Thomas Ortel

Overview:

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.

Positions:

Chief, Division of Hematology in the Department of Medicine

Medicine, Hematology
School of Medicine

Professor of Medicine

Medicine, Hematology
School of Medicine

Professor of Pathology

Pathology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 1983

Indiana University at Bloomington

M.D. 1985

Indiana University at Indianapolis

Medical Resident, Medicine

Duke University

Fellow in Hematology-Oncology, Medicineq

Duke University

Grants:

An integrated and diverse genomic medicine program for undiagnosed diseases

Administered By
Pediatrics, Medical Genetics
Awarded By
National Institutes of Health
Role
Collaborator
Start Date
End Date

Mentored Clinical Research Scholar Program

Administered By
Medicine, Infectious Diseases
Awarded By
National Institutes of Health
Role
Mentor
Start Date
End Date

Development of Prognostic Platelet RNA Biomarkers To Tailor Antiplatelet Therapy

Administered By
Duke Center for Applied Genomics and Precision Medicine
Awarded By
National Institutes of Health
Role
Co Investigator
Start Date
End Date

Phase I Clinical Trial Describing the Pharmacogenomics of Aspirin

Administered By
Duke Center for Applied Genomics and Precision Medicine
Awarded By
National Institutes of Health
Role
Co Investigator
Start Date
End Date

Adherence to Venous Thromboembolism Prophylaxis Guidelines in Hospitalized Elders

Administered By
Center for the Study of Aging and Human Development
Awarded By
National Institutes of Health
Role
Collaborator
Start Date
End Date

Publications:

Influence of Sex on Platelet Reactivity in Response to Aspirin.

Background There are sex differences in the efficacy and safety of aspirin for the prevention of myocardial infarction and stroke. Whether this is explained by underlying differences in platelet reactivity and aspirin response remains poorly understood. Methods and Results Healthy volunteers (n=378 208 women) and patients with coronary artery disease or coronary artery disease risk factors (n=217 112 women) took aspirin for 4 weeks. Light transmittance aggregometry using platelet-rich plasma was used to measure platelet reactivity in response to epinephrine, collagen, and ADP at baseline, 3 hours after the first aspirin dose, and after 4 weeks of daily aspirin therapy. A subset of patients underwent pharmacokinetic and pharmacodynamic assessment with levels of salicylate and cyclooxygenase-1-derived prostaglandin metabolites and light transmittance aggregometry in response to arachidonic acid and after ex vivo exposure to aspirin. At baseline, women had increased platelet aggregation in response to ADP and collagen. Innate platelet response to aspirin, assessed with ex vivo aspirin exposure of baseline platelets, did not differ by sex. Three hours after the first oral aspirin dose, platelet aggregation was inhibited in women to a greater degree in response to epinephrine and to a lesser degree with collagen. After 4 weeks of daily therapy, despite higher salicylate concentrations and greater cyclooxygenase-1 inhibition, women exhibited an attenuation of platelet inhibition in response to epinephrine and ADP. Conclusions We observed agonist-dependent sex differences in platelet responses to aspirin. Despite higher cyclooxygenase-1 inhibition, daily aspirin exposure resulted in a paradoxical attenuation of platelet inhibition in response to epinephrine and ADP over time in women but not in men.
Authors
Friede, KA; Infeld, MM; Tan, RS; Knickerbocker, HJ; Myers, RA; Dubois, LG; Thompson, JW; Kaddurah-Daouk, R; Ginsburg, GS; Ortel, TL; Voora, D
MLA Citation
Friede, Kevin A., et al. “Influence of Sex on Platelet Reactivity in Response to Aspirin.J Am Heart Assoc, vol. 9, no. 14, July 2020, p. e014726. Pubmed, doi:10.1161/JAHA.119.014726.
URI
https://scholars.duke.edu/individual/pub1452145
PMID
32654613
Source
pubmed
Published In
Journal of the American Heart Association
Volume
9
Published Date
Start Page
e014726
DOI
10.1161/JAHA.119.014726

Recurrent thrombosis in patients with antiphospholipid antibodies and an initial venous or arterial thromboembolic event: A systematic review and meta-analysis.

