Deep Venous Thrombosis (DVT)


Risk Factors for Venous Thromboembolism

General Comments

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

Inherited Hypercoagulable States (see Hypercoagulable States)

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

Acquired Hypercoagulable States (see Hypercoagulable States)

Cardiovascular Disease

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

Central Venous Catheter/Lead/Device

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

Chronic Myeloproliferative Disease (see Chronic Myeloproliferative Diseases)

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

Endocrinologic Therapy/Disease

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

Gastrointestinal/Hepatic Disease

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

Hyperviscosity Syndrome

Immobilization

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

Infection

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

Malignancy

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

Neurologic Disease

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

Obesity (see Obesity)

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

Renal Disease

Rheumatologic Disease/Autoimmune Disease/Vasculitis (see Vasculitis)

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

Surgery

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

Trauma

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

Vascular Disease

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

Drug/Toxin

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

Other

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


Physiology

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

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

Lower Extremity Venous Anatomy

Superficial Veins

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

Deep Veins

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

Perforator Veins

  • Thigh Perforator Vein
  • Calf Perforator Vein

Upper Extremity Venous Anatomy

Superficial Veins

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

Deep Veins

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

Lower Extremity Deep Venous Thrombosis

Calf Vein (Distal) Deep Venous Thrombosis

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

Proximal Deep Venous Thrombosis

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

Upper Extremity Deep Venous Thrombosis

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

Source of Pulmonary Embolism

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

Clinical Consequences of Acute Pulmonary Embolism

Pulmonary Infarction

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

Abnormal Gas Exchange

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

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

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

Increased Alveolar Dead Space Fraction

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

Resolution of Acute Pulmonary Embolism

  • Embolus in the Pulmonary Vasculature Lyses over Hours-Days


Diagnosis

Plasma D-Dimer (see Plasma D-Dimer)

Assay

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

Interpretation

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

Clinical Efficacy

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

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

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

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

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

Lower Extremity Venogram (see Lower Extremity Venogram)

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

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

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

Clinical Efficacy-Occlusiveness of Deep Venous Thrombosis

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

Clinical Efficacy-Other

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

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

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

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

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

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

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

Recommendations

  • See Below

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

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

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

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

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

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

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

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

Advantages

  • No Exposure to Iodinated Radiographic Contrast
  • No Radiation Exposure

Disadvantages

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

Recommendations

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

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

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

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

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

Lower Extremity Impedance Plethysmography (IPG)

  • Indications
    • Sensitive for Above the Knee Deep Venous Thrombosis

Lower Extremity Radiofibrinogen Study

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

Recommendations for Diagnostic Testing for Suspected Lower Extremity Deep Venous Thrombosis (Chest Antithrombotic Therapy and Prevention of Thrombosis 2012 Guidelines) [MEDLINE]

Recommended Diagnostic Testing for Suspected First Lower Extremity Deep Venous Thrombosis if Risk Stratification is NOT USED to Classify Patient (By Pretest Probability)

  • Recommendations for Diagnostic Testing for Patients with No Risk Stratification with First Lower Extremity Deep Venous Thrombosis (Chest Antithrombotic Therapy and Prevention of Thrombosis 2012 Guidelines) [MEDLINE]
    • Proximal or Whole Leg Lower Extremity Compression Venous Doppler Ultrasound is Recommended (Grade 1B Recommendation vs No Testing, Grade 2B vs D-Dimer Testing)
    • CT Lower Extremity Venogram: may be alternatively used when lower extremity venous ultrasound is not practical or possible
      • Not Recommended as the Routine Initial Diagnostic Test (Grade 1C Recommendation)
    • Gadolinium-Enhanced Magnetic Resonance Lower Extremity Venogram: may be alternatively used when lower extremity venous ultrasound is not practical or possible
      • Not Recommended as the Routine Initial Diagnostic Test (Grade 1C Recommendation)

Recommended Diagnostic Testing for Suspected First Lower Extremity Deep Venous Thrombosis if Risk Stratification is USED to Classify Patient (By Pretest Probability)

