Thomas L. Ortel, MD, PhD

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Services

• Hematology

Director, Anticoagulation Management Service
Director, Duke Clinical Coagulation and Platelet Immunology Laboratories

Department / Division:
Medicine / Hematology

Address:
DUMC 3422
Durham, NC 27710

Appointment Telephone:
(919) 668-6688

Office Telephone:
(919) 684-5350

Fax Telephone:
(919) 681-6160

• M.D., Ph.D., Indiana University School of Medicine, 1985, 1983

• Internal Medicine, Duke University Medical Center, North Carolina, 1985-1988
• Hematology/Oncology, Duke University Medical Center, North Carolina, 1988-1991

Clinical Interests:
Inherited thrombotic and hemorrhagic disorders, antiphospholipid antibody syndromes, heparin induced thrombocytopenia, coagulation factor inhibitors, anticoagulant therapy management, hemophilia and other bleeding disorders

Research Interests:
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.

Representative Publications:
Su Z, Izumi T, Thames EH, Lawson JH, Ortel TL. Antiphospholipid antibodies after surgical exposure to topical bovine thrombin. J Lab Clin Med. 2002 Jun;139(6):349-56. (2002) Abstract

Hansen KE, Kong DF, Moore KD, Ortel TL. Risk factors associated with thrombosis in patients with antiphospholipid antibodies. J Rheumatol. 2001 Sep;28(9):2018-24. (2001) Abstract

Lundblad RL, Bradshaw RA, Gabriel D, Ortel TL, Lawson J, Mann KG. A review of the therapeutic uses of thrombin. Thromb Haemost. 2004 May;91(5):851-60. (2004) Abstract

Potti A, Rusconi CP, Sullenger BA, Ortel TL. Regulatable aptamers in medicine: focus on antithrombotic strategies. Expert Opin Biol Ther. 2004 Oct;4(10):1641-7. (2004) Abstract

Erkan D, Ortel TL, Lockshin MD. Warfarin in antiphospholipid syndrome - time to explore new horizons. J Rheumatol. 2005 Feb;32(2):208-12. (2005) 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 Nov 1;104(9):2783-90. (2004) Abstract

Lewis DA, Pound ML, Ortel TL. Contributions of Asn(2198), Met(2199), and Phe(2200) in the factor VIII C2 domain to cofactor activity, phospholipid-binding, and von Willebrand factor-binding. Thromb Haemost. 2003 May;89(5):795-802. (2003) 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 Sep 5;419(6902):90-4. (2002) Abstract

Ortel TL, Mercer MC, Thames EH, Moore KD, Lawson JH. Immunologic impact and clinical outcomes after surgical exposure to bovine thrombin. Ann Surg. 2001 Jan;233(1):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 Rheum. 1999 Feb;42(2):318-27. (1999) 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. Thromb Haemost. 2001 Jun;85(6):1048-54. (2001) 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 Apr 15;99(8):2828-34. (2002) 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. Thromb Haemost. 2002 Oct;88(4):620-6. (2002) Abstract

O'shea SI, Lawson JH, Reddan D, Murphy M, Ortel TL. Hypercoagulable states and antithrombotic strategies in recurrent vascular access site thrombosis. J Vasc Surg. 2003 Sep;38(3):541-8. (2003) 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. Thromb Haemost. 2001 Feb;85(2):260-4. (2001) 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. Am J Obstet Gynecol. 2004 Aug;191(2):449-55. (2004) Abstract