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, 2012)
  • HIT antibody testing by ELISA
    • Perform if 4T's clinical probability score is intermediate or high
    • Clinical scoring systems have high negative predictive value but poor positive predictive value for HIT syndrome
      • Positive ELISA results are sensitive but relatively nonspecific for HIT because they do not indicate whether the antibodies have platelet-activating properties
        • Results should always be interpreted in the context of clinical findings, platelet counts, and other laboratory testing
        • False positives – high in post cardiac surgery 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) – higher probability of HIT than low-positive values
        • 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
        • Occasional false negatives occur
  • Functional assays
    • Serotonin release assay 
      • Higher specificity for HIT than ELISA
      • 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 test but requires close clinical correlation

Differential Diagnosis

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 or obstetric 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
    • Clinically significant IgG antibodies form and are directed against heparin-PF4 complexes
    • Immune complexes assemble on the platelet surface, resulting in platelet activation
    • Platelet activation propagates release of more PF4, creating positive feedback loop

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

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
Test Name and Number Recommended Use Limitations Follow Up
CBC with Platelet Count 0040002
Method: Automated Cell Count

Initial test for HIT; perform serial measurements in heparinized patients to assess degree/timing of thrombocytopenia

Not specific for HIT diagnosis

 
Heparin-Induced Thrombocytopenia (HIT) Antibodies, PF4 IgG/IgM/IgA by ELISA with Reflex to Serotonin Release Assay (Heparin Dependent Platelet Antibody), Unfractionated Heparin 0051249
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Serotonin Release Assay

Use in confirming diagnosis of HIT

Perform if 4T’s clinical probability score is intermediate to high

If ELISA result is positive, serotonin release assay (SRA) will be added

SRA is a technically demanding, functional assay; extra turnaround time required

HIT antibody testing has frequent false positives, especially in post cardiac surgery patients; interpret results in conjunction with clinical findings, platelet counts, and other laboratory testing; consider optical density (OD) value of result

 
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
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; consider OD value of result

Serotonin Release Assay (Heparin Dependent Platelet Antibody), Unfractionated Heparin 2005631
Method: Qualitative Serotonin Release Assay

Technically demanding assay; extra turnaround time required; gold standard test

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