What is the diagnostic approach for Heparin-Induced Thrombocytopenia (HIT)?

Diagnostic Approach for Heparin-Induced Thrombocytopenia (HIT)

Begin with the 4Ts clinical scoring system to stratify pre-test probability, then proceed with anti-PF4 antibody immunoassay testing for intermediate or high probability cases, followed by functional confirmatory testing (serotonin release assay) when immunoassays are positive. 1, 2

Step 1: Calculate the 4Ts Score

The 4Ts score evaluates four clinical parameters, each scored 0-2 points 1:

Thrombocytopenia Severity

• 2 points: Platelet fall >50% AND platelet nadir ≥20 G/L (no surgery in previous 3 days) 1
• 1 point: Platelet fall >50% but surgery in previous 3 days, OR platelet fall 30-50%, OR platelet nadir 10-19 G/L 1
• 0 points: Platelet fall <30% OR platelet nadir <10 G/L 1

Timing of Platelet Count Fall

• 2 points: Day 5-10 after heparin start (or ≤1 day if heparin exposure in previous 5-30 days) 1
• 1 point: Consistent with days 5-10 fall but unclear timing, OR >10 days, OR ≤1 day with heparin exposure 30-100 days prior 1
• 0 points: Platelet fall <4 days without recent heparin exposure 1

Thrombosis or Other Sequelae

• 2 points: New thrombosis, skin necrosis, or acute systemic reaction after heparin bolus 1
• 1 point: Progressive or recurrent thrombosis, erythematous skin lesions 1
• 0 points: None 1

Other Causes of Thrombocytopenia

• 2 points: No other evident explanation 1
• 1 point: Possible other cause 1
• 0 points: Definite other cause 1

Score Interpretation

• 0-3 points: Low probability (HIT prevalence 0-3%) 2, 3
• 4-5 points: Intermediate probability 1, 2
• 6-8 points: High probability (HIT prevalence approaching 30%) 1, 2, 4

Important caveat: The 4Ts score is not suitable after cardiac surgery with cardiopulmonary bypass; instead, analyze for a "biphasic" platelet count evolution pattern, which indicates high HIT probability 1

Step 2: Initial Laboratory Testing Based on 4Ts Score

Low Probability (4Ts Score 0-3)

• No HIT testing required 1, 2
• Continue heparin if clinically indicated 1
• The negative predictive value is 100% 3, 5
• Search for alternative causes of thrombocytopenia with close platelet monitoring 1

Intermediate or High Probability (4Ts Score ≥4)

• Immediately discontinue all heparin products 1, 2
• Start alternative non-heparin anticoagulation at therapeutic doses without waiting for test results 1, 2
• Order anti-PF4 antibody immunoassay (ELISA or chemiluminescent assay) immediately 1, 6
• Obtain baseline coagulation studies: PT, aPTT, fibrinogen, D-dimers to exclude DIC 1
• Perform ultrasound screening of lower extremities (or upper extremities if central catheter present) 1

Step 3: Immunoassay Interpretation

Before Drawing Blood

• Collect samples ≥4 hours after stopping unfractionated heparin infusion 6
• Collect samples ≥12 hours after last low-molecular-weight heparin dose 6
• Verify sample tube for clots and examine blood smear to exclude platelet aggregates causing pseudothrombocytopenia 1

Immunoassay Results

Immunoassays detect IgG, IgM, and IgA antibodies against PF4-heparin complexes 1:

• Excellent sensitivity (negative predictive value ~100%) 1, 6, 7
• Limited specificity: Anti-PF4 antibodies appear in up to 50% of cardiac surgery patients without HIT 1
• Quantitative results improve specificity: Higher optical density values correlate with true HIT 1
• IgG-specific assays have better positive predictive value than pan-immunoglobulin assays 1

If Immunoassay is Negative

• HIT is excluded 1, 2
• Resume heparin if clinically indicated 1
• Continue monitoring platelet count 1
• No further HIT-specific testing needed 1

If Immunoassay is Positive

• Proceed to functional confirmatory testing 1, 6, 2
• Continue alternative anticoagulation 1, 2

Step 4: Functional Confirmatory Testing

The serotonin release assay (SRA) is the gold standard functional test 1, 6, 2:

SRA Characteristics

• Detects only platelet-activating IgG antibodies capable of causing clinical HIT 1, 2
• Sensitivity 97.2% with specificity approaching 100% 1, 2
• Uses washed platelets from control donors with radiolabeled serotonin 1
• Demonstrates heparin-dependent platelet activation 1

Alternative Functional Tests

• Heparin-Induced Platelet Activation (HIPA) test: Similar performance to SRA but rarely used 1
• Platelet aggregation test (PAT): Less sensitive than SRA but more widely available 1
• Heparin-induced multi-electrode aggregometry (HIMEA): Emerging alternative 6

Limitations of Functional Testing

• Technically demanding and requires specialized laboratories 1, 6
• Requires human platelets from known reactive donors 6
• Involves working with radioactive materials (SRA) 6
• Results may take several days 1
• Do not delay treatment while awaiting functional test results 1

Step 5: Final Diagnosis

HIT Confirmed

• Positive functional test (SRA) + intermediate/high clinical probability + positive immunoassay 1, 2
• Continue alternative anticoagulation 1, 2

HIT Excluded

• Negative immunoassay regardless of 4Ts score 1, 2
• OR negative functional test with positive immunoassay in intermediate probability setting 1

Critical Pitfalls to Avoid

• Never wait for laboratory results before discontinuing heparin and starting alternative anticoagulation in intermediate/high probability cases 1, 2
• 24-61% of patients with high 4Ts scores do not actually have HIT—confirmatory testing is essential 2
• Positive immunoassays alone cannot distinguish pathogenic from non-pathogenic antibodies—functional testing is required for confirmation before prolonged alternative anticoagulation 2
• Do not use the 4Ts score in post-cardiac surgery patients—look for biphasic platelet pattern instead 1
• Consider other causes of thrombocytopenia: DIC, post-transfusion purpura, drug-induced thrombocytopenia, antiphospholipid syndrome, thrombotic thrombocytopenic purpura 1
• Over-testing is common: 46% of tested patients in one study had low pre-test probability and should not have been tested 8