Reversible Platelet Integrin αIIbβ3 Activation and Thrombus Instability

Abstract

Integrin αIIbβ3 activation is essential for platelet aggregation and, accordingly, for hemostasis and arterial thrombosis. The αIIbβ3 integrin is highly expressed on platelets and requires an activation step for binding to fibrinogen, fibrin or von Willebrand factor (VWF). A current model assumes that the process of integrin activation relies on actomyosin force-dependent molecular changes from a bent-closed and extended-closed to an extended-open conformation. In this paper we review the pathways that point to a functional reversibility of platelet αIIbβ3 activation and transient aggregation. Furthermore, we refer to mouse models indicating that genetic defects that lead to reversible platelet aggregation can also cause instable thrombus formation. We discuss the platelet agonists and signaling pathways that lead to a transient binding of ligands to integrin αIIbβ3. Our analysis points to the (autocrine) ADP P2Y1 and P2Y12 receptor signaling via phosphoinositide 3-kinases and Akt as principal pathways linked to reversible integrin activation. Downstream signaling events by protein kinase C, CalDAG-GEFI and Rap1b have not been linked to transient integrin activation. Insight into the functional reversibility of integrin activation pathways will help to better understand the effects of antiplatelet agents.

Increase in venous thromboembolism in SARS‐CoV‐2 infected lung tissue: proteome analysis of lung parenchyma, isolated endothelium, and thrombi

“…10,11 A decrease of integrin and other platelet-related proteins in COVID-19 thrombi compared to influenza thrombi may indicate a thrombus origin. Integrin signalling has been described to have a key role in thrombosis in arteries 12,13 ; downregulation of the integrin signalling pathway could thus mean a relative decrease of arterial in situ thrombosis. Additionally, the decrease of platelet transmembrane proteins integrin and ephrin in thrombi suggests an overall reduction of platelets in COVID-19 thrombi, as arterial thrombi contain more platelets compared to venous thrombi.…”

Study on the Mechanism of the Adrenaline-Evoked Procoagulant Response in Human Platelets

“…During platelet activation in a prothrombotic environment (e.g., collagen-rich surface), two populations of activated platelets—proaggregatory and procoagulant—are formed [ 12 ]. Procoagulant (PS-exposed) platelets are characterized by initial activation of GPIIb/IIIa, which subsequently become inactivated [ 63 , 64 , 65 ]. The initial activation of GPIIb/IIIa seems therefore to be an indispensable event in developing both proaggregatory and procoagulant phenotypes.…”

Renal Vein Thrombosis Secondary to Pyelonephritis: Targeting a Thrombo-Inflammatory Entity

“…Platelets have the capacity to migrate inside vessels. This migratory ability is mediated by the cytoskeleton protein actomyosin as well as by the interaction of aIIbβ3 integrin with fibrinogen [ 23 , 24 , 25 , 26 , 27 , 28 , 29 ]. Integrins are a family of at least 24 members, which promote cell adhesion, migration, and proliferation [ 28 , 29 ].…”

“…This migratory ability is mediated by the cytoskeleton protein actomyosin as well as by the interaction of aIIbβ3 integrin with fibrinogen [ 23 , 24 , 25 , 26 , 27 , 28 , 29 ]. Integrins are a family of at least 24 members, which promote cell adhesion, migration, and proliferation [ 28 , 29 ]. These molecules, which contain different combinations of alpha and beta chains, consist of extracellular domains, a membrane-spanning domain, and an intracellular domain or “tail” of the integrins.…”