Coagulation Factor XIIIa and Activated Protein C Activate Platelets via GPVI and PAR1

Ilaria De Simone, Constance C F M J Baaten, Martine Jandrot-Perrus, Jonathan M Gibbins, Hugo Ten Cate, Johan W M Heemskerk, Chris I Jones*, Paola E J van der Meijden*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Platelet and coagulation activation are highly reciprocal processes driven by multi-molecular interactions. Activated platelets secrete several coagulation factors and expose phosphatidylserine, which supports the activation of coagulation factor proteins. On the other hand, the coagulation cascade generates known ligands for platelet receptors, such as thrombin and fibrin. Coagulation factor (F)Xa, (F)XIIIa and activated protein C (APC) can also bind to platelets, but the functional consequences are unclear. Here, we investigated the effects of the activated (anti)coagulation factors on platelets, other than thrombin. Multicolor flow cytometry and aggregation experiments revealed that the 'supernatant of (hirudin-treated) coagulated plasma' (SCP) enhanced CRP-XL-induced platelet responses, i.e., integrin αIIbβ3 activation, P-selectin exposure and aggregate formation. We demonstrated that FXIIIa in combination with APC enhanced platelet activation in solution, and separately immobilized FXIIIa and APC resulted in platelet spreading. Platelet activation by FXIIIa was inhibited by molecular blockade of glycoprotein VI (GPVI) or Syk kinase. In contrast, platelet spreading on immobilized APC was inhibited by PAR1 blockade. Immobilized, but not soluble, FXIIIa and APC also enhanced in vitro adhesion and aggregation under flow. In conclusion, in coagulation, factors other than thrombin or fibrin can induce platelet activation via GPVI and PAR receptors.

Original languageEnglish
Article number10203
Number of pages14
JournalInternational journal of molecular sciences
Volume23
Issue number18
DOIs
Publication statusPublished - 6 Sept 2022

Keywords

  • Blood Platelets/metabolism
  • Factor XIIIa/metabolism
  • Fibrin/metabolism
  • Hirudins/metabolism
  • P-Selectin/metabolism
  • Phosphatidylserines/metabolism
  • Platelet Activation
  • Platelet Aggregation
  • Platelet Glycoprotein GPIIb-IIIa Complex/metabolism
  • Platelet Membrane Glycoproteins/metabolism
  • Protein C/metabolism
  • Receptor, PAR-1/metabolism
  • Syk Kinase/metabolism
  • Thrombin/metabolism

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