Essential Points

  1. GPVI is the major collagen receptor in platelets as well as a receptor for fibrinogen/fibrin and signals intracellularly by activating SYK kinase.

  2. Deletion of GPVI in contrast to SYK inhibitor treatment has a mild but significant effect on jugular vein puncture wound bleeding cessation in the murine model. The SYK inhibitor was used at a concentration sufficient to inhibit ferric chloride induced occlusive clotting.

  3. Deletion of either GPVI or SYK inhibition inhibits the induction of a high platelet activation state at the collagen/thrombus interface and results in a thinning of the extravascular cap that leads to bleeding cessation in the jugular puncture wound model.

  4. The GPVI knockout has a profound effect on the tightness of platelet packing in a 5-min post puncture wound and affects thrombus structure in general through the formation of a very loose intravascular thrombus crown. In contrast, SYK inhibition has little effect on thrombus structure in general.

  5. The substantial effect of GPVI knockout on platelet adhesion and intravascular crowning of the puncture wound thrombus indicates a significant late role of GPVI in thrombus formation that is presumably mediated by GPVI-fibrinogen/fibrin interactions.

  6. These findings have clinical implications in terms of targeting GPVI to inhibit thrombosis. Is targeting the intracellular SYK pathway versus extracellular domains of GPVI safer? The SYK inhibitor Bi 1002494 is known to preferentially affect thrombosis versus hemostasis (van Eeuwijk et al, 2016; present work)

Literature Cited

Van Eeuwjk JM, Steger D, Lamb DJ, Kraft P, Beck S, Thielmann I, Keifer F, Walzog B, Stoll G, and Nieswandt B. 2916. The novel oral Syk Inhibitor, Bi 1002494, protects mice from arterial thrombosis and thromboinflammatory brain infarction. Arterscler Throm Vasc Biol 36:1247-1253.

Disclosures

No relevant conflicts of interest to declare.

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2024
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