Acute Pulmonary Embolism (PE)


Epidemiology

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 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: 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

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

  • 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)
      • 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)
      • 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]
    • Tuberculosis (Active) (see Tuberculosis)
      • 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
    • Clinical Venous Thromboembolism Occurs in 5% of All Cancer Patients
    • Cancer (Particularly Metastatic Cancer) is a Moderate Risk Factor for Venous Thromboembolism (with Odds Ratio >2-9) (Eur Heart J, 2020) [MEDLINE]
    • Approximately 20% of Patients with Deep Venous Thrombosis Have a Known Active Malignancy
    • 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: study may not have been able to fully account for all of the confounding risks of venous thrombombolism related to the underlying disease itself (for which the glucocorticoids were prescribed): 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 to 3.99), and Fractures (Incidence Rate Ratio 1.87, 95% CI: 1.69 to 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)
  • 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: inherited or acquired hypercoagulable state

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

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

Perforator Veins

  • Thigh Perforator Vein
  • Calf Perforator Vein

Upper Extremity Venous Anatomy

Superficial Veins

  • Basilic Vein
    • Common site of PICC placement
  • Cephalic Vein
  • Median Antebrachial Vein
  • Median Antecubital Vein
  • Accessory Cephalic Vein

Deep Veins

  • Radial Vein
  • Ulnar Vein
  • Interosseous Vein: in the forearm
  • Brachial Vein
    • Common site for PICC-related DVT
  • Axillary Vein
    • Common site for PICC-related DVT
  • Subclavian Vein
    • Common site for PICC-related DVT
  • Internal Jugular Vein
    • Most common site for CVC-related deep venous thrombosis

Lower Extremity Deep Venous Thrombosis

  • Calf Vein (Distal) DVT
    • Progression: left untreated, distal DVT will progress to proximal DVT in approximately 33% of cases
      • 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 DVT 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 DVT: risk of distal DVT embolization is approximately 50% the risk of proximal DVT embolization [MEDLINE]
  • Proximal DVT: thrombi in lower extremities develop within minutes, then organize, and fibrinolyse (stabilizing within 7-10 days)
    • Risk of Pulmonary Embolism with Proximal DVT: the risk of (symptomatic or asymptomatic) PE is approximately 50%
    • Highest Risk Period for Embolization of Proximal DVT: within first few days after DVT formation

Upper Extremity Deep Venous Thrombosis

Source of Pulmonary Embolism

  • In Situ Pulmonary Artery Thrombosis: rare
  • Lower Extremity Deep Venous Thrombosis (DVT): 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 (DVT)
  • Arteriovenous Hemodialysis Fistula (see Arteriovenous Hemodialysis Fistula): thrombectomy (including cases with paradoxical arterial embolism) may lead to pulmonary embolism
  • Upper Extremity Deep Venous Thrombosis (DVT): usually near venous valves

Clinical Consequences of Acute Pulmonary Embolism

  • Pulmonary Infarction: occurs in 10% of 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
    • Mechanical Obstruction of Pulmonary Vascular Bed, Resulting in Alteration of V/Q Ratio: hypoxemia
    • Surfactant Dysfunction and Atelectasis, Resulting in Functional Intrapulmonary Shunting: hypoxemia
    • Inflammation Resulting in Respiratory Drive Stimulation: hypocapnia with respiratory alkalosis
  • 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: due to occluded vasculature with remaining ventilation
    • Most Patients with Acute PE 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 PE

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 ED patients and is more accurate than a standard threshold of 500 ng/dL. Our findings support the adoption of an age-adjusted D-dimer cutoff in community EDs
  • 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)

Clinical Efficacy

  • xxx

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)

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

  • 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)

  • Serum Brain Natriuretic Peptide 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)

Serum Troponin (see Serum Troponin)

  • May Be Elevated: 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

Combined Elevated Serum NT-proBNP level + Elevated Serum Troponin (see Serum Brain Natriuretic Peptide and Serum Troponin)

