Strong Binding of Platelet Integrin ?IIb?3 to Fibrin Clots: Potential Target to Destabilize Thrombi.

ABSTRACT: The formation of platelet thrombi is determined by the integrin ?IIb?3-mediated interactions of platelets with fibrinogen and fibrin. Blood clotting in vivo is catalyzed by thrombin, which simultaneously induces fibrinogen binding to ?IIb?3 and converts fibrinogen to fibrin. Thus, after a short time, thrombus formation is governed by ?IIb?3 binding to fibrin fibers. Surprisingly, there is little understanding of ?IIb?3 interaction with fibrin polymers. Here we used an optical trap-based system to measure the binding of single ?IIb?3 molecules to polymeric fibrin and compare it to ?IIb?3 binding to monomeric fibrin and fibrinogen. Like ?IIb?3 binding to fibrinogen and monomeric fibrin, we found that ?IIb?3 binding to polymeric fibrin can be segregated into two binding regimes, one with weaker rupture forces of 30-60?pN and a second with stronger rupture forces >60?pN that peaked at 70-80?pN. However, we found that the mechanical stability of the bimolecular ?IIb?3-ligand complexes had the following order: fibrin polymer?>?fibrin monomer?>?fibrinogen. These quantitative differences reflect the distinct specificity and underlying molecular mechanisms of ?IIb?3-mediated reactions, implying that targeting platelet interactions with fibrin could increase the therapeutic indices of antithrombotic agents by focusing on the destabilization of thrombi rather than the prevention of platelet aggregation.

SUBMITTER: Hook P 

PROVIDER: S-EPMC5636895 | biostudies-other | 2017 Oct

REPOSITORIES: biostudies-other