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NHLBI Working Group Report on Thrombophilia and Thrombosis

June 27, 2005

Thrombosis may precipitate heart disease, stroke, and thromboembolic disorders, which are the leading causes of death and disability. Formation of a blood clot is a complex process, and both genetic risk factors and environmental conditions are needed to precipitate disease. The National Heart, Lung, and Blood Institute convened a Working Group of scientific experts and physicians on June 27, 2005 in Bethesda, MD to identify research priorities in the diagnosis, treatment and prevention of thrombophilia and thrombosis. Pan Ganguly, Ph.D. welcomed the participants and discussed the objective and charge to the group. Sally Crudder, R.N., MPH provided an overview of the CDC program in thrombophilia. The chairman, Barry Coller, M.D., introduced the subject of the meeting and the scientific concepts from the participants. The discussion topics were classified into the following broad groups - Clinical Trials, New Observational Correlations, Basic Studies and Training Needs - and the following recommendations were made.


Deep Vein Thrombosis and Pulmonary Embolism

The annual incidence of deep vein thrombosis (DVT) is 250,000 cases. The mortality rate is about 60,000 per year, mainly from pulmonary embolism (PE). Approximately 500,000 individuals are hospitalized every year from DVT/PE and these rates have not changed in the last 20 years. One of the troubling facts is that about 50% of the DVT is "silent" and often the first symptom of the disease is a fatal PE. The overall NIH support for research on DVT continues to be small and the group clearly recognized the need for a comprehensive approach for additional support in both basic and clinical research. The following areas were recommended as being in need of further development.

Characterization of venous vasculature and expression of coagulant activity

Diagnosis of DVT/PE, Development of biomarkers - microparticles, Functional imaging - PET/CT fusion scan of labeled cells, Fibrin D-dimers

  • Natural history of DVT/PE, Correlates of thrombus resolution and clinical outcome
  • Identification of risk factors for DVT/PE
  • Duration of anticoagulation treatment
  • Core facility for specimens, data repository and analysis of risk factors and pharmacogenetics
  • Training opportunities in DVT/PE

Multi-Institute Clinical Studies

The group recognized a number of significant public health concerns in which more than one NIH Institute has overlapping interest. Additional studies on the pathogenesis and treatment options in the following areas were discussed and recommended for further consideration for implementation.

  • Women's health: Placental thrombosis, recurrent fetal loss and its prevention; Hormone replacement therapy and increased thrombotic risk (with NICHD)
  • Thrombosis in neonatal and pediatric population (with NICHD)
  • Thrombosis in the elderly population (with NIA)
  • DVT, cancer, and anticoagulation therapy (with NCI)

Basic Science Studies

The group recognized the need for new information in the following critical areas of basic sciences for future application to clinical research.

  • New tests for heparin-induced thrombocytopenia / thrombosis (HIT/T)
  • Platelets in inflammation, immunity and atherothrombosis
  • Gender and thrombosis

Recommendation for Further Development

The working group strongly felt the need for technology development on the genomic basis of thrombosis to significantly move this field forward. The objective is to develop a multiplex genotyping capability (thrombo-chip) for all known polymorphisms and mutations that predispose to thrombosis, bleeding, and inflammation. One may then search for additional SNPs in these genes. To be useful, it needs to be coupled to a phenotype database containing laboratory data and decoded patient information. An alternative approach proposed was to look at intermediate phenotypes rather than clinical phenotypes. One may perform a broader gene scan analysis and correlate with discrete laboratory measurables, for example, levels of specific coagulation factors and fibrinolytic proteins.

There was considerable discussion and enthusiasm for a genomic approach to thrombosis. However, it was clearly recognized that thrombosis is a complex disease in which environmental factors play critical roles and genotype may not be the primary mediator of the disease. Thus, the phenotype may have to include factors such as resolution of the clot, response to therapy, and development of post-thrombotic syndrome. The consensus was: (1) to further develop the idea of a genomic approach with the help of experts in genomics, biostatistics, informatics, and thrombosis in a follow up working group, and (2) to consider implementing these research ideas sequentially.

List of Members

Barry S. Coller, Chair; The Rockefeller University
Paul F. Bray; Baylor College of Medicine
Desmond Fitzgerald; University College Dublin
Charles W. Francis; University of Rochester
Brian F. Gage; Washington University
Marilyn J. Manco-Johnson; University of Colorado
Diane J. Nugent; Children's Hospital of Orange County
Thomas Ortel, Duke University
Uri Seligsohn, Chaim Sheba Medical Center
Paula B. Tracy, University of Vermont
Thomas W. Wakefield, University of
Michigan Guy A. Zimmerman, University of Utah


Pan Ganguly
Rebecca Link
Ahmed Hasan
Rita Sarkar
R. Blaine Moore

CDC Staff

Sally Crudder

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