The role of Coagulation in Normal and Pathologic Orthopaedic Related Wounds
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.
Clinically, 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 “standard” 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.
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.
Schoenecker, J, Mignemi, N, Stutz, C, Liu, Q, Edwards, J, Lynch, C, Holt, G, Schwartz, H, Mencio, G, Hamm, H. 2010 Young Investigator Award winner: Therapeutic aprotinin stimulates osteoblast proliferation but inhibits differentiation and bone matrix mineralization. Spine (Phila Pa 1976), 35(9), 1008-16, 2010.
Schoenecker, JG, Kim, YJ, Ganz, R. Treatment of traumatic separation of the proximal femoral epiphysis without development of osteonecrosis: a report of two cases. J Bone Joint Surg Am, 92(4), 973-7, 2010.
Fields, RC, Schoenecker, JG, Hart, JP, Hoffman, MR, Pizzo, SV, Lawson, JH. Protease-activated receptor-2 signaling triggers dendritic cell development. Am J Pathol, 162(6), 1817-22, 2003. PMCID:1868121
Schoenecker, JG, Johnson, RK, Fields, RC, Lesher, AP, Domzalski, T, Baig, K, Lawson, JH, Parker, W. Relative purity of thrombin-based hemostatic agents used in surgery. J Am Coll Surg, 197(4), 580-90, 2003.
Schoenecker, JG, Johnson, RK, Lesher, AP, Day, JD, Love, SD, Hoffman, MR, Ortel, TL, Parker, W, Lawson, JH. Exposure of mice to topical bovine thrombin induces systemic autoimmunity. Am J Pathol, 159(5), 1957-69, 2001. PMCID:1867043
Schoenecker, JG, Hauck, RK, Mercer, MC, Parker, W, Lawson, JH. Exposure to topical bovine thrombin during surgery elicits a response against the xenogeneic carbohydrate galactose alpha1-3galactose. J Clin Immunol, 20(6), 434-44, 2000. PMCID:1867043
Cluss, RG, Goel, AS, Rehm, HL, Schoenecker, JG, Boothby, JT. Coordinate synthesis and turnover of heat shock proteins in Borrelia burgdorferi: degradation of DnaK during recovery from heat shock. Infect Immun, 64(5), 1736-43, 1996. PMCID:173986