β3 Integrin PSI Domain Thiol Isomerase Activity: A Novel Role in Blood Coagulation Implications of the L33P Polymorphism

Abstract

αIIbβ3 integrin is the most highly expressed receptor on platelet surface. αIIbβ3 is essential for platelet aggregation. Our lab discovered that the plexin-semaphorin-integrin (PSI) domain of β3 exerts thiol isomerase activity. Monoclonal antibodies binding PSI can inhibit platelet activation, and aggregation. Our work displays that recombinant PSI domain enhanced extrinsic pathway coagulation. Anti PSI-B1 antibody inhibited extrinsic pathway coagulation more than JAN-D1 αIIbβ3 antibody. Anti PSI-B1 antibody inhibited clot retraction significantly more and decreased fibrin branching in scanning electron microscopy relative to other β3 antibodies. This work reveals a thiol isomerase (PSI) that stimulates the activation of coagulation factors through the extrinsic pathway. Furthermore, we have discovered elevated thiol isomerase activity of L33P polymorphism. Anti-PSI domain antibodies are the first inhibitors to target αIIbβ3 at an allosteric site. Typically used αIIbβ3 blockers lead to bleeding risk. Anti-PSI antibodies attenuate platelet aggregation and blood coagulation and are a promising therapeutic agent