Differential Effects of Erythropoietin Administration and Overexpression on Venous Thrombosis in Mice

Abstract

Background Deep vein thrombosis (DVT) is a common condition associated with significant mortality due to pulmonary embolism. Despite advanced prevention and anticoagulation therapy, the incidence of venous thromboembolism remains unchanged. Individuals with elevated hematocrit and/or excessively high erythropoietin (EPO) serum levels are particularly susceptible to DVT formation. We investigated the influence of short-term EPO administration compared to chronic EPO overproduction on DVT development. Additionally, we examined the role of the spleen in this context and assessed its impact on thrombus composition.

Methods We induced ligation of the caudal vena cava (VCC) in EPO-overproducing Tg(EPO) mice as well as wildtype mice treated with EPO for two weeks, both with and without splenectomy. The effect on platelet circulation time was evaluated through FACS analysis, and thrombus composition was analyzed using immunohistology.

Results We present evidence for an elevated thrombogenic phenotype resulting from chronic EPO overproduction, achieved by combining an EPO-overexpressing mouse model with experimental DVT induction. This increased thrombotic state is largely independent of traditional contributors to DVT, such as neutrophils and platelets. Notably, the pronounced prothrombotic effect of red blood cells (RBCs) only manifests during chronic EPO overproduction and is not influenced by splenic RBC clearance, as demonstrated by splenectomy. In contrast, short-term EPO treatment does not induce thrombogenesis in mice. Consequently, our findings support the existence of a differential thrombogenic effect between chronic enhanced erythropoiesis and exogenous EPO administration.

Conclusion Chronic EPO overproduction significantly increases the risk of DVT, while short-term EPO treatment does not. These findings underscore the importance of considering EPO-related factors in DVT risk assessment and potential therapeutic strategies.

Keywords

deep vein thrombosis - red blood cells - spleen - erythropoietin - sterile inflammation - fibrin

Authors' Contribution

K.S., S.M., and S.S. conceived and designed the experiments. S.S., I.S., A.-L.S., and S.C. planned and performed histological and immunohistochemical analysis. B.K., I.S., A.-L.S., F.W., and M.v.B. did surgery for IVC flow reduction in mice. F.W. injected EPO into C57Bl/6J mice. I.S. performed splenectomy on mice. I.S. determined platelet circulation time. B.K. performed platelet clearance essay in liver and spleen FACS experiments. I.O. provided Tg(EPO) mice. S.S. and K.S. wrote the manuscript. All the authors reviewed and edited the manuscript.

Publikationsverlauf

Eingereicht: 17. September 2022

Angenommen: 06. August 2023

Artikel online veröffentlicht:
16. Oktober 2023

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