, 2013) [MEDLINE]
        • Parenteral Anticoagulant Dosing in Morbid Obesity (see Obesity)
          • Enoxaparin (Lovenox) (see Enoxaparin)
            • Proposed Dosing Regimen (NEJM, 2014) [MEDLINE]
              • Dose = 0.75 mg/kg (Actual Body Weight) Has Been Suggested for Patients with a Body Mass Index (BMI) >40 or Weight >200 kg (441 lb)
            • Anti-Factor Xa Activity (see Anti-Factor Xa Activity): should be considered in this population
          • Unfractionated Heparin (see Heparin)
            • Proposed Dose Adjustment Formulas (Pharmacotherapy, 2010) [MEDLINE]
              • Dosing Weight = Ideal Body Weight + 0.3 (Actual Body Weight – Ideal Body Weight)
              • Dosing weight = Ideal Body Weight + 0.4 (Actual Body Weight – Ideal Body Weight)

        Long-Term Treatment of Venous Thromboembolism without Cancer

        Agents

        • First-Line Agents (Oral Anticoagulants)
          • General Comments
            • Risk of Bleeding with DOAC’s (and Particularly Intracranial Bleeding) is Less with DOAC’s than with Coumadin Therapy (Chest, 2021) [MEDLINE]
            • On the Basis of Patients with Atrial Fibrillation, Gastrointestinal Bleeding May Be Higher with Dabigatran, Edoxaban, and Rivaroxaban than with Coumadin Therapy, Although This Has Not Been Seen in Patients with Venous Thromboembolism (Chest, 2021) [MEDLINE]
            • However, on the Basis of Indirect Comparisons and Studies Reporting on DOAC’s for the Treatment of Cancer-Associated Thrombosis, the Risk of Bleeding May Be Lower with Apixaban than with Other DOAC’s (Chest, 2021) [MEDLINE]
            • Specific Reversal Agents for DOAC’s Have Been Approved (Yet Even Before the Availability of These, the Risk that a Major Bleed Will Be Fatal Appears to Be No Higher for DOAC’s than for Coumadin Therapy) (Chest, 2021) [MEDLINE]
          • Apixaban (Eliquis) (see Apixaban)
            • Direct Comparison Between DOAC’s is Very Limited, But Suggests that Apixaban May Carry a Lower Risk of Bleeding than Other DOAC’s (Chest, 2021) [MEDLINE]
          • Dabigatran (Pradaxa) (see Dabigatran)
          • Edoxaban (Savaysa, Lixiana) (see Edoxaban)
          • Rivaroxaban (Xarelto) (see Rivaroxaban)
        • Second-Line Agents (Vitamin K Antagonists)
          • Coumadin (see Coumadin)
            • Recommended INR Range: 2-3 (ACCP Antithrombotic Guidelines; Chest, 2012) [MEDLINE]
        • Third-Line Agents (Low Molecular Weight Heparins) (see Low Molecular Weight Heparins)

        Recommendations (American Society of Hematology Guidelines for the Management of Venous Thromboembolism, 2020) (Blood Adv, 2020) [MEDLINE]

        • For Patients with Venous Thromboembolism, Use of Direct Oral Anticoagulants (DOAC’s) is Recommended Over Coumadin (Conditional Recommendation, Moderate Certainty in the Evidence)
        • For Patients with Venous Thromboembolism, There is No Recommendation of One DOAC Over Another (Conditional Recommendation, Very Low Certainty in the Evidence)
          • Factors Which May Influence the Selection of a Specific DOAC
            • Cancer
            • Concomitant Medications (Need for a Concomitant Drug Metabolized Through the CYP3A4 Enzyme or P-Glycoprotein)
            • Once vs Twice Daily Dosing
            • Out-of-Pocket Cost
            • Renal Function
            • Requirement for Lead-In Parenteral Anticoagulation
        • For Patients with Deep Venous Thrombosis and/or Acute Pulmonary Embolism with Stable Cardiovascular Disease Who Initiate Anticoagulation and were Previously Taking Aspirin for Cardiovascular Risk Modification, Suspending Aspirin is Recommended Over Continuing it for the Duration of Anticoagulation Therapy (Conditional Recommendation, Very Low Certainty in the Evidence)
          • A Critical Review of the Indication for Aspirin Therapy is Needed at the Time Anticoagulant Therapy is Initiated, Considering the Increased Risk of Bleeding vs the Potential Benefit in Terms of Cardiovascular Prevention
          • This Recommendation Does Not Apply to Patients with a Recent Acute Coronary Event or Coronary Intervention

        Recommendations (Chest Antithrombotic Therapy for VTE Disease 2021 Guidelines) (Chest, 2021) [MEDLINE]

        • In Patients with Venous Thromboembolism (Lower Extremity Deep Venous Thrombosis or Acute Pulmonary Embolism), Apixaban/Dabigatran/Edoxaban/Rivaroxaban are Recommended Over Coumadin as the Treatment-Phase (First 3 Months) Anticoagulant Therapy (Strong Recommendation, Moderate-Certainty Evidence)

        Long-Term Treatment of Venous Thromboembolism with Cancer

        Agents

        • First-Line Agents (Oral Xa Inhibitors)
          • General Comments
            • Risk of Bleeding with DOAC’s (and Particularly Intracranial Bleeding) is Less with DOAC’s than with Coumadin Therapy (Chest, 2021) [MEDLINE]
            • On the Basis of Patients with Atrial Fibrillation, Gastrointestinal Bleeding May Be Higher with Dabigatran, Edoxaban, and Rivaroxaban than with Coumadin Therapy, Although This Has Not Been Seen in Patients with Venous Thromboembolism (Chest, 2021) [MEDLINE]
            • However, on the Basis of Indirect Comparisons and Studies Reporting on DOAC’s for the Treatment of Cancer-Associated Thrombosis, the Risk of Bleeding May Be Lower with Apixaban than with Other DOAC’s (Chest, 2021) [MEDLINE]
            • Specific Reversal Agents for DOAC’s Have Been Approved (Yet Even Before the Availability of These, the Risk that a Major Bleed Will Be Fatal Appears to Be No Higher for DOAC’s than for Coumadin Therapy) (Chest, 2021) [MEDLINE]
            • In Patients with Venous Thromboembolism and Cancer (Cancer-Associated Thrombosis, There is a Higher Risk for Recurrence as Well as a Higher Risk for Major Bleeding than in Patients with Venous Thromboembolism without Cancer (Chest, 2021) [MEDLINE]
          • Apixaban (Eliquis) (see Apixaban)
          • Edoxaban (Savaysa, Lixiana) (see Edoxaban)
          • Rivaroxaban (Xarelto) (see Rivaroxaban)
        • Other Agents

        Clinical Efficacy

        • Systematic Review and Meta-Analysis of Treatment of Venous Thromboembolism in Patients with Cancer (Lancet Oncol, 2008) [MEDLINE]
          • Long-Term Full-Dose Low Molecular Weight Heparin is More Effective than Coumadin in the Secondary Prophylaxis of Venous Thromboembolism in Patients with Cancer of Any Stage, Performance Status, or Prognosis
          • Optimum Treatment Duration is Unclear, But Because the Prothrombotic Tendency Will Persist in Patients with Advanced Cancer, Indefinite Treatment is Generally Recommended

        Recommendations (American Society of Hematology Guidelines for the Management of Venous Thromboembolism, 2020) (Blood Adv, 2020) [MEDLINE]

        • For Patients with Venous Thromboembolism, Use of Direct Oral Anticoagulants (DOAC’s) is Recommended Over Coumadin (Conditional Recommendation, Moderate Certainty in the Evidence)
        • For Patients with Venous Thromboembolism, There is No Recommendation of One DOAC Over Another (Conditional Recommendation, Very Low Certainty in the Evidence)
          • Factors Which May Influence the Selection of a Specific DOAC
            • Cancer
            • Concomitant Medications (Need for a Concomitant Drug Metabolized Through the CYP3A4 Enzyme or P-Glycoprotein)
            • Once vs Twice Daily Dosing
            • Out-of-Pocket Cost
            • Renal Function
            • Requirement for Lead-In Parenteral Anticoagulation

        Recommendations (Chest Antithrombotic Therapy for VTE Disease 2021 Guidelines) (Chest, 2021) [MEDLINE]

        • In Patients with Venous Thromboembolism (Lower Extremity Deep Venous Thrombosis or Acute Pulmonary Embolism) in the Setting of Cancer (Cancer-Associated Thrombosis), Oral Xa Inhibitors (Apixaban, Edoxaban, Rivaroxaban) are Recommended Over Low Molecular Weight Heparin for the Initiation and Treatment Phases of Anticoagulant Therapy (Strong Recommendation, Moderate-Certainty Evidence)
          • Edoxaban and Rivaroxaban Appear to Be Associated with a Higher Risk of Gastrointestinal Major Bleeding than Low Molecular Weight Heparins in Patients with Cancer-Associated Thrombosis and a Luminal Gastrointestinal Malignancy, While Apixaban Does Not
          • Consequently, Apixaban or Low Molecular Weight Heparins May Be the Preferred Options in Patients with Luminal Gastrointestinal Malignancies