  • Recommendations for Diagnostic Testing for Patients with Low Pretest Probability of First Lower Extremity Deep Venous Thrombosis (Chest Antithrombotic Therapy and Prevention of Thrombosis 2012 Guidelines) [MEDLINE]: one of the following
    • Moderate-Sensitivity D-Dimer (Grade 1B Recommendation): D-dimer is the preferred initial diagnostic test if there are no comorbid conditions which might be expected to elevate the D-dimer (Grade 2C Recommendation)
      • If D-Dimer is Negative, No Further Testing is Recommended (Grade 1B Recommendation)
      • If D-Dimer is Positive, Compression Proximal Lower Extremity Venous Doppler Ultrasound is Recommended (Grade 2C Recommendation)
    • High-Sensitivity D-Dimer (Grade 1B Recommendation): D-dimer is the preferred initial diagnostic test if there are no comorbid conditions which might be expected to elevate the D-dimer (Grade 2C Recommendation)
      • If D-Dimer is Negative, No Further Testing is Recommended (Grade 1B Recommendation)
      • If D-Dimer is Positive, Compression Proximal Lower Extremity Venous Doppler Ultrasound is Recommended (Grade 2C Recommendation)
    • Proximal Lower Extremity Compression Venous Doppler Ultrasound (Grade 1B Recommendation): ultrasound is the preferred initial diagnostic test if there are comorbid conditions which might be expected to elevate the D-dimer
      • If Proximal Ultrasound is Negative, No Further Testing is Recommended (Grade 1B Recommendation)
    • CT Lower Extremity Venogram: may be alternatively used when lower extremity venous ultrasound is not practical or possible
    • Gadolinium-Enhanced Magnetic Resonance Lower Extremity Venogram: may be alternatively used when lower extremity venous ultrasound is not practical or possible
  • Recommendations for Diagnostic Testing for Patients with Moderate Pretest Probability of First Lower Extremity Deep Venous Thrombosis (Chest Antithrombotic Therapy and Prevention of Thrombosis 2012 Guidelines) [MEDLINE]: one of the following
    • High-Sensitivity D-Dimer (Grade 1B Recommendation): high-sensitivity D-dimer is the preferred initial diagnostic test if there are no comorbid conditions which might be expected to elevate the D-dimer (Grade 2C Recommendation)
      • If D-Dimer is Negative, No Further Testing is Recommended (Grade 1B Recommendation)
      • If D-Dimer is Positive, Proximal or Whole Leg Ultrasound is Recommended (Grade 1B Recommendation)
    • Proximal or Whole Leg Lower Extremity Compression Venous Doppler Ultrasound (Grade 1B Recommendation): ultrasound is the preferred initial diagnostic test if there are comorbid conditions which might be expected to elevate the D-dimer
      • If Proximal Ultrasound is Performed First and is Negative, Moderate/High-Sensitivity D-Dimer Immediately or Repeat Ultrasound in 7 Days is Recommended (Grade 1C Recommendation)
      • If Proximal Ultrasound is Negative, But D-Dimer is Positive, Repeat Ultrasound in 7 Days is Recommended (Grade 1B Recommendation)
      • If Whole Leg Ultrasound is Negative, No Further Testing is Recommended (Grade 1B Recommendation)
      • If Isolated Distal DVT is Detected, Serial Lower Extremity Ultrasound to Rule Out Proximal Extension is Recommended (Grade 2C Recommendation): patients with severe symptoms and risk factors for extension are more likely to benefit from treatment over repeat ultrasound (see treatment below)
    • CT Lower Extremity Venogram: may be alternatively used when lower extremity venous ultrasound is not practical or possible
    • Gadolinium-Enhanced Magnetic Resonance Lower Extremity Venogram: may be alternatively used when lower extremity venous ultrasound is not practical or possible
  • Recommendations for Diagnostic Testing for Patients with High Pretest Probability of First Lower Extremity Deep Venous Thrombosis (Chest Antithrombotic Therapy and Prevention of Thrombosis 2012 Guidelines) [MEDLINE]
    • Moderate/High-Sensitivity D-Dimer Should Not Be Used as Standalone Tests in Patients with High Pretest Probability of DVT (Grade 1B Recommendation)
    • Proximal or Whole Leg Lower Extremity Compression Venous Doppler Ultrasound is Recommended (Grade 1B Recommendation)
      • Whole Leg Ultrasound is Preferred Over Proximal Ultrasound in Patients Who are Unable to Return for Serial Lower Extremity Ultrasound Testing and Those with Severe Symptoms Consistent with Distal DVT
    • CT Lower Extremity Venogram: may be alternatively used when lower extremity venous ultrasound is not practical or possible
    • Gadolinium-Enhanced Magnetic Resonance Lower Extremity Venogram: may be alternatively used when lower extremity venous ultrasound is not practical or possible
    • If Proximal Lower Extremity Compression Venous Doppler Ultrasound is Negative, Repeat Proximal/Whole Leg Lower Extremity Compression Venous Doppler Ultrasound or High Sensitivity D-Dimer in 7 Days is Recommended (Grade 1B Recommendation)
    • If Proximal Lower Extremity Compression Venous Doppler Ultrasound is Negative, But D-Dimer is Positive, Repeat Proximal/Whole Leg Lower Extremity Compression Venous Doppler Ultrasound in 7 Days is Recommended (Grade 1B Recommendation)
    • If Whole Leg Lower Extremity Compression Venous Doppler Ultrasound is Negative, No Further Testing is Recommended (Grade 1B Recommendation)
    • If Unexplained Lower Extremity Swelling is Present with Negative Lower Extremity Ultrasound and Negative/Positive D-Dimer, Iliac Veins Should Be imaged to Exclude Isolated Iliac Vein DVT

Recommended Diagnostic Testing for Suspected Recurrent Lower Extremity Deep Venous Thrombosis

  • Recommendations for Diagnostic Testing for Patients with Recurrent Lower Extremity Deep Venous Thrombosis (Chest Antithrombotic Therapy and Prevention of Thrombosis 2012 Guidelines) [MEDLINE]
    • Proximal Lower Extremity Compression Venous Doppler Ultrasound or High-Sensitivity D-Dimer is Recommended (Grade 1B Recommendation)
    • If High-Sensitivity D-Dimer is Positive, Proximal Lower Extremity Compression Venous Doppler Ultrasound is Recommended (Grade 1B Recommendation)
    • If Proximal Lower Extremity Compression Venous Doppler Ultrasound is Negative, Repeat Proximal Lower Extremity Compression Venous Doppler Ultrasound or High-Sensitivity D-Dimer in 7 Days is Recommended (Grade 1B Recommendation)

Recommended Diagnostic Testing for Suspected Pregnancy-Associated Lower Extremity Deep Venous Thrombosis

  • Recommendations for Diagnostic Testing for Pregnant Patients with Suspected Lower Extremity Deep Venous Thrombosis (Chest Antithrombotic Therapy and Prevention of Thrombosis 2012 Guidelines) [MEDLINE]
    • Proximal Lower Extremity Compression Venous Doppler Ultrasound is Recommended (Grade 2C Recommendation)
    • If Proximal Lower Extremity Compression Venous Doppler Ultrasound is Negative, Repeat Proximal Lower Extremity Compression Venous Doppler Ultrasound in 3 and 7 Days (Grade 1B Recommendation) or Sensitive D-Dimer at Time of Presentation (Grade 2B Recommendation) is Recommended
    • If Isolated Iliac Vein DVT is Suspected, But Proximal Lower Extremity Compression Venous Doppler Ultrasound is Negative, Ultrasound of Iliac Vein (Grade 2C Recommendation), Venography (Grade 2C Recommendation), or Direct MRI (Grade 2C Recommendation) is Recommended

Recommendations for Diagnostic Testing for Suspected Upper Extremity Deep Venous Thrombosis

  • 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)
  • Clinical Use of Diagnostic Algorithms in Upper Extremity Deep Venous Thrombosis
    • Use of Diagnostic Algorithm for Upper Extremity DVT (2014) [MEDLINE]
      • Study: multi-center international study (n = 406 inpatients) in Europe/US using algorithm with sequential application of a clinical decision score, D-dimer testing, and ultrasonography
      • Main Findings: combination of a clinical decision score, D-dimer testing, and ultrasonography can safely and effectively exclude the diagnosis of upper extremity DVT

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 Manifestations of Lower Extremity Deep Venous Thrombosis

General Comments

Anatomic Site of Deep Venous Thrombosis (DVT)

  • Proximal Deep Venous Thrombosis (DVT)
    • Femoral Veins
    • Iliac Veins
    • Popliteal Veins
  • Distal (Calf) Deep Venous Thrombosis (DVT)
    • Crural Calf Veins
      • Anterior Tibial Veins
      • Posterior Tibial Veins
      • Peroneal Veins
    • Muscular Calf Veins
      • Gastrocnemius Veins
      • Soleal Veins
      • Other Muscular Calf Veins

