Platelet-Derived TGF-β1 Promotes Deep Vein Thrombosis

Abstract

Background Transforming growth factor-β1 (TGF-β1) modulates multiple cellular functions during development and tissue homeostasis. A large amount of TGF-β1 is stored in platelet α-granules and released upon platelet activation. Whether platelet-derived TGF-β1 plays a role in venous thrombosis remains unclear. This study intends to assess the role of platelet-derived TGF-β1 in the development of venous thrombosis in mice.

Material and Methods TGF-β1^flox/flox and platelet-specific TGF-β1^−/− mice were utilized to assess platelet function in vitro, arterial thrombosis induced by FeCl₃, tail bleeding time, prothrombin time (PT), activated partial thromboplastin time (APTT), and deep vein thrombosis induced through ligation of the inferior vena cava (IVC). The IVC sample was collected to measure accumulation of neutrophils, monocytes, and the formation of neutrophil extracellular traps (NETs) by immunofluorescence staining.

Results TGF-β1 deficiency in platelets did not affect the number of circulating platelets, platelet aggregation, adenosine triphosphate release, and integrin αIIbβ3 activation. Meanwhile, TGF-β1 deficiency did not alter the arterial thrombus formation, hemostasis, and coagulation time (PT and APTT), but significantly impaired venous thrombus formation, inhibited the recruitment and accumulation of neutrophils and monocytes in thrombi, as well as reduced formation of NETs and platelet-neutrophil complex. In addition, adoptive transfer of TGF-β1^flox/flox platelets to TGF-β1^−/− mice rescued the impaired venous thrombus formation, recruitment of leukocytes and monocytes, as well as the NETs formation.

Conclusion In conclusion, platelet-derived TGF-β1 positively modulates venous thrombus formation in mice, indicating that targeting TGF-β1 might be a novel approach for treating venous thrombosis without increasing the risk of bleeding.

Keywords

platelets - TGF-β1 - venous thrombosis - neutrophils extracellular traps - bleeding

Authors' Contribution

S.Z., Y.L., and J.Z. performed research, analyzed data, and wrote the manuscript. X.C., Y.S., X.G., H.T., Y.D., W.J., M.X., and Z.L. performed research and analyzed data. L.Z., K.X., and J.Q. conceived and designed the study and wrote the manuscript.

^* These authors contributed equally to this study.

^** These authors shares equal senior authorship.

Publication History

Received: 06 July 2023

Accepted: 17 December 2023

Accepted Manuscript online:
27 December 2023

Article published online:
15 January 2024

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