Blockade of platelet GPIIB-IIIA (Integrin alphaII(b)beta(3)) in flowing human blood leads to passivation of prothrombotic surfaces.
We examined the impact of platelet activation on platelet adhesion to collagen in flowing human blood. ADP activation of platelets in ex vivo flowing blood resulted in paradoxical inhibition of platelet deposition on collagen. Blockade of fibrinogen binding to platelets by Lamifiban, a competitive antagonist of GPIIb-IIIa (integrin alpha(IIb)beta(3)), reversed this inhibition, leading to a marked increase in integrin alpha(2)beta(1)-dependent platelet adhesion. Analysis of integrin alpha(2)beta(1)-dependent platelet adhesion to collagen indicated that ADP-induced suppression of platelet adhesion is the result of trans-dominant inhibition of integrin alpha(2)beta(1) caused by fibrinogen binding to integrin GPIIb-IIIa. Lamifiban blocked fibrinogen binding, reversing the trans-dominant inhibition of alpha(2)beta(1) dependent adhesion to collagen. The GPIIb-IIIa antagonist resulted in the formation of a non-thrombogenic, passivated surface comprised of an adherent platelet monolayer. This unexpected consequence of blocking fibrinogen binding to GPIIb-IIIa may explain the long-term benefits of short-term GPIIb-IIIa antagonist treatment of Acute Coronary Syndrome patients.
Riederer
Markus A
MA
Department of Vascular and Metabolic Diseases, F. Hoffman-La Roche Ltd., CH-4070 Basel, Switzerland.
Ginsberg
Mark H
MH
Steiner
Beat
B
D000244:Adenosine Diphosphate / Q000494:pharmacology; D003094:Collagen / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism; D018056:Hemorheology; D006801:Humans; D038982:Integrin alpha2beta1; D015539:Platelet Activation / Q000187:drug effects; D010973:Platelet Adhesiveness / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D011485:Protein Binding; D013927:Thrombosis / Q000209:etiology* / Q000517:prevention & control
D038982:Integrin alpha2beta1; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D000244:Adenosine Diphosphate; D005340:Fibrinogen; D003094:Collagen