        Specific Duration of Anticoagulation

        General Comments

        • Subgroups of Patients with Venous Thromboembolism (Chest, 2021) [MEDLINE]
          • Venous Thromboembolism Provoked by Surgery (a Major Transient Risk Factor): 3% recurrence rate at 5 yrs
          • Venous Thromboembolism Provoked by a Nonsurgical Transient Risk Factor (Estrogen Therapy, Pregnancy, Leg Injury, Flight of >8 hrs): 15% recurrence rate at 5 yrs
          • Unprovoked (Idiopathic) Venous Thromboembolism (Not Meeting Criteria for Provocation by a Transient Risk Factor or by Cancer): 30% recurrence rate at 5 yrs

        Recommendations (American Society of Hematology Guidelines for the Management of Venous Thromboembolism, 2020) (Blood Adv, 2020) [MEDLINE]

        • For Primary Treatment of Patients with Venous Thromboembolism (Whether Provoked by a Transient Risk Factor or by a Chronic Risk Factor or Unprovoked, Use of a Shorter Course of Anticoagulation for Primary Treatment (3-6 mos) is Recommended Over a Longer Course of Anticoagulation for Primary Treatment (6-12 mos) (Conditional Recommendations, Moderate Certainty in the Evidence
          • These Recommendations are Intended to Address the Duration of Primary Anticoagulant Treatment for All Patients with Deep Venous Thrombosis and/or Acute Pulmonary Embolism, Defined as the Minimal Length of Time for Treatment of the Initial Venous Thromboembolism
          • Most Patients with Deep Venous Thrombosis and/or Acute Pulmonary Embolism Provoked by Temporary Risk Factors Will Discontinue Anticoagulant Therapy After Completion of the Primary Treatment
          • In Contrast, Many Patients with Deep Venous Thrombosis and/or Acute Pulmonary Embolism Provoked by Chronic Risk Factors, as Well as Patients with Unprovoked Deep Venous Thrombosis and/or Acute Pulmonary Embolism, May Continue Anticoagulant Therapy Indefinitely for Secondary Prevention After Completion of the Primary Treatment
          • However, if Patient and Clinician Decides to Stop Anticoagulation, Use of a Longer Course of Primary Anticoagulant Therapy (6-12 mos) is Not Recommended
          • For Selected Patients with a Chronic Risk Factor for Which Some Improvement is Expected Over Time (Due to Improved Mobility with Rehabilitation, etc), a Longer Course of Anticoagulation for the Primary Treatment Phase (6-12 mos) Could Be Justified
        • For Patients with Unprovoked Deep Venous Thrombosis and/or Acute Pulmonary Embolism, Routine Use of Prognostic Scores, D-Dimer Testing, or Ultrasound to Detect Residual Vein Thrombosis are Not Recommended to Guide the Duration of Anticoagulation (Conditional Recommendations, Very Low Certainty in the Evidence)
          • Indefinite Anticoagulation is Probably Appropriate for the Majority of Patients with Unprovoked Venous Thromboembolism
          • However, in Certain Circumstances, Such as When Patients are Undecided or the Balance Between Risks and Benefits is Uncertain, Clinicians and Patients May Use Prognostic Scores, D-Dimer Testing, or Ultrasound Assessment for Residual Thrombosis from an Initial Deep Venous Thrombosis to Aid in Reaching a Final Decision
        • After Completion of Primary Treatment of Deep Venous Thrombosis and/or Acute Pulmonary Embolism Provoked by a Chronic Risk Factor, Indefinite Antithrombotic Therapy is Recommended Over Stopping Anticoagulation (Conditional Recommendation, Moderate Certainty in the Evidence)
          • Patients with Deep Venous Thrombosis and/or Acute Pulmonary Embolism Provoked by a Transient Risk Factor Typically Do Not Require Antithrombotic Therapy after Completion of Primary Treatment
          • This Recommendation Refers to Patients with Deep Venous Thrombosis and/or Acute Pulmonary Embolism Provoked by a Chronic Persistent Risk Factor
          • However, This Recommendation Does Not Apply to Patients Who Have a High Risk for Bleeding Complications
        • After Completion of Primary Treatment for Patients with Unprovoked Deep Venous Thrombosis and/or Acute Pulmonary Embolism, Indefinite Antithrombotic Therapy is Recommended Over Stopping Anticoagulation (Conditional Recommendation, Moderate Certainty in the Evidence)
          • This Recommendation Does Not Apply to Patients Who Have a High Risk for Bleeding Complications
        • For Patients with Deep Venous Thrombosis and/or Acute Pulmonary Embolism Who Have Completed Primary Treatment and Will Continue to Receive Secondary Prevention, the Use of Anticoagulation is Recommended Over Aspirin (Conditional Recommendation, Moderate Certainty in the Evidence)
        • For Patients with Deep Venous Thrombosis and/or Acute Pulmonary Embolism Who Have Completed Primary Treatment and Will Continue Coumadin as Secondary Prevention, the Use of International Normalized Ratio (INR) Range of 2-3 is Recommended Over a Lower INR Range (1.5-1.9) (Strong Recommendation, Moderate Certainty in the Evidence)
        • For Patients with Deep Venous Thrombosis and/or Acute Pulmonary Embolism Who Have Completed Primary Treatment and Will Continue with a DOAC for Secondary Prevention, Use of Either a Standard-Dose DOAC or a Lower-Dose DOAC is Recommended (Conditional Recommendation, Moderate Certainty in the Evidence)
          • Lower-Dose DOAC Regimens Which May Be Considered for Patients Who Have Completed Primary Treatment and Will Continue with a DOAC Include the Following
            • Apixaban: 2.5 mg BID
            • Rivaroxaban: 10 mg daily

        Recommendations (Chest Antithrombotic Therapy for VTE Disease 2021 Guidelines) (Chest, 2021) [MEDLINE]

        • In Patients with Acute Venous Thromboembolism Who Do Not Have a Contraindication, a 3 Month Treatment Phase of Anticoagulation is Recommended (Strong Recommendation, Moderate-Certainty Evidence)
          • Upon Completion of the 3 Month Treatment Phase of Therapy, All Patients Should Be Assessed for Extended-Phase Therapy
        • In Patients with Venous Thromboembolism Diagnosed in the Setting of a Major Transient Risk Factor, Extended-Phase Anticoagulation is Not Recommended (Strong Recommendation, Moderate-Certainty Evidence)
          • Major Transient Risk Factors
            • Cesarean Section (see Cesarean Section)
            • Confinement to Bed in Hospital (Only “Bathroom Privileges”) for ≥3 Days with an Acute Illness
            • Surgery with General Anesthesia for >30 min
        • In Patients with Venous Thromboembolism Diagnosed in the Setting of a Minor Transient Risk Factor, Extended-Phase Anticoagulation is Not Recommended (Weak Recommendation, Moderate-Certainty Evidence)
          • Minor Transient Risk Factors
            • Admission to Hospital for <3 Days with an Acute Illness
            • Confinement to Bed Out of Hospital for ≥3 Days with an Acute Illness
            • Leg Injury Associated with Reduced Mobility for ≥3 Days
            • Estrogen Therapy (see Estrogen)
            • Pregnancy or Puerperium (see Pregnancy)
            • Surgery with General Anesthesia for <30 min
        • In Patients with Venous Thromboembolism Diagnosed in the Absence of Transient Provocation (Unprovoked Venous Thromboembolism or Provoked by Persistent Risk Factor), Extended-Phase Anticoagulation with a DOAC is Recommended (Strong Recommendation, Moderate-Certainty Evidence)
        • In Patients with Venous Thromboembolism Diagnosed in the Absence of Transient Risk Factor (Unprovoked Venous Thromboembolism or Provoked by a Persistent Risk Factor) Who Cannot Receive a DOAC, Extended-Phase Anticoagulation with Coumadin is Recommended (Weak Recommendation, Moderate-Certainty Evidence)
          • The Recommendation to Offer Extended-Phase Anticoagulation Would Not Automatically Imply that All Patients with Unprovoked Venous Thromboembolism Receive Extended Therapy
            • Patient Preference and Predicted Risk of Recurrent Venous Thromboembolism or Bleeding Should Also Influence the Decision to Proceed with, or Continue, Extended-Phase Anticoagulation Therapy
          • Patients Who Receive Extended-Phase Anticoagulation Should Have This Decision Reevaluated at Least Annually, and at Times of Significant Change in Health Status
          • Extended-Phase anticoagulation Does Not Have a Predefined Stop Date
            • However, Studies of Extended-Phase anticoagulation Monitored Patients for Durations of About 2-4 yrs
            • Although Most Patients in These Studies Did Not Stop Anticoagulation Therapy at the End of Follow-Up, the Risk-to-Benefit Balance of Continuing Extended Anticoagulation Therapy Beyond THis Time is Uncertain
        • In Patients Offered Extended-Phase Anticoagulation, Use of Reduced-Dose Apixaban (2.5 mg BID) or Rivaroxaban (10 mg qday) is Recommended Over Full-Dose Apixaban or Rivaroxaban (Weak Recommendation, Very Low-Certainty Evidence)
        • In Patients Offered Extended-Phase Anticoagulation, Reduced-Dose DOAC (Apixaban 2.5 mg BID or Rivaroxaban 10 mg qday) is Recommended Over Aspirin or No Therapy (Strong Recommendation, Low-Certainty Evidence) and Rivaroxaban is Recommended Over Aspirin (Weak Recommendation, Moderate-Certainty Evidence)
          • Rivaroxaban is the Only DOAC to Be Directly Compared to Aspirin for Secondary Prevention of Venous Thromboembolism
          • Several Other DOACs, as Well as Coumadin, are Also Acceptable for Secondary Prevention (Extended-Phase Therapy) After Venous Thromboembolism
        • In Patients with an Unprovoked Proximal Deep Venous Thrombosis or Acute Pulmonary Embolism Who are Stopping Anticoagulation and Do Not Have a Contraindication to Aspirin, Aspirin is Recommended Over No Aspirin to Prevent Recurrent Venous Thromboembolism (Weak Recommendation, Low-Certainty Evidence)
          • Because Aspirin Has Been Shown to Be Much Less Effective at Preventing Recurrent Venous Thromboembolism than Anticoagulants, and Because Some Anticoagulants Confer a Similar Risk of Bleeding to Aspirin, We Do Not Consider Aspirin a Reasonable Alternative to Anticoagulation in Patients Who Want Extended Therapy
            • However, if a Patient Has Decided to Stop Anticoagulation, Prevention of Recurrent Venous Thromboembolism is One of the Benefits of Aspirin Which Needs to Be Balanced Against Aspirin’s Risk of Bleeding and Inconvenience
            • Use of Aspirin Should Also Be Reevaluated

