Heparin-induced thrombocytopenia: the role of platelet activation and therapeutic implications.
In the past, heparin has been the sole anticoagulant for interventional cardiovascular procedures. Today, several alternate approaches to anticoagulate patients with heparin-induced thrombocytopenia (HIT) are under consideration. Antiplatelet drugs, such as the ADP receptor antagonists and inhibitors of glycoprotein (GP) IIb/IIIa, are currently in development. We investigated the effect of two anti-platelet agents on platelet activation induced by HIT serum (n = 5 HIT positive sera, n = 5 HIT negative sera and n = 4 donor platelets) and heparin, using the traditional platelet aggregation assay, a Lumi-aggregation assay to also determine platelet release, and flow cytometry. By all methods, the GP IIb/IIIa inhibitor-GPI 562 (Novartis; Nürnberg, Germany)-produced a concentration dependent (6.25 to 125 ng/mL) decrease in platelet activation, as shown by platelet aggregation, platelet microparticle 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 microg/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 activation 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 antiplatelet agents may be useful in the clinical management of HIT patients.
Haas
S
S
Technical University of Munich, Germany.
Walenga
J M
JM
Jeske
W P
WP
Fareed
J
J
D000255:Adenosine Triphosphate / Q000378:metabolism; D000925:Anticoagulants / Q000009:adverse effects*; D001596:Benzylamines; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006493:Heparin / Q000009:adverse effects*; D006801:Humans; D015539:Platelet Activation / Q000187:drug effects / Q000502:physiology; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D010979:Platelet Function Tests; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors; D013921:Thrombocytopenia / Q000097:blood / Q000139:chemically induced* / Q000517:prevention & control; D013988:Ticlopidine / Q000494:pharmacology
D000925:Anticoagulants; D001596:Benzylamines; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C099231:SDZ GPI 562; D000255:Adenosine Triphosphate; D006493:Heparin; D013988:Ticlopidine