Hypercoagulable States

Hypercoagulable States – Chris Cann

Background

  • Virchow’s triad: 1. Hypercoagulability 2. Blood flow 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
  • Separated into Acquired and Hereditary factors:
    • Hereditary: Factor V Leiden, Prothrombin mutation, Protein C/S deficiency, Antithrombin deficiency
    • Acquired:
      • APLS
      • HIT
      • Major surgery/trauma
      • Nephrotic Syndrome
      • Smoking
      • Pregnancy
      • Oral Contraceptives
      • Immobilization (bedridden, hip/knee replacement) Infection in past 3 months
      • Active malignancy
      • Estrogen replacement therapy
  • 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):

Background

  • Most common acquired factor (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

 

Evaluation

  • 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

 

Management

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

 

 

 

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)

 

Evaluation

  • 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

 

Management

  • 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

Evaluation

  • 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

 

Management

  • 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

Evaluation: PCR of G20210A mutation (2-4% Europeans carry mutation)

 

Management: VTE treatment same as general population & Avoid OCPs

 

Protein C & S Deficiency

Background

  • 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

 

Evaluation

  • Functional Protein C & S assays
    • Used for screening prior to use of immunologic methods to measure free protein levels

 

Management

  • 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

Background

  • 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 

 

Evaluation

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

 

Management

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