Abstract Number: OC 14.3
Meeting: ISTH 2020 Congress
Background: Deep vein thrombosis (DVT) is a dramatic consequence of hypercoagulability to which contributes an inflammatory condition. Thrombi formed in the lower limbs frequently embolize causing pulmonary thromboembolism. DVT results from the cooperative action of leukocytes and platelets that interact with activated endothelial cells. We have previously shown that the proline-rich tyrosine kinase Pyk2 is a critical regulator of platelet activation and arterial thrombosis and a promoter of vascular inflammation.
Aims: In this study we investigated the role of Pyk2 in DVT and we analysed the function of this kinase in the crosstalk between endothelial cells, leukocytes and platelets.
Methods: DVT was induced in mice by inferior vena cava (IVC) partial ligation. The contribution of Pyk2 in cell activation was analysed using a specific Pyk2 pharmacological inhibitor, PF-4594755, and confirmed in transgenic Pyk2 knock out mice (Pyk2-KO).
Results: We have demonstrated that Pyk2 is required for venous thrombosis in vivo, as no venous thrombi were formed in a model of IVC partial ligation in Pyk2-KO mice compared to WT littermates. Moreover, coagulation was impaired in Pyk2-KO mice, with a significant prolongation of the extrinsic pathway. Tissue factor expression by endothelial cells and monocytes was dependent on Pyk2 activity. Pyk2 also mediated the expression of pro-adhesive ICAM and P-selectin on stimulated endothelial cells and supported the release of von Willebrand factor. Accordingly, rolling and adhesion of neutrophils on endothelial cells under flow condition as well as adhesion of platelets on endothelial cells through released VWF were dependent on Pyk2. Finally, we found that Pyk2 also regulated the pro-coagulant NETs formation by neutrophils and phosphatidylserine exposure by platelets.
Conclusions: Altogether our results demonstrate a critical role of Pyk2 in endothelial cells, leukocytes and platelets for the development of venous thrombosis, suggesting that Pyk2 may be a promising target in the treatment of DVT.
To cite this abstract in AMA style:Momi S, Canino J, Falcinelli E, Guglielmini G, Galgano L, Vismara M, Guidetti G, Gresele P, Torti M, Canobbio I. The Proline-Rich Tyrosine Kinase Pyk2 Contributes to Venous Thrombosis [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/the-proline-rich-tyrosine-kinase-pyk2-contributes-to-venous-thrombosis/. Accessed January 28, 2022.
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