Gowthami M. Arepally, MD
- Medicine / Medicine - Hematology
- Pathology
Address
DUMC 3486
Durham, NC 27710
Appointment Telephone
919-660-4363
Office Telephone
919-668-3696
Fax Telephone
919-287-2437
- MD, Vanderbilt University School of Medicine (Tennessee), 1989
- Internal Medicine, Emory University Hospitals (Georgia), 1993
- Hematology-Oncology, Hospital of the University of Pennsylvania, 1997
Clinical Interests
Treatment of thrombocytopenia, inherited or acquired disorders of clotting, bleeding disorders
Research Interests
Our laboratory investigates mechanisms of disease in Heparin-Induced Thrombocytopenia and Thrombosis (HIT), a clinically devastating thrombotic disorder occurring in 1-3% of patients exposed to heparin. HIT is an immune disorder caused by antibodies directed to Platelet Factor 4 (PF4) and heparin. PF4/heparin antibodies are not only detected in the vast majority of patients with HIT/T, but also occur asymptomatically in a number of clinical settings.
Our research currently focuses on the following aspects of the immune and cellular biology of HIT/T: 1) Initiation of the PF4/heparin immune response using murine models. Little is known about the early events that trigger PF4/heparin immune responses. To investigate the cellular mechanisms of HIT, we have developed two murine models to study PF4/heparin seroconversion. Our first model was developed using active immunization with murine PF4 (mPF4) and heparin complexes. In this model, mice form mPF4/heparin antibodies with serological properties that are similar to human PF4/heparin antibodies. Our second model utilizes in vivo platelet activation to elicit mPF4/heparin antibodies. Using these two murine models, we are investigating the role of B- and T-cell responses to antigen, the anatomic location of antigen uptake and processing, immunoregulatory mechanisms and role of peripheral tolerance in HIT. 2) Mechanisms of hypercoagulability in HIT. The mechanisms by which PF4/heparin antibodies trigger thrombosis in HIT are not well-understood. HIT is associated with platelet activation and significant thrombin generation. Although both in vitro and in vivo studies have demonstrated a critical role of platelets and platelet Fc receptors in triggering antibody-induced platelet activation, the mechanisms by which thrombin generation occurs is unknown. Using our murine models, we are exploring the effects of antbody titer, in role of activating human Fc receptors and/or vascular disease (apoE-knockout mice) on thrombotic manifestations. 3) Studies of PF4/heparin antibodies in humans. Our studies in humans focus on factors predisposing to HIT. Our on-going studies suggest that 0.5-4% of healthy subjects develop PF4/heparin antibodies without prior heparin exposure. Addtionally, data showing genetic differences in platelet PF4, Fc receptor expression indicate that individuals may be predisposed to developing PF4/heparin antibodies and/or complications of HIT. We propose to study HIT predisposition in healthy subjects using serologic, genomic and proteomic studies.
This faculty member (or a member of their immediate family) has a working relationship (i.e. consulting, research, and/or educational services) with the companies listed below. These relations have been reported to the health system leadership and, when appropriate, management plans are in place to address potential conflicts.
- Amgen
- GlaxoSmithKline
- Teva Pharmaceuticals
- University of New Mexico STC
Representative Publications
Arepally, GM; Hursting, MJ. Platelet factor 4/heparin antibody (IgG/M/A) in healthy subjects: a literature analysis of commercial immunoassay results. Journal of Thrombosis and Thrombolysis. 2008;26:55-61.
(2008)
Abstract
Suvarna, S; Qi, R; Hollingsworth, JW; Arepally, GM. Platelet factor 4-heparin complexes trigger immune responses independently of the MyD88 pathway. British Journal of Haematology. 2008;142:671-673.
(2008)
Abstract
Cines, DB; Rauova, L; Arepally, G; Reilly, MP; McKenzie, SE; Sachais, BS; Poncz, M. Heparin-induced thrombocytopenia: an autoimmune disorder regulated through dynamic autoantigen assembly/disassembly. Journal of Clinical Apheresis. 2007;22:31-36.
(2007)
Abstract
Suvarna, S; Espinasse, B; Qi, R; Lubica, R; Poncz, M; Cines, DB; Wiesner, MR; Arepally, GM. Determinants of PF4/heparin immunogenicity. Blood. 2007;110:4253-4260.
(2007)
Abstract
Suvarna, S; Rauova, L; McCracken, EK; Goss, CM; Sachais, BS; McKenzie, SE; Reilly, MP; Gunn, MD; Cines, DB; Poncz, M; Arepally, G. PF4/heparin complexes are T cell-dependent antigens. Blood. 2005;106:929-931.
(2005)
Abstract
