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.
Recommendations
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
NHLBI Staff
Pan Ganguly Rebecca Link Ahmed Hasan Rita
Sarkar R. Blaine Moore
CDC Staff
Sally Crudder
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