Fibrin activates GPVI in human and mouse platelets

Area of Science:

• Hematology
• Vascular Biology
• Platelet Signaling

Background:

• Glycoprotein VI (GPVI) is a primary platelet receptor for collagen, essential for thrombus initiation.
• GPVI-deficient mice show delayed thrombus occlusion, not initiation, in FeCl3 injury models, suggesting a role beyond collagen interaction.

Purpose of the Study:

• To investigate the role of GPVI in thrombus development beyond its known function as a collagen receptor.
• To determine if GPVI interacts with fibrin and mediates downstream signaling.

Main Methods:

• Platelet activation assays measuring tyrosine phosphorylation (Syk, FcRγ chain) induced by thrombin with fibrinogen.
• Platelet spreading assays on fibrin vs. fibrinogen, assessing Src kinase inhibition and GPVI deficiency.
• Fibrin binding assays using immobilized fibrin and GPVI ectodomain.
• FeCl3 injury model in GPVI-deficient mice to evaluate thrombus occlusion and embolization.

Main Results:

• Thrombin, in the presence of fibrinogen, induced significant tyrosine phosphorylation in human and mouse platelets, dependent on GPVI.
• Platelet spreading and procoagulant activity on fibrin were observed, requiring GPVI and Src kinase activity.
• GPVI directly binds to both monomeric and polymerized fibrin.
• GPVI-deficient mice exhibited increased embolization and delayed thrombus occlusion in FeCl3 injury models.

Conclusions:

• GPVI functions as a direct receptor for fibrin, mediating platelet activation and thrombus stabilization.
• The interaction of GPVI with fibrin contributes to thrombus growth, stability, and prevention of embolization.
• This study reveals a novel function for GPVI in vascular injury response, extending its role beyond collagen recognition.