Laboratory diagnosis of heparin-induced thrombocytopenia and monitoring of alternative anticoagulants.

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 II- induced thrombosis (HITTS)) (i.e., deep vein thrombosis, pul- monary 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 de- terminant (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. Subse- quently, PF4/heparin-antibody complexes induce platelet acti- vation, 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 hepa- rins (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. Neg- ative 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 an- ticoagulation 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 con- sumption, and significance, and (ii) the alternative anticoagu- lants, including their characteristics and indications in certain clinical settings.