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Platelets are small blood cells known primarily for their ability to adhere and aggregate at injured vessels to arrest
bleeding. However, when triggered under pathological conditions, the same adaptive mechanism of platelet adhesion and
aggregation may cause thrombosis, a primary cause of heart attack and stroke. Over recent decades, research has made considerable progress in uncovering the intricate and dynamic interactions that regulate these processes. Integrins are heterodimeric cell surface receptors expressed on all metazoan cells that facilitate cell adhesion, movement, and signaling, to drive
biological and pathological processes such as thrombosis and hemostasis. Recently, our group discovered that the plexinsemaphorin-integrin (PSI) domains of the integrin β subunits exert endogenous thiol isomerase activity derived from their
two highly conserved CXXC active site motifs. Given the importance of redox reactions in integrin activation and its location in the knee region, this PSI domain activity may be critically involved in facilitating the interconversions between integrin
conformations. Our monoclonal antibodies against the β3 PSI domain inhibited its thiol isomerase activity and proportionally
attenuated fibrinogen binding and platelet aggregation. Notably, these antibodies inhibited thrombosis without significantly impairing hemostasis or causing platelet clearance. In this review, we will update mechanisms of thrombosis and hemostasis including platelet versatilities and immune-mediated thrombocytopenia, discuss critical contributions of the newly discovered PSI
domain thiol isomerase activity, and its potential as a novel target for anti-thrombotic therapies and beyond.
Protein disulfide isomerase mutant lacking its isomerase activity accelerates protein folding in the cell