BACKGROUND: Patients with antiphospholipid antibodies (aPL) and thromboembolism (TE) are at risk for recurrent TE. Few studies, however, distinguish patients based on the initial event. OBJECTIVES: We performed a systematic review and meta-analysis to investigate patients with aPL and venous TE (VTE), provoked or unprovoked, and patients with arterial TE (ATE). PATIENTS/METHODS: We conducted searches in PubMed, CINAHL, Cochrane, and EMBASE. Inclusion criteria were prospective trials or cohort studies investigating patients with aPL and ATE or VTE. Excluded studies did not provide estimated recurrence rates, did not specify whether the incident event was ATE or VTE, included patients with multiple events, or included <10 patients. Two-year summary proportions were estimated using a random effects model. RESULTS: Ten studies described patients with VTE, 2 with ATE, and 5 with VTE or ATE. The 2-year proportion for recurrent TE in patients with VTE who were taking anticoagulant therapy was 0.054 (95% confidence interval [CI], 0.037-0.079); the 2-year proportion for patients not taking anticoagulant therapy was 0.178 (95% CI, 0.150-0.209). Most studies did not distinguish whether VTE were provoked or unprovoked. The 2-year proportion for recurrent TE in patients with ATE who were taking anticoagulant therapy was 0.220 (95% CI, 0.149-0.311); the 2-year proportion for patients taking antiplatelet therapy was 0.216 (95% CI, 0.177-0.261). CONCLUSIONS: Patients with aPL and ATE may benefit from a different antithrombotic approach than patients with aPL and VTE. Prospective studies with well-defined cohorts with aPL and TE are necessary to determine optimal antithrombotic strategies.
Authors
Ortel, TL; Meleth, S; Catellier, D; Crowther, M; Erkan, D; Fortin, PR; Garcia, D; Haywood, N; Kosinski, AS; Levine, SR; Phillips, MJ; Whitehead, N
URI
https://scholars.duke.edu/individual/pub1447238
PMID
32484606
Source
pubmed
Published In
J Thromb Haemost
Published Date
DOI
10.1111/jth.14936

Methodology for the American Society of Hematology VTE guidelines: current best practice, innovations, and experiences.

BACKGROUND: Methods for the development of clinical guidelines have advanced dramatically over the past 2 decades to strive for trustworthiness, transparency, user-friendliness, and rigor. The American Society of Hematology (ASH) guidelines on venous thromboembolism (VTE) have followed these advances, together with application of methodological innovations. OBJECTIVE: In this article, we describe methods and methodological innovations as a model to inform future guideline enterprises by ASH and others to achieve guideline standards. Methodological innovations introduced in the development of the guidelines aim to address current challenges in guideline development. METHODS: We followed ASH policy for guideline development, which is based on the Guideline International Network (GIN)-McMaster Guideline Development Checklist and current best practices. Central coordination, specialist working groups, and expert panels were established for the development of 10 VTE guidelines. Methodological guidance resources were developed to guide the process across guidelines panels. A methods advisory group guided the development and implementation of methodological innovations to address emerging challenges and needs. RESULTS: The complete set of VTE guidelines will include >250 recommendations. Methodological innovations include the use of health-outcome descriptors, online voting with guideline development software, modeling of pathways for diagnostic questions, application of expert evidence, and a template manuscript for publication of ASH guidelines. These methods advance guideline development standards and have already informed other ASH guideline projects. CONCLUSIONS: The development of the ASH VTE guidelines followed rigorous methods and introduced methodological innovations during guideline development, striving for the highest possible level of trustworthiness, transparency, user-friendliness, and rigor.
Authors
Wiercioch, W; Nieuwlaat, R; Akl, EA; Kunkle, R; Alexander, KE; Cuker, A; Rajasekhar, A; Alonso-Coello, P; Anderson, DR; Bates, SM; Cushman, M; Dahm, P; Guyatt, G; Iorio, A; Lim, W; Lyman, GH; Middeldorp, S; Monagle, P; Mustafa, RA; Neumann, I; Ortel, TL; Rochwerg, B; Santesso, N; Vesely, SK; Witt, DM; Schünemann, HJ
MLA Citation
Wiercioch, Wojtek, et al. “Methodology for the American Society of Hematology VTE guidelines: current best practice, innovations, and experiences.Blood Adv, vol. 4, no. 10, May 2020, pp. 2351–65. Pubmed, doi:10.1182/bloodadvances.2020001768.
URI
https://scholars.duke.edu/individual/pub1442177
PMID
32453843
Source
pubmed
Published In
Blood Adv
Volume
4
Published Date
Start Page
2351
End Page
2365
DOI
10.1182/bloodadvances.2020001768

