Heparin-Induced Thrombocytopenia - HIT

Diagnosis

Indications for Testing

  • Heparin administration in association with thrombocytopenia occurring between days 5-10 after initiation of heparin
  • Clinical suspicion for heparin-induced thrombocytopenia (HIT)
    • HIT is a clinicopathologic diagnosis – laboratory testing is only an adjunct to clinical impression

Criteria for Diagnosis

  • Perform screening for HIT if 4T's clinical probability score is intermediate or high or otherwise clinical suspicion
  • Clinical scoring systems have high negative predictive value (<2% with low 4T score will have HIT [Crowther, 2014]) but poor positive predictive value for HIT syndrome
  • 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)
  • ELISA immunoassay
    • Sensitive but relatively nonspecific for HIT because it does not indicate whether the PFA4 antibodies have platelet-activating properties
      • Results should always be interpreted in the context of clinical findings, platelet counts, and other laboratory testing
      • ELISA optical density (OD) values
        • Increases specificity of test
        • High OD values more likely to represent pathologic antibodies capable of platelet activation resulting in clinical HIT syndrome
    • High negative predictive value
      • Persistently negative results – strong evidence against HIT
      • Occasional false negatives occur – perform serotonin release assay (SRA) if clinical suspicion is high for HIT
  • Serotonin release assay (SRA)
    • Functional assay – gold standard
    • Higher specificity for HIT than ELISA
    • Can be used for evaluation of weak or unexpected ELISA results
    • Use to confirm a positive ELISA if clinically indicated
    • Uses high and low concentrations of heparin
      • High concentration disrupts immune complexes
        • Presence of positive test in high concentration suggests against HIT

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 are at risk for developing arterial or venous thromboses.

Epidemiology

  • Prevalence – 0.5-5% of patients receiving heparin (ACCP, 2012)
  • Age – adults; rare in children

Risk Factors

  • More common in surgical patients than in medical or obstetric patients
  • Heparin association
    • Greater risk with unfractionated heparin than with low-molecular-weight heparin
    • May occur even with very small heparin exposures (eg, heparin flushes for maintaining line patency)

Pathophysiology

  • Heparin binds to platelet factor 4 (PF4) which is released from activated platelets
  • In some patients, the 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 additional PF4, creating positive feedback loop

Clinical Presentation

  • Thrombocytopenia – thrombocytopenia 5-10 days after heparin exposure
    • Rapid-onset HIT may occur in patients with recent exposure to heparin due to presence of preformed HIT antibodies
    • Thrombocytopenia during heparin therapy does not necessarily indicate HIT
    • Typically have 50% drop in count from baseline
  • 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
    • Fatal in 5-10% of patients

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
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

Gold standard reflex test for confirming diagnosis of HIT

Reflex pattern – if ELISA result is positive, serotonin release assay (SRA) will be added

Clinical sensitivity/specificity – >90%

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

Occasional false negatives occur – does not exclude HIT if suspicion is high

Results should always be correlated with clinical findings

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

Gold standard test for diagnosis of HIT

Clinical sensitivity/specificity – >90%

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

Occasional false negatives occur – does not exclude HIT if suspicion is high

Results should always be correlated with clinical findings

 
Heparin-Induced Thrombocytopenia (HIT) Antibodies, PF4 IgG/IgM/IgA by ELISA 0051052
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Initial screening for HIT

Confirmation with SRA may be necessary depending on clinical presentation

Negative result does not exclude HIT

 
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
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

Platelets 0040235
Method: Automated Cell Count
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