        Specific Treatment of Acute Pulmonary Embolism with Hypotension

        Therapeutic Choices

        • Systemic Thrombolytic Therapy
          • Systemic Thrombolytic Therapy Accelerates Resolution of Pulmonary Embolism (with More Rapid Lowering of Pulmonary Artery Pressure, Improved Hypoxemia, and Resolution of Perfusion Scan Defects)
            • However, Systemic Thrombolytic Therapy Also Increases the Risk of Hemorrhage
          • Alteplase (Activase, t-PA) (see Alteplase)
            • Acute Pulmonary Embolism with Cardiac Arrest: 50 mg IV push (may repeat x1 in 15 min)
              • May Use Intraosseous if Intravenous Access Cannot Be Secured
            • Massive Pulmonary Embolism: 100 mg IV over 2 hrs
            • Submassive Pulmonary Embolism: 50 mg IV over 2 hrs
          • Tenecteplase (TNK) (see Tenecteplase)
            • Acute Pulmonary Embolism with Cardiac Arrest/Massive Pulmonary Embolism/Submassive Pulmonary Embolism
              • Weight <60 kg: 30 mg push (over 5-10 sec)
              • Weight ≥60 to <70 kg: 35 mg push (over 5-10 sec)
              • Weight ≥70 to <80 kg: 40 mg push (over 5-10 sec)
              • Weight ≥80 to <90 kg: 45 mg push (over 5-10 sec)
              • Weight ≥90 kg: 50 mg push (over 5-10 sec) (max dose = 50 mg)
        • Catheter-Based Thrombus Removal Without Thrombolytic Therapy (Suction Thrombectomy)
          • Commercial Suction Thrombectomy Catheters
            • Angiodynamics AngioVac
            • Angiodynamics AlphaVac
            • Inari FlowTriever: 20 Fr sheath
            • Penumbra Indigo: 4/6/8 Fr sheath
          • Catheter-Based (Mechanical-Only) Techniques for Thrombus Removal Involve Fragmentation of the Thrombus Using Various Types of Catheters (Some of Which are Designed for this Purpose)
            • Thrombus Fragmentation Results in Distal Displacement of the Thrombus with/without Suctioning and Removal of Some of the Thrombus Through the Catheter
        • Catheter-Directed Thrombolysis
          • Commercial Ultrasound-Assisted Thrombolysis Catheters
            • Boston Scientific EKOS: 5.2 Fr sheath
            • Catheter-Directed Thrombolysis Uses Approximately 33% of the Dose of Thrombolytic That Systemic Thrombolysis Uses (Lowering the Risk of Hemorrhage in Brain, Gastrointestinal Trac, etc)
            • Catheter-Directed Thrombolysis Achieves Higher Local Concentrations of Thrombolytics at the Site of the Pulmonary Embolism and Also Facilitates Thrombus Fragmentation and Permeability Via the Catheter
        • Venoarterial Extracorporeal Membrane Oxygenation (VA-ECMO) (see Venoarterial Extracorporeal Membrane Oxygenation)
          • Systematic Review of Venoarterial Extracorporeal Membrane Oxygenation in Massive Acute Pulmonary Embolism (Crit Care Med, 2021) [MEDLINE]
            • Venoarterial Extracorporeal Membrane Oxygenation Has an Emerging Role in the Management of Massive Acute Pulmonary Embolism-Related Cardiac Arrest with 61% Survival
            • Systemic Thrombolysis Preceding Venoarterial Extracorporeal Membrane Oxygenation Did Not Confer a Statistically Significant Increase in the Risk of Death, Yet Age >65 y/o and Cannulation During Cardiopulmonary Resuscitation were Associated with a 3-Fold and 6-Fold Risks of Death, Respectively

          Absolute Contraindications to Systemic Thrombolytic Therapy (Chest Antithrombotic Therapy and Prevention of Thrombosis 2012 Guidelines) [MEDLINE]

          • Active Hemorrhage (Excluding Menses)
          • Coagulopathy (see Coagulopathy)
          • History of Intracranial Hemorrhage
          • History of Ischemic Cerebrovascular Accident (CVA) within Last 3 mos (Excluding Cerebrovascular Accident within the Last 3-4.5 hrs) (see Ischemic Cerebrovascular Accident)
          • Malignant Intracranial Neoplasm
          • History of Traumatic Brain Injury (TBI)/Facial Trauma within Last 3 mos (see Traumatic Brain Injury)
          • Suspected Aortic Dissection (see Aortic Dissection)
          • Structural Intracranial Disease

          Relative Contraindications to Systemic Thrombolytic Therapy (Chest Antithrombotic Therapy and Prevention of Thrombosis 2012 Guidelines) [MEDLINE]

          • Age ≥75 y/o
          • Active Peptic Ulcer Disease (PUD) (see Peptic Ulcer Disease)
          • Anticoagulation (Coumadin with INR >1.7, etc)
          • Chronic, Poorly-Controlled Hypertension
          • Diabetic Retinopathy (see Diabetic Retinopathy)
          • Internal Hemorrhage within Last 2-4 wks
          • Ischemic Cerebrovascular Accident (CVA) within >3 mos Prior (see Ischemic Cerebrovascular Accident)
          • Major Surgery within Last 3 wks
          • Non-Compressible Vascular Puncture
          • Pericarditis/Pericardial Effusion (see Acute Pericarditis and Pericardial Effusion)
          • Pregnancy (see Pregnancy)
          • Recent Invasive Procedure
          • Severe Uncontrolled Hypertension on Presentation (Systolic BP >180 mm Hg, Diastolic BP >100 mm Hg)
          • Traumatic/Prolonged (>10 min) Cardiopulmonary Resuscitation (CPR) within Last 3 wks (see Cardiopulmonary Resuscitation)
          • For Streptokinase/Anistreplase, Prior Exposure (>5 Days Prior) or Prior Allergic Reaction to these Agents

          Clinical Efficacy of Systemic Thrombolysis in Acute Pulmonary Embolism

          • Meta-Analysis of Thrombolyis in Acute PE (JAMA, 2014) [MEDLINE]: meta-analysis (16 trials, n = 2115)
            • Thrombolysis Decreased the Mortality Rate (2.17%), as Compared to Anticoagulation Alone (3.89%)
              • No Mortality Benefit was Observed in Patients >65 y/o, a Population in Whom the Risk of Hemorrhage was the Greatest
            • Thrombolysis Decreased the Risk of Recurrent PE (1.17%) as Compared to Anticoagulation Alone (3.04%)
            • Thrombolysis Increased the Risk of Major Hemorrhage (9.2%), as Compared to Anticoagulation Alone (3.4%)
              • No Significant Difference in Major Hemorrhage in Patients ≤65 y/o
            • Thrombolysis Increased the Risk of Intracranial Hemorrhage (1.5%), as Compared to Anticoagulation Alone (0.2%)
          • PEITHO Trial of Thrombolytics in Intermediate-Risk Pulmonary Embolism (NEJM, 2014) [MEDLINE]: RCT of tenecteplase (n = 1006), intention-to-treat analysis in normotensive, intermediate-risk PE patients (RV dysfunction on Echo or CT, elevated serum troponin)
            • Thrombolysis Decreased Hemodynamic Decompensation (2.6%), as Compared to Placebo Group (5.6%)
            • Thrombolysis (1.2%) Had No Impact on 7-Day Mortality Rate, as Compared to Placebo Group (1.8%)
            • Thrombolysis Had No Impact on the 30-Day Mortality Rate
            • Thrombolysis Increased the Risk of Major Hemorrhage and Stroke
            • Death or Hemodynamic Decompensation Occurred in 2.6% of Patients in the Tenecteplase Group vs 5.6% of Patients in the Placebo Group (Odds Ratio 0.44; 95% Confidence Interval: 0.23-0.87; P = 0.02)
            • Mean Time Between Randomization and Death/Hemodynamic Compensation was 1.79 ± 1.6 Days in the Heparin Only (Placebo) Arm
              • Therefore, in Patients with Intermediate Risk Acute Pulmonary Embolism, Anticoagulation with Unfractionated Heparin/Low Molecular Weight Heparin for 2-3 Days Seems Reasonable Before Switching to Oral Anticoagulation (Eur Heart J, 2020) [MEDLINE]

