Platelet-Derived TGF-β1 Promotes Deep Vein Thrombosis

Zhang, Sixuan
Li, Yingying
Zhang, Jie
Sun, Yueyue
Chu, Xiang
Gui, Xiang
Tong, Huan
Ding, Yangyang
Ju, Wen
Xu, Mengdi
Li, Zhenyu
Zeng, Lingyu
Xu, Kailin
Qiao, Jianlin

¹Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
²Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
³Key Laboratory of Bone Marrow Stem Cell, Xuzhou, China

^*These authors contributed equally to this study.

^**These authors shares equal senior authorship.

Address for correspondence Jianlin Qiao, PhD, Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China (e-mail: [email protected]).

Conflict of Interest None declared.

received July 6, 2023

accepted after revision December 17, 2023

accepted manuscript online December 27, 2023

article published online January 15, 2024

Thrombosis and Haemostasis 124(7):p 641-648, July 2024. | DOI: 10.1055/a-2235-7485

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 plateletderived 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 tomeasure 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-β1flox/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.