Maintaining the balance: the critical role of plasmin activity in orthopedic surgery injury response

The musculoskeletal system plays vital roles in the body, facilitating movement, protecting vital structures, and regulating hematopoiesis and mineral metabolism. Injuries to this system are common and can cause chronic pain, loss of range of motion, and disability. The acute phase response (APR) is a complex process necessary for surviving and repairing injured musculoskeletal tissue. To conceptualize the APR, it is useful to divide it into 2 distinct phases, survival and repair. During the survival-APR, a "damage matrix" primarily composed of fibrin, via thrombin activity, is produced to contain the zone of injury. Once containment is achieved, the APR transitions to the repair phase, where reparative inflammatory cells use plasmin to systematically remove the damage matrix and replace it with new permanent matrices produced by differentiated mesenchymal stem cells. The timing of thrombin and plasmin activation during their respective APR phases is crucial for appropriate regulation of the damage matrix. This review focuses on evidence indicating that inappropriate exuberant activation of plasmin during the survival-APR can result in an overactive APR, leading to an "immunocoagulopathy" that may cause "immunothrombosis" and death. Conversely, preclinical data suggest that too little plasmin activity during the repair-APR may contribute to failed tissue repair, such as a fracture nonunion, and chronic inflammatory degenerative diseases like osteoporosis. Future clinical studies are required to affirm these findings. Therefore, the temporal-spatial functions of plasmin in response to musculoskeletal injury and its pharmacologic manipulation are intriguing new targets for improving orthopedic care.