Abstract Number: OC 11.2
Meeting: ISTH 2021 Congress
Background: The formation of a stable platelet thrombus in vivo is accompanied by the generation of thrombin and the conversion of fibrinogen to cross-linked fibrin. While the interaction of platelets with fibrinogen has been studied in detail, the interaction with cross-linked fibrin is poorly defined, despite its biological and clinical importance in thrombus stabilization and clot retraction.
Aims: To expand our studies on platelet-fibrin interaction using the DW assay.
Methods: We recently studied the interaction of washed platelets with polymerizing fibrin by preventing the interaction of fibrinogen with the RGD pocket with the peptide RGDW, but stimulating platelets with 0.2 u/ml thrombin to achieve both fibrin polymerization. Under these conditions, platelets undergo a fibrin-mediated delayed wave (DW) of aggregation ~4-5 min after thrombin stimulation.
Results: Our studies with platelets from a Glanzmann Thrombasthenia patient demonstrated that αIIbβ3 was the dominant receptor mediating the platelet-fibrin interaction Figure 1A). The αIIbβ3 antagonists RGDW, eptifibatide and mAb 7E3 inhibited the interactions nearly completely, but it required much higher concentrations than needed to inhibit fibrinogen-mediated platelet aggregation-initiated thrombin-related peptide (T6) (Figure1B-C). The mAb 10E5 (Figure1C), which inhibits T6-induced platelet aggregation, did not inhibit the DW, suggesting that fibrin binding relies less on interactions with the αIIb cap domain than fibrinogen. The monovalent Fab fragment of mAb 7E3 (abciximab) was also ineffectual (Figure1C), suggesting that the multivalency of fibrin resulted in higher avidity by engaging multiple αIIbβ3 receptors simultaneously, and this was supported by scanning electron micrographs (Figure2A) and, SPR analysis that demonstrate no significant differences in the affinity of purified αIIbβ3 for fibrinogen vs. polymerizing fibrin (Figure2B).
Conclusions: Activated αIIbβ3 is the primary mediator of platelet-fibrin interactions, that the interaction is of high avidity and, is mediated by a mechanism that subtly differs from that of the interaction of αIIbβ3 with fibrinogen.
To cite this abstract in AMA style:Buitrago CL, Bentur O, Coller B. Platelet Binding to Polymerizing Fibrin is Avidity-driven and Requires Activated αIIbβ3 [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/platelet-binding-to-polymerizing-fibrin-is-avidity-driven-and-requires-activated-%ce%b1iib%ce%b23/. Accessed February 28, 2024.
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