Heparin-Induced Thrombocytopenia

General Principles

Definition

Heparin-induced thrombocytopenia (HIT) is an acquired hypercoagulable disorder associated with the use of heparin/heparin-like products due to autoantibodies that target platelet factor 4 (PF4) complexes. HIT typically presents with thrombocytopenia or a decrease in platelet count by at least 50% from preexposure baseline after exposure to heparin products. Major complications of HIT consist of arterial and venous thromboembolic events.

Epidemiology

The incidence of HIT ranges from 0.1% to 1.0% in medical and obstetric patients receiving prophylactic/therapeutic unfractionated heparin (UFH) to >1%–5% in patients receiving UFH after cardiothoracic surgery. Patients exposed only to LMWH have a low incidence of HIT. HIT rarely occurs in association with the synthetic pentasaccharide fondaparinux.1

Etiology

Autoantibodies that bind to PF4/heparin complexes can activate platelets causing thrombocytopenia and lead to clot formation through increased thrombin generation.

Diagnosis

Clinical Presentation

  • HIT usually develops within 5–14 days of heparin exposure (typical-onset HIT). Exceptions include delayed-onset HIT, which occurs after stopping heparin, and early-onset HIT, starts within 24 hours of heparin exposure in patients with recent exposure to heparin.
  • The 4T scoring system (Table 20-3) calculates HIT pretest probability (NPV > 95%).2
  • HIT rarely causes severe thrombocytopenia (platelet count < 20 × 109/L) or bleeding.
  • Thromboembolic complications occur in 30%–75% of HIT patients. Thrombosis can precede, be concurrent with, or follow thrombocytopenia.
    • HIT causing venous thrombi at heparin injection sites produces full-thickness skin infarctions, sometimes in the absence of thrombocytopenia.
  • HIT can cause systemic allergic responses following an IV bolus of heparin characterized by fever, hypotension, dyspnea, and cardiac arrest.
Table 20-3: 4T Scoring System for Pretest Probability of Heparin-Induced Thrombocytopenia
T Category0 Points1 Point2 Points
ThrombocytopeniaPLT fall <30% or nadir <10 × 109/LPLT fall 30%–50% or nadir 10–19 × 109/LPLT fall >50% and nadir ≥20 × 109/L
Timing of thrombocytopenia≤4 d without prior exposureLikely within 5–10 d, not clear; >10 d; ≤1 d (with exposure 31–100 d)Within 5–10 d of exposure or ≤1 d (with exposure in last 30 d)
Thrombotic eventNo thrombusThrombus recurrence or progression; erythematous skin lesion; suspected thrombusConfirmed thrombus; skin necrosis; acute reaction after UFH bolus
Other causes for thrombocytopeniaDefinitePossibleNone apparent

Sum the points for each of the four categories to determine the clinical probability: high (6–8 points), intermediate (4–5 points), low (0–3 points).

PLT, platelets; UFH, unfractionated heparin.

Data from Lo GK, Juhl D, Warkentin TE, Sigouin CS, Eichler P, Greinacher A. Evaluation of pretest clinical score (4 T’s) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings. J Thromb Haemost. 2006;4(4):759-765  [PMID:16634744] and Warkentin TE, Linkins LA. Non-necrotizing heparin-induced skin lesions and the 4T’s score. J Thromb Haemost. 2010;8(7):1483-1485.  [PMID:20403090]

Diagnostic Testing

  • Obtain surveillance platelet counts every 2–3 days during heparin exposure in patients with >1% risk of HIT.
  • For suspected HIT, laboratory tests for PF4 antibodies improve diagnostic accuracy.
    • PF4 antibody testing is a sensitive screening test but lacks specificity.
    • Specificity improves when a positive enzyme-linked immunosorbent assay (ELISA) is quantified in optical density (OD) units. The higher the OD, the more likely the patient has HIT.
    • Rapid tests for PF4 antibodies (i.e., latex immunoturbidimetric assays [LIA]) have a lower sensitivity than ELISA (96.8% vs. 100%).
  • Two functional assays test for HIT: serotonin release assay (SRA) and heparin-induced platelet activation (HIPA).
    • Both detect PF4 antibodies in patients’ serum that can activate control platelets in the presence of heparin.
    • Both tests have high specificity for HIT but lower sensitivity than PF4 antibody testing.
  • For a low clinical probability of HIT, testing for HIT antibodies is not indicated.
  • For a moderate to high clinical probability of HIT, PF4 ELISA testing is indicated. A negative PF4 antibody test effectively rules out HIT.
  • A positive PF4 antibody test should lead to confirmatory functional testing (SRA or HIPA).

Treatment

  • Because HIT test results are not often immediately available, clinical assessment should determine initial management.
  • When HIT is strongly suspected, or confirmed, eliminate all heparin/LMWH exposure.
  • Since patients with HIT have a high risk for VTE, they should undergo anticoagulation with a parenteral direct thrombin inhibitor (DTI)3 (i.e., argatroban or bivalirudin), although fondaparinux also has been used.4
  • Assess (e.g., venous compression ultrasound) for symptomatic and asymptomatic VTE because of the high risk for VTE and the subsequent indication for a full course of anticoagulation.3
  • Start warfarin only after starting a DTI and when the platelet count normalizes to >150 × 109/L, at an initial dose no greater than 5 mg daily. Then, overlap warfarin with the DTI for 5 days to reduce the risk of limb gangrene due to ongoing hypercoagulable conditions and depletion of proteins C and S.
  • Evidence is increasing for the safety and efficacy of direct oral anticoagulant (DOACs) in HIT.5
  • The recommended duration of anticoagulation therapy for HIT depends on the clinical scenario: 4–6 weeks for isolated HIT (without thrombosis) and 3 months for HIT-associated thrombosis.3

References

  1. Shen YM, Wolfe H, Barman S. Evaluating thrombocytopenia during heparin therapy. JAMA. 2018;319(5):497-498. doi:10.1001/jama.2017.21898  [PMID:29411014]
  2. Lo GK, Juhl D, Warkentin TE, Sigouin CS, Eichler P, Greinacher A. Evaluation of pretest clinical score (4 T’s) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings. J Thromb Haemost. 2006;4(4):759-765. doi:10.1111/j.1538-7836.2006.01787.x  [PMID:16634744]
  3. Cuker A, Arepally GM, Chong BH, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia. Blood Adv. 2018;2(22):3360-3392. doi:10.1182/bloodadvances.2018024489  [PMID:30482768]
  4. Warkentin TE, Pai M, Sheppard JI, Schulman S, Spyropoulos AC, Eikelboom JW. Fondaparinux treatment of acute heparin-induced thrombocytopenia confirmed by the serotonin-release assay: a 30-month, 16-patient case series. J Thromb Haemost. 2011;9(12):2389-2396. doi:10.1111/j.1538-7836.2011.04487.x  [PMID:21883878]
  5. Warkentin TE, Pai M, Linkins LA. Direct oral anticoagulants for treatment of HIT: update of Hamilton experience and literature review. Blood. 2017;130(9):1104-1113. doi:10.1182/blood-2017-04-778993  [PMID:28646118]

Outline


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