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Hypercoagulable States

Chris Cann


  • Virchow’s triad: 1. Hypercoagulability 2. Stasis 3. Endothelial injury
  • Diagnostic thrombophilia testing indications:
    • Idiopathic or recurrent VTE
    • First VTE at <40 years old
    • VTE in the setting of strong family history
    • VTE in unusual vascular site (cerebral, renal, mesenteric)
    • Recurrent pregnancy loss
  • Must consider if thrombophilia testing will change clinical management
  • If the unprovoked VTE warrants indefinite anticoagulation then testing may not be helpful
  • However, if VTE provoked by minor risk factor (OCPs) with an underlying thrombophilia might change the decision, then testing may be informative
  • Separated into Acquired and Hereditary conditions:
    • Hereditary: Factor V Leiden mutation, Prothrombin mutation, Protein C or S deficiency, Antithrombin deficiency
    • Acquired:
      • Antiphospholipid Syndrome (APLS)
      • Heparin induced thrombocytopenia (HIT)
      • Major surgery/trauma
      • Nephrotic Syndrome
      • Smoking
      • Pregnancy
      • Oral Contraceptives
      • Immobilization (bedridden, hip/knee replacement)
      • Active malignancy
      • Estrogen replacement therapy
      • Note: Travel (plane, train, automobile) is NOT on this list and this is NOT considered a provoking risk factor
    • Testing: all specific testing for hereditary disorders and APS should be performed at least 4-6 weeks after an acute thrombotic event or discontinuation of anticoagulant/thrombolytic therapies to avoid interference

Antiphospholipid antibody syndrome (APLS)


  • Most common acquired disorder (anti-phospholipid antibodies present in 3-5% population)
  • Recurrent pregnancy loss, provoked DVT in young, unprovoked VTE and arterial thrombosis in young, thrombosis unusual sites, thrombosis in autoimmune disease
  • This is a clinicopathologic diagnosis (need both clinical and laboratory criteria)


  • Positive for at least 1 lab criterion on at least 2 occasions, at least 12 weeks apart:
    • Lupus anticoagulant: can occur in relation to drugs or infection; transient are associated with thrombotic risk
    • Anticardiolipin antibodies
    • B2GP1 (anti-beta2-glycoprotein) antibodies
  • Must also meet at least 1 of the following clinical criteria:
    • Vascular thrombosis: DVT, arterial thrombosis, or small vessel thrombosis of any organ
    • Pregnancy loss: there are specific criteria for this – consult UpToDate or other resource


  • Aspirin for primary prevention; warfarin for treatment (INR 2-3)
  • Do NOT use DOACs for triple positive APLS (see TRAPS trial: rivaroxaban inferior to warfarin)
  • Rituximab for recurrent thrombosis despite anticoagulation (controversial) – call hematology

Heparin-induced thrombocytopenia (HIT)

Type 1: Mild and self-limited (not immune-mediated)

  • Occurs within the first 2 days of first-time exposure
  • Platelet count normalizes with continued heparin therapy

Type 2 (what we typically refer to as HIT): Immune mediated

  • Fall in plt 30% to over 50% (even if plt count >150) and/or thrombotic event has occurred
  • 4-10 days after new exposure to heparin derivative OR≤
  • 1 day after restarting heparin derivative that had been used 30-100 days prior
    • If exposed to heparin within 100 days, will have platelet drop within 24 hr
  • Frequency: unfractionated heparin > LMWH; Surgical wards > medical wards
  • 50% will have thrombotic event in 30 days if HIT is untreated, with 20% mortality
  • Arterial thrombi are common in HIT
  • HIT results from antibodies to complexes of platelet factor 4 (PF4) and heparin, further activating platelets (the activated platelets aggregate causing thrombocytopenia)


  • 4T score (0-8 points):
    • Thrombocytopenia (0-2 pts): degree and nadir of platelet count drop
    • Timing (0-2 pts): timing of fall after initial or recurrent heparin exposure
    • Thrombosis (0-2 pts): thrombosis, skin necrosis, non-necrotizing lesions, acute systemic reaction to heparin
    • Other causes of thrombocytopenia (0-2 pts): more points if no alternate cause
  • Solid-phase ELISA for heparin-PF4 antibodies:
    • 0.2-0.4 is indeterminate
    • 0.4 is positive

    • 1.4 HIT is likely

    • 2 confirms HIT

    • The lab at VUMC will perform functional SRA reflexively for all values >0.2


  • 0-3 points: Low concern for HIT; can restart heparin
  • 4-5 points: Intermediate probability (~10%) - hold heparin, start non-heparin anticoagulant
  • 6 points: High probability (~50%) - hold heparin, start non-heparin anticoagulant
  • Argatroban (direct thrombin inhibitor) for prophylaxis and treatment of thrombosis
  • Avoid platelet transfusions as can increase thrombogenic effect
  • Avoid warfarin until complete platelet recovery as may cause microthrombosis
  • Hematology consult for all confirmed HIT

Factor V Leiden mutation


  • Activated protein C resistance assay
    • APC ratio in patient vs normal
    • normal >2.0, heterozygotes 1.5-2.0, homozygotes <1.5
  • FVL mutation is then determined via PCR
  • Screen with APC assay rather than PCR initially; cost effective


  • VTE treatment same as general population
  • VTE 4-8x risk in heterozygotes; 80x risk in homozygotes
  • Avoid OCPs: increased risk for VTE

Prothrombin gene mutation


  • PCR of G20210A mutation (2-4% prevalence)


  • VTE treatment same as general population & avoid OCPs

Protein C & S Deficiency


  • Autosomal dominant; first event occurs between 10-50 years of age
  • Synthesized in liver and Vit K dependent, therefore low levels in hepatic dysfunction and warfarin use/vitamin K deficiency
  • Protein C: low in settings of thrombosis, DIC, nephrotic syndrome, intra/post-op
  • Protein S: low in infectious (HIV) and autoimmune processes (IBD)
  • Protein S decreases during pregnancy (decreased free Protein S, normal total Protein S)
  • Do not misdiagnose a pregnant patient with PS deficiency


  • Functional Protein C & S assays


  • VTE treatment same as general population
  • Avoid OCPs
  • High risk patients may require protein C concentrate prior to surgery
  • Increased risk of warfarin-induced skin necrosis

Antithrombin deficiency


  • Autosomal dominant, does not skip generations
  • VTE in unusual sites (cerebral sinuses, renal veins)
  • Present < 50 y/o, but rarely in first two decades
  • Decreased in liver disease, nephrotic syndrome, protein losing enteropathy, burn, trauma, bypass surgery, metastatic tumors, premenopausal, OCP use, pregnancy


  • Functional antithrombin activity (AT-heparin cofactor assay)
  • Then perform antigen quantity testing


  • Can use Argatroban as does not require antithrombin function
  • Warfarin preferred in VTE (titrate up based on expression of antithrombin deficiency)

Last update: 2022-06-24 23:35:57