Reversible Platelet Integrin aIIbß3 Activation and Thrombus Instability

Jinmi Zou, Frauke Swieringa, Bas de Laat, Philip G de Groot, Mark Roest, Johan W M Heemskerk*

*Corresponding author for this work

Research output: Contribution to journal(Systematic) Review article peer-review

Abstract

Integrin aIIbß3 activation is essential for platelet aggregation and, accordingly, for hemostasis and arterial thrombosis. The aIIbß3 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 aIIbß3 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 aIIbß3. Our analysis points to the (autocrine) ADP P2Y and P2Y 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.
Original languageEnglish
Article number12512
Number of pages16
JournalInternational Journal of Molecular Sciences
Volume23
Issue number20
DOIs
Publication statusPublished - 19 Oct 2022
Externally publishedYes

Keywords

  • ADP
  • collagen
  • fibrinogen
  • integrin
  • platelets
  • thrombin
  • Mice
  • Animals
  • Platelet Glycoprotein GPIIb-IIIa Complex/metabolism
  • von Willebrand Factor/metabolism
  • Platelet Aggregation Inhibitors/pharmacology therapeutic use metabolism
  • Actomyosin/metabolism
  • Proto-Oncogene Proteins c-akt/metabolism
  • Platelet Activation
  • Platelet Aggregation
  • Blood Platelets/metabolism
  • Thrombosis/metabolism
  • Fibrinogen/metabolism
  • Protein Kinase C/metabolism
  • Adenosine Diphosphate/metabolism
  • Fibrin/metabolism
  • Phosphatidylinositols/metabolism

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