Rivaroxaban attenuates neutrophil maturation in the bone marrow niche

Area of Science:

• Hematology
• Cardiovascular Medicine
• Pharmacology

Background:

• Rivaroxaban, a factor Xa inhibitor, offers cardioprotection and has anti-inflammatory effects, but its impact on bone marrow (BM) is unknown.
• Bone marrow activation is crucial in cardiovascular disease (CVD) development and progression.
• Understanding rivaroxaban's BM effects is vital for elucidating its full therapeutic potential in CVD.

Purpose of the Study:

• To investigate the effects of rivaroxaban on bone marrow composition under homeostatic conditions.
• To determine if rivaroxaban impacts bone marrow function during cardiovascular events like ischemia/reperfusion (I/R) injury.
• To explore the clinical relevance of rivaroxaban's effects on leukocyte numbers in ST-elevation myocardial infarction (STEMI) patients.

Main Methods:

• Mice were treated with rivaroxaban for 7 days to assess effects on bone marrow homeostasis.
• Cardiac ischemia/reperfusion (I/R) injury model was used to evaluate rivaroxaban's impact during simulated cardiovascular events.
• Analysis included bone marrow cell composition, leukocyte differentiation markers (Spi1, Csfr1), and circulating leukocyte counts.
• Clinical data from ST-elevation MI patients treated with rivaroxaban were analyzed for circulating leukocyte levels.

Main Results:

• Rivaroxaban treatment reduced mature leukocytes in mouse bone marrow by arresting neutrophil maturation at the progenitor stage.
• This inhibitory effect on myelopoiesis was observed under homeostatic conditions but was largely abolished during I/R injury (emergency hematopoiesis).
• Rivaroxaban pretreatment reduced cardiac inflammation and circulating leukocytes post-I/R, and STEMI patients showed similar reductions in leukocyte counts.

Conclusions:

• Rivaroxaban attenuates neutrophil maturation in the bone marrow under homeostatic conditions.
• The anti-leukopoietic effect of rivaroxaban is transient and overcome during emergency hematopoiesis following cardiovascular injury.
• These findings suggest rivaroxaban may limit excessive immune responses after cardiac events like I/R injury.