Pharmacological inhibition of factor Xa by rivaroxaban has been shown to mediate cardioprotection and is frequently used in patients with, e.g., atrial fibrillation. Rivaroxaban's anti-inflammatory actions are well known, but the underlying mechanisms are still incompletely understood. To date, no study has focused on the effects of rivaroxaban on the bone marrow (BM), despite growing evidence that the BM and its activation are of major importance in the development/progression of cardiovascular disease. Thus, we examined the impact of rivaroxaban on BM composition under homeostatic conditions and in response to a major cardiovascular event. Rivaroxaban treatment of mice for 7 days markedly diminished mature leukocytes in the BM. While apoptosis of BM-derived mature myeloid leukocytes was unaffected, lineage-negative BM cells exhibited a differentiation arrest at the level of granulocyte–monocyte progenitors, specifically affecting neutrophil maturation via downregulation of the transcription factors Spi1 and Csfr1. To assess whether this persists also in situations of increased leukocyte demand, mice were subjected to cardiac ischemia/reperfusion injury (I/R): 7 d pretreatment with rivaroxaban led to reduced cardiac inflammation 72 h after I/R and lowered circulating leukocyte numbers. However, BM myelopoiesis showed a rescue of the leukocyte differentiation arrest, indicating that rivaroxaban's inhibitory effects are restricted to homeostatic conditions and are mainly abolished during emergency hematopoiesis. In translation, ST-elevation MI patients treated with rivaroxaban also exhibited reduced circulating leukocyte numbers. In conclusion, we demonstrate that rivaroxaban attenuates neutrophil maturation in the BM, which may offer a therapeutic option to limit overshooting of the immune response after I/R.

利伐沙班对 Xa 因子的药理学抑制已被证明可以介导心脏保护作用，并且经常用于患有心房颤动等患者。利伐沙班的抗炎作用众所周知，但其潜在机制仍不完全清楚。迄今为止，尚无研究关注利伐沙班对骨髓 (BM) 的影响，尽管越来越多的证据表明 BM 及其激活对于心血管疾病的发生/进展至关重要。因此，我们研究了利伐沙班在稳态条件下和对主要心血管事件的反应中对 BM 成分的影响。利伐沙班治疗小鼠 7 天后，BM 中的成熟白细胞明显减少。虽然 BM 来源的成熟骨髓白细胞的凋亡不受影响，但谱系阴性 BM 细胞在粒细胞-单核细胞祖细胞水平上表现出分化停滞，特别是通过转录因子Spi1和Csfr1的下调影响中性粒细胞成熟。为了评估这种情况在白细胞需求增加的情况下是否也持续存在，对小鼠进行心脏缺血/再灌注损伤（I/R）：利伐沙班预处理 7 天，可在 I/R 后 72 小时减少心脏炎症，并降低循环白细胞数量。然而，骨髓造血显示白细胞分化停滞得到挽救，表明利伐沙班的抑制作用仅限于稳态条件，并且主要在紧急造血过程中被消除。反过来，接受利伐沙班治疗的 ST 段抬高型心肌梗死患者也表现出循环白细胞数量减少。总之，我们证明利伐沙班可减弱 BM 中的中性粒细胞成熟，这可能为限制 I/R 后免疫反应过度提供一种治疗选择。