Heparin-induced Thrombocytopenia

Links:

American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia

  •  Incidence:
    • Incidence of both PF4-Heparin antibodies and HIT are higher in Orthopedic and Cardiac Surgery patients than in General Medicine patients.
    • Incidence of PF4-Heparin antibody formation much, much higher than clinical HIT – estimated incidence of antibody formation up to 19% in acutely ill inpatients.
    • Incidence higher with UFH than with LMWH use.
  • Clinical Features:
    • Thrombocytopenia
      • Typical onset is 5-10 days after starting UFH
      • Rapid onset can occur in <1 day following re-exposure to heparin
      • Mild to moderate thrombocytopenia is typical: median platelet count is ~60,000/µL
        • Platelet count falls below 20,000/µL in only 15% of cases
      • Absolute thrombocytopenia NOT required to consider the diagnosis – an otherwise unexplained drop in platelet count of >50% suggests the development of HIT regardless of total platelet count
    • Thrombosis
      • Seen in >50% of HIT cases
      • Observed irrespective of platelet count nadir
      • Thrombosis can even precede platelet decline
      • Thromboses can be either venous or arterial, though venous are more common
        • Venous locations: DVT > PE >> adrenal vein thrombosis > cerebral sinus thrombosis
        • Arterial locations: limb artery > stroke syndrome > MI > mesenteric artery
      • Prothrombotic complications if treatment initiated with warfarin:
        • warfarin-induced skin necrosis and venous limb gangrene
      • Skin lesions at heparin injection sites
        • Severity ranges from erythematous plaques to skin necrosis
      • Acute systemic reactions following IV heparin boluses
        • Acute inflammatory or cardio-respiratory symptoms and abrupt fall in platelet count
      • Laboratory Features:
        • Absolute or relative thrombocytopenia
        • Antigen Assay (Screening Test), aka “:
          • Typically EIA platform
          • Very sensitive, not very specific
          • Often detects clinically insignificant antibodies
        • Activation Assay (Confirmation Test)
          • Usually Serotonin Release Assay (SRA)
          • Highly specific
          • Requires specialized laboratory testing, not available in many laboratories (i.e.: will be a “send out”, and have a multi-day wait for a result)
        • Pathophysiology:
          • HIT antibodies recognize platelet factor 4 (PF4) in complex with heparin
            • PF4 antigenic epitopes exposed via conformational changed induced by heparin binding
            • Resulting antibodies preferentially bind large multi-molecular complexes of PF4-heparin
              • UFH more efficient substrate for complex formation than LMWH
            • PF4-heparin-antibody complex bind and crosslink platelet Fc receptors, resulting in platelet activation and release of procoagulant microparticles
          • Diagnosis:
            • HIT is diagnosed using a combination of clinical and laboratory criteria
            • Warkentin’s 4T Scoring System can be used to assess pre-test probability, and better inform use of specific HIT testing (EIA and/or SRA):
4T’s Category 2 points 1 point 0 point
Thrombocytopenia Platelet count fall 50% from baseline and platelet nadir ≥20×109/L Platelet count fall 30% – 50% from baseline or platelet nadir 10 – 19×109/L Platelet count fall 30% from baseline or platelet nadir 10×109/L
Timing of platelet count fall Clear onset between days 5 and 10 or platelet fall ≤ 1-day, with heparin exposure within 30 prior days. Fall in platelet counts consistent with onset between days 5 and 10 but timing is not clear due to missing platelet counts or onset after day 10 of heparin exposure or fall in platelet counts ≤ 1-day with prior heparin exposure (between 30 and 100 days ago). Platelet count fall within 4 days, without recent heparin exposure.
Thrombosis or other sequelae New thrombosis, skin necrosis, or acute systemic reaction after unfractionated heparin exposure. Progressive/recurrent thrombosis or unconfirmed but clinically suspected thrombosis. No thrombosis or thrombosis preceding heparin exposure.
Other causes of thrombocytopenia None apparent. Possible other causes present. Probable other causes present.
  • A score of 6-8 indicates a high pre-test probability of HIT, 4-5 intermediate, and 0-3 low probability
  • If 4T score is >4, consider EIA (“HIT Antibody”) testing; if ≤3, antibody testing not indicated
  • Many interpretative algorithms available, e.g.:

  • Treatment:
    • Initiate immediate anticoagulation with an alternative, non-heparin anticoagulant:
      • Bivalirudin
        • Reversible, direct thrombin inhibitor
        • Short half-life (25-30 minutes)
        • Dosing for HIT unclear, but suggested initiation at 0.15-0.25 mg/kg/hr and adjusted to PTT of 1.5-2.0 times baseline
        • Reduce dose in setting of renal disease/ESRD
      • Argatroban
        • Small molecule direct thrombin inhibitor
        • Treatment of choice for HIT
        • Initiate gtt at 2 µg/kg/min, titrate to maintain PTT 1.5-3.0 times baseline (keep less than 100)
          • Do not follow PT/INR when on Argatroban – effects highly unpredictable and do not correlate with therapeutic effects
        • Reduce dosing for liver disease, heart failure, anasarca
      • Transitioning to oral anticoagulation:
        • Warfarin
          • Should never be initiated until patient is adequately anticoagulated with bivalirudin or argatroban
          • Reasonable to wait to initiate until platelet count has normalized
          • Warfarin should overlap with IV anticoagulant for at least 5 days, and until INR therapeutic for >48 hours
        • Duration of Treatment:
          • HIT antibodies are transient – median time to negative EIA (“Heparin Antibody”) is 85 days
          • HIT without thrombosis – therapeutic anticoagulation at least until platelet count is normal; some experts suggest continuing anticoagulation for up to 4 weeks
          • HIT with thrombosis – therapeutic anticoagulation for at least 3-6 months
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