The role of coagulation in normal and pathologic orthopaedic related wounds
Jonathan G. Schoenecker, MD, PhD, is the Assistant Professor of Orthopaedics, Pediatrics, Pathology and Pharmacology at Vanderbilt University, Nashville, TN. He is a pediatric orthopaedic surgeon with a strong interest in defining the role of the vascular system in bone biology. This focus stems from his surgical training in musculoskeletal diseases in combination with basic science training in vascular and bone biology. From his observations in clinical practice combined with historical work defining vascularity in bone biology and studies conducted in his lab, he developed the hypothesis that the reason the skeleton of a child is more resilient to bone fragility and has a greater capacity to heal is due to differences of a child’s capacity to produce and maintain blood vessels. Dr. Schoenecker’s clinical research is focused on pathologic processes of bone in children with a presumed vascular etiology such as; Legg-Calve-Perthes disease, avascular necrosis, fracture non-union, slipped capital femoral epiphysis, osteosarcoma and infection induced bone necrosis. The goal of these studies is to define how changes in vascularity imposes subsequent pathology in bone biology with the long term hope of addressing the vascular insult to prevent or treat these devastating diseases in children.
We are developing new measures of coagulation to quantify hypercoaguability. Current clinical tests of coagulation are incapable of quantifying hypercoaguability. Instead, it can only be measured through surrogate markers such as the development of a DVT. These markers represent the end-stage complications of hypercoaguability and are impractical measures. Furthermore, because the extent and duration of orthopaedic and surgically related hypercoaguability has not been reported, it is unknown how long treatment of hypercoaguable plasma with anticoagulation is required. As a result, patients are treated in the post-surgical period with a â€œstandardâ€ dose of anticoagulant due to the absence of methods to inform accurate dosing or duration of therapy. This approach places patients at serious risk for developing complications either from i) under-treatment leaving the patient unprotected from hypercoaguability or ii) over-treatment, putting the patient at risk for hemorrhage, hematoma and complications of traumatic and surgical wound healing. Our preliminary data suggest that thrombin generation assays enable the sensitive detection orthopaedic and surgically related hypercoaguability. Therefore, clinically I propose that utilization of this assay will provide rational dose regiments for anticoagulant therapy for these patients. These studies have been initiated and will likely encompass the next 10 years of my clinical research program. Further, recent evidence suggests that many diseases treated by pediatric orthopaedic surgeons are secondary to a hypercoaguable state, such as; Legg-Calves-Perthes disease, osteosarcoma, osteomyelitis and cerebral palsy. We hope over the next five years to apply our novel clinical test to these diseases with the goal of diagnosing and treating the coagulation aspects of these diseases.
My research laboratory is dedicated to define the integrated role of coagulation and inflammation on orthopaedic related wound healing. My unique focus stems from my surgical training in musculoskeletal diseases in combination with my basic science training in coagulation and bone biology.
Our initial experiments have employed models of bone growth, tumor and wound healing to characterize and manipulate cell membrane associated coagulation receptors including tissue factor, thrombomodulin and protease activated receptors. Utilizing these same models, we are investigating how the currently used coagulation associated orthobiologics affect bone growth. Over the next 5-10 years I propose to develop novel coagulation based pharmaceuticals capable of manipulating fracture healing in osteoporotic bone or inhibiting bone based tumors and infections.
The strength of this research program is its uniqueness and clinical relevance. Coagulation research and its pharmaceutical application have already been identified by major cross-disciplinary clinical and research organizations for subject directed funding. The major innovation of this research is that it will i) provide a quantitative measure of hypercoaguability and ii) determine the critical threshold of hypercoaguability that is required for optimal skin and bone wound healing. These studies will have direct and immediate implications for patients undergoing orthopaedic surgery by defining optimal treatment strategies that prevent the complications of the hypercoaguable state, but permit wound healing. They will also allow potentially provide a novel understanding of the pathophysiology of many common diseases specific to pediatric orthopaedics.