Extravascular coagulation in hematopoietic stem and progenitor cell regulation

Area of Science:

• Hematology
• Vascular Biology
• Stem Cell Biology

Background:

• The hemostatic system is crucial for injury repair and immunity.
• Emerging evidence highlights its non-traditional roles in maintaining hematopoietic stem cells (HSCs) within bone marrow (BM) niches.
• These roles extend to both steady-state conditions and responses to stress.

Purpose of the Study:

• To review the evidence for the hemostatic system's involvement in HSC maintenance.
• To explore the mechanisms by which coagulation, fibrinolysis, and anticoagulant pathways regulate HSC behavior.
• To assess the therapeutic potential of modulating these pathways for BM failure.

Main Methods:

• Review of existing literature on the hemostatic system and HSC biology.
• Analysis of expression patterns of coagulation factors and receptors in BM niches.
• Examination of signaling pathways involved in HSC adhesion, retention, and mobilization.

Main Results:

• Extravascular coagulation, involving tissue factor, regulates endosteal and vascular HSC niches.
• Endothelial protein C receptor (EPCR) and activated protein C (aPC) enforce HSC adhesion and chemotherapy resistance via integrin α4 and CXCL12-CXCR4.
• Protease-activated receptor 1 (PAR1) signaling by EPCR-aPC maintains HSC retention, while thrombin promotes HSC motility and egress.
• Fibrinolytic and complement cascades enhance HSC mobilization under stress.
• Coagulation and fibrinolysis synergize with HSC progeny to restore perivascular HSC niches during BM stress.

Conclusions:

• The hemostatic system profoundly influences HSC maintenance and behavior in the BM.
• EPCR-aPC signaling is critical for HSC retention, whereas thrombin drives mobilization.
• Therapeutic restoration of anticoagulation shows preclinical efficacy in radiation-induced BM failure.
• Further research is needed to understand how antithrombotic therapies affect extravascular coagulation in HSC maintenance and hematopoiesis.