My research program investigates the molecular mechanisms whereby various congenital and acquired abnormalities result in ‘dysfunctional’ hemostasis (i.e., hemorrhage or thrombosis) to better understand the molecular mechanisms and interactions that are necessary for normal hemostasis. We are particularly interested in the mechanisms whereby antibodies and other inhibitors can interfere with normal hemostatic mechanisms. Several projects extensively overlap and focus on the assembly and function of procoagulant (e.g., factor X-ase and prothrombinase) and anticoagulant (e.g., activated protein C complex) phospholipid membrane-dependent complexes.
We utilize a variety of approaches in these studies. Monoclonal antibodies, single-chain variable domain fragments, polyclonal antibodies prepared from patients with factor VIII inhibitors, and site-specific mutagenesis have all been used to characterize structure-function relationships in coagulation factor VIII. Our laboratory has also extensively characterized anti-factor V antibodies, investigating autoantibodies as well as xenogenic antibodies developing after exposure to topical bovine thrombin preparations which contain trace amounts of contaminating bovine factor V. We have also characterized how antiphospholipid antibodies interfere with the activated protein C complex, a lipid-dependent natural anticoagulant complex that proteolytically inactivates factor Va and factor VIIIa.
Our current studies are focusing on two antibody-mediated thrombotic syndromes, heparin-induced thrombocytopenia and antiphospholipid antibody syndrome. First, we are initiating a large clinical trial investigating the incidence of clinically-significant heparin-induced thrombocytopenia in patients who develop anti-heparin/platelet factor 4 antibodies following cardiac bypass procedures. While these antibodies are commonly seen following cardiac bypass, the true incidence of thromboembolic complications related to these prothrombotic antibodies remains unknown. We are also collaborating with investigators in the Center for Human Genetics on a large, multi-center study exploring the genetics of familial antiphospholipid antibody syndrome. In addition, we have used a genomic strategy to investigate patients with antiphospholipid antibody syndrome and have identified a gene expression profile that appears to be unique to patients with this syndrome in contrast to patients with venous thromboembolism who do not have these autoantibodies.
We also participate in a variety of collaborative research efforts, both with individual investigators as well as participating in multi-center clinical research studies. For example, we are one of seventeen centers participating in the NIH-supported Transfusion Medicine/Hemostasis Network, and we are currently conducting a trial through this network to define the optimal dose of platelets for patients needing platelet transfusions for hypoproliferative thrombocytopenia. We are also part of a multi-center registry of patients with thrombotic thrombocytopenic purpura, and we are one of eight centers in the Hemostasis and Thrombosis Center pilot program sponsored by the Centers for Disease Control and Prevention. Participation in these registries and networks provides us with access to the patient populations that we study in the research laboratory.
Education and Training
- Fellow in Hematology-Oncology, Medicineq, Duke University, 1988 - 1991
- Medical Resident, Medicine, Duke University, 1985 - 1988
- M.D., Indiana University at Indianapolis, 1985
- Ph.D., Indiana University at Bloomington, 1983
- Postdoctoral training in genomic medicine research
- Transfusion Medicine and Hematology
- A Whole Blood Collection from subjects clinicially diagnosed with PNH
- A Phase I/II Open-Label Safety and Dose-Finding Study of Adeno- Associated Virus (AAV) rh10-Mediated Gene Transfer of Human Factor IX in Adults With Moderate/Severe to Severe Hemophilia B
- Defining the role of therapeutic plasma exchange in heparin induced thrombocytopenia
- U.S. External Site Protocol for Evaluation of Precision Performances of STA-THROMBIN ON STA-SATELLITE
- External Evaluation of Assay Applications on The Sysmex CS2500 and CS-5100 Analyzer (Wave C)
- Development Of Prognostic Platelet RNA Biomarkers To Tailor Antiplatelet Therapy
- Duke-UNC Clinical Hematology and Transfusion Research Career Development Program
- An integrated and diverse genomic medicine program for undiagnosed diseases
- Improving Pain in Sickle Cell Patients With Targeted Antithrombotic Therapy