NHLBI Working Group Translational and Clinical Research in Thrombosis and Hemostasis

Executive Summary

On June 19, 2009, the National Heart, Lung and Blood Institute convened a Working Group of expert scientists and clinicians to discuss the status of translational and clinical research in thrombosis and hemostasis and identify research priorities. The group also evaluated the current SCCOR program for its ability to address the needs of the research community. Dr. Keith Hoots, Director of the Division of Blood Diseases and Resources, welcomed the participants and requested their advice and recommendations in advancing translational and clinical research.

Background:

Most Americans at some time will be afflicted by a thrombotic disease or will receive treatment to prevent thrombosis. Thrombosis is the critical event in myocardial infarction and stroke, and antithrombotic agents are widely used for preventive therapy in high risk populations. Thromboembolic stroke is a dreaded complication for the growing number of patients with atrial fibrillation. There is significant risk of venous thrombosis and pulmonary embolism associated with many orthopedic procedures, and it is a serious complication of diabetes, metabolic syndrome, sickle cell disease, hereditary diseases of the clotting system, pulmonary arterial hypertension, bone marrow disorders, and certain cancers, especially in the context of an aging population.

Maintaining hemostatic control and treatment of bleeding events is a challenge for hereditary and nonhereditary bleeding disorders such as hemophilia and platelet disorders. Acquired bleeding states represent a major complication of trauma, gastrointestinal ulcers and drugs used to treat and prevent thrombosis. Hemorrhagic stroke can be the fatal result of high blood pressure, aneurysms, arterovenous malformation or medications. Research is needed to better understand the mechanisms of thrombosis and hemorrhage, and the regulatory systems that normally maintain the balance between the two. This could also lay the groundwork for development of safer anti-thrombotic therapies and their efficacious use.

Currently available knowledge and tools to assess an individual’s risk in a particular situation, or response to hemostatic or antithrombotic therapy can lead to over-treatment of some and under-treatment of others. A better understanding of human mechanisms and improved laboratory analysis are required to enable personalized clinical management. Multi-disciplinary teams are needed to determine the impact of hemostatic and thrombotic mechanisms in the pathology of diverse disease entities and clinical conditions, develop efficient, cost effective diagnostic tools, and improve clinical options to treat and prevent thrombotic or bleeding events.

Translational and clinical research topics:

The potential topics for translational and clinical research in thrombosis and hemostasis were considered to be broad and diverse. The greatest impact on moving the field forward would be achieved by bringing together basic, translational and clinical investigators with varied expertise to address hemostatic and thrombotic problems and questions. The following areas were discussed, but it was recognized that there are many other important challenges in thrombosis and hemostasis.

  • Thrombotic disease associated with metabolic syndrome and diabetes
  • Thrombotic risk associated with pregnancy, hormonal methods of birth control and post menopausal hormone therapy
  • Identification of a biomarker(s) of in vivo platelet activation with which to assess platelet activation in human disease and evaluate the effectiveness of anti-platelet therapy
  • System biology and unbiased -omics (proteomic, genomic, lipidomic, metabolomic) approaches to understand bleeding/thrombotic set point or response to disease or therapy
  • Diagnostic tools to evaluate platelet function, understand integration of agonist-induced pathways of platelet aggregation, monitor efficacy of anti-platelet agents
  • Risk of thrombotic or bleeding events in children, improved therapies to treat or prevent thrombosis in children
  • Biomarkers or imaging methods to assess bleeding and thrombotic tendency; monitor response to therapy with current and new pharmaceuticals
  • Biochemical or imaging methods to monitor thrombosis progression and resolution; thrombosis associated with erosion or rupture of atherosclerotic plaques and understand the role of the vasculature
  • Diagnostic criteria to evaluate bleeding risk with antithrombotic therapy or thrombotic risk to surgical procedures
  • Robust animal models for arterial and venous thrombosis; biomarkers to validate and translate finding from animal model to human; interplay between patient-based and animal model studies

Training of the next generation of investigators:

Training programs are needed to ensure that there will be a next generation of hemostasis/thrombosis research investigators. These programs should include cross-training between clinical and basic research for all levels of investigators, and between scientists in different clinical disciplines. There is a critical need for experimental medicine investigators doing patient-based studies in non-malignant hematology. The training program should interact with other existing programs such as Clinical and Translational Science Awards, Career Development (K) Awards, and institutional training grants and programs. The scientific environment in a productive translational and clinical research program could be an ideal setting for inspiring and training future translational investigators.

Recommendations:

A strong integrated program is required to address the translational and clinical research needs in thrombosis and hemostasis. An effective multi-disciplinary approach cannot be accomplished with investigator initiated programs alone. Therefore a new program should be developed that would relate mechanistic studies to human physiology and pathology. Because of the scale and scope of the clinical problem and the potential impact of a translational and clinical research program, ten centers are recommended. The new expanded program should include increased interaction of participating investigators and an effective training component. Suggested program characteristics include:

  • Multi-project programs that are thematically unified addressing an important translational or clinical research topic; may be multi-institutional
  • Multi-disciplinary teams involving interaction between clinical and basic investigators and human mechanistic studies
  • A significant clinical research component for each program
  • A strong training component that encourages training at multiple levels and outreach to investigators in other disciplines
  • A structure that encourages interaction and knowledge integration within and across individual programs

Working Group Members:

Chair:

  • Kenneth Mann, Ph.D., University of Vermont

Members:