Heparin-Induced Thrombocytopenia - HIT

Diagnosis

Indications for Testing

• Heparin administration in association with decreasing platelet counts
• Clinical suspicion for heparin-induced thrombocytopenia (HIT)
  • HIT is a clinicopathologic diagnosis – laboratory testing is only an adjunct to clinical impression

Criteria for Diagnosis

• Assess clinical risk for HIT with the 4T’s Scoring System – score each category; add all points to determine maximum score (maximum possible score = 8)
  • Pretest probability – low = ≤3; intermediate = 4-5; high = 6-8
    • Thrombocytopenia
      • 0 points = <30% fall or nadir <10x10⁹/L
      • 1 point = 30-50% fall or nadir 10-19x10⁹/L
      • 2 points = >50% fall and nadir 20-100x10⁹/L
    • Timing of platelet count fall
      • 0 points = <4 days without recent exposure
      • 1 point =  consistent with day 5-10 (but not clear), or >10 days, or ≤1 day (with heparin 30-100 days prior)
      • 2 points = day 5-10 or ≤1 day if recent heparin (within 30 days)
    • Thrombosis
      • 0 points = none
      • 1 point = progressive, recurrent, or silent thromboses
      • 2 points = proven thrombosis, skin necrosis, or acute systemic reaction with heparin bolus
    • Other causes for thrombocytopenia
      • 0 points = definite
      • 1 point = possible
      • 2 points = none evident

Laboratory Testing

• Platelet count
  • Serial counts required to evaluate trends and degree/timing of thrombocytopenia
  • Patients receiving heparin should have a platelet count test every 2-3 days (American College of Chest Physicians, 2008)
• HIT antibody testing by ELISA – perform if 4T's clinical probability score is intermediate or high
  • Positive ELISA results are relatively nonspecific for HIT – frequent false-positives
    • Results should always be interpreted in the context of clinical findings, platelet counts, and other laboratory testing
    • False positives – high in postcardiac patients
    • High ELISA optical density (OD) values – more likely to represent pathologic antibodies capable of platelet activation resulting in clinical HIT syndrome
    • Strong-positive ELISA (high OD value, usually >1.00) – high-probability, suggestive of HIT
    • Low-positive ELISA OD values – less likely to be pathologic
  • Negative ELISA results – generally high negative predictive value
    • Persistently negative results – strong evidence against HIT
    • Occasionally false negatives occur
• Functional assays
  • Serotonin release assay or the heparin-induced platelet activation assay
    • Higher specificity for HIT
    • Can be used for further evaluation of weak or unexpected ELISA results
    • Use to confirm a positive ELISA, if clinically indicated
  • Technically demanding tests with long turnaround times
  • Generally considered gold standard for diagnosis

Differential Diagnosis

• Antiphospholipid syndrome
• Autoimmune thrombocytopenic purpura
• Drug-induced thrombocytopenia caused by
  • Diclofenac
  • Ibuprofen
  • Quinidine
  • Quinine
  • Trimethoprim-sulfa
• Hemolytic uremic syndrome
• Malignancy
• Sepsis-induced thrombocytopenia and disseminated intravascular coagulation
• Systemic lupus erythematosus
• Vasculitis

Clinical Background

Heparin-induced thrombocytopenia (HIT) is an immune-mediated thrombocytopenia that occurs in patients treated with heparin. Patients with immune-mediated HIT, previously called type II HIT, are at risk for developing arterial or venous thromboses. Type I HIT is not immune-mediated and is generally thought to be a benign condition.

Epidemiology

• Prevalence – 1-5% of patients receiving unfractionated heparin
• Age – adults; rare in children

Etiology of Thrombosis

• Activation of platelets
• Accelerated thrombin generation due to formation of platelet-derived microparticles
• Endothelial damage with tissue factor release
• Possible release of tissue factor by monocytes

Risk Factors

• More common in surgical patients than in medical patients
• Heparin type
  • Greater risk with unfractionated heparin than with low-molecular-weight heparin
  • May occur even with very small heparin exposures

Pathophysiology

• In vivo heparin binds to platelet factor 4 (PF4) – PF4 released from activated platelets
• In some patients, heparin-PF4 complexes trigger an immune response
  • Immune complexes assemble on the platelet surface, resulting in platelet activation
  • Platelet activation propagates release of more PF4, creating positive feedback loop
  • Clinically significant IgG antibodies form and are directed against heparin-PF4 complexes

Clinical Presentation

• Thrombocytopenia – decrease in platelet count 5-10 days after heparin therapy
  • Rapid-onset HIT may occur in patients with recent exposure to heparin due to presence of preformed HIT antibodies
    • Refer to the Diagnosis section for additional information
  • Thrombocytopenia during heparin therapy does not necessarily indicate HIT
• Thrombosis
  • Venous thromboses are most common
    • Deep vein thrombosis
    • Pulmonary embolism
    • Venous limb gangrene
    • Cerebral vein thrombosis
    • Adrenal hemorrhage
    • Full-thickness skin necrosis
  • Arterial  thromboses also occur
    • Stroke
    • Myocardial infarction
    • Acute limb ischemia
    • Organ infarction

Treatment

• Discontinue heparin therapy
• Use direct thrombin inhibitors or factor Xa inhibitors for anticoagulation

Indications for Laboratory Testing

• Tests generally appear in the order most useful for common clinical situations
• Click on number for test-specific information in the ARUP Laboratory Test Directory

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Platelets 0040235 Method: Automated Cell Count
Heparin-Induced Thrombocytopenia (HIT) Antibodies, PF4 IgG/IgM/IgA by ELISA 0051052 Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay	Positive results not specific for a diagnosis of HIT; interpret results in conjunction with clinical findings
Serotonin Release Assay (Heparin Dependent Platelet Antibody), Unfractionated Heparin 2005631 Method: Qualitative Serotonin Release Assay	Technically demanding assay; extra turnaround time required; gold standard
Heparin-Induced Thrombocytopenia (HIT) Antibodies, PF4 IgA and IgM by ELISA 2007145 Method: Enzyme-Linked Immunosorbent Assay
Heparin-Induced Thrombocytopenia (HIT) Antibody, PF4 IgG by ELISA 2007140 Method: Enzyme-Linked Immunosorbent Assay