Provoked vs Unprovoked Deep Venous Thrombosis (DVT)

  • Provoked Deep Venous Thrombosis: deep venous thrombosis attributable to an identifiable etiology or provoking event
  • Unprovoked Deep Venous Thrombosis: deep venous thrombosis with no identifiable etiology or provoking event

Symptomatic vs Asymptomatic Deep Venous Thrombosis (DVT)

  • Asymptomatic Deep Venous Thrombosis: DVT diagnosed with a lack of clinical symptoms (ie incidentally diagnosed on radiologic study performed in an asymptomatic patient)
  • Symptomatic Deep Venous Thrombosis: presence of clinical symptoms that would lead to the radiologic diagnosis of DVT

Cardiovascular Manifestations

Atrial Fibrillation (AF) (see Atrial Fibrillation)

  • Epidemiology
    • 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)

Rheumatologic/Orthopedic/Vascular Manifestations

Lower Extremity Pain (see Lower Extremity Pain)

  • Epidemiology
    • Lower Extremity Pain is Common

Peripheral Edema (see Peripheral Edema)

  • Epidemiology
    • Peripheral Edema (Particularly Unilateral) is Common

Free-Floating Deep Venous Thrombosis

  • Clinical Data
    • Study of Clinical Significance of Free-Floating Thrombus (J Vasc Surg, 1990) [MEDLINE]
      • Free-Floating Thrombus Occurred in 10% of Cases of Acute Deep Venous Thrombosis
      • Only 13% of Free-Floating Thrombi were Associated with Clinically Significant Pulmonary Embolism (by Ventilation-Perfusion Scanning)
      • When Followed by Serial Lower Extremity Dopplers, Most Free-Floating Thrombi Do Not Embolize, But Rather They Become Attached to the Vein Wall or Resolve
    • French Prospective Trial Examining the Impact of Detecting Free-Floating Thrombus (on Lower Extremity Doppler Ultrasound) in Deep Venous Thrombosis (Arch Intern Med, 1997) [MEDLINE]
      • Doppler Ultrasound Had a Sensitivity of 68% and a Specificity of 86% for the Diagnosis of Free-Floating Thrombus on Doppler Ultrasound
      • In the Setting of Appropriate Anticoagulation Therapy (Almost All of the Subjects Received the Low Molecular Weight Heparin, Nadroparin, and Only One Subject Received Unfractionated Heparin Drip), the Presence of Free-Floating Thrombus on a Lower Extremity Doppler Study Did Not Increase the Risk of Acute Pulmonary Embolism (At Day 10, the Incidence of Pulmonary Embolism was 3% in Free-Floating Group vs 4% in the Occlusive Group; p = 0.92)
      • Importantly, the Trial was Performed in 1992-1993 (Using Only Unfractionated Heparin and Low Molecular Weight Heparin) and the Results Cannot Be Applied to Patients Who Receive Direct Oral Anticoagulants (DOAC’s), Which Were Not Available for Use at That Time

Phlegmasia Cerulea Dolens

  • Epidemiology
    • Age: peak in 5th-6th decade of life
    • Sex: F>M
  • Precipitating Factors
  • Physiology
    • Acute Massive Proximal (Iliofemoral) Venous Thrombosis with Obstructed Venous Drainage of Lower Extremity
    • Left Lower Extremity Involvement
      • Left Lower Extremity is Involved 3-4x as Often as the Right Lower Extremity
    • Upper Extremity Involvement
      • Upper Extremity Involvement Occurs in <5% of Cases
  • Clinical Manifestations
    • Blebs/Bullous Skin Lesions (see Vesicular-Bullous-Pustular Skin Lesions)
    • Peripheral Edema (see Peripheral Edema)
    • Cyanosis (Cerulea) (see Cyanosis)
      • Cyanosis is Usually a Characteristic Finding
      • Progresses from Distal to Proximal Lower Extremity
    • Phlegmasia Alba Dolens: blanching (alba) without cyanosis
    • Sudden Onset of Severe Lower Extremity Pain (see Lower Extremity Pain)
      • Pain is Usually Constant and Severe (Usually Starts at the Femoral Triangle and Progresses to Involve the Entire Lower Extremity)
      • Symptoms May be Gradual in Onset in Some Cases
    • Venous Gangrene
      • Venous Gangrene is a Late Finding
    • Extremity Compartment Syndrome (see Extremity Compartment Syndrome)

Post-Thrombotic (Post-Phlebitic) Syndrome

  • Epidemiology
    • XXXXX
  • Clinical
    • XXXX

Other Manifestations

Fever (see Fever)

  • Epidemiology
    • Study of Data from the RIETE Registry of Symptomatic Deep Venous Thrombosis Cases (J Thromb Thrombolysis, 2011) [MEDLINE]: n = 14,480
      • Fever was Present (at Presentation) in 4.9% of Symptomatic Deep Venous Thrombosis Cases
      • Patients Initially Presenting with Fever Had a Higher Mortality Rate, as Compared to Those without Fever (5.8% vs 2.9%; Odds Ratio 2.6; 95% CI: 1.9-3.5)
      • Among the Causes of Death, Pulmonary Embolism (0.7% vs 0.1%) and Infection (1.1% vs 0.3%) were Significantly More Common in Symptomatic Deep Venous Thrombosis Patients Presenting with Fever
      • Multivariate Analysis Confirmed that Deep Venous Thrombosis Patients with Fever Had an Increased Mortality (Hazard Ratio 2.00; 95% CI: 1.44-2.77), Irrespective of the Patient Age, Body Weight, and Risk Factors for Venous Thromboembolism


Clinical Manifestations of Upper Extremity Deep Venous Thrombosis

Rheumatologic/Orthopedic Manifestations

Upper Extremity Pain (see Upper Extremity Pain)

  • xxxxx

Upper Extremity Peripheral Edema (see Peripheral Edema)

  • xxxx


Prophylaxis

High-Risk Medical Patients

Rationale

  • Patients Remain at Increased Risk for Venous Thromboembolism for Up to 3 Months Following Hospital Discharge (Mayo Clin Proc, 2001) [MEDLINE]
    • Peak Risk for Venous Thromboembolism Appears to Be with the First 4 Weeks Following Hospital Discharge (Mayo Clin Proc, 2001) [MEDLINE]