Initiation of Emicizumab Therapy in an Adult Patient With Hemophilia A With Inhibitors and Associated Drug Cost Savings

© The Author(s) 2020. Objective: To report the utilization of emicizumab in a patient with severe hemophilia A with inducible inhibitors and the reduction of drug costs related to decreased on-demand recombinant factor VIIa use. Case Summary: A 65-year-old African American man with established hemophilia A with an inducible factor VIII inhibitor presented with a bleeding hematoma from the right posterior thigh. The patient was historically managed on frequent administration of recombinant factor VIIa to achieve hemostasis and was started on every 2-hour dosing during this admission. Emicizumab, a new therapy for hemophilia A, became available during this admission, and the patient discontinued recombinant factor VIIa and transitioned to weekly emicizumab injections. The patient did not require any recombinant factor VIIa during the following 12 months resulting in substantial drug cost savings. Discussion: After initiation of emicizumab therapy, the patient no longer required on-demand treatment with recombinant factor VIIa for bleeds. Through this reduction in recombinant factor VIIa, there was a large decrease in inpatient drug costs and inpatient admissions for bleeding events. Conclusion: The potential reduction in drug costs and inpatient admissions should be considered when determining if emicizumab therapy is appropriate for hemophilia A patients with inhibitors. Further research is needed to confirm that continued long-term use of emicizumab remains associated with a reduction in on-demand treatment.
Authors
Root, AG; Raiff, RD; Ortel, TL; Hodulik, KL
MLA Citation
Root, A. G., et al. “Initiation of Emicizumab Therapy in an Adult Patient With Hemophilia A With Inhibitors and Associated Drug Cost Savings.” Journal of Pharmacy Technology, vol. 36, no. 3, June 2020, pp. 110–13. Scopus, doi:10.1177/8755122520906291.
URI
https://scholars.duke.edu/individual/pub1435835
Source
scopus
Published In
Journal of Pharmacy Technology
Volume
36
Published Date
Start Page
110
End Page
113
DOI
10.1177/8755122520906291

Home vs hospital treatment of low-risk venous thromboembolism: a systematic review and meta-analysis.

Increasing evidence supports the safety and effectiveness of managing low-risk deep vein thrombosis (DVT) or pulmonary embolism (PE) in outpatient settings. We performed a systematic review to assess safety and effectiveness of managing patients with DVT or PE at home compared with the hospital. Medline, Embase, and Cochrane databases were searched up to July 2019 for relevant randomized clinical trials (RCTs), and prospective cohort studies. Two investigators independently screened titles and abstracts of identified citations and extracted data from relevant full-text papers. Risk ratios (RRs) were calculated, and certainty of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation (GRADE). Seven RCTs (1922 patients) were included in meta-analyses on managing patients with DVT. Pooled estimates indicated decreased risk of PE (RR = 0.64; 95% confidence interval [CI], 0.44-0.93) and recurrent DVT (RR = 0.61; 95% CI, 0.42-0.90) for home management, both with moderate certainty of the evidence. Reductions in mortality and major bleeding were not significant, both with low certainty of the evidence. Two RCTs (445 patients) were included in meta-analyses on home management of low-risk patients with PE. Pooled estimates indicated no significant difference in all-cause mortality, recurrent PE, and major bleeding, all with low certainty of the evidence. Results of pooled estimates from 3 prospective cohort studies (234 patients) on home management of PE showed similar results. Our findings indicate that low-risk DVT patients had similar or lower risk of patient-important outcomes with home treatment compared with hospital treatment. In patients with low-risk PE, there was important uncertainty about a difference between home and hospital treatment.
Authors
Khatib, R; Ross, S; Kennedy, SA; Florez, ID; Ortel, TL; Nieuwlaat, R; Neumann, I; Witt, DM; Schulman, S; Manja, V; Beyth, R; Clark, NP; Wiercioch, W; Schünemann, HJ; Zhang, Y
MLA Citation
Khatib, Rasha, et al. “Home vs hospital treatment of low-risk venous thromboembolism: a systematic review and meta-analysis.Blood Adv, vol. 4, no. 3, Feb. 2020, pp. 500–13. Pubmed, doi:10.1182/bloodadvances.2019001223.
URI
https://scholars.duke.edu/individual/pub1431981
PMID
32040553
Source
pubmed
Published In
Blood Adv
Volume
4
Published Date
Start Page
500
End Page
513
DOI
10.1182/bloodadvances.2019001223