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.

Epidemiology

The incidence of HIT ranges from 0.1% to 1.0% in medical and obstetric patients receiving prophylactic/therapeutic unfractionated heparin (UFH) to gt;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.²²

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 gt; 95%).²³

TABLE 20-3

4T SCORING SYSTEM FOR PRETEST PROBABILITY OF HEPARIN-INDUCED THROMBOCYTOPENIA

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 and Warkentin TE, Linkins LA. Non-necrotizing heparin-induced skin lesions and the 4T's score. J Thromb Haemost. 2010;8(7):1483-1485.

• HIT rarely causes severe thrombocytopenia (platelet count lt; 20 ? 10⁹#8725;L) or bleeding.

• Thromboembolic complications occur in 30%-75% of HIT patients. Thrombosis can precede, be concurrent with, or follow thrombocytopenia.

î 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.

Diagnostic Testing

• Obtain surveillance platelet counts every 2-3 days during heparin exposure in patients with gt;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.

î 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.

î 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).

î Both detect PF4 antibodies in patients' serum that can activate control platelets in the presence of heparin.

î 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)²⁴ (i.e., argatroban or bivalirudin), although fondaparinux also has been used.²⁵

• 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.²⁴

• Start warfarin only after starting a DTI and when the platelet count normalizes to gt;150 ? 10⁹#8725;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.

î DTIs prolong the INR and require careful monitoring when transitioning from DTI to warfarin (see Medications under Approach to Venous Thromboembolism).

• Evidence is increasing for the safety and efficacy of direct oral anticoagulant (DOACs) in HIT.²⁶

• 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.²⁴