Tissue factor and regenerative medicine: shaping cell and extracellular vesicle-based therapeutic approaches

Regenerative medicine, characterized by breakthroughs in stem cell technology, cell-free therapies, and tissue engineering, holds immense promise for treating various diseases. However, along with the encouraging advancements in translational and clinical research, emerging evidence has demonstrated a potential risk of developing instant blood-mediated inflammatory reactions (IBMIRs) and venous thromboembolism (VTE) with the intravascular delivery of cellular products that do not naturally come into contact with blood. Tissue factor (TF), an initiator of the extrinsic coagulation cascade, plays a pivotal role in these processes. In this comprehensive review, we summarize the biological properties and multifaceted functions of TF in both health and disease. By understanding its physiological and pathological roles, we discuss the implications of TF for IBMIR and VTE in patients receiving cell therapy and extracellular vesicle (EV) therapy. VTEs, including deep vein thrombosis and pulmonary embolism, might have life-threatening consequences. During IBMIR, the recipient's innate immune cells and humoral coagulation factors drive a hyperacute thromboinflammatory response that traps the infused products, leading to rapid intravascular clearance and compromised therapeutic outcomes. Additionally, we introduce transplantation protocols that demonstrate prevention and monitoring strategies for TF-induced negative effects. Given the increasing complexity of clinical studies and the diverse applications of cell-based therapies, mitigating TF-induced thrombosis is crucial for safer and more effective treatments.