          Clinical Efficacy of Catheter-Directed Therapy in Acute Pulmonary Embolism

          • Catheter-Based Thrombus Removal Without Thrombolytic Therapy (Suction Thrombectomy)
            • FlowTriever
              • FLARE Trial (JACC Cardiovasc Interv, 2019) [MEDLINE]
                • Percutaneous Mechanical Thrombectomy with the FlowTriever System was Safe and Effective in Patients with Acute Intermediate-Risk Pulmonary Embolism, with Significant Improvement in RV/LV Ratio and Minimal Major Bleeding
            • Indigo
              • EXTRACT PE Trial (JACC Cardiovasc Interv, 2021) [MEDLINE]
                • In this Prospective, Multicenter Study, the Indigo Aspiration System was Associated with a Significant Reduction in the RV/LV Ratio and a Low Major Adverse Event Rate in Submassive Pulmonary Embolism
                • Intraprocedural Thrombolytic Drugs were Avoided in 98.3% of Patients
          • Catheter-Directed Thrombolysis
            • EkoSonic
              • ULTIMA Randomized Trial of Ultrasound-Assisted Catheter-Directed Thrombolysis in Acute Pulmonary Embolism (Circulation, 2014) [MEDLINE]:
                • In Intermediate Risk Patients, Catheter-Directed Thrombolysis was Superior to Anticoagulation Alone in Reversing Right Ventricular Dilatation at 24 hrs (With No Increase in Risk of Bleeding Complications)
              • SEATTLE II Trial (JACC Cardiovasc Interv, 2015) [MEDLINE]
                • Ultrasound-Facilitated, Catheter-Directed, Low-Dose Fibrinolysis Decreased RV Dilation, Reduced Pulmonary Hypertension, Decreased Anatomic Thrombus Burden, and Minimized Intracranial Hemorrhage in Patients with Acute Massive and Submassive Pulmonary Embolism
              • OPTALYSE-PE Trial (JACC Cardiovasc Interv, 2018) [MEDLINE]
                • Treatment with Using a Ultrasound Catheter-Directed Thrombolysis with Shorter Delivery Duration and Lower-Dose tPA was Associated with Improved Right Ventricular Function and Reduced Clot Burden, as Compared with baseline
                • Major Bleeding Rate was Low, But One Intracranial Hemorrhage Event Did Occur

          Recommendations (European Society of Cardiology and European Respiratory Society Guidelines for the Diagnosis and Management of Acute Pulmonary Embolism, 2019) (Eur Heart J, 2020) [MEDLINE]

          • High-Risk Acute Pulmonary Embolism (Characterized by Hemodynamic Instability)
            • In Suspected High-Risk Acute Pulmonary Embolism, Intravenous Anticoagulation with Unfractionated Heparin (Including Weight-Adjusted Bolus) is Recommended without Delay (Class I, Level C)
            • Systemic Thrombolytic Therapy is Recommended (Class I, Level B)
            • In Patients in Whom Thrombolysis is Contraindicated or Has Failed, Surgical Pulmonary Embolectomy is Recommended (Class I, Level C)
            • In Patients in Whom Thrombolysis is Contraindicated or Has Failed, Percutaneous Catheter-Directed Treatment Should Be Considered (Class IIa, Level C)
            • Norepinephrine and/or Dobutamine Should Be Considered (Class IIa, Level C)
            • In Patients with Refractory Circulatory Collapse or Cardiac Arrest, Venoarterial Extracorporeal Membrane Oxygenation (VA-ECMO) May Be Considered, in Combination with Surgical Embolectomy or Catheter-Directed Treatment (Class IIb, Level C)
            • In Patients with Hemodynamic Deterioration on Anticoagulation Treatment, Rescue Thrombolytic Therapy (Class I, Level B) or Alternatively, Surgical Embolectomy or Percutaneous Catheter-Directed Treatment (Class IIa, Level C), are Recommended

          Recommendations for Systemic Thrombolysis (Consensus Practice from the PERT Consortium, 2019) (Clin Appl Thromb Hemost, 2019) [MEDLINE]

          • Consider Full-Dose Systemic Thrombolytics in the Following Groups
            • High-Risk Acute Pulmonary Embolism without Contraindications to Systemic Thrombolytics
          • Consider Reduced-Dose Systemic Thrombolytics in the Following Groups
            • High-Risk Acute Pulmonary Embolism with Relative Contraindications to Thrombolysis
            • Selected Intermediate to High-Risk Acute Pulmonary Embolism with Evidence of or Risk of Clinical Deterioration Based on Vital Signs, Severity of Right Ventricular Dysfunction, Tissue Perfusion, and/or Gas Exchange, and Presence of Low Bleeding Risk
          • Consider Systemic Thrombolytics in Patients with Cardiac Arrest and Suspected Acute Pulmonary Embolism
          • Consider Systemic Thrombolytics in Selected Patients with Intermediate or High-Risk Acute Pulmonary Embolism with Thrombus-in-Transit

          Recommendations for Catheter-Directed Therapy (Consensus Practice from the PERT Consortium, 2019) (Clin Appl Thromb Hemost, 2019) [MEDLINE]

          • Consider Catheter-Directed Thrombolysis in the Following Groups
            • Intermediate to High-Risk Acute Pulmonary Embolism with Risk for Clinical Deterioration Based on Vital Signs, Severity of Right Ventricular Dysfunction, Tissue Perfusion, and/or Gas Exchange, and without Absolute Contraindication to Thrombolysis
            • High-Risk Acute Pulmonary Embolism with Relative Contraindications to Systemic Thrombolysis<
          • Consider Catheter Embolectomy in the Following Groups
            • Intermediate to High-Risk Acute Pulmonary Embolism with Risk for Clinical Deterioration Based on Vital Signs, Severity of Right Ventricular Dysfunction, Tissue Perfusion, and/or Gas Exchange, with Absolute or Relative Contraindications to Thrombolysis
            • High-Risk Acute Pulmonary Embolism with Absolute Contraindications to Systemic Thrombolysis
            • After Failed Systemic Thrombolysis or Catheter-Directed Thrombolysis
            • Thrombus-in-Transit in the Right Atrium or Right Ventricle (AngioVac System)

          Recommendations for Surgical Embolectomy (Consensus Practice from the PERT Consortium, 2019) (Clin Appl Thromb Hemost, 2019) [MEDLINE]

          • High-Risk Acute Pulmonary Embolism with Contraindications to, or Failure of Systemic Thrombolysis or Catheter-Directed Thrombolysis
          • Intermediate to High Risk Acute Pulmonary Embolism, with Contraindications to, or Failure of Systemic Thrombolysis or Catheter-Directed Thrombolysis, with Risk for Clinical Deterioration Based on Vital Signs, Severity of Right Ventricular Dysfunction, Tissue Perfusion, and/or Gas Exchange
          • Right Heart Thrombi, Especially with Large Thromboembolic Burden
          • Thrombus-in-Transit Across a Patent Foramen Ovale (PFO)

          Recommendations for Mechanical Hemodynamic Support (Consensus Practice from the PERT Consortium, 2019) (Clin Appl Thromb Hemost, 2019) [MEDLINE]

          • Consider Mechanical Mechanical Hemodynamic Support in High-Risk Acute Pulmonary Embolism with Cardiac Arrest, Refractory Shock, and/or Contraindications to or Failure of Systemic Thrombolysis

          Recommendations (American Society of Hematology Guidelines for the Management of Venous Thromboembolism, 2020) (Blood Adv, 2020) [MEDLINE]

          • For Patients with Acute Pulmonary Embolism and Hemodynamic Compromise, Use of Thrombolytic Therapy Followed by Anticoagulation is Recommended Over Anticoagulation Alone (Strong Recommendation, Low Certainty in the Evidence
            • In this Case, the High Mortality of Patients with Acute Pulmonary Embolism and Hemodynamic Compromise, as Well as the Potential Lifesaving Effect of Thrombolytics, Warranted a Strong Recommendation
          • For Patients with Acute Pulmonary Embolism with Echocardiography and/or Biomarkers Compatible with Right Ventricular Dysfunction But without Hemodynamic Compromise (Submassive Pulmonary Embolism), Anticoagulation Alone is Recommended Over the Routine Use of Thrombolysis in Addition to Anticoagulation (Conditional Recommendation, Low Certainty in the Evidence
            • Thrombolysis is Reasonable to Consider for Submassive Pulmonary Embolism and Low Risk for Bleeding in Selected Younger Patients or for Patients at High Risk for Decompensation Due to Concomitant Cardiopulmonary Disease
            • Patients with Submassive Pulmonary Embolism Should Be Monitored Closely for the Development of Hemodynamic Compromise
          • For Patients with Acute Pulmonary Embolism in Whom Thrombolysis is Considered Appropriate, Use of Systemic Thrombolysis is Recommended Over Catheter-Directed Thrombolysis (Conditional Recommendation, Very Low Certainty in the Evidence)
            • This Recommendation Reflects Uncertainty About Catheter-Directed Thrombolysis for Acute Pulmonary Embolism Rooted in the Paucity of Randomized Trial Data and Variability in Procedural Experience Across Centers
            • In Centers with the Appropriate Infrastructure, Clinical Staff, and Procedural Experience, Catheter-Directed Thrombolysis May Be an Alternative to Systemic Thrombolysis, Especially for Patients with an Intermediate to High Risk for Bleeding, Because the Total Dose and Duration of Administration of Thrombolytic Agents are Lower When Delivered by Catheter

