Heparin Induced Thrombocytopenia

Aka: Heparin Induced Thrombocytopenia, Heparin-Induced Thrombocytopenia

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II. Epidemiology

  1. Incidence: 1 to 3% of those on Heparin >4 days
    1. LMWH is much less likely (only 1/6 of Heparin risk)

III. Pathophysiology

  1. Immune mediated disorder
    1. IgG Antibody against Heparin-Platelet factor 4 (PF4) complex
  2. Onset 4-10 days after Heparin exposure
    1. Onset earlier with prior Heparin exposure
  3. Two types
    1. Type I is mild, and just requires monitoring
    2. Type II is severe, life-threatening

IV. Risk Factors

  1. Heparin type
    1. Bovine is higher risk than porcine is higher risk than Low Molecular Weight Heparin
  2. Patient type
    1. Surgical patients are more likely than medical patients to have HIT
      1. Orthopedic surgery is most likely to have Clinically Significant HIT
      2. Cardiovascular surgery is most likely to form heparin Antibody
        1. But typically do not manifest HIT clinically
    2. Medical patients are moderately likely to have HIT
    3. Obstetrics patients are very low risk for developing HIT

V. Signs

  1. Onset typically 5-10 days after initial Heparin exposure (range is 4-14 days)
    1. May present in first 24 hours if prior Heparin exposure (within last 90 days)
  2. Often presents as a new thrombotic event while on Heparin therapy
    1. Thrombosis (skin necrosis, extremity gangrene, CVA) occurs in up to one third of HIT patients
  3. Type II HIT is a clinically devastating event
    1. Associated with DIC-type findings
  4. Bleeding is uncommon despite Thrombocytopenia

VI. Signs: Presentations

  1. Deep Vein Thrombosis (50%)
  2. Pulmonary Embolism (25%)
  3. Skin lesions at injection site (10–20%)
  4. Acute Limb Ischemia (5–10%)
  5. Warfarin-associated venous limb gangrene (5–10%)
  6. Acute thrombotic stroke or Myocardial Infarction (3–5%)
  7. Acute systemic reactions following intravenous bolus (25%)

VII. Diagnosis

  1. Identify Thrombocytopenia
    1. Absolute Thrombocytopenia or
    2. Relative Thrombocytopenia (30-50% Platelet Count decrease from baseline)
  2. Consider other Thrombocytopenia Causes
    1. See Thrombocytopenia Causes
  3. Evaluate Pre-Test Probability
    1. See Heparin Induced Thrombocytopenia Pre-Test Scoring System
    2. Low probability for HIT
      1. Do not obtain Hep-PF4 AntibodyELISA
      2. Consider alternative causes of Thrombocytopenia
    3. Moderate probability for HIT
      1. Treat if Hep-PF4 AntibodyELISA positive and Platelet SRA positive
      2. Consider other causes of Thrombocytopenia if testing negative
    4. High probability for HIT
      1. Treat if Hep-PF4 AntibodyELISA Positive
      2. Consider other causes of Thrombocytopenia if testing negative

VIII. Labs: Complete Blood Count

  1. Platelet Count decrease
    1. Marked and sudden Thrombocytopenia following Heparin therapy initiation
    2. Platelet Count drops 30-50% from baseline
    3. Median Platelet nadir is 50,000 (drops to 15,000 in only 5% of patients)

IX. Labs: Diagnosis

  1. HIT is a clinical diagnosis driving initial withdrawal of Heparin and testing should be considered confirmatory
    1. Start with the Hep-PF4 AntibodyELISA and if positive, confirm with Platelet SRA
    2. If Hep-PF4 AntibodyELISA is negative, or Platelet SRA on confirmation is negative, HIT is unlikely
      1. May reintroduce Heparin on Consultation with hematology
  2. Hep-PF4 AntibodyELISA
    1. First line test due to ready availability, speed of testing, and high sensitivity
    2. Efficacy in diagnosis of HIT
      1. High Test Sensitivity (>97%)
      2. Low Test Specificity (74 to 86%)
        1. False Positive Rate:1% in Dialysis patients
        2. False Positive Rate: 20% following vascular surgery
    3. Incidence of positive Antibody in patients on Heparin (UFH) with Thrombocytopenia
      1. Orthopedic surgery patient: 14% positive Antibody (with 3-5% with clinical HIT)
      2. Cardiac surgery patient: 25-50% positive Antibody (with 1-2% with clinical HIT)
      3. General medicine patient: 8-20% positive Antibody (with 0.8-3% with clinical HIT)
    4. References
      1. Arepally (2006) N Engl J Med 355: 809-17 [PubMed]
  3. Serotonin release assay (Platelet SRA)
    1. High Test Sensitivity and Test Specificity
    2. Slow and difficult test with limited testing locations
    3. Second-line test
      1. Used as a confirmatory test

X. Imaging

  1. Venous Doppler Ultrasound
    1. Evaluate for asymptomatic DVT in legs (and arms if upper extremity central venous catheter) in all HIT patients

XI. Management: Intermediate to High Probability for HIT

  1. Stop all Heparin forms (including Low Molecular Weight Heparin and line flushes)
  2. Consult hematology
  3. Screen for Deep Vein Thrombosis with all four limbs
  4. Start non-heparin Anticoagulant (consult with hematology regarding choice of agent)
    1. Agents confer risk - do not use if low index of suspicion
    2. Direct Thrombin Inhibitor (Lepirudin, Argatroban or Bivalirudin) OR
    3. Fondaparinux (Arixtra) OR
    4. Factor Xa Inhibitor (Apixaban, Rivaroxaban)
  5. Continue Anticoagulation for at least 4 weeks to 3 months (up to 3 to 6 months if HIT induced thrombosis)
  6. Do not transfuse Platelets unless bleeding (bleeding is rare in HIT)
    1. Transfused Platelets can activate in HIT and result in thrombosis
  7. Do not use Warfarin alone (prothrombotic)
    1. If on Warfarin, at HIT diagnosis
      1. Stop Warfarin and give Vitamin K
      2. Do not restart Warfarin until Platelet Count normalizes
    2. Only start Warfarin after Platelet Count has recovered to >100,000 and preferably 150,000
    3. When Warfarin started, do not exceed 5 mg daily dose initially
    4. Overlap non-heparin Anticoagulant and Coumadin concurrent use
      1. Use together for at least 5 days and
      2. Platelet Count should be constant and stable and
      3. INR therapeutic for at least 2 days
    5. Duration of Warfarin therapy
      1. Thrombosis present: Set duration based on clot type, site and Thrombophilia risks
      2. Thrombosis absent: Variable recommendations (1-6 months)

XII. Prognosis

  1. Life and limb threatening thrombotic events in 20-50% of untreated HIT
  2. Thrombotic risk can persist for weeks after Platelet Count normalizes

XIII. References

  1. Merrill and Gillen (2016) Crit Dec Emerg Med 30(3): 3-8
  2. Reding (2009) UMN CME Internal Medicine Review, Minneapolis
  3. Arepally (2006) N Engl J Med 355: 809-17 [PubMed]
  4. Castelli (2007) Cardiovasc Hematol Disord Drug Targets 7(3):153-62 [PubMed]
  5. Fabris (2000) Haematologica 85(1):72-81 [PubMed]
  6. Shantsila (2009) Chest 135(6):1651-64 [PubMed]

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