Heparin-Induced Thrombocytopenia - HIT

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.

  • Diagnosis
  • Background
  • Lab Tests
  • References
  • Related Topics
  • Videos

Indications for Testing

  • Heparin administration in association with thrombocytopenia occurring between 5-10 days after initiation of or reexposure to 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

  • Clinical scoring systems have high negative predictive value (<2% with low 4T's 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 decrease
        • 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
  • Screening for HIT if 4T's clinical probability score is intermediate or high, or otherwise clinical suspicion

Laboratory Testing

  • Do not test or treat for suspected HIT in patients with a low pretest probability of HIT (Choosing Wisely: Ten Things Physicians and Patients Should Question, 2015; American Society of Hematology)
  • Platelet count
    • Serial counts required to evaluate trends and degree/timing of thrombocytopenia
    • High-risk patients (>1%) receiving heparin should have a platelet count test every 2-3 days between days 4 and 14 (American College of Chest Physicians, 2012)
  • ELISA immunoassay
    • Often used as first-line test for HIT
      • Reflex to serotonin release assay (SRA) recommended for confirmation
    • Sensitive but relatively nonspecific
      • Does not indicate whether the PF4 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 (eg, >1.5-2.0) 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 SRA if clinical suspicion is high for HIT
  • SRA
    • Functional assay – gold standard
      • Negative test essentially rules out HIT
    • Use to confirm a positive ELISA if clinically indicated
    • Higher specificity for HIT than ELISA
    • Can be used for evaluation of weak or unexpected ELISA results
    • Uses high and low concentrations of heparin
      • High concentration disrupts immune complexes
      • Presence of positive test in high concentration suggests against HIT
    • Almost never available first day ordered – doesn’t help with immediate decision making

Differential Diagnosis


  • Prevalence – 1-5% of patients receiving heparin (ACCP, 2012)
  • Age – adults; rare in children

Risk Factors

  • More common in surgical patients than in medical or obstetric patients
    • Major surgery much greater risk than minor surgery
  • 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)


  • 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 usually 5-10 days after heparin exposure
    • Rapid-onset HIT may occur if patient has recently developed HIT antibodies and is reexposed to heparin
    • Thrombocytopenia during heparin therapy does not necessarily indicate HIT
    • 50% drop in count from baseline is typical
  • Thromboses
    • 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
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.

Heparin-Induced Thrombocytopenia (HIT) PF4 Antibody, IgG with Reflex to Serotonin Release Assay (Heparin Dependent Platelet Antibody), Unfractionated Heparin 2012181
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Serotonin Release Assay


Occasional false negatives occur with HIT testing; does not exclude HIT if clinical 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


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) PF4 Antibody, IgG 2012179
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay


Choosing Wisely. An initiative of the ABIM Foundation. [Accessed: Nov 2017]

Linkins L, Dans AL, Moores LK, Bona R, Davidson BL, Schulman S, Crowther M. Treatment and prevention of heparin-induced thrombocytopenia: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012; 141(2 Suppl): e495S-e530S. PubMed

General References

Ahmed I, Majeed A, Powell R. Heparin induced thrombocytopenia: diagnosis and management update. Postgrad Med J. 2007; 83(983): 575-82. PubMed

Chong BH, Isaacs A. Heparin-induced thrombocytopenia: what clinicians need to know. Thromb Haemost. 2009; 101(2): 279-83. PubMed

Crowther M, Cook D, Guyatt G, Zytaruk N, McDonald E, Williamson D, Albert M, Dodek P, Finfer S, Vallance S, Heels-Ansdell D, McIntyre L, Mehta S, Lamontagne F, Muscedere J, Jacka M, Lesur O, Kutsiogiannis J, Friedrich J, Klinger JR, Qushmaq I, Burry L, Khwaja K, Sheppard J, Warkentin TE, PROTECT collaborators, Canadian Critical Care Trials Group, Australian and New Zealand Intensive Care Society Clinical Trials Group. Heparin-induced thrombocytopenia in the critically ill: interpreting the 4Ts test in a randomized trial. J Crit Care. 2014; 29(3): 470.e7-15. PubMed

Cuker A, Gimotty PA, Crowther MA, Warkentin TE. Predictive value of the 4Ts scoring system for heparin-induced thrombocytopenia: a systematic review and meta-analysis. Blood. 2012; 120(20): 4160-7. PubMed

Greinacher A. CLINICAL PRACTICE. Heparin-Induced Thrombocytopenia. N Engl J Med. 2015; 373(3): 252-61. PubMed

Otis SA, Zehnder JL. Heparin-induced thrombocytopenia: current status and diagnostic challenges. Am J Hematol. 2010; 85(9): 700-6. PubMed

Smock KJ, Perkins SL. Thrombocytopenia: an update. Int J Lab Hematol. 2014; 36(3): 269-78. PubMed

Warkentin TE, Arnold DM, Nazi I, Kelton JG. The platelet serotonin-release assay Am J Hematol. 2015; 90(6): 564-72. PubMed

Warkentin TE, Sheppard JI, Moore JC, Sigouin CS, Kelton JG. Quantitative interpretation of optical density measurements using PF4-dependent enzyme-immunoassays. J Thromb Haemost. 2008; 6(8): 1304-12. PubMed

Warkentin TE. HIT paradigms and paradoxes. J Thromb Haemost. 2011; 9 Suppl 1: 105-17. PubMed

Wirth SM, Macaulay TE, Armitstead JA, Steinke DT, Blechner MD, Lewis DA. Evaluation of a clinical scoring scale to direct early appropriate therapy in heparin-induced thrombocytopenia. J Oncol Pharm Pract. 2010; 16(3): 161-6. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Pendleton R, Wheeler MM, Rodgers GM. Argatroban dosing of patients with heparin-induced thrombocytopenia and an elevated aPTT due to antiphospholipid antibody syndrome. Ann Pharmacother. 2006; 40(5): 972-6. PubMed

Smock KJ, Perkins SL. Thrombocytopenia: an update. Int J Lab Hematol. 2014; 36(3): 269-78. PubMed

Sono-Koree NK, Crist RA, Frank EL, Rodgers GM, Smock KJ. A high-performance liquid chromatography method for the serotonin release assay is equivalent to the radioactive method. Int J Lab Hematol. 2016; 38(1): 72-80. PubMed

Medical Reviewers

Last Update: January 2018