Extravascular coagulation in hematopoietic stem and progenitor cell regulation.

The hemostatic system plays pivotal roles in injury repair, innate immunity, and adaptation to inflammatory challenges. We review the evidence that these vascular-protective mechanisms have nontraditional roles in hematopoietic stem cell (HSC) maintenance in their physiological bone marrow (BM) niches at steady-state and under stress. Expression of coagulation factors and the extrinsic coagulation initiator tissue factor by osteoblasts, tissue-resident macrophages, and megakaryocytes suggests that endosteal and vascular HSC niches are functionally regulated by extravascular coagulation. The anticoagulant endothelial protein C receptor (EPCR; Procr) is highly expressed by primitive BM HSCs and endothelial cells. EPCR is associated with its major ligand, activated protein C (aPC), in proximity to thrombomodulin-positive blood vessels, enforcing HSC integrin α4 adhesion and chemotherapy resistance in the context of CXCL12-CXCR4 niche retention signals. Protease-activated receptor 1-biased signaling by EPCR-aPC also maintains HSC retention, whereas thrombin signaling activates HSC motility and BM egress. Furthermore, HSC mobilization under stress is enhanced by the fibrinolytic and complement cascades that target HSCs and their BM niches. In addition, coagulation, fibrinolysis, and HSC-derived progeny, including megakaryocytes, synergize to reestablish functional perivascular HSC niches during BM stress. Therapeutic restoration of the anticoagulant pathway has preclinical efficacy in reversing BM failure following radiation injury, but questions remain about how antithrombotic therapy influences extravascular coagulation in HSC maintenance and hematopoiesis.