  • Provide Prognostic Information
  • Troponin-T >0.07 µg/L + NT-proBNP >600 ng/L are 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

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]

Simplified Wells Criteria

Revised Geneva Score

Simplified Revised Geneva Score

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

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

Pulmonary Embolism Rule Out Criteria (PERC)

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

Clinical Efficacy

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

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]

Clinical Grading/Risk Stratification of Pulmonary Embolism Severity

Clinical Data

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]

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)

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

Supraventricular Tachycardia (SVT) (see Supraventricular Tachycardia)

  • Epidemiology
    • May Occur in Some Cases

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)

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]
  • Right Ventricular Heave/Lift (see xxxx)
    • Epidemiology
      • RV Heave Occurs in 4% of Pulmonary Embolism Cases (Chest, 1991) [MEDLINE]
  • Third Heart Sound (S3) (see Third Heart Sound)
    • Epidemiology
      • Occurs in 3% of Pulmonary Embolism Cases (Chest, 1991) [MEDLINE]

Hemodynamic Findings

  • Hypotension/Cardiogenic Shock (see Hypotension and Cardiogenic Shock)
    • 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
  • 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%

Other Cardiovascular Findings

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

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 (see XXXXX)
    • 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]

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 IsolatedDeep Venous ThrombosisDVT, 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)

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

General Comments

Strength of Clinical Indication for Anticoagulation in Lower Extremity Proximal vs Distal Deep Venous Thrombosis

  • Comparative Risks of Pulmonary Embolism: the risk of pulmonary embolism is higher with proximal lower extremity DVT than with distal lower extremity DVT
    • Over 90% of Pulmonary Emboli Arise from Proximal Lower Extremity Veins (Lancet, 1974) [MEDLINE] (Acta Chir Scand Suppl, 1977) [MEDLINE]
    • Comparative Mortality Rates
    • Proximal Lower Extremity DVT: 8% mortality rate (Data from OPTIMEV Study) (Thromb Haemost, 2009) [MEDLINE]
    • Distal Lower Extremity DVT: 4.4% mortality rate (Data from OPTIMEV Study) (Thromb Haemost, 2009) [MEDLINE]

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

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

Initial Treatment of Venous Thromboembolism

Parenteral Anticoagulation

Long-Term Treatment of Venous Thromboembolism without Cancer (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]

Recommended Agents

Long-Term Treatment of Venous Thromboembolism with Cancer (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]

Recommended Agents

Specific Duration of Anticoagulation (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]

Pulmonary Embolism Response Team (PERT)

General Comments

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]

Specific Treatment of Acute Pulmonary Embolism with Hypotension

Therapeutic Choices

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

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

Clinical Efficacy of Systemic Thrombolysis in Acute Pulmonary Embolism

Clinical Efficacy of Catheter-Directed Thrombolysis in Acute Pulmonary Embolism

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

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]

Specific Treatment of Acute Subsegmental Pulmonary Embolism

Rationale/Background

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

Specific Treatment of Low-Risk Acute Pulmonary Embolism

Criteria

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

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]

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

Rationale

Risk Factors for Recurrent Venous Thromboembolism

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

Specific Use of Aspirin for Extended Treatment of Venous Thromboembolism

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

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

Historical Perspective

Indications for Inferior Vena Cava (IVC) Filter

Technique

Clinical Efficacy

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

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]

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

Outpatient vs Inpatient Therapy

Ambulation

Graduated Compression Stockings

Presence of Free-Floating Thrombus in Deep Venous Thrombosis

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

Treatment of Isolated Distal (Calf) Deep Venous Thrombosis (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]

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

Anticoagulation

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


Prognosis


References

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

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

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)

Clinical Decision Rules

Clinical Manifestations

Treatment

General

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

Embolectomy

Thrombolytics

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

Prognosis