Blockade of Platelet GPIIB-IIIA (Integrin α_IIbβ₃) in Flowing Human Blood Leads to Passivation of Prothrombotic Surfaces

Summary

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 α_IIbβ₃), reversed this inhibition, leading to a marked increase in integrin α₂β₁-dependent platelet adhesion. Analysis of integrin α₂β₁-dependent platelet adhesion to collagen indicated that ADP-induced suppression of platelet adhesion is the result of trans-dominant inhibition of integrin α₂β₁ caused by fibrinogen binding to integrin GPIIb-IIIa. Lamifiban blocked fibrinogen binding, reversing the trans-dominant inhibition of α₂β₁ dependent adhesion to collagen. The GPIIb-IIIa antagonist resulted in the formation of a nonthrombogenic, 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.

Keywords

Platelet - flow - GPIIb-IIIa - α₂β₁ - trans-dominant inhibition

• References

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