          Recommendations (Chest Antithrombotic Therapy for VTE Disease 2021 Guidelines) (Chest, 2021) [MEDLINE]

          • In Patients with Acute Pulmonary Embolism Associated with Hypotension (Systolic Blood Pressure <90 mm Hg) Who Do Not Have a High Bleeding Risk, Systemic Thrombolytic Therapy is Recommended (Weak Recommendation, Low-Certainty Evidence)
            • Studies of Systemically Administered Thrombolytic Therapy Have Utilized Different Agents at Varying Doses
              • Due to Lack of Comparative Data Between These Approaches, No Agent/Dosing Strategy is Favored Over Another
          • In Most Patients with Acute Pulmonary Embolism Which is Not Associated with Hypotension, Systemic Thrombolytic Therapy is Not Recommended (Strong Recommendation, Low-Certainty Evidence
          • In Selected Patients with Acute Pulmonary Embolism Who Clinically Deteriorate After Starting Anticoagulation But Have Yet to Develop Hypotension and Who Have an Acceptable Bleeding Risk, Systemically Administered Thrombolytic Therapy is Recommended (Weak Recommendation, Low-Certainty Evidence)
            • Deterioration (Which Has Not Resulted in Hypotension) May Include Any of the Following
              • Progressive Tachycardia
              • Decrease in Systolic Blood Pressure (But Remains >90 mm Hg)
              • Increase in Jugular Venous Pressure
              • Worsening Gas Exchange
              • Signs of Shock (Cold Sweaty Skin, Reduced Urine Output, Confusion)
              • Progressive Right Heart Dysfunction (on Echocardiogram)
              • Increase in Cardiac Biomarkers
          • In Patients with Acute Pulmonary Embolism Who are Treated with a Thrombolytic Agent, Systemic Thrombolytic Therapy Using a Peripheral Vein is Recommended Over Catheter-Directed Thrombolysis (Weak Recommendation, Low-Certainty Evidence)
            • No Randomized Trials or Observational Studies Have Compared Contemporary Catheter-Assisted Thrombus Removal with Systemic Thrombolytic Therapy
          • In Patients with Acute Pulmonary Embolism Associated with Hypotension Who Also Have High Bleeding Risk, Failed Systemic Thrombolysis, or Shock Which is Likely to Cause Death Before Systemic Thrombolysis Can Take Effect (within Hours), if Appropriate Expertise and Resources are Available, Catheter-Directed Therapy is Suggested (Weak Recommendation, Low-Certainty Evidence)

          Specific Treatment of Asymptomatic Acute Pulmonary Embolism

          Rationale

          • Asymptomatic Pulmonary Embolism is Diagnosed in About 1% of Outpatients and About 4% of Inpatients Who Have Contrast-Enhanced Chest CT Scans (Chest, 2021) [MEDLINE]
            • Most Asymptomatic Pulmonary Emboli are Found in Patients with Known Malignancy and are Reported on CT Scans Which Have Been Obtained for Another Indication (Such as Cancer Staging, Surveillance, or Treatment Response Evaluation) (Chest, 2021) [MEDLINE]
            • About 50% Involve the Lobar or More Central Pulmonary Arteries, While the Remaining 50% Involve More Distal Pulmonary Arteries (Chest, 2021) [MEDLINE]

          Recommendations (Chest Antithrombotic Therapy for VTE Disease 2021 Guidelines) (Chest, 2021) [MEDLINE]

          • In Patients Who are Incidentally Found to Have Asymptomatic Pulmonary Embolism, the Standard Initiation and Treatment with Anticoagulation is Recommended, as for Patients with Symptomatic Acute Pulmonary Embolism (Weak Recommendation, Moderate-Certainty Evidence

          Specific Treatment of Acute Subsegmental Pulmonary Embolism

          Rationale/Background

          • Improvements in CT Angiography Have Led Increased Diagnosis of Subsegmental PE’s
            • Subsegmental PE’s Have Increased from Approximately 5% to >10% of All Detected PE’s
          • Due to Small Size of Subsegmental PE’s, They are More Likely to Be a False-Positive Finding than a PE in the Segmental/More Proximal Pulmonary Arteries
            • Subsgmental PE is More Likely to Be a Real Finding if the Following Features are Present
              • Computed Tomography (CT) Pulmonary Artery Angiogram is of High Quality with Good Opacification of the Distal Pulmonary Arteries
              • Presence of Multiple Intraluminal Defects
              • Defects Involve More Proximal (Larger) Subsegmental Arteries
              • Defects are Seen on >1 Image
              • Defects are Surrounded by Contrast, Rather than Adherent to Pulmonary Artery Walls
              • Defects are Seen on >1 Projection
              • Patient is Symptomatic (as Opposed to Pulmonary Embolism Being an Incidental Finding)
              • Presence of High Clinical Pretest Probability for Pulmonary Embolism
              • Elevated Plasma D-Dimer without Another Explanation
          • Since a True Subsegmental PE is Likely to Have Arisen From a Small DVT, the Risk of Progressive or Recurrent VTE Without Anticoagulation is Expected to Be Lower Than in Patients with a Larger PE

          Recommendations (Chest Antithrombotic Therapy for VTE Disease 2021 Guidelines) (Chest, 2021) [MEDLINE]

          • Subsequent Evaluation of Acute Subsegmental Pulmonary Embolism Should Include Lower Extremity Venous Doppler Studies to Classify the Patient According to One of the Following
          • Subsegmental Acute Pulmonary Embolism + No Lower Extremity Proximal Deep Venous Thrombosis + Low Risk of Recurrent Venous Thromboembolism
            • Clinical Surveillance (with Serial Lower Extremity Dopplers, etc) is Recommended Over Anticoagulation (Weak Recommendation, Low-Certainty Evidence)
            • Factors Associated with Low Risk of Recurrent Venous Thromboembolism
              • Absence of Active Cancer
              • Normal Mobility
              • Outpatient Status
              • Presence of Reversible Risk Factor for Venous Thromboembolism (Recent Surgery, etc)
            • Presence of High Risk of Bleeding May Favor Clinical Surveillance Strategy Over Anticoagulation
          • Subsegmental Acute Pulmonary Embolism + No Lower Extremity Proximal Deep Venous Thrombosis + High Risk of Recurrent Venous Thromboembolism
            • Anticoagulation is Recommended Over Clinical Surveillance (Weak Recommendation, Low-Certainty Evidence)
            • Factors Associated with High Risk of Recurrent Venous Thromboembolism
              • Active Cancer (Especially if Metastatic or on Chemotherapy)
              • Decreased Mobility
              • Hospitalization
              • Absence of Reversible Risk Factor for Venous Thromboembolism (Recent Surgery, etc)
              • Pregnancy (see Pregnancy)
            • Presence of Low Cardiopulmonary Reserve May Favor Anticoagulation Over Surveillance Strategy

          Specific Treatment of Low-Risk Acute Pulmonary Embolism

          Criteria

          • Criteria for Outpatient Treatment of Acute PE (or Early Discharge to Home)
            • Clinically Stable with Good Cardiopulmonary Reserve
            • No Specific Contraindications, Such as Recent Bleeding, Severe Renal Disease, Severe Liver Disease, or Severe Thrombocytopenia (Platelets <70k)
            • Patient is Expected to be Compliant with Treatment
            • Patient Feels Well Enough to Be Treated at Home
          • Other Criteria-Pulmonary Embolism Severity Index (PESI): score <85
          • Other Criteria-Simplified Pulmonary Embolism Severity Index (Simplified PESI): score 0
          • Other Factors Which Might Merit Inpatient Treatment Instead of Outpatient Treatment
            • Increased Cardiac Biomarker Levels
            • Presence of Right Ventricular Dysfunction

          Recommendations (Chest Antithrombotic Therapy for VTE Disease 2021 Guidelines) (Chest, 2021) [MEDLINE]

          • In Patients with Low-Risk Acute Pulmonary Embolism, Outpatient Treatment is Recommended (Provided There is Access to Medications, Ability to Access Outpatient Care, and Adequate Home Circumstances (Strong Recommendation, Low-Certainty Evidence)

          Recommendations (European Society of Cardiology and European Respiratory Society Guidelines for the Diagnosis and Management of Acute Pulmonary Embolism, 2019) (Eur Heart J, 2020) [MEDLINE]

          • Carefully Selected Patients with Low-Risk Acute Pulmonary Embolism Should Be Considered for Early Discharge and Continuation of Treatment at Home, if Proper Outpatient Care and Anticoagulant Treatment Can Be Provided (Class IIa, Level A)

          Recommendations (American Society of Hematology Guidelines for the Management of Venous Thromboembolism, 2020) (Blood Adv, 2020) [MEDLINE]