Methods of Deep Venous Thrombosis Prophylaxis in High-Risk Medical Patients

Clinical Efficacy-General

  • RandomizedEXCLAIM Trial of Extended-Duration Enoxaparin (28 +/- 4 Days, After Receiving Open Label Enoxaparin for an Initial 10 +/4 Days) in Acutely Ill Medical Patients with Decreased Mobility (Ann Intern Med, 2010) [MEDLINE]
    • Extended-Duration Enoxaparin Decreases VTE More than it Increases Major Bleeding Events in Acutely Ill Medical Patients with Level 1 Immobility, Tose >75 y/o, and Women
  • InternationalEconomic Evaluation of Pharmacologic Deep Venous Thrombosis Prophylaxis vs Weekly Ultrasound Screening in Intensive Care Unit Patientsin Canada/US/Australia (Am J Resp Crit Care Med, 2011) [MEDLINE]
    • Study Used Markov Decision Analysis Comparing Weekly Ultrasound Screening (Case Finding) to Pharmacologic Prophylaxis (Limitation: There are No Randomized Trials Examining Screening for Deep Venous Thrombosis in Critically Ill Patients)
    • In ICU Patients Who Received Standard Deep Venous Thrombosis Prophylaxis, Weekly Doppler Compression Ultrasound Screening Cost >$200k/QALY (At >50-$100k/QALY, This is Not Considered Cost-Effective)
      • Although Increased Venous Thromboembolism Detection was Noted, Screening was Associated with More Bleeding Events (Due to a Greater Frequency of Anticoagulation and Higher Number of False-Positive Studies for Deep Venous Thrombosis)
      • Very Small Improvements in Quality-Adjusted Survival Did Not Justify the Additional Costs of Routine Weekly Screening
    • Appropriate Pharmacologic Prophylaxis Combined with Deep Venous Thrombosis Case Finding was at Least as Effective, Less Time-Consuming, and Less Expensive than Routine Weekly Ultrasound Screening
    • Agrees with Prior Study Which Failed to Demonstrate Benefit of Routine Ultrasound Deep Venous Thrombosis Screening in Critically Ill Patients (Although Weekly Ultrasound Screening was Found Effective in Subset with Femoral Central Venous Catheters) (Am J Resp Crit Care Med, 2003) [MEDLINE]
    • However, when the Risk of Proximal Deep Venous Thrombosis During Critical Illness was ≥16%, Ultrasound Screening Cost <$50k/QALY and was Cost-Effective
      • In Patients with Multiple Trauma, Acute Brain/Spinal Cord Injury, Cancer, and in Critically Ill Patients Who Do Not Receive Pharmacologic Prophylaxis, the Risk of Deep Venous Thrombosis May Approach the 16% Level (Arch Intern Med, 2001) [MEDLINE]
      • In a Study of Critically Injured Trauma Patients Who Did Not Receive Pharmacologic Prophylaxis, the Risk of Proximal DVT was 18% (NEJM, 1994) [MEDLINE]
    • Therefore, in Intensive Care Unit Patients, Pharmacologic Deep Venous Thrombosis Prophylaxis Should Be Provided (if Possible)
      • However, in Select High-Risk Patient Populations (as Noted Above), Weekly Ultrasound Screening May Be Cost-Effective
  • LIFENOX Trial of Enoxaparin with Elastic Graduated Compression Stockings vs Elastic Graduated Compression Stockings Alone Hospitalized Acutely Ill Medical Patients (NEJM, 2011) [MEDLINE]: RCT (n = 8307)
    • In Hospitalized Acutely Ill Medical Patients, Enoxaparin Plus Elastic Graduated Compression Stockings, as Compared with Elastic Graduated Compression Stockings Alone, was Not Associated with Decreased All-Cause Mortality Rate
  • PROTECT Trial of Dalteparin vs Unfractionated Heparin Deep Venous Thrombosis Prophylaxis (NEJM, 2011) [MEDLINE]: n = 1873
    • Dalteparin was Not Superior to Unfractionated Heparin Deep Venous Thrombosis Prophylaxis, in Terms of Incidence of Proximal Deep Venous Thrombosis
  • Economic Evaluation of Data Derived from the PROTECT Trial (JAMA, 2014) [MEDLINE]: n = 2,344 (23 centers in 5 countries)
    • In Critically Ill Medical-Surgical Patients Undergoing Pharmacologic Deep Venous Thrombosis Prophylaxis, Dalteparin Had a Lower Acute Pulmonary Embolism Rate, Lower Heparin-Induced Thrombocytopenia (HIT) Rate, and Similar or Lower Cost, as Compared to Unfractionated Heparin Deep Venous Thrombosis Prophylaxis
  • Systematic Review and Network Meta-Analysis of Deep Venous Thrombosis Prophylaxis in Acutely Ill Hospitalized Inpatients (BMJ, 2022) [MEDLINE]: n = 90,095 (44 randomized controlled trials)
    • Evidence of Low-Moderate Quality Indicated that None of the Interventions Decreased All-Cause Mortality, as Compared to Placebo
    • Low-Molecular Weight Heparin in an Intermediate Dose Conferred the Best Balance of Benefits/Harms for Prevention of Venous Thromboembolism
    • Unfractionated Heparin (in Particular the Intermediate Dose) and Direct Oral Anticoagulants Had the Least Favorable Profile
    • Main Limitations of This Study Include the Quality of Evidence (Which was Generally Low-Moderate Due to Imprecision and Within-Study Bias) and Statistical Inconsistency

Clinical Efficacy-Deep Venous Thrombosis Prophylaxis in the Setting of Critical Illness

  • Systematic Review and Meta-Analysis of Venous Thromboembolism Prophylaxis in Critically Ill Adults (Chest, 2022) [MEDLINE]: n = 9,619 (from 13 randomized controlled trials)
    • Low Molecular Weight Heparin Decreased the Incidence of Deep Venous Thrombosis (Odds Ratio 0.59; 95% Credible Interval: 0.33-0.90; High Certainty), as Compared to Control (Either No Prophylaxis, Placebo, or Compression Stockings Only)
    • Unfractionated Heparin May Have Decreased the Incidence of Deep Venous Thrombosis (Odds Ratio 0.82; 95% Credible Interval: 0.47-1.37; Low Certainty), as Compared to Control
    • Mechanical Compressive Devices May Have Decreased the Incidence of Deep Venous Thrombosis (Odds Ratio 0.85; Credible Interval: 0.50-1.50; Low Certainty), as Compared to Control
    • Low Molecular Weight Heparin was Probably More Effective than Unfractionated Heparin in Decreasing the Incidence of Deep Venous Thrombosis (Odds Ratio 0.72 [95% Credible Interval: 0.46-0.98; Moderate Certainty)
      • Low Molecular Weight Heparin Should Be Considered the Primary Pharmacologic Agent for Thromboprophylaxis
    • Combination Pharmacologic Therapy and Mechanical Compressive Devices Demonstrated an Unclear Effect on the Incidence of Deep Venous Thrombosis, as Compared with Either Therapy Alone (Very Low Certainty)

