heparin-induced thrombocytopenia; heparin-associated antibody syndrome (HIT)

Etiology

• immune-mediated
  • reactivation is due to circulating IgG antibodies to heparin-platelet factor IV complex
• non-immune form
  • direct weak activation of platelets by heparin
• may occur with therapeutic dose, prophylaxis or intravenous flushes
• low molecular weight heparin is significantly less likely to cause HIT than unfractionated heparin

Epidemiology

• 1 in 5000 hospitalized patients
• 10-folder higher among patients receiving unfractionated heparin vs LMW heparin
• 1% at 7 days, 3% at 14 days in patients receiving unfractionated heparin
• often occurs in patients initially treated with heparin for antithrombotic prophylaxis for atrial fibrillation

Pathology

• immune-mediated
  • life-threatening venous & arterial thrombotic complications
  • in-vivo platelet activation
  • generation of procoagulant platelet-derived micro-particles
  • IgG antiheparin antibody that reacts with:
    • circulating heparin
    • platelet factor-4 (PF4) (an alpha-granule protein)
  • immune complex binds to circulating platelets & activates Fc receptors which promote intravascular platelet aggregation
  • immune complex also bind vascular endothelial cells & induce endothelial cell expression of tissue factor
  • venous thrombosis in > 80% of patients
  • arterial thrombosis may also occur
  • IgG antiheparin antibody declines to undetectable levels at about 2 months
• non-immune form
  • generally NOT associated with adverse clinical outcomes
  • spontaneous resolves or resolves with heparin withdrawal

Clinical manifestations

• immune form (type 2)
  • generally occurs from 5-10 days (4-10 days) after initiation of unfractionated heparin therapy
  • may occur much earlier (< 10 hours) in patients previously exposed (within 100 days) to unfractionated heparin (re-activation)
  • may occur AFTER hospital discharge
  • hypercoagulability
    • arterial thromboembolism or venous thromboemboism (DVT)
• non-immune form (type 1)
  • generally occurs within 1st 2 days of heparin administration

Laboratory

• complete blood count (CBC)
  • thrombocytopenia (or decrease in platelet count of > 50%)
• 4T score prior to confirmatory testing
  • estimate pretest probability of HIT
  • can be useful in guiding therapy
  • most patients on heparin who develop thrombocytopenia but have a low 4T score need no further evaluation
• screening with antigen assays based upon reactivity with platelet factor 4 (PF4) complexed with heparin, Heparin-PF4 ELISA
• confirmation with functional heparin-induced thrombocytopenia assay
  • heparin-induced platelet aggregation or serotonin-release assay*
• platelet-activating IgG prior to subsequent heparin exposure
  • heparin-associated platelet antibody
    • high negative predictive value
    • low positive predictive value
    • heparin-platelet factor 4 antibody
  • platelet antibody in serum
• see ARUP consult

* gold standard

Complications

• thromboembolic event 5-10 days after starting heparin
  • may occur much earlier (< 10 hours) in patients previously exposed (within 100 days) to unfractionated heparin (re-activation)

Management

• discontinue heparin
  • cessation of all forms of heparin therapy including removal of heparin-coated catheters
• stabilize patient with direct thrombin inhibitor or danaparoid
  • argatroban (avoid in hepatic insufficiency)
  • lepirudin (avoid in renal insufficiency)
  • danaparoid (anti factor Xa)
  • fondaparinux
    • more cost effective than argatroban or bivalirudin ($151 vs. $1250 or $1466, respectively) & less likely associated with adverse events
  • direct oral anticoagulants are safe & effective for acute HIT
  • avoid warfarin in patients with acute HIT
• bivalirudin is indicated for patients undergoing cardiac procedures
• dextran followed by warfarin has also been used; dextran has been used as a substitute for heparin to prevent large artery thrombosis
• low-molecular weight heparin has about 90% cross-reactivity
  • substituting LMW heparin for unfractionated heparin reduces cases of HIT from 10.7 to 2.2 per 10,000 admissions (RRR=79%) & HIT with thrombosis from 4.6 to 0.4 per 10,000 admissions (RRR=91%)
• promising agents
  • anacrod (defibrinogenating snake venom)
  • heparinoid
• risk for inducing a second episode of heparin-induced thrombocytopenia by reexposure to heparin is low

Notes

• 4Ts predictive scoring system should be used prior to diagnostic testing or treatment
• clinical syndrome closely resembling heparin-induced thrombocytopenia, but not provoked by heparin is described

More general terms

• thrombocytopenia
• hypercoagulability

Additional terms

• 4T score