
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
- Indiana University at Bloomington, Ph.D. 1983
- Indiana University at Indianapolis, M.D. 1985
- Duke University, Medical Resident, Medicine
- Duke University, Fellow in Hematology-Oncology, Medicineq
Selected Grants and Awards
- An integrated and diverse genomic medicine program for undiagnosed diseases
- Postdoctoral Training in Genomic Medicine Research
- Warfarin versus Direct Oral Anticoagulants for Secondary Prevention of Recurent Venous Thromboembolism
- Transfusion Medicine and Hematology
- ThRombosis exelUsion STudy for STA - Liatest D-DiXL (TRUST)
- A Whole Blood Collection from subjects clinicially diagnosed with PNH
- L0022511987 Rev 01 Hemosil, Liquid Anti-Xa Assay with Apixaban Calibrators and Controls Performance Evaluation and Fresh vs Frozen Stability Protocol on ACL. TOP 50 Family Series Analyzers
- L0022511991 Rev 01 Liquid Anti-Xa Assay with Rivaroxaban Calibrators and Controls Performance Evaluation Protocol on ACL TOP
- LOO22511932 Rev 01 Hemosil Direct Thrombin Inhibitor (DTI) Assay with Dabigatran Calibrators and Controls
- IL ASP Clinical Outcome Study Agreement
- Defining the role of therapeutic plasma exchange in heparin induced thrombocytopenia
- IL APS Fresh vs Frozen Clinical Agreement
- Development Of Prognostic Platelet RNA Biomarkers To Tailor Antiplatelet Therapy
- Duke-UNC Clinical Hematology and Transfusion Research Career Development Program
- Task Order 1 under Master Eval Agreement #17072705
- 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)
- 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
- Improving Pain in Sickle Cell Patients With Targeted Antithrombotic Therapy
- Training Program in Inflammatory and Immunological Diseases
- STA - Coag Control ABN PLUS Precision Study
- Evaluation of an Automated Information Extraction Tool for Identification of Venous Thromboembolism in Electronic Health Records (EHRs)
- Population-based Surveillance And Ourcomes of Venous Thromboembolism
- Anticoagulation Withdrawal in Antiphospholipid Syndrome
- BRIDGE CCC
- Siemens CS-2100i and CS-5100 New Generation Analyzers
- Precision Performance of STA® -COAG CONTROL (N + ABN) PLUS ON STA -SATELLITE®
- ALXN1007
- Field Study to evaluate the activity of a site specific of B-Domain Deleted (BDD) pegylated recombinant FVIII protein (BAY 94-9027) in plasma samples measured with both chromogenic and one stage assa
- Public Health Surveillance of Bleeding
- Adherence to Venous Thromboembolism Prophylaxis Guidelines in Hospitalized Elders
- Promoting the Health of Individuals with Clotting Disorders
- Population-based Surveillance And Outcomes of Venous Thromboembolism
- 12091912 INR Project
- Transfusion Medicine/Hemostasis Core Clinical Center
- Clinical Significance of protamine/heparin antibodies after CPB
- Responses of Myocardial Ischemia to Sertraline Treatment
- Thrombosis and Hemostasis Centers Research and Prevention Network
- Phase I Clinical Trial Describing the Pharmacogenomics of Aspirin
- Molecular Biology Of Human Coagulation Factor V
- Rare Thrombotic Diseases Clinical Research Network
- Lung Injury Protection by Coagulation Blockade
- Pharmacologic Prevention of Arteriovenous Graft Thrombosis
- Biomarker Studies for Novel Anti-Cancer Agents
- Hormone replacement therapy and ischemic stroke severity
- Integrated Program for Persons with Hemostatic Disorders
- Mentored Clinical Research Scholar Program
- Does NO mediate clinical anti-VEGF vascular effects
- Genetic Analysis of Hereditary Macrothrombocytopenias
- Pathophysiology of Antiphospholipid Antibody Syndromes