          • For Patients with Acute Pulmonary Embolism with a Low Risk for Complications, Offering Home Treatment is Recommended Over Hospital Treatment (Conditional Recommendation, Very Low Certainty in the Evidence
            • At Best, Clinical Prediction Scores Have a Moderate Ability to Predict Patient Outcomes and, Therefore, Do Not Replace Clinical Judgment
              • However, They May Help to Select Patients at Low Risk for Complications
              • Pulmonary Embolism Severity Index (PESI) and Simplified PESI Have Been the Most Widely Validated Scores
            • This Recommendation Does Not Apply to Patients Who Have Other Conditions Which Might Require Hospitalization, Have Limited or No Home Support, Cannot Afford Medications, or Have a History of Poor Compliance
            • Patients with Submassive Pulmonary Embolism (Intermediate-High Risk) or Massive Pulmonary Embolism (High-Risk) or at High Risk for Bleeding and Those Requiring Intravenous Analgesics May Benefit from Initial Treatment in the Hospital

          Specific Treatment of Recurrent Venous Thromboembolism While Not on Anticoagulation

          Recommendations (American Society of Hematology Guidelines for the Management of Venous Thromboembolism, 2020) (Blood Adv, 2020) [MEDLINE]

          • For Patients Who Develop Deep Venous Thrombosis and/or Acute Pulmonary Embolism Provoked by a Transient Risk Factor and Have a History of Previous Unprovoked Venous Thromboembolism or Venous Thromboembolism Provoked by a Chronic Risk Factor, Use of Indefinite Antithrombotic Therapy is Recommended Over Stopping Anticoagulation After Completing Primary Treatment (Conditional Recommendation, Moderate Certainty in the Evidence)
          • For Patients Who Develop Deep Venous Thrombosis and/or Acute Pulmonary Embolism Provoked by a Transient Risk Factor and Have a History of a Previous Venous Thromboembolism Also Provoked by a Transient Risk Factor, Stopping Anticoagulation After Completion of Primary Treatment is Recommended Over Indefinite Antithrombotic Therapy (Conditional Recommendation, Moderate Certainty in the Evidence
          • For Patients with a Recurrent Unprovoked Deep Venous Thrombosis and/or Acute Pulmonary Embolism, Indefinite Antithrombotic Therapy is Recommended Over Stopping Anticoagulation After Completion of Primary Treatment (Strong Recommendation, Moderate Certainty in the Evidence)

          Specific Treatment of Recurrent Venous Thromboembolism While on Anticoagulation (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) (Chest, 2016) [MEDLINE]

          Rationale

          • Risk of Recurrent Venous Thromboembolism Decreases Rapidly After Starting Anticoagulation
            • Based on This, a Recurrence Soon After Therapy Can Generally Be Managed by Increasing the Intensity of Anticoagulation
            • When Oral Anticoagulation is Managed Well, the Risk of Recurrence is Approximately 2 Per 100 Patient-Years (Blood, 2017) [MEDLINE]
              • The Main Reasons for Breakthrough Events are Underlying Disease and Subtherapeutic Drug Levels

          Risk Factors for Recurrent Venous Thromboembolism

          Recommendations (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]

          • Treatment of Recurrent Venous Thromboembolism on a Non-Low Molecular Weight Heparin (Coumadin or Oral Agent)
            • Switch to Low Molecular Weight Heparin is Recommended, at Least Temporarily (Grade 2C Recommendation)
          • Treatment of Recurrent Venous Thromboembolism on a Low Molecular Weight Heparin
            • Higher Dose of Low Molecular Weight Heparin (by 25-33%) is Recommended (Grade 2C Recommendation)

          Recommendations (American Society of Hematology Guidelines for the Management of Venous Thromboembolism, 2020) (Blood Adv, 2020) [MEDLINE]

          • For Patients with Breakthrough Deep Venous Thrombosis and/ or Acute Pulmonary Embolism During Therapeutic Coumadin Treatment, Use of Low Molecular Weight Heparin is Recommended Over DOAC Therapy (Conditional Recommendation, Very Low Certainty in the Evidence)
            • Patients Who Present with a New Venous Thromboembolism Event During Therapeutic Coumadin Treatment Should Be Further Investigated to Identify Potential Underlying Etiologies
            • This Recommendation Does Not Apply to Patients Who Develop Breakthrough Venous Thromboembolism in the Setting of Poor INR Control, in Whom a DOAC May Be a Reasonable Option

          Inferior Vena Cava (IVC) Filter Placement (see Inferior Vena Cava Filter)

          Historical Perspective

          • Inferior Vena Cava Filter Use in the Management of Venous Thromboembolism Has Increased Over the Last Few Decades (Arch Intern Med, 2010) [MEDLINE] (Am J Med, 2011) [MEDLINE]
          • Although Most IVC Filters are Currently Designed to Be Retrieved, Many Remain in Patients for Extended Durations or Permanently, Even When the Original Reason for IVC Filter Placement Has Resolved (Chest, 2021) [MEDLINE]

          Indications for Inferior Vena Cava (IVC) Filter

          • Absolute Contraindication to Anticoagulation
            • Active Hemorrhage
            • Fall Risk (Particularly in Older Patient)
            • History of Intracranial Hemorrhage
            • Major Trauma
            • Recent or Planned Emergency Surgery/Procedure
            • Severe Coagulopathy (see Coagulopathy)
            • Severe or Uncontrolled Gastrointestinal Hemorrhage (see Gastrointestinal Hemorrhage)
            • Severe Thrombocytopenia (Platelet Count <50k) (see Thrombocytopenia)
            • Unstable Aortic Dissection (see Aortic Dissection)
          • Relative Contraindication to Anticoagulation
          • Complication of Anticoagulation
            • Anticoagulation Failure: objectively documented extension of existing deep venous thrombosis (or new deep venous thrombosis) or pulmonary embolism while therapeutically anticoagulated
            • Coumadin Skin Necrosis (see Coumadin)
            • Drug Reaction
            • Hemorrhage (Major or Minor)
            • Heparin-Induced Thrombocytopenia (HIT) (see Heparin-Induced Thrombocytopenia)
            • Poor Compliance with Anticoagulation Regimen
          • Failure of Previous Device to Prevent Pulmonary Embolism (Due to Central Extension of Thrombus Through an Existing Inferior Vena Cava Filter or Recurrent Pulmonary Embolism)
          • In Association with Thrombectomy, Embolectomy, or Lytic Therapy
          • Prophylaxis with No Thromboembolic Disease
          • Prophylaxis with Thromboembolism in Addition to Anticoagulation

          Technique

          • Filter Positioning
            • Inferior Vena Cava Filters are Typically Placed Infrarenally, Since Suprarenal Filters May Lead to Renal Vein Compromise, if They Become Clotted
          • Retrievable Inferior Vena Cava Filters
            • May Remain in Place for Approximately 2 mos
          • There is No Data to Support One Inferior Vena Cava Filter Brand Over Another

          Clinical Efficacy

          • Prévention du Risque d’Embolie Pulmonaire par Interruption Cave Study Group (PREPIC) Trial (NEJM, 1998) [MEDLINE]
            • At 2 Years, Inferior Vena Cava Filter Had No Impact on the Rate of Symptomatic Pulmonary Embolism or Mortality Rate
            • However, Inferior Vena Cava Filter Placement Increased the Rate of Recurrent Deep venous Thrombosis
          • Randomized, Open-Label PREPIC2 Trial of IVC Filter Added to Anticoagulation in Severe Acute PE Requiring Hospitalization (JAMA, 2015) [MEDLINE]
            • Retrievable Inferior Vena Cava Filter Has No Clinical Cenefit Over Anticoagulation Alone (in Terms of Decreasing the Risk of Recurrent Pulmonary Embolism at 3/6 Months or 3-Month/6-Month Mortality Rate)
            • Based on These Data, Inferior Vena Cava Filter is Not Indicated in Anticoagulated Acute Pulmonary Embolism Patients on the Basis of Poor Cardiopulmonary Reserve, Large Clot Burden, or Suspected Risk of Recurrence

          Recommendations (European Society of Cardiology and European Respiratory Society Guidelines for the Diagnosis and Management of Acute Pulmonary Embolism, 2019) (Eur Heart J, 2020) [MEDLINE]

          • Inferior Vena Cava (IVC) Filters Should Be Considered in Patients with Acute Pulmonary Embolism and Absolute Contraindications to Anticoagulation (Class IIa, Level C)
          • Inferior Vena Cava (IVC) Filters Should Be Considered in Cases of Acute Pulmonary Embolism Recurrence Despite Therapeutic Anticoagulation (Class IIa, Level C)
          • Routine Use of Inferior Vena Cava (IVC) Filters is Not Recommended (Class III, Level A)

          Recommendations for Inferior Vena Cava (IVC) Filter (Consensus Practice from the PERT Consortium, 2019) (Clin Appl Thromb Hemost, 2019) [MEDLINE]

          • Consider an Inferior Vena Cava (IVC) Filter for Patients with Contraindications to or Failure of Therapeutic Anticoagulation and for Highly Selected Patients with Intermediate or High-Risk Acute Pulmonary Embolism
          • Consider an Inferior Vena Cava (IVC) Filter in Select Patients When Large, Free-Floating, Proximal DVT is Identified

          Recommendations (American Society of Hematology Guidelines for the Management of Venous Thromboembolism, 2020) (Blood Adv, 2020) [MEDLINE]

