Rare Thrombotic Disorders

Speaker:
Prof Thomas Ortel
Director, Anticoagulation Management Service, Duke University School of Medicine Director,
Duke Clinical Coagulation and Platelet Immunology Laboratories

Host:
Prof Thomas Coffman
Program Director of Cardiovascular & Metabolic Disorders Research Program
Duke-NUS Graduate Medical School

Date:
Tuesday, February 14, 2012

Time:
1.00pm to 2.00pm
(Light refreshments will be served at 12.30pm)

Venue:
Amphitheatre, Level 2
Duke-NUS Graduate Medical School
8 College Road, Singapore 169857
(opposite Singapore General Hospital, Block 6/7)

Contact Person:
Ms Jacqueline Goh, Duke-NUS Research Affairs Department
Tel: 6601 2275 or Email: jacqueline.goh@duke-nus.edu.sg

Synopsis:
Rare thrombotic disorders include a variety of clinical syndromes characterized by thrombosis in unusual locations as well as recurrent thrombotic events that can be particularly aggressive in nature. Heparin-induced thrombocytopenia (HIT) and antiphospholipid syndrome (APS) are two immune-mediated thrombotic disorders clinically characterized by arterial as well as venous thromboembolism requiring careful management of antithrombotic therapy to prevent recurrent events. We have used clinical and laboratory-based research strategies to facilitate accurate diagnosis of these immune-mediated syndromes and improve our ability to distinguish patients with antibodies associated with a high-risk for thromboembolism from individuals with antibodies that do not appear to confer a pathologic risk. For patients with APS, we are also interested in the genetic risk factors associated with development of the syndrome, and whether patients with primary APS have the same hypercoagulable risk factors as patients with APS associated with other autoimmune disorders. For patients with even rarer prothrombotic disorders, such as thrombotic storm or catastrophic APS, enrolling a sufficient number of patients to study is complicated by the extreme rarity of the syndrome, difficulties with accurate ascertainment of the phenotype, and the fact that the disorder is frequently fatal. We recently formed the Thrombotic Storm study group to address these issues, and have enrolled almost two dozen patients with thrombotic storm or catastrophic APS along with targeted family members to search for novel genetic risk factors that predispose these individuals to this extreme clinical phenotype in the context of a ‘common’ triggering event (e.g., pregnancy, minor trauma). Using next-generation sequencing technologies, we have applied whole exome sequencing to a limited number of small Mendelian families in order to identify novel genetic mutations that may explain the atypical thrombotic course. Initial results have identified several potential pathogenic variants that are excellent candidates for thrombotic storm risk, and current efforts are focused on elucidating potential thrombotic mechanisms and expanding the number of patients and families studied.

Biography:
After completing a combined M.D./Ph.D. program at Indiana University in 1985, I was accepted into the Internal Medicine Residency Training Program at Duke University Medical Center. Subsequently, I pursued fellowship training in Hematology/Medical Oncology at Duke. During time, my interests in hemostasis and thrombosis grew, leading to my pursuit of a career as a hematologist with a primary clinical and research focus in hemostatic and thrombotic disorders. Currently, my primary clinical interest focuses on the diagnosis and management of patients with immune-mediated thrombotic disorders, specifically, the antiphospholipid syndrome (APS) and heparin-induced thrombocytopenia (HIT). I am also the Medical Director of the Duke Anticoagulation Management Service, which manages ~650 patients on chronic anticoagulant therapy, and the Duke Clinical Coagulation Laboratory, which provides all coagulation-based testing for Duke University Medical Center as well as referral laboratory services for specialty coagulation testing. My primary research interests are in the diagnostic evaluation of patients with hypercoagulable disorders, identification of high-risk prothrombotic states, and the effective and safe utilization of prophylactic and therapeutic antithrombotic therapy. My research program spans basic and translational laboratory activities through participation in Phase III clinical research trials. We also provide core laboratory services to investigators interested in complex coagulation testing for pharmacokinetic and pharmacodynamic testing, particularly in specific patient populations (e.g., dialysis-dependent patients with venous thromboembolism). Our Thrombosis & Hemostasis Center is one of five programs supported by the Centers for Disease Control & Prevention as part of the Thrombosis Centers Clinical & Research Network. As part of this program, we maintain a registry of all patients seen in our Center, and these individuals agree to participate in future clinical research studies. I have also participated in the development of Guidelines for the diagnosis and management of von Willebrand Disease (for the National Heart, Lung, & Blood Institute) and venous thromboembolism in patients with malignancy (for the National Comprehensive Cancer Network), and I was the co-Chairman of the Surgeon General’s Workshop on Deep Vein Thrombosis held in May 2006 which led to the Surgeon General’s Call to Action to Prevent Deep Vein Thrombosis and Pulmonary Embolism, issued in September 2008. I am also currently the Chairman of the Scientific Subcommiteee on Lupus Anticoagulants and Antiphospholipid Antibodies of the International Society on Thrombosis and Haemostasis.