Updated Understanding of Platelets in Thrombosis and Hemostasis: The Roles of Integrin PSI Domains and their Potential as Therapeutic Targets

Abstract

: 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.

Thymic stromal lymphopoietin induces platelet mitophagy and promotes thrombosis in Kawasaki disease

“…Our work identifies that upregulated TSLP expression at least partially underlies platelet activation and thrombosis in KD. TSLP-induced platelet mitophagy and activation likely promotes thrombosis by promoting platelet aggregation, 43,44 and to expose PS on its surface, which promotes a hypercoagulable state through cell-based thrombin generation. 32,45 Current anti-thrombotic therapies may not effectively inhibit TSLP-induced thrombosis in KD given its unique mechanism, which may explain the persistent platelet activation and thrombosis in treated patients.…”

Role of Semaphorins in Ischemic Stroke

“…Moreover, semaphorins play an important role in the pathological processes of the diseases in these organ systems. In CNS, semaphorins have been shown to be involved in many diseases, and several semaphorin members have been reported to participate in pathogenic process of ischemic stroke ( Sawano et al, 2015 ; You et al, 2019 ; MacKeigan et al, 2020 ). These evidences point to a role of semaphorins in the regulation of ischemic stroke.…”

GPIbα is the driving force of hepatic thrombopoietin generation

“…Increasingly recognized for their versatility, platelets have implications in the immune system, 2,10,11 angiogenesis and liver regeneration, 2,12 and tumor metastasis, 13 among others, in addition to hemostasis. 14,15 At the site of vascular injury, subendothelial matrix proteins, such as collagen, are exposed, which is subsequently anchored with von Willebrand factor (VWF) and allows for glycoprotein (GP) Ibα interaction, mediating platelet tethering, particularly at high shear rates. [16][17][18] The transient VWF-GPIbα interactions slow platelets down, allowing for GPVI-collagen interactions for further platelet activation.…”