          • For Patients with Proximal Deep Venous Thrombosis and Significant Preexisting Cardiopulmonary Disease, as Well as for Patients with Acute Pulmonary Embolism and Hemodynamic Compromise, Anticoagulation Alone is Recommended Over Anticoagulation Plus Inferior Vena Cava (IVC) Filter Placement (Conditional Recommendation, Low Certainty in the Evidence)
            • These Recommendations Apply to Patients Who are Eligible to Receive Anticoagulation
            • For Patients with a Contraindication to Anticoagulation, Insertion of a Retrievable Inferior Vena Cava (IVC) Filter May Be Indicated with Retrieval as Soon as the Patient is Able to Receive Anticoagulation

          Recommendations (Chest Antithrombotic Therapy for VTE Disease 2021 Guidelines) (Chest, 2021) [MEDLINE]

          • In Patients with Acute Lower Extremity Deep Venous Thrombosis, Inferior Vena Cava (IVC) Filter is Not Recommended in Addition to Anticoagulation (Strong Recommendation, Moderate-Certainty Evidence)
            • Because it is Uncertain if There is Benefit to Placement of an Inferior Vena Cava (IVC) Filter in Anticoagulated Patients with High-Risk Acute Pulmonary Embolism (with Hypotension), the Recommendation Against Insertion of an Inferior Vena Cava (IVC) Filter in Patients with Acute Pulmonary Embolism Who are Anticoagulated May Not Apply to this Select Subgroup of Patients
          • In Patients with Acute Lower Extremity Proximal Deep Venous Thrombosis and a Contraindication to Anticoagulation, Inferior Vena Cava (IVC) Filter is Recommended (Strong Recommendation, Moderate-Certainty Evidence)
            • In These Patients, the Inferior Vena Cava (IVC) Filter Should Be Promptly Removed When Anticoagulation Has Been Instituted

          Specific Treatment of Lower Extremity Deep Venous Thrombosis (DVT) (see Deep Venous Thrombosis)

          Outpatient vs Inpatient Therapy

          • Criteria for Outpatient Therapy (Patient Must Have All of These to Be Considered for Outpatient Therapy)
            • Hemodynamically Stable
            • Low Risk of Hemorrhage
            • No Renal Insufficiency
            • Feasible Administration/Monitoring of Anticoagulation at Home (Adequate Mental Capacity to Manage Medications and Monitoring, Adequate Living Conditions, Caregiver Support, Telephone Access, etc)
          • Contraindications to Outpatient Therapy (Can Fam Physician, 2005) [MEDLINE]
            • Massive Deep Venous Thrombosis (Iliofemoral Deep Venous Thrombosis, Phlegmasia Cerulea Dolens, etc)
            • Concurrent Symptomatic Pulmonary Embolism
            • High Risk of Hemorrhage on Anticoagulation
            • Comorbid Conditions or Other Factors Which Require Inpatient Care
          • Recommendations (American Society of Hematology Guidelines for the Management of Venous Thromboembolism, 2020) (Blood Adv, 2020) [MEDLINE]
            • For Patients with Uncomplicated Deep Venous Thrombosis, Offering Home Treatment is Recommended Over Hospital Treatment (Conditional Recommendation Based, Low Certainty in Evidence)
              • Recommendation Does Not Apply to Patients Who Have Other Conditions Which Might Require Hospitalization, Have Limited or No Home Support, Cannot Afford Medications, or Have a History of Poor Compliance
              • Patients with Limb-threatening Deep Venous Thrombosis or a High Risk for Bleeding and Those Requiring Intravenous Analgesics May Benefit from Initial Treatment in the Hospital

          Ambulation

          • Ambulation is Indicated as Soon as Possible (Despite the Theoretical Risk for Embolization)
            • Usually a Gradual Increase in Ambulation is Advisable
            • Ambulation Has Not Been Demonstrated to Increase the Risk of Fatal Pulmonary Embolism

          Graduated Compression Stockings

          • Rationale
            • May Provide Symptomatic Relief and Facilitate Ambulation
            • Theoretical Goal of Therapy is the Prevention of Post-Phlebitic Syndrome (Although Data are Conflicting as to Their Efficacy in this Regard)
          • Contraindications
            • Allergy to the Stocking Material
            • Inability to Apply Stockings
            • Severe Arterial Insufficiency
            • Skin Ulceration
          • Recommendations (American Society of Hematology Guidelines for the Management of Venous Thromboembolism, 2020) (Blood Adv, 2020) [MEDLINE]
            • For Patients with Deep Venous Thrombosis, with or without an Increased Risk for Postthrombotic Syndrome, the Routine Use of Compression Stockings is Not Recommended (Conditional Recommendations, Very Low Certainty in the Evidence)
              • Although the Majority of Patients May Not Benefit from the Use of Stockings to Reduce the Risk of Postthrombotic Syndrome, Stockings May Help to Reduce Edema and pain associated with Acute Deep Venous Thrombosis in Selected Patients
          • Recommendations (Chest, 2021) (Chest Antithrombotic Therapy for VTE Disease 2021 Guidelines) [MEDLINE]
            • In Patients with Acute Lower Extremity Deep Venous Thrombosis, Use of Routine Compression Stockings to Prevent Post-Thrombotic Syndrome is Not Recommended (Weak Recommendation, Low-Certainty Evidence)
              • No Evidence Exists that the Use of Graduated Compression Stockings Following Deep Venous Thrombosis Reduces the Risk for Recurrent Deep Venous Thrombosis

          Presence of Free-Floating Thrombus in Deep Venous Thrombosis

          • Free-Floating Thrombus Occurs in 10% of All Deep Venous Thromboses (J Vasc Surg, 1990) [MEDLINE]
            • Only 13% are Associated with Clinically-Significant Pulmonary Emboli by V/Q Scan (Usually the Pulmonary Embolism Occurred Before the Diagnosis of the Free-Floating Thrombus)
            • Most Free-Floating Thrombi Followed Noninvasively by Duplex Scanning Do Not Embolize, But Rather Become Attached to the Vein Wall or Resolve
          • Assuming Adequate Anticoagulation with Unfractionated Heparin/Low Molecular Weight Heparin (Nadroparin Calcium), Studies Suggest that Presence of DVT with Free-Floating Thrombus Does Not Increase the Risk of Acute Pulmonary Embolism (Arch Intern Med, 1997) [MEDLINE]
            • However, Similar Studies Have Not Been Done Using Direct Oral Anticoagulants
              • This is Critical Since Direct Oral Anticoagulants May Have Slower Onsets of Action Than Heparins
                • Apixaban Has a Peak Onset of Action of 3-4 hrs (see Apixaban)
                • Rivaroxaban Does Not reach Peak Plasma Levels Until 2-4 hrs Later (see Rivaroxaban)

          Catheter-Directed Thrombolysis of Acute Lower Extremity Deep Venous Thrombosis (see Deep Venous Thrombosis)

          • Clinical Efficacy
            • Retrospective Analysis of Catheter-Directed Thrombolysis for Lower Extremity DVT (JAMA Int Med, 2014) [MEDLINE]
              • Catheter-Directed Thrombolysis of Lower Extremity DVT is Associated with 2x-Increased Risk of Transfusion, 3x-Increased Risk of Intracranial Hemorrhage, 1.5x-Increased Risk of Acute PE, and 2x-Increased Risk of IVC Filter Insertion: long-term outcomes were not reported
          • Indications (Patients Most Likely to Benefit from Catheter-Directed Thrombolysis of Lower Extremity DVT) (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]
            • Failure of Anticoagulation
            • Good Functional Status
            • Iliofemoral DVT/Phlegmasia Cerulea Dolens
            • Life Expectancy of At Least 1 Year
            • Low Risk of Hemorrhage
            • Symptoms for <14 Days
          • Recommendations (American Society of Hematology Guidelines for the Management of Venous Thromboembolism, 2020) (Blood Adv, 2020) [MEDLINE]
            • In Most Patients with Proximal Deep Venous Thrombosis, Anticoagulation Therapy Alone is Recommended Over Thrombolytic Therapy in Addition to Anticoagulation (Conditional Recommendation, Low Certainty in the Evidence)
              • Thrombolysis is Reasonable to Consider for Patients with Limb-Threatening Deep Venous Thrombosis (Phlegmasia Cerulea Dolens) and for Selected Younger Patients at Low Risk for Bleeding with Symptomatic Deep Venous Thrombosis Involving the Iliac and Common Femoral Veins (Higher Risk for More Severe Postthrombotic Syndrome)
                • Patients in These Categories Who Value Rapid Resolution of Symptoms, are Averse to the Possibility of Postthrombotic Syndrome, and Accept the Added Risk of Major Bleeding May Prefer Thrombolysis
              • Use of Thrombolysis Should Be Rare for Patients with Deep Venous Thrombosis Limited to Veins Below the Common Femoral Vein
            • For Patients with Extensive Deep Venous Thrombosis in Whom Thrombolysis is Considered Appropriate, Use of Catheter-Directed Thrombolysis is Recommended Over Systemic Thrombolysis (Conditional Recommendation, Very Low Certainty in the Evidence)
          • Recommendations (Chest Antithrombotic Therapy for VTE Disease 2021 Guidelines) (Chest, 2021) [MEDLINE]
            • In Patients with Acute Lower Extremity Deep Venous Thrombosis, Anticoagulation Alone is Recommended Over Interventional (Thrombolytic, Mechanical, or Pharmacomechanical) Therapy (Weak Recommendation, Moderate-Certainty Evidence)

