Hypercoagulable states

A hypercoagulable state, i.e., thrombophilia, is characterized by an increased predisposition to form blood clots. Depending on the etiology, one or more factors from Virchow's triad (stasis, hypercoagulability, endothelial damage) may be involved. Hypercoagulability may be acquired or inherited and can affect veins and/or arteries. The most common presentation is recurrent deep venous thrombosis of the lower extremities and pulmonary embolism. Arterial involvement increases the risk of myocardial infarction, stroke, and spontaneous abortion. Evaluation for hypercoagulability includes assessment of potential risk factors (e.g., immobilization, smoking, oral contraceptive use, and malignancy) and laboratory tests to assess anomalies of the clotting cascade (e.g., factor V Leiden, antiphospholipid antibody syndrome). Treatment is based on the underlying condition and typically includes a reduction of risk factors and/or the administration of anticoagulants.

The etiology of thrombophilia can be classified into two categories:

• Hereditary
  • Factor V Leiden (autosomal dominant inheritance): most common genetic cause of hypercoagulability in white populations
  • Protein C deficiency
  • Protein S deficiency
  • Antithrombin III deficiency
    • Autosomal dominant inheritance
    • Occasionally acquired
      • Renal failure
      • Liver failure
      • Nephrotic syndrome (urinary loss of antithrombin)
  • Prothrombin G20210A mutation
  • Hyperhomocysteinemia
  • Plasminogen deficiency
  • Sickle cell anemia
  • MTHFR gene mutation
• Acquired
  • Pregnancy
  • Advanced age
  • Smoking
  • Obesity
  • Surgery
  • Immobilization
  • Trauma
  • Malignancy (especially adenocarcinoma)
  • Antiphospholipid syndrome
  • Nephrotic syndrome
  • Oral contraceptive pills (OCPs)/hormone replacement therapy (HRT)
  • Systemic lupus erythematosus (SLE)
  • Heparin-induced thrombocytopenia

Thrombophilia is characterized by recurrent thromboembolism.

• Venous thromboembolism (most common)
  • Blood clots that form within the venous vascular system, dislodge, and travel to a distant location
  • E.g., deep venous thrombosis, pulmonary embolism
• Arterial thromboembolism
  • Blood clots that form within the arterial vascular system, dislodge, and travel to a distant location
  • Usually, an acute event that results in ischemic tissue damage (e.g., stroke, acute mesenteric ischemia, acute limb ischemia, acute coronary syndrome, pulmonary infarction)

• The hereditary thrombophilias below follow an autosomal dominant inheritance pattern, with the exception of hyperhomocysteinemia.
• Very rare: hereditary plasminogen deficiency, dysfibrinogenemia

• History
  • A family history of thromboembolism should raise suspicion of a hereditary etiology.
  • Inquire about acquired causes and risk factors (e.g., medications, obstetric history, trauma).
• Laboratory tests
  • Coagulation studies: active partial thromboplastin time (prolonged in antiphospholipid antibody syndrome)
  • ESR: elevated in malignancy or lupus
  • Antiphospholipid antibody panel (lupus anticoagulant, anticardiolipin, beta2-glycoprotein I antibody)
  • Heparin-induced thrombocytopenia tests: complete blood count (thrombocytopenia with heparin use), serotonin release assay (positive), antiplatelet factor 4 antibody (positive)
  • Hypercoagulability panel: APC resistance/factor V Leiden assay, prothrombin gene molecular analysis, protein C and S levels, antithrombin-heparin cofactor assay
• Imaging: consider CT scan if a malignancy is suspected

Approach

• Anticoagulant administration (therapeutic heparin bridged to warfarin): for pulmonary embolism or deep vein thrombosis
  • 1^st episode: 3 months
  • 2^nd episode: minimum of 6 months
  • > 3 events: lifetime anticoagulation
• Consider an inferior vena cava filter if anticoagulant therapy is contraindicated.
• Reduce risk factors
  • Avoid oral contraceptive pills
    • Patients with factor V Leiden
    • Women > 35 years old who smoke
  • Smoking cessation
  • Weight loss

Special considerations

• Avoid anticoagulation in trauma, hemorrhage, and severe hypertension.
• Heparin is contraindicated in patients with heparin-induced thrombocytopenia type II. Argatroban or lepirudin should be prescribed instead.
• Heparin is less effective in antithrombin III deficiency and may require also antithrombin concentrate to be effective
• Administering warfarin to a person with protein C and S deficiencies can precipitate warfarin-induced skin necrosis.

The risk of venous thromboembolism is reduced with administration of an anticoagulant (e.g., heparin) following surgery!

References:^[7]

Consider prophylaxis in the following high-risk groups:

• Postoperative patients
• Prolonged immobilization or hospitalization
• Malignancy
• Orthopedic conditions

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