Clinical Efficacy-Deep Venous Thrombosis Prophylaxis in the Setting of Low Body Weight and Obesity

  • Study of High-Dose Heparin Deep Venous Thrombosis Prophylaxis in Hospitalized Morbidly Obese Patients (>100 kg and BMI ≥40) (Thromb Haemost, 2014) [MEDLINE]: n = 3,928
    • High-Dose Heparin Deep Venous Thrombosis (Unfractionated Heparin 7500 U TID or Enoxaparin 40 mg BID) Halved the Odds of Symptomatic Venous Thromboembolism (0.77%), as Compared to Standard Dose Heparin Deep Venous Thrombosis (Unfractionated Heparin 5000 U BID/TID or Enoxaparin 40 mg qday) (1.48%) (Odds Ratio 0.52; 95% Confidence Interval: 0.27-1.00; p = 0.050)
    • Bleeding Rates were Similar in Both Groups
  • Retrospective Study of High-Dose Unfractionated Heparin Deep Venous Thrombosis Prophylaxis in Overweight Neurocritical Care Patients (>100 kg) (J Thromb Thrombolysis, 2015) [MEDLINE]
    • High-Dose Unfractionated Heparin Deep Venous Thrombosis Prophylaxis Group (7500 U q8hrs) and Standard Dose Unfractionated Heparin Deep Venous Thrombosis Prophylaxis Group (5000 U q8hrs) Had Similar Venous Thromboembolism Rates
    • Both Groups Had Similar Rates of Bleeding Complications
  • Single-Center Retrospective Studies of DVT Prophylaxis in Hospitalized Overweight/Obese Patients (>100 kg) (Pharmacotherapy, 2016) [MEDLINE]: n = 1,335
    • High-Dose Unfractionated Heparin Deep Venous Thrombosis Prophylaxis (7500 U q8hrs), as Compared to Standard Dose Unfractionated Heparin Deep Venous Thrombosis Prophylaxis (5000 U q8hrs) Had Similar Venous Thromboembolism Rates for All BMI Classes (BMI 25-29.9 kg/m2, BMI 30-34.9 kg/m2, BMI 35-39.9 kg/m2, and BMI ≥ 40 kg/m2)
    • Bleeding Rate was Higher in the High-Dose Group
  • Literature Review of Enoxaparin Dosing for Patients at Extremes of Weight (Ann Pharmacother, 2018) [MEDLINE]
    • Low Body Weight Patients May Benefit from Enoxaparin 30 mg SQ qday for Venous Thromboembolism Prophylaxis, and Standard Weight-Based Dosing for Venous Thromboembolism Treatment
    • In Patients with BMI ≥40 kg/m2, Enoxaparin 40 mg SQ BID is Recommended for Venous Thromboembolism Prophylaxis
    • In Patients with BMI ≥50 kg/m2, Consideration Should Be Given for Higher Doses for Venous Thromboembolism Prophylaxis

Clinical Efficacy-Apixaban (Eliquis) (see Apixaban)

  • ADOPT Trial Examining Prolonged Apixaban (For 30 Days) vs Enoxaparin (For ≥6 Days) for Deep Venous Thrombosis Prophylaxis After Hospital Discharge in Medical Patients (NEJM, 2011) [MEDLINE]: double-blind, double-dummy, placebo-controlled trial (n = 6528)
    • In Medically Ill Patients, an Extended Course of Apixaban Deep Venous Thrombosis Prophylaxis was not Superior to a Shorter Course with Enoxaparin
    • Apixaban was Associated with Significantly More Major Bleeding Events (0.47%) than Enoxaparin (0.19%) at Day 30

Clinical Efficacy-Betrixaban (see Betrixaban)

  • APEX Trial of Extended-Duration Betrixaban (35-42 Days) After Initial Enoxaparin (x 10 +/- 4 Days) for DVT Prophylaxis in Hospitalized, Acutely Ill Medical Patients (Am Heart J, 2017) [MEDLINE]: randomized, double-blind, double-dummy, active-controlled, multi-national
    • Betrixaban (Only at the Higher Dose of 80 mg) + Initial Enoxaparin (x 10 +/- 4 Days) was Superior to Initial Enoxaparin Alone (x 10 +/- 4 Days), in Terms of Venous Thromboembolism at Day 42, without an Increased Risk of Bleeding

Clinical Efficacy-Rivaroxaban (Xarelto) (see Rivaroxaban)

  • MAGELLAN Non-Inferiority Trial Comparing Rivaroxaban (x 35 +/- 4 Days) to Enoxaparin (x 10 +/- 4 Days) for DVT Prophylaxis in Acutely Ill Medical Patients (NEJM, 2013) [MEDLINE]: multi-center, randomized ( n = 8101)
    • At Day 10: Rivaroxaban was Equivalent (2.7%) to Enoxaparin (2.7%), in Terms of Venous Thromboembolism
    • At Day 35: Rivaroxaban was Superior (4.4%) to Enoxaparin (5.7%), in Terms of Venous Thromboembolism
    • At Day 10: Rivaroxaban Had Significantly Higher Bleeding Risk (2.8%) vs Enoxaparin (1.2%)
    • At Day 35: Rivaroxaban Had Significantly Higher Bleeding Risk (4.1%) vs Enoxaparin (1.7%)
  • MARINER Trial of Prophylactic Rivaroxaban Begun and Continuing After Hospital Discharge (x 45 Days) in High-Risk Medical Patients (Thromb Haemost, 2016) [MEDLINE]: randomized, double-blind, placebo-controlled
    • In Process: endpoints of symptomatic VTE and VTE-related death

Clinical Efficacy-Use of Sequential Compression Devices (SCD’s) in Addition to Pharmacologic Deep Venous Thrombosis Prophylaxis (see Sequential Compression Device)