          Treatment of Isolated Distal (Calf) Deep Venous Thrombosis (Chest, 2021) (Chest Antithrombotic Therapy for VTE Disease 2021 Guidelines) [MEDLINE]

          • Rationale
            • Approximately 15% of Untreated Distal Deep Venous Thromboses Will Ultimately Extend Proximally into the Popliteal Vein and May Cause Acute Pulmonary Embolism (Chest, 2016) [MEDLINE]
            • Patients at High Risk for Bleeding are More Likely to Benefit from Serial Imaging
            • General Factors Which Favor Anticoagulation
              • Active Cancer
              • Elevated Plasma D-Dimer (Particularly When Markedly So without an Alternative Explanation) (see Elevated Plasma D-Dimer)
              • Extensive Thrombosis (>5 cm in Length, Involves Multiple Veins, >7 mm in Maximum Diameter)
              • Highly Symptomatic Patient
              • History of Venous Thromboembolism
              • Inpatient Status
              • No Reversible Provoking Factor for Deep Venous Thrombosis
              • Severe Acute Respiratory Syndrome Coronavirus-2 (SARS CoV-2/COVID-19) Infection (see Severe Acute Respiratory Syndrome Coronavirus-2)
              • Thrombus Close to the Proximal Veins
              • Patient Prefers to Avoid Repeat Imaging
            • General Factors Which Favor Serial Lower Extremity Imaging
              • Thrombus Confined to Muscular Calf Veins (i.e. Soleus, Gastrocnemius)
              • Moderate/High Risk of Bleeding
              • Patient Prefers to Avoid Anticoagulation
          • Isolated Distal Deep Venous Thrombosis without Severe Symptoms or Risk Factors for Extension (See Below)
            • Serial Lower Extremity Dopplers x 2 wks are Recommended (Weak Recommendation, Moderate-Certainty Evidence)
              • Serial Lower Extremity Dopplers Should Be Performed Once Weekly or with Worsening Symptoms
            • During Surveillance
              • If Thrombus Does Not Extend within the Distal Veins, Anticoagulation is Not Recommended (Strong Recommendation, Moderate-Certainty Evidence)
              • If Thrombus Extends within the Distal Veins, Anticoagulation is Suggested (Weak Recommendation, Very Low-Certainty Evidence)
              • If Thrombus Extends into the Proximal Veins, Anticoagulation is Recommended (Strong Recommendation, Moderate-Certainty Evidence)
          • Isolated Distal Distal Deep Venous Thrombosis with Severe Symptoms or Risk Factors for Extension (See Below)
            • Anticoagulation is Recommended (Weak Recommendation, Low-Certainty Evidence)
            • Risk Factors for Extension of Distal Deep Venous Thrombosis
              • Active Cancer
              • Elevated Plasma D-Dimer (Particularly When Markedly So without an Alternative Explanation) (see Elevated Plasma D-Dimer)
              • Extensive Thrombosis (>5 cm in Length, Involves Multiple Veins, >7 mm in Maximum Diameter)
              • History of Venous Thromboembolism
              • Inpatient Status
              • No Reversible Provoking Factor for Distal Deep Venous Thrombosis
              • Thrombosis Close to Proximal Veins
                • Note: Thrombosis Confined to the Muscular Veins of the Calf (Soleus, Gastrocnemius) has a Lower Risk of Extension than Thrombosis that Involves the Axial (True Deep: Peroneal, Tibial) Veins

            Treatment of Lower Extremity Superficial Venous Thrombosis (SVT)

            Recommendations (Chest, 2021) (Chest Antithrombotic Therapy for VTE Disease 2021 Guidelines) [MEDLINE]

            • In Patients with Lower Extremity Superficial Venous Thrombosis (SVT) at Increased Risk of Clot Progression to Deep Venous Thrombosis or Acute Pulmonary Embolism (Per the Factors Below), Anticoagulation for 45 Days is Recommended Over No Anticoagulation (Weak Recommendation, Moderate-Certainty Evidence)
              • Factors Which Favor the Use of Anticoagulation in Patients with Superficial Venous Thrombosis
                • Active Cancer
                • Extensive Superficial Venous Thrombosis
                • History of Venous Thromboembolism or Superficial Venous Thrombosis
                • Involvement Above the Knee (Particularly if Close to the Saphenofemoral Junction)
                • Involvement of the Greater Saphenous Vein
                • Recent Surgery
                • Severe Symptoms
            • In Patients with Superficial Venous Thrombosis Who are Treated with Anticoagulation, Fondaparinux (2.5 mg Daily) is Recommended Over Other Anticoagulant Regimens Such as Prophylactic or Therapeutic Dose Low Molecular Weigh Heparins (Weak Recommendation, Low-Certainty Evidence)
            • In Patients with Superficial Venous Thrombosis Who Refuse or are Unable to Use Parenteral Anticoagulation, Rivaroxaban 10 mg Daily is Recommended as a Reasonable Alternative to Fondaparinux (2.5 mg Daily) (Weak Recommendation, Low-Certainty Evidence)

            Specific Treatment of Upper Extremity Deep Venous Thrombosis (DVT) (see Deep Venous Thrombosis)

            Anticoagulation

            • Recommendations (Chest Antithrombotic Therapy and Prevention of Thrombosis 2012 Guidelines) [MEDLINE]
              • Anticoagulation is Recommended for Upper Extremity Deep Venous Thrombosis Involving the Axillary or More Proximal Veins

            Catheter-Directed Thrombolysis of Upper Extremity Deep Venous Thrombosis Which Involves Axillary or More Proximal Veins

            • Indications (Patients Most Likely to Benefit from Catheter-Directed Thrombolysis of Upper Extremity DVT) (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]
              • Good Functional Status
              • Life Expectancy of ≥1 Year
              • Low Risk of Hemorrhage
              • Severe Symptoms
              • Symptoms Present for <14 Days
              • Thrombus Involving Most of the Axillary and Subclavian Vein
            • Recommendations (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]
              • Anticoagulation is Recommended Over Catheter-Directed Thrombolysis in Upper Extremity Deep Venous Thrombosis (Grade 2C Recommendation)
              • In Patients Who Undergo Catheter-Directed Thrombolysis of Upper Extremity Deep Venous Thrombosis, the Same Intensity/Duration of Anticoagulation is Recommended as in Those Who Do Not Undergo Thrombolysis (Grade 1B Recommendation)

            Follow-Up of Acute Pulmonary Embolism

            Recommendations for Follow-Up of Acute Pulmonary Embolism (Consensus Practice from the PERT Consortium, 2019) (Clin Appl Thromb Hemost, 2019) [MEDLINE]

            • Acute Pulmonary Embolism Patients Should Have a Short Interval Follow-Up Visit (2 wks-3 mos) Post-Pulmonary Embolism, or Sooner if Symptoms or Patient Complexity Suggest the Need for This
              • Expert Follow-Up with the PERT Team is Recommended
            • The Initial Post-Discharge Visit Should Focus on the Patient’s Clinical Status, Anticoagulation Regimen (Type, Dose, Duration, Compliance, and Tolerance), Consideration for Inferior Vene Cave Filter Removal, Evaluation of Thrombophilia and Age-Appropriate Cancer Screening
            • Patients with Persistent or Recurrent Symptoms, Particularly After 3 mos, Merit Follow-Up Testing
            • If Chronic Thromboembolic Pulmonary Hypertension (CTEPH) is Highly Suspected or Confirmed, the Patient Should Be Referred to an Expert CTEPH Center


            Prognosis


            References

            American College of Chest Physicians Evidence-Based Clinical Practice Guidelines 2012 (9th Edition)

            European Society of Cardiology/European Respiratory Society Clinical Practice Guidelines 2014

            American College of Chest Physicians Evidence-Based Clinical Practice Guidelines 2016

            European Society of Cardiology/European Respiratory Society Clinical Practice Guidelines 2019

            PERT Consortium Clinical Practice Guidelines 2019

            American Society of Hematology Clinical Practice Guidelines 2020

            American College of Chest Physicians Evidence-Based Clinical Practice Guidelines 2021

            General

            Risk Factors

            Physiology

            Deep Venous Thrombosis (DVT) Prophylaxis (see Deep Venous Thrombosis)

            Upper Extremity Deep Venous Thrombosis (DVT) (see Deep Venous Thrombosis)

            Other

            Diagnosis

            General

            Electrocardiogram (EKG) (see Electrocardiogram)

            Plasma D-Dimer (see Plasma D-Dimer)

            Computed Tomography (CT) Pulmonary Artery Angiogram (see Computed Tomography Pulmonary Artery Angiogram)

            Point-of-Care Ultrasound (see Point-of-Care Ultrasound)

            Clinical Decision Rules

            Clinical Manifestations

            Treatment

            General

            Inferior Vena Cava (IVC) Filter (see Inferior Vena Cava Filter)

            Embolectomy/Catheter-Directed Therapy

            Thrombolytics

            Venoarterial Extracorporeal Membrane Oxygenation (VA-ECMO) (see Venoarterial Extracorporeal Membrane Oxygenation)

            Prognosis