Director, Anticoagulation Management Service
Director, Duke Clinical Coagulation and Platelet Immunology Laboratories
Durham, NC 27710
Inherited thrombotic and hemorrhagic disorders, antiphospholipid antibody syndromes, heparin-induced thrombocytopenia, coagulation factor inhibitors, anticoagulant therapy management, hemophilia and other bleeding disorders
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.
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.
Erkan, D; Ortel, TL; Lockshin, MD. Warfarin in antiphospholipid syndrome--time to explore new horizons. Journal of Rheumatology. 2005;32:208-212. (2005) Abstract
James, AH; Lukes, AS; Brancazio, LR; Thames, E; Ortel, TL. Use of a new platelet function analyzer to detect von Willebrand disease in women with menorrhagia. American Journal of Obstetrics and Gynecology. 2004;191:449-455. (2004) Abstract
Lundblad, RL; Bradshaw, RA; Gabriel, D; Ortel, TL; Lawson, J; Mann, KG. A review of the therapeutic uses of thrombin. Thrombosis and Haemostasis. 2004;91:851-860. (2004) Abstract
Potti, A; Rusconi, CP; Sullenger, BA; Ortel, TL. Regulatable aptamers in medicine: focus on antithrombotic strategies. Expert Opinion on Biological Therapy. 2004;4:1641-1647. (2004) Abstract
Rand, JH; Wu, XX; Lapinski, R; van Heerde, WL; Reutelingsperger, CP; Chen, PP; Ortel, TL. Detection of antibody-mediated reduction of annexin A5 anticoagulant activity in plasmas of patients with the antiphospholipid syndrome. Blood. 2004;104:2783-2790. (2004) Abstract
Lewis, DA; Pound, ML; Ortel, TL. Contributions of Asn2198, Met2199, and Phe2200 in the factor VIII C2 domain to cofactor activity, phospholipid-binding, and von Willebrand factor-binding. Thrombosis and Haemostasis. 2003;89:795-802. (2003) Abstract
O'shea, SI; Lawson, JH; Reddan, D; Murphy, M; Ortel, TL. Hypercoagulable states and antithrombotic strategies in recurrent vascular access site thrombosis. Journal of Vascular Surgery. 2003;38:541-548. (2003) Abstract
Izumi, T; Pound, ML; Su, Z; Iverson, GM; Ortel, TL. Anti-beta(2)-glycoprotein I antibody-mediated inhibition of activated protein C requires binding of beta(2)-glycoprotein I to phospholipids. Thrombosis and Haemostasis. 2002;88:620-626. (2002) Abstract
Rusconi, CP; Scardino, E; Layzer, J; Pitoc, GA; Ortel, TL; Monroe, D; Sullenger, BA. RNA aptamers as reversible antagonists of coagulation factor IXa. Nature. 2002;419:90-94. (2002) Abstract
Su, Z; Izumi, T; Thames, EH; Lawson, JH; Ortel, TL. Antiphospholipid antibodies after surgical exposure to topical bovine thrombin. Translational Research: the journal of laboratory and clinical medicine. 2002;139:349-356. (2002) Abstract
van den Brink, EN; Bril, WS; Turenhout, EA; Zuurveld, M; Bovenschen, N; Peters, M; Yee, TT; Mertens, K; Lewis, DA; Ortel, TL; Lollar, P; Scandella, D; Voorberg, J. Two classes of germline genes both derived from the V(H)1 family direct the formation of human antibodies that recognize distinct antigenic sites in the C2 domain of factor VIII. Blood. 2002;99:2828-2834. (2002) Abstract
Hansen, KE; Kong, DF; Moore, KD; Ortel, TL. Risk factors associated with thrombosis in patients with antiphospholipid antibodies. Journal of Rheumatology. 2001;28:2018-2024. (2001) Abstract
Izumi, T; Kim, SW; Greist, A; Macedo-Ribeiro, S; Fuentes-Prior, P; Bode, W; Kane, WH; Ortel, TL. Fine mapping of inhibitory anti-factor V antibodies using factor V C2 domain mutants. Identification of two antigenic epitopes involved in phospholipid binding. Thrombosis and Haemostasis. 2001;85:1048-1054. (2001) Abstract
Lewis, DA; Moore, KD; Ortel, TL. Factor VIII Arg2304 --> His binds to phosphatidylserine and is a functional cofactor in the factor X-ase complex. Thrombosis and Haemostasis. 2001;85:260-264. (2001) Abstract
Ortel, TL; Mercer, MC; Thames, EH; Moore, KD; Lawson, JH. Immunologic impact and clinical outcomes after surgical exposure to bovine thrombin. Annals of Surgery. 2001;233:88-96. (2001) Abstract
Goel, N; Ortel, TL; Bali, D; Anderson, JP; Gourley, IS; Smith, H; Morris, CA; DeSimone, M; Branch, DW; Ford, P; Berdeaux, D; Roubey, RA; Kostyu, DD; Kingsmore, SF; Thiel, T; Amos, C; Seldin, MF. Familial antiphospholipid antibody syndrome: criteria for disease and evidence for autosomal dominant inheritance. Arthritis and Rheumatism. 1999;42:318-327. (1999) Abstract