  • Systematic Review and Meta-Analysis of the Use of Sequential Compression Devices (SCD’s) in Addition to Pharmacologic Deep Venous Thrombosis Prophylaxis in Hospitalized Adults (Crit Care Explor, 2022) [MEDLINE]: n = 8,796 (17 trials)
    • Intermittent Pneumatic Compression Device was Mostly Applied Tp to the Thigh and Pharmacological Thromboprophylaxis Consisted of Primarily Low-Molecular-Weight Heparin
    • Adjunctive Intermittent Pneumatic Compression was Associated with a Decreased Risk of Venous Thromboembolism (15 Trials, RR = 0.53; 95% CI: 0.35-0.81]) and Deep Venous Thrmbosis (14 Trials, RR = 0.52; 95% CI: 0.33-0.81), But Not Pulmonary Embolism (7 Trials, RR = 0.73; 95% CI: 0.32-1.68)
    • The Quality of Evidence was Graded as Low, Downgraded by Risk of Bias and Inconsistency
    • Moderate and Very Low Quality Evidence Respectively, Suggests that Adjunctive Intermittent Pneumatic Compression is Unlikely to Change the Risk of All-Cause Mortality or Adverse Events
    • Subgroup Analyses Indicate a More Evident Apparent Benefit in Industry-Funded Trials

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

  • Asymptomatic Hypercoagulable State
    • Mechanical/Pharmacologic Prophylaxis is Not Recommended (Grade 1C Recommendation)
  • Chronically Immobilized Patients
    • Pharmacologic Prophylaxis is Not Recommended (Grade 2C Recommendation)
  • Critically Ill Patients
    • For Critically Ill Patients Routine Ultrasound Screening for Deep Venous Thrombosis is Not Recommended (Grade 2B Recommendation)
    • Low Molecular Weight Heparin or Low Dose Unfractionated Heparin Prophylaxis is Recommended (Grade 2C Recommendation)
    • For Critically Ill Patients with High Risk for Major Hemorrhage, Graduated Compression Stockings/Sequential Compression Devices are Recommended Until Bleeding Risk Decreases (at Which Time Pharmacologic Prophylaxis Should Be Substituted for Mechanical Prophylaxis) (Grade 2C Recommendation)
  • Hospitalized Acutely Ill Medical Patients
    • Hospitalized Acutely Ill Medical Patients with High Risk of Thrombosis, Low Molecular Weight Heparin, Low Dose Unfractionated Heparin Prophylaxis BID/TID, or Fondaparinux is Recommended (Grade 1B Recommendation)
    • For Hospitalized Acutely Ill Medical Patients with High Risk of Thrombosis and High Risk for Major Hemorrhage, Graduated Compression Stockings/Sequential Compression Devices are Recommended Until Bleeding Risk Decreases (at Which Time Pharmacologic Prophylaxis Should Be Substituted for Mechanical Prophylaxis) (Grade 2C Recommendation)
    • Hospitalized Acutely Ill Medical Patients with Low Risk of Thrombosis, No Pharmacologic or Mechanical Prophylaxis is Recommended
    • For Hospitalized Acutely Ill Medical Patients Who Receive an Initial Course of Prophylaxis, Extension of Duration Beyond the Period of Patient Immobilization or the Acute Hospital Stay is Not Recommended (Grade 2B Recommendation)
  • Persons Traveling Long Distance with Increased Risk of Venous Thrombembolism (Active Malignancy, Advanced Age, Estrogen Use, Known Hypercoagulable State, Limited Mobility, Pregnancy, Previous Venous Thromboembolism, Recent Surgery/Trauma, Severe Obesity)
    • Graduated Venous Compression Stockings (with 15-30 mm Hg of Pressure at the Ankle) are Recommended (Grade 2C Recommendation)

Other Recommendations

  • Deep Venous Thrombosis Prophylaxis in the Setting of Obesity
    • Unfractionated Heparin (Thromb Haemost, 2014) [MEDLINE] (J Thromb Thrombolysis, 2015) [MEDLINE] (Pharmacotherapy, 2016) [MEDLINE]
      • Heparin 5000-7500 U BID SQ is Probably Preferred (with Individualized Dosing Considered for Specific Patients)
    • Enoxaparin (Lovenox) (Obes Surg, 2002) [MEDLINE] (Surg Obes Relat Dis, 2008) [MEDLINE]
      • BMI 30-39 kg/m2: enoxaparin 30 mg q12hrs or 40 mg qday
      • BMI ≥40 kg/m2: enoxaparin 40 mg q12hrs
      • High Venous Thromboembolism-Risk Bariatric Surgery with BMI ≤50 kg/m2: enoxaparin 40 mg q12hrs
      • High Venous Thromboembolism-Risk Bariatric Surgery with BMI >50 kg/m2: enoxaparin 60 mg q12hrs

Abdominal-Pelvic Surgery Patients

Clinical Efficacy

  • Systematic Review of Risk of Heparin-Induced Thrombocytopenia in Post-Operative Patients Comparing Unfractionated Heparin vs Low Molecular Weight Heparin DVT Prophlaxis (Cochrane Database Syst Rev, 2012) [MEDLINE]
    • Lower incidence of HIT and HIT Complicated by Venous Thromboembolism in Postoperative Patients Undergoing Low Molecular Weight Heparin DVT Prophylaxis, as Compared to Unfractionated Heparin DVT Prophylaxis
  • Economic Evaluation Data Derived from PROTECT Trial (JAMA, 2014) [MEDLINE]: economic evaluation of dalteparin vs unfractionated heparin prophylaxis in medical and surgical critically ill patients (n = 2344 in 23 centers in 5 countries)
    • In Critically Ill Medical-Surgical Patients Undergoing Pharmacologic DVT Prophylaxis, Dalteparin Exhibited a Lower PE Rate, Lower Heparin-Induced Thromobcytopenia (HIT) Rate, and Similar or Lower Cost, as Compared to Unfractionated Heparin DVT Prophylaxis

