The Role of Fibrinogen-Mediated Platelet Aggregation in Subsequent Platelet-Driven Blood Clot Contraction

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Abstract Background Blood clot contraction/retraction depends on the force-generating actomyosin and on the platelet integrin αIIbβ3, which transmits intracellular forces to fibrin. Before clotting, fibrinogen binds to activated integrin αIIbβ3, mediating platelet aggregation. The relationship between platelet aggregation and subsequent platelet-driven clot contraction remains unclear. Methods We investigated the effects of platelet aggregation on clot contraction by selectively blocking the αIIbβ3-fibrinogen binding using the RGDW peptide. The ability of RGDW to disrupt αIIbβ3-fibrinogen binding was assessed by platelet aggregometry. The time-course of clot contraction was monitored optically in whole blood or platelet-rich plasma and modeled mathematically. Clot stiffness was assessed using Thromboelastography. The effect of the RGDW peptide on the structure of PRP-clots was examined using scanning electron microscopy. Results The RGDW peptide dose-dependently inhibited TRAP-induced platelet aggregation. Both in whole blood and in plasma, the peptide dose-dependently prolonged the lag-period and slowed the rate without affecting the final extent of contraction. Thromboelastography showed that RGDW dose-dependently increased maximum clot stiffness in blood. Scanning electron microscopy revealed that RGDW treatment resulted in formation of smaller fibrin agglomerates surrounding non-aggregated platelets. A theoretical model allowed us to decipher mechanisms underlying the kinetic effects of RGDW. Conclusion Blocking the binding of integrin αIIbβ3 to fibrinogen and preventing platelet aggregation delays and slows subsequent clot contraction without affecting the final degree of shrinkage. These findings indicate a modulatory role of fibrinogen-mediated platelet aggregation in clot contraction and highlight the unforeseen effects of selective inhibitors of platelet aggregation on the contraction of blood clots and thrombi.

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