This Reactome event shows binding of the platelet glycoprotein IIb/IIIa complex (integrin αIIbβ3, GPIIb/IIIa, ITGA2B:ITGB3) to the fibrin multimer.
Inside-out signaling during platelet activation induces conformational changes in the integrin αIIbβ3 (ITGA2B:ITGB3), facilitating its transition from a low-affinity to a high-affinity state. This transition is essential for the effective binding of αIIbβ3 to ligands such as fibrinogen and fibrin (Dai A et al., 2015; reviewed in Janus-Bell E & Mangin PH 2023). Integrin αIIbβ3 interacts with ligands-containing Arg-Gly-Asp (RGD) or Ala--Gly-Asp (AGD) motifs in the presence of divalent metal ions (Springer TA et al., 2008; Coller BS 2015; Litvinov RI et al., 2016; Kononova O et al., 2017). The activation of αIIbβ3 not only promotes platelet aggregation but also influences the stability and architecture of the forming clot (Zhang Y et al., 2018; reviewed by Janus-Bell E & Mangin PH 2023). Upon clot formation, thrombin cleaves fibrinogen molecules, producing fibrin monomers, which then polymerize and form protofibrils. Fibrin in its polymeric form exhibits stronger and more stable interactions with αIIbβ3 than fibrinogen or fibrin monomers, with the stability order being fibrin polymer > fibrin monomer > fibrinogen (Litvinov RI et al., 2016; Höök P et al., 2017). Fibrinogen, a soluble plasma protein, binds to αIIbβ3 on the surface of activated platelets, contributing to platelet aggregation, while the stronger interaction of fibrin with αIIbβ3 stabilizes the thrombus (Savage B et al., 1992; Zafar H et al., 2017; Litvinov RI et al., 2016; Höök P et al., 2017). The interaction between fibrin and αIIbβ3 occurs through multiple binding sites within the β-propeller domain of αIIbβ3, distinct from those used by fibrinogen (Podolnikova NP et al., 2014). In addition, fibrin (and fibrinogen) and activated αIIbβ3 (ITGA2B:ITGB3) promote association of phosphatidylserine (PS)-bearing activated platelets with factor XIII (FXIII), a transglutaminase, which stabilizes the clot by cross-linking fibrin fibers (Mattheij NJA 2016; Kotova YN et al., 2019).