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

  • Low Risk General/Abdominal-Pelvic Surgery (Approximately 1.5%; Rogers Score: 7-10; Caprini Score: 1-2)
    • Mechanical Prophylaxis (Preferably Sequential Compression Devices) is Recommended (Grade 2C Recommendation)
  • Moderate Risk General/Abdominal-Pelvic Surgery (Approximately 3.0%; Rogers Score: >10; Caprini Score: 3-4) without High Risk for Major Bleeding
    • Low Molecular Weight Heparin (Grade 2B Recommendation), Low Dose Unfractionated Heparin (Grade 2B Recommendation), or mechanical prophylaxis (preferably sequential compression devices) (Grade 2C Recommendation) are recommended
  • Moderate Risk General/Abdominal-Pelvic Surgery (Approximately 3.0%; Rogers Score: >10; Caprini Score: 3-4) with High Risk for Major Bleeding
    • Mechanical Prophylaxis (Preferably Sequential Compression Devices) is Recommended (Grade 2C Recommendation)
  • High Risk General/Abdominal-Pelvic Surgery (Approximately 6.0%; Caprini Score: At Least 5) without High Risk for Major Bleeding
    • Low Molecular Weight Heparin (Grade 1B Recommendation) or Low Dose Unfractionated Heparin (Grade 1B Recommendation), AND mechanical prophylaxis (preferably sequential compression devices)
  • High Risk General/Abdominal-Pelvic Surgery (Approximately 6.0%; Caprini Score: At Least 5) with High Risk for Major Bleeding
    • Mechanical Prophylaxis (Preferably Sequential Compression Devices) is Recommended (Grade 2C Recommendation)

Cardiac Surgery Patients

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

  • Cardiac Surgery with Uncomplicated Post-Operative Course: mechanical prophylaxis (preferably sequential compression devices) is recommended (Grade 2C Recommendation)
  • Cardiac Surgery with Hospital Course Complicated by One or More Non-Hemorrhagic Surgical Complications: mechanical prophylaxis (preferably sequential compression devices) AND either low-dose unfractionated heparin or low molecular weight heparin prophylaxis is recommended (Grade 2C Recommendation)

Thoracic Surgery Patients

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

  • Thoracic Surgery with Moderate Risk of Venous Thromboembolism (Without Risk for Post-Operative Hemorrhage): sequential compression devices (Grade 2C Recommendation), low-dose unfractionated heparin (Grade 2B Recommendation), or low molecular weight heparin prophylaxis (Grade 2B Recommendation) is recommended

Craniotomy Patients

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

  • Craniotomy: mechanical prophylaxis (preferably sequential compression devices) is recommended (Grade 2C Recommendation)
  • Craniotomy with Very High Risk for Venous Thromboembolism (Craniotomy Performed for Malignant Disease): mechanical prophylaxis (preferably sequential compression devices) is recommended with addition of pharmacologic prophylaxis once hemostasis is established and the risk of bleeding decreases (Grade 2C Recommendation)

Spinal Surgery Patients

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

  • Spinal Surgery: sequential compression devices (Grade 2C Recommendation), low-dose unfractionated heparin (Grade 2C Recommendation), or low molecular weight heparin prophylaxis (Grade 2C Recommendation) is recommended
  • Spinal Surgery with Very High Risk for Venous Thromboembolism (Spinal Surgery Performed for Malignant Disease or Surgery with Combined Anterior-Posterior Approach): mechanical prophylaxis (preferably sequential compression devices) is recommended with addition of pharmacologic prophylaxis once hemostasis is established and the risk of bleeding decreases (Grade 2C Recommendation)

Major Trauma Patients (Traumatic Brain Injury, Traumatic Spinal Injury, Spine Surgery for Trauma)

Clinical Efficacy

  • Cost-Effectiveness Retrospective Analysis of DVT Surveillance in Trauma Patients (n = 4234) in the ICU (PLoS One, 2014) [MEDLINE]
    • Ultrasound Screening of Trauma Patients is Cost-Effective: cost is $29,102/QALY

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

  • Major Trauma: sequential compression devices (Grade 2C Recommendation), low-dose unfractionated heparin (Grade 2C Recommendation), or low molecular weight heparin prophylaxis (Grade 2C Recommendation) is recommended
  • Major Trauma with Very High Risk for Venous Thromboembolism: mechanical prophylaxis (preferably sequential compression devices) should be added to pharmacologic prophylaxis if not contraindicated by lower extremity injury (Grade 2C Recommendation)
  • Major Trauma with Contraindications to Low-Dose Unfractionated Heparin/Low Molecular Weight Heparin: mechanical prophylaxis (preferably sequential compression devices) is recommended (when not contraindicated by presence of lower extremity injury) (Grade 2C Recommendation), with addition of low-dose unfractionated heparin/low molecular weight heparin when bleeding risk decreases or contraindication heparin resolves (Grade 2C)
  • IVC Filter Placement as Primary Prevention of Venous Thromboembolism in Major Trauma: not recommended (Grade 2C Recommendation)
  • Screening Lower Extremity Doppler Ultrasound in Major Trauma: not recommended (Grade 2C Recommendation)

Orthopedic Surgery Patients (Total Hip Arthroplasty, Total Knee Arthroplasty, Hip Fracture Surgery)

