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

IF 5 2区 医学 Q1 HEMATOLOGY Thrombosis and haemostasis Pub Date : 2024-11-01 Epub Date: 2023-10-16 DOI:10.1055/s-0043-1775965
Sven Stockhausen, Badr Kilani, Irene Schubert, Anna-Lena Steinsiek, Sue Chandraratne, Franziska Wendler, Luke Eivers, Marie-Luise von Brühl, Steffen Massberg, Ilka Ott, Konstantin Stark
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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.

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促红细胞生成素给药和过表达对小鼠静脉血栓形成的不同影响。
背景: 深静脉血栓形成(DVT)是一种常见的疾病,与肺栓塞导致的显著死亡率有关。尽管有先进的预防和抗凝治疗,静脉血栓栓塞的发生率仍然没有变化。红细胞压积升高和/或红细胞生成素(EPO)血清水平过高的个体特别容易形成DVT。我们研究了短期EPO给药与长期EPO过量给药对DVT发展的影响。此外,我们检查了脾脏在这方面的作用,并评估了其对血栓成分的影响。方法: 我们在EPO过量产生的Tg(EPO)小鼠以及用EPO处理两周的野生型小鼠中诱导了尾腔静脉(VCC)的结扎,无论是否进行脾切除。通过FACS分析评估对血小板循环时间的影响,并使用免疫组织学分析血栓成分。结果: 我们通过将EPO过表达小鼠模型与实验性DVT诱导相结合,提出了慢性EPO过量产生导致血栓形成表型升高的证据。这种增加的血栓状态在很大程度上独立于DVT的传统因素,如中性粒细胞和血小板。值得注意的是,红细胞(RBCs)的显著凝血酶原作用仅在慢性EPO过量产生时表现出来,不受脾脏红细胞清除率的影响,如脾切除所示。相反,短期EPO治疗不会诱导小鼠血栓形成。因此,我们的研究结果支持慢性红细胞生成增强和外源性EPO给药之间存在差异性的血栓形成作用。结论: 慢性EPO过量产生会显著增加DVT的风险,而短期EPO治疗则不会。这些发现强调了在DVT风险评估和潜在治疗策略中考虑EPO相关因素的重要性。
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来源期刊
Thrombosis and haemostasis
Thrombosis and haemostasis 医学-外周血管病
CiteScore
11.90
自引率
9.00%
发文量
140
审稿时长
1 months
期刊介绍: Thrombosis and Haemostasis publishes reports on basic, translational and clinical research dedicated to novel results and highest quality in any area of thrombosis and haemostasis, vascular biology and medicine, inflammation and infection, platelet and leukocyte biology, from genetic, molecular & cellular studies, diagnostic, therapeutic & preventative studies to high-level translational and clinical research. The journal provides position and guideline papers, state-of-the-art papers, expert analysis and commentaries, and dedicated theme issues covering recent developments and key topics in the field.
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