Department / Division:
Medicine / Hematology

Address:
DUMC 3486
Durham, NC 27710

Appointment Telephone:
919-668-6688

Office Telephone:
919-668-3696

Fax Telephone:
919-684-2420

• MD, Vanderbilt University School of Medicine (Tennessee), 1989

• Internal Medicine, Emory University Hospitals (Georgia), 1993

• Hematology/Oncology, University of Pennsylvania, 1997

Clinical Interests:
Treatment of thrombocytopenia, inherited or acquired disorders of clotting, and 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.    

Representative Publications:
Suvarna S, Qi R, Hollingsworth JW, Arepally GM. Platelet factor 4-heparin complexes trigger immune responses independently of the MyD88 pathway. Br J Haematol. 2008 Aug;142(4):671-3. (2008) Abstract

Arepally GM, Hursting MJ. Platelet factor 4/heparin antibody (IgG/M/A) in healthy subjects: a literature analysis of commercial immunoassay results. J Thromb Thrombolysis. 2008 Aug;26(1):55-61. (2008) Abstract

Suvarna S, Espinasse B, Qi R, Lubica R, Poncz M, Cines DB, Wiesner MR, Arepally GM. Determinants of PF4/heparin immunogenicity. Blood. 2007 Dec 15;110(13):4253-60. (2007) 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. J Clin Apher. 2007 Feb;22(1):31-6. (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 Aug 1;106(3):929-31. (2005) Abstract