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

  • Type of DVT Prophylaxis for Total Hip Arthroplasty/Total Knee Arthroplasty: one of the following is recommended for a minimum of 10-14 days
    • Apixaban (Eliquis) (see Apixaban) (Grade 1B Recommendation)
    • Aspirin (see Acetylsalicylic Acid) (Grade 1B Recommendation)
    • Coumadin (see Coumadin) (Grade 1B Recommendation)
    • Dabigatran (Pradaxa) (see Dabigatran) (Grade 1B Recommendation)
    • Low Molecular Weight Heparin (Grade 1B Recommendation): low molecular weight heparin (if started pre-operatively, started 12 hrs before surgery) is suggested as the preferred agent for DVT prophylaxis (in terms of bleeding risk, efficacy, and long-term safety data) for total hip arthroplasty/total knee arthroplasty (Grade 2C Recommendation vs apixaban/dabigatran/fondaparinux/low-dose unfractionated heparin/rivaroxaban; Grade 2C Recommendation vs aspirin/coumadin)
    • Fondaparinux (Arixtra) (see Fondaparinux) (Grade 1B Recommendation)
    • Low-Dose Unfractionated Heparin Prophylaxis (see Heparin) (Grade 1B Recommendation)
    • Rivaroxaban (Xarelto) (see Rivaroxaban) (Grade 1B Recommendation)
    • Sequential Compression Device (SCD) (see Sequential Compression Device) (Grade 1C Recommendation): suggested to be used alone if bleeding risk contraindicates use of an antithrombotic agent (Grade 2C Recommendation)
  • Type of DVT Prophylaxis Hip Fracture Surgery: one of the following is recommended for 10-14 days
    • Aspirin (see Acetylsalicylic Acid) (Grade 1B Recommendation)
    • Coumadin (see Coumadin) (Grade 1B Recommendation)
    • Low Molecular Weight Heparin (Grade 1B Recommendation): low molecular weight heparin (if started pre-operatively, started at least 12 hrs before surgery) is suggested as the preferred agent for DVT prophylaxis (in terms of bleeding risk, efficacy, and long-term safety data) for hip fracture surgery (Grade 2C Recommendation vs fondaparinux/low-dose unfractionated heparin; Grade 2C Recommendation vs aspirin/coumadin)
    • Fondaparinux (Arixtra) (see Fondaparinux) (Grade 1B Recommendation)
    • Low-Dose Unfractionated Heparin Prophylaxis (see Heparin) (Grade 1B Recommendation)
    • Sequential Compression Device (SCD) (see Sequential Compression Device) (Grade 1C Recommendation): suggested to be used alone if bleeding risk contraindicates use of an antithrombotic agent (Grade 2C Recommendation)
  • Dual DVT Prophylaxis with Antithrombotic Agent and Sequential Compression Device for Total Hip Arthroplasty/Total Knee Arthroplasty and Hip Fracture Surgery During the Hospital Stay: recommended (Grade 2C Recommendation)
  • Timing of Initiation of DVT Prophylaxis for Total Hip Arthroplasty/Total Knee Arthroplasty and Hip Fracture Surgery: starting DVT prophylaxis at least 12 hrs pre-operatively or 12 or more hrs post-operatively is recommended (Grade 1B Recommendation)
  • Duration of DVT Prophylaxis for Total Hip Arthroplasty/Total Knee Arthroplasty and Hip Fracture Surgery: duration of prophylaxis in the outpatient period for up to 35 days from the date of surgery is suggested (Grade 2B Recommendation)
  • IVC Filter Placement as Primary Prevention of Venous Thromboembolism in Total Hip Arthroplasty/Total Knee Arthroplasty and Hip Fracture Surgery: not recommended (Grade 2C Recommendation)
  • Screening Lower Extremity Doppler Ultrasound in Asymptomatic Total Hip Arthroplasty/Total Knee Arthroplasty and Hip Fracture Surgery Prior to Hospital Discharge: not recommended (Grade 1B Recommendation)

Isolated Lower Leg Injury (Distal to Knee) Patients

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

  • Isolated Lower Leg Injury Requiring Immobilization: no prophylaxis is recommended (Grade 2C Recommendation)

Knee Arthroscopy Patients

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

  • Knee Arthroscopy without Prior History of Venous Thromboembolism: no prophylaxis is recommended (Grade 2B Recommendation)


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 Admission
      • 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 Decreases Risk of DVT Recurrence and Mortality Rate (Lancet, 1960) [MEDLINE]
    • Anticoagulation Decreases 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)

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

Risk Factors for Anticoagulation-Associated Hemorrhage

Absolute Risk of Major Hemorrhage

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

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

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

Initial Treatment of Venous Thromboembolism

Parenteral Anticoagulation

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

Long-Term Treatment of Venous Thromboembolism without Cancer

Agents

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

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

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

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

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

Long-Term Treatment of Venous Thromboembolism with Cancer

Agents

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

Clinical Efficacy

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

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

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

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

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

Specific Duration of Anticoagulation

General Comments

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

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

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

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

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

Specific Treatment of Acute Pulmonary Embolism with Hypotension

Therapeutic Choices

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

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

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

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

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

Clinical Efficacy of Systemic Thrombolysis in Acute Pulmonary Embolism

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

Clinical Efficacy of Catheter-Directed Therapy in Acute Pulmonary Embolism

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Specific Treatment of Asymptomatic Acute Pulmonary Embolism

Rationale

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

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

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

Specific Treatment of Acute Subsegmental Pulmonary Embolism

Rationale/Background

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

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

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

Specific Treatment of Low-Risk Acute Pulmonary Embolism

Criteria

  • Criteria for Outpatient Treatment of Acute PE (or Early Discharge to Home)
    • Clinically Stable with Good Cardiopulmonary Reserve
    • No Specific Contraindications, Such as Recent Bleeding, Severe Renal Disease, Severe Liver Disease, or Severe Thrombocytopenia (Platelets <70k)
    • Patient is Expected to be Compliant with Treatment
    • Patient Feels Well Enough to Be Treated at Home
  • Other Criteria-Pulmonary Embolism Severity Index (PESI): score <85
  • Other Criteria-Simplified Pulmonary Embolism Severity Index (Simplified PESI): score 0
  • Other Factors Which Might Merit Inpatient Treatment Instead of Outpatient Treatment
    • Increased Cardiac Biomarker Levels
    • Presence of Right Ventricular Dysfunction Recommendations (Chest Antithrombotic Therapy for VTE Disease 2021 Guidelines) (Chest, 2021) [MEDLINE]
  • In Patients with Low-Risk Acute Pulmonary Embolism, Outpatient Treatment is Recommended (Provided There is Access to Medications, Ability to Access Outpatient Care, and Adequate Home Circumstances (Strong Recommendation, Low-Certainty Evidence)

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

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

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

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

Specific Treatment of Recurrent Venous Thromboembolism While Not on Anticoagulation

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

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

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

Rationale

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

Risk Factors for Recurrent Venous Thromboembolism

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

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

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

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

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

Historical Perspective

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

Indications for Inferior Vena Cava (IVC) Filter

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

Technique

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

Clinical Efficacy

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

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

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

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

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

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

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

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

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

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

Outpatient vs Inpatient Therapy

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

Ambulation

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

Graduated Compression Stockings

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

Presence of Free-Floating Thrombus in Deep Venous Thrombosis

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

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

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

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

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

Treatment of Lower Extremity Superficial Venous Thrombosis (SVT)

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

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

Specific Treatment of Upper Extremity Deep Venous Thrombosis

Anticoagulation

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

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

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

Follow-Up of Acute Pulmonary Embolism

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

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


References

American College of Chest Physicians Evidence-Based Clinical Practice Guidelines 2012

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

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

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

PERT Consortium Clinical Practice Guidelines 2019

American Society of Hematology Clinical Practice Guidelines 2020

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

General

Risk Factors

Diagnosis

Clinical

Prophylaxis

Upper Extremity Deep Venous Thrombosis (DVT)

Treatment

General

Inferior Vena Cava Filter (see Inferior Vena Cava Filter)

Embolectomy/Catheter-Directed Therapy

Thrombolytics

Catheter-Directed Thrombolysis