Laboratory Diagnosis of Heparin-Induced Thrombocytopenia and Monitoring of Alternative Anticoagulants

Abstract

The major complication in the therapeutic or prophylactic use of heparin in medical treatment is type II heparin-induced thrombocytopenia (HIT II), a unique form of drug-induced immune-mediated thrombocytopenia. Due to the extensive use of heparin, this side effect is widespread; up to 3% of patients treated with unfractionated heparin (UFH) develop HIT II (69). Clinically, HIT II is characterized by thrombocytopenia which paradoxically is associated with thrombosis (HIT IIinduced thrombosis [HITTS]) (i.e., deep vein thrombosis, pulmonary embolism, and venous gangrene) in about 50% of the cases.In the pathogenesis of HIT II, the formation of platelet factor 4 (PF4)/heparin complexes seems to be the major determinant (2, 3, 20). The binding of PF4 to heparin induces antibody production directed against a neoepitope created by the three-dimensional assembly of PF4 and heparin. Subsequently, PF4/heparin-antibody complexes induce platelet activation, followed by the shedding of platelet microparticles, thrombin generation, and the involvement of endothelial cells (Fig. 1).Remarkably, the incidence of HIT II, HIT II-associated thrombotic complications, and PF4/heparin-antibodies (HIT II antibodies) in patients receiving therapy with UFH is clearly dependent on the clinical setting of the patient. Cardiosurgical patients are at a high risk to develop HIT II antibodies, while orthopedic patients undergoing hip replacement have a high risk for developing thromboembolic complications (Iceberg model [66]). In medical patients the risk for developing HIT II is substantially lower. Comparing low-molecular-weight heparins (LMWH) with UFH, the use of LMWH coincides with a substantially lower risk of HIT II, but this effect holds true only within the same group of patients (77,78).It is generally accepted that the clinical diagnosis of HIT II should be followed by immediate cessation of heparin therapy and initiation of therapy with alternative anticoagulants. Negative results in the concomitant laboratory testing should not serve as the sole criterion for restarting heparin therapy.In almost every case of HIT II, administration of alternative anticoagulants is essential either to continue prophylactic anticoagulation or to treat and prevent thrombotic complications due to HIT II. Three substances (danaparoid, hirudin, and argatroban) are available. Since these substances have not been compared directly with each other in the treatment of HIT II, criteria such as half-life and/or route of excretion should be considered for selection. This review focuses on (i) the present laboratory methods for diagnosing HIT II, including their principles, time consumption, and significance, and (ii) the alternative anticoagulants, including their characteristics and indications in certain clinical settings. LABORATORY ASSAYS FOR HIT II DIAGNOSISLaboratory testing in the diagnosis of HIT II is based on either the immunological detection of antibodies directed against the PF4/heparin complex or the functional plateletactivating potential of t...

Thrombocytopenia in Patients Treated with Heparin, Combination Antiplatelet Therapy, and Intra‐Aortic Balloon Pump Counterpulsation

“…This immune‐mediated, hypercoagulable state paradoxically arises despite severe thrombocytopenia. HIT occurs in 1–3% of all patients receiving heparin and classically occurs 5–10 days after heparin exposure begins 12–16 . In one report, 4.5% of 764 IABP patients were diagnosed with HIT; of those, 48.6% experienced a thromboembolic event, and 42% died 18 …”

“…Thus, should platelet counts decline, clinicians confront the uncertainty of the thrombocytopenia being IABP‐associated or due to heparin‐induced thrombocytopenia (HIT). Although only a small minority of heparinized patients (1–3%) 12–16 experience this reaction, the clinical consequences can be severe 17,18 …”

“…Thus, should platelet counts decline, clinicians confront the uncertainty of the thrombocytopenia being IABP-associated or due to heparin-induced thrombocytopenia (HIT). Although only a small minority of heparinized patients (1-3%) [12][13][14][15][16] experience this reaction, the clinical consequences can be severe. 17,18 Many contemporary IABP patients are now treated with one or more antiplatelet medications including the glycoprotein IIb/IIIa receptor (GP IIb/IIIa) antagonists (abciximab, eptifibatide, and tirofiban) and the thienopyridine clopidogrel.…”

Impact of an Immunoglobulin G–Specific Enzyme‐Linked Immunosorbent Assay on the Management of Heparin‐Induced Thrombocytopenia

“…Due to the limitations of available laboratory tests, many medical centers use a combination of different laboratory tests, such as an immunoassay in combination with a functional assay, to reach a diagnosis of HIT . Functional assays, such as the SRA, monitor platelet aggregation and are considered the gold standard for the laboratory evaluation of HIT.…”

Heparin‐induced thrombocytopenia: An international assessment of the quality of laboratory testing

“…Both the SRA and the HIPA are highly specific for clinical HIT and are considered reference standards . However, similar to immunoassays there is a balance of ease of use, test performance, and interlaboratory agreement among the different functional assays . The choice of which functional assay to use will likely become even more complex with the introduction of newer methods such as the PF4‐dependent P‐selectin expression assay …”