CC BY-NC-ND 4.0 · Thromb Haemost 2024; 124(11): 1027-1039
DOI: 10.1055/s-0043-1775965
Stroke, Systemic or Venous Thromboembolism

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

1   Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Ludwig-Maximilians-Universität, Munich, Germany
2   German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany
3   Walter-Brendel Center of Experimental Medicine, Ludwig-Maximilians-Universität, Munich, Germany
,
Badr Kilani
1   Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Ludwig-Maximilians-Universität, Munich, Germany
2   German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany
3   Walter-Brendel Center of Experimental Medicine, Ludwig-Maximilians-Universität, Munich, Germany
,
Irene Schubert
1   Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Ludwig-Maximilians-Universität, Munich, Germany
2   German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany
3   Walter-Brendel Center of Experimental Medicine, Ludwig-Maximilians-Universität, Munich, Germany
,
Anna-Lena Steinsiek
4   Department of cardiology, German Heart Center, Munich, Germany.
,
Sue Chandraratne
1   Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Ludwig-Maximilians-Universität, Munich, Germany
2   German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany
3   Walter-Brendel Center of Experimental Medicine, Ludwig-Maximilians-Universität, Munich, Germany
,
Franziska Wendler
1   Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Ludwig-Maximilians-Universität, Munich, Germany
2   German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany
3   Walter-Brendel Center of Experimental Medicine, Ludwig-Maximilians-Universität, Munich, Germany
,
Luke Eivers
1   Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Ludwig-Maximilians-Universität, Munich, Germany
2   German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany
3   Walter-Brendel Center of Experimental Medicine, Ludwig-Maximilians-Universität, Munich, Germany
,
Marie-Luise von Brühl
1   Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Ludwig-Maximilians-Universität, Munich, Germany
2   German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany
3   Walter-Brendel Center of Experimental Medicine, Ludwig-Maximilians-Universität, Munich, Germany
,
Steffen Massberg
1   Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Ludwig-Maximilians-Universität, Munich, Germany
2   German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany
3   Walter-Brendel Center of Experimental Medicine, Ludwig-Maximilians-Universität, Munich, Germany
,
Ilka Ott
4   Department of cardiology, German Heart Center, Munich, Germany.
,
Konstantin Stark
1   Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Ludwig-Maximilians-Universität, Munich, Germany
2   German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany
3   Walter-Brendel Center of Experimental Medicine, Ludwig-Maximilians-Universität, Munich, Germany
› Author Affiliations
Funding This project is supported by the ERC starting grant T-MEMORE project 947611 (K.S.). This study was supported by the Deutsche Forschungsgemeinschaft through the collaborative research center 1123 project A07 (K.S., S.M.) and the collaborative research center 914 project B02 (K.S., S.M.). We thank for the support by the grant from the Deutsche Gesellschaft für Kardiologie project DGK09/2020 and the Förderprogramm für Forschung und Lehre (FöFoLe) project 1123 (S.S).


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.

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.


Supplementary Material



Publication History

Received: 17 September 2022

Accepted: 06 August 2023

Article published online:
16 October 2023

© 2023. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

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