Approach to Venous Thromboembolism

Approach to Venous Thromboembolism is a topic covered in the Washington Manual of Medical Therapeutics.

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General Principles


  • Thrombosis refers to a blood clot that occur in veins, arteries, or chambers of the heart.
  • VTE refers to deep vein thrombosis (DVT) and associated pulmonary embolism (PE).
  • Thrombophlebitis consists of inflammation in a vein due to a blood clot.
  • Superficial venous thrombophlebitis refers to thrombosis and inflammation in a nondeep vein.


The anatomic location of DVT/PE, clot burden, and sequelae may affect prognosis and treatment recommendations.

  • DVT can be deep or superficial and proximal or distal.
    • Proximal lower extremity DVTs occur in deep veins from the common femoral vein to the popliteal vein (or the confluence of tibial and peroneal veins); distal lower extremity DVTs occur in the tibial and peroneal veins.
    • Proximal upper extremity DVTs occur in the subclavian, brachiocephalic, axillary, and brachial veins, whereas distal upper extremity DVTs occur in the cephalic and basilic veins.
    • Other important venous thromboses sites include the vena cava (superior and inferior), abdominal veins (hepatic, portal, superior mesenteric, and splenic), pelvic veins (iliac, ovarian, penile), retinal veins, and cerebral veins, and cavernous sinus.
  • PE anatomic location in the pulmonary arterial system characterizes PE as central/proximal (main pulmonary artery, lobar, or segmental) or distal (subsegmental).
  • Chest imaging may also classify PE severity based on clot burden.
  • PE severity classification may refer to cardiovascular dysfunction variables that define submassive PE (e.g., right ventricular [RV] strain, RV dysfunction, elevated troponin, elevated NT-proBNP) or massive PE (systemic hypotension). (Table 20-5)
    Table 20-5: European Society of Cardiology Morality Risk Classification of Patients Who Have Acute Pulmonary Embolism

    Risk Parameters and Scores
    Early Mortality RiskShock or HypotensionPESI Class III-V 
or sPESI ≥1Signs of RV Dysfunction on an Imaging TestaCardiac Laboratory Biomarkersb
    IntermediateIntermediate- high+Both positive
    Intermediate- low+Either one (or none) positived
    Assessment optional; if assessed, both negatived

    Reprinted from Konstantinides SV, Torbicki A, Agnelli G, et al. 2014 ESC Guidelines on the diagnosis and management of acute pulmonary embolism: the task force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC) Endorsed by the European Respiratory Society (ERS). Eur Heart J. 2014;35:3033-3073 with permission from Oxford University Press.  [PMID:25173341]

    aEchocardiographic criteria of RV dysfunction include RV dilation and/or an increased end-diastolic RV–LV diameter ratio (e.g., ≥1), hypokinesia of the free RV wall, or increased velocity of the tricuspid regurgitation jet. Computed tomographic (CT) angiography criterion for RV dysfunction is an increased end-diastolic RV/LV diameter ratio (e.g., ≥1.0).

    bMarkers of myocardial injury or of heart failure as a result of right ventricular dysfunction.

    cClassify shock or hypotension as high risk, despite any PESI or sPESI score.

    dClassify low-risk PESI (Class I–II) or sPESI patients (score of 0) who have elevated cardiac biomarkers or signs of RV dysfunction on imaging tests.

    LV, left ventricular; PESI, pulmonary embolism severity index; RV, right ventricular; sPESI, simplified PESI.


  • Without treatment, half of patients with proximal lower extremity DVT develop PE.
  • DVTs in the upper extremities often occur with an indwelling catheter and may cause PE.
  • DVT may occur concomitantly with superficial thrombophlebitis.
  • Untreated acute symptomatic PE has a 10%–30% short-term mortality.1,2
  • Patients who have hemodynamic instability associated with acute PE have a >15% risk of death in the subsequent 30 days, despite treatment.
  • Patients who have acute PE without shock or hypotension but with signs of right ventricular dysfunction or myocardial injury have a 3%–15% 30-day mortality risk.
  • Patients who have acute symptomatic PE with normal blood pressure and RV function have a 30-day mortality risk of <1%.
  • The 3-month mortality after the initiation of anticoagulant therapy in low-risk patients averages around 2%.3


  • Venous thromboemboli arise under conditions of blood stasis, hypercoagulability (changes in the soluble and formed elements of the blood), or venous endothelial dysfunction/injury (Virchow’s triad).
  • Hypercoagulable states may have an inherited or acquired etiology (see Risk Factors section).
  • VTEs are classified as provoked or unprovoked, where provoked are attributed to an identifiable risk factor (e.g., surgery) and unprovoked have no identifiable cause.
  • Superficial thrombophlebitis occurs in association with varicose veins, trauma, infection, and hypercoagulable disorders.
  • Causes of pulmonary arterial occlusion not due to thromboemboli include embolism of marrow/fat, amniotic fluid, and foreign substances that enter the venous system, in situ thrombi (e.g., sickle cell disease), malignancy (e.g., pulmonary artery sarcoma), and inflammation/fibrosis (e.g., fibrosing mediastinitis).

Risk Factors

  • Risk factors for VTE can be categorized as inherited, acquired, or unknown (idiopathic).
  • Inherited thrombophilia are suggested by spontaneous VTE at a young age (<50 years), recurrent VTE, VTE in first-degree relatives, thrombosis in unusual anatomic locations (i.e., abdominal), and recurrent fetal loss.
  • The most common inherited risk factors for VTE include gene mutations (factor V Leiden and prothrombin gene G20210A) and deficiencies of the natural anticoagulants protein C, protein S, and AT.
  • Homocystinuria, a rare autosomal recessive disorder caused by deficiency of cystathionine-β-synthase, leads to extremely high plasma homocysteine and causes early-onset arterial and venous thromboembolic events. However, mild elevation of homocysteine may be caused by a mutation in methylenetetrahydrofolate reductase (MTHFR) but does not cause VTE.4,5 Therefore, thrombophilia testing should not include MTHFR mutation testing.
  • Spontaneous VTE in unusual locations, such as cavernous sinus, mesenteric vein, or portal vein, may be the initial presentation of paroxysmal nocturnal hemoglobinuria (PNH) or myeloproliferative disorders (JAK2 mutation).
  • Spontaneous (idiopathic) VTEs have a high risk of recurrence (8%–10% per year) after stopping anticoagulant therapy, regardless of the presence of an inherited thrombophilia.6
  • Acquired hypercoagulable states may arise secondary to malignancy, immobilization, infection, trauma, surgery, collagen vascular diseases, nephrotic syndrome, HIT, DIC, medications (e.g., estrogen), and pregnancy.
  • Acquired autoantibodies associated with HIT and antiphospholipid syndrome (APS) can cause arterial or venous thrombi.
  • APS is a hypercoagulable disorder that requires the presence of at least one clinical and one laboratory criterion.7
    • APS clinical criteria:
      • Unprovoked arterial or venous thrombosis in any tissue or organ or
      • Pregnancy morbidities (unexplained late fetal death; premature birth complicated by eclampsia, pre-eclampsia, placental insufficiency; or ≥ three unexplained consecutive spontaneous abortions at <10 weeks of gestation or one at ≥10 weeks).
    • APS laboratory criteria:
      • Presence of autoantibodies such as LA, anticardiolipin, or β2-glycoprotein-1 antibodies
      • Approximately 10% of patients with SLE have an LA; however, most patients with an LA do not have SLE
      • Confirmation of positive autoantibody tests (must be done at least 12 weeks apart)
    • APS may include other features, such as thrombocytopenia, valvular heart disease, livedo reticularis, neurologic manifestations, and nephropathy.


Identifying patients at high risk for VTE and instituting prophylactic measures should remain a high priority (see Chapter 1, Inpatient Care in Internal Medicine).

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