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
- Integrated Training in Anesthesiology Research
- Neurocognition & Greater Maintenance of Sinus Rhythm in AF (NOGGIN AF)
- The Role of RBC Reactive Oxygen Species in Regulating Thrombotic Events During Aging
- Phase II, of oral SKI-O-703 in Chronic Immune Thrombocytopenia (ITP)
- (Takeda cTTP-2) A Phase 3b, open-label, continuation study of prophylactic and on-demand treatment of cTTP with TAK-755 (rADAMTS-13, also known as BAX 930/SHP655)
- Developing apheresis-specific outcomes to facilitate a multi-center study of therapeutic plasma exchange in heparin-induced thrombocytopenia
- ASP002 A Phase 2, multicenter, open-label extension study to evaluate the long-term safety and tolerability of rozanolixizumab in adult study participants with primary antiphospholipid syndrome.
- HITSOVA Danaporiod vs Argatroban Phase III open-label, randomized trial
- A randomized Phase 2 study evaluating the efficacy, safety, pharmacokinetics, and pharmacodynamics of rozanolixizumab relative to placebo in participants with primary antiphospholipid syndrome.
- IL ASP Clinical Outcome Study Agreement
- Follow-up Study for Patients who Completed Study ALX0681-C301 (Post-HERCULES)
- A Phase 2, Uncontrolled, Two-stage, Dose-escalations Cohort Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics, Immunogenicity, and Clinical activity of OMS721 in Adults with Thrombotic Microangiopathies
- Role of myeloid KLF2 in antiphospholipid antibody-mediated thrombosis
- ACTIV IV COVID-19 Post-hospital Thrombosis Prevention Study
- Postdoctoral Training in Genomic Medicine Research