Heparin-induced thrombocytopenia: The role of platelet activation and therapeutic implications

In the past, heparin has been the sole anticoagulant for interventional car diovascular procedures. Today, several alternate approaches to anticoagulat e patients with heparin-induced thrombocytopenia (HIT) are under considerat ion. Antiplatelet drugs, such as the ADP receptor antagonists and inhibitor s of glycoprotein (GP) IIb/IIIa, are currently in development. We investiga ted the effect of two anti-platelet agents on platelet activation induced b y HIT serum (n = 5 HIT positive sera, n = 5 HIT negative sera and n = 4 don or platelets) and heparin, using the traditional platelet aggregation assay , a Lumi-aggregation assay to also determine platelet release, and flow cyt ometry. By all methods, the GIP IIb/IIIa inhibitor-GPI 562 (Novartis; Nurnb erg, Germany)-produced a concentration dependent (6.25 to 125 ng/mL) decrea se in platelet activation, as shown by platelet aggregation, platelet micro particle formation, P-selectin expression, and ATP release. Similar results were obtained with the thienopyridine ADP receptor antagonist ticlopidine (Sanofi Recherche; Toulouse, France) in vitro at high concentrations of 5.0 to 50 mu g/mL and ex vivo in a patient dosed at 250 mg/day. These studies show that GP IIb/IIIa and ADP receptor inhibitors can block platelet activa tion induced by HIT serum/heparin, providing evidence that the mechanism of HIT may be multifactorial involving not only the generation of the heparin -PF4 or other antibodies but also involving platelet-specific processes and , potentially, the generation of proaggregatory substances. The new antipla telet agents may be useful in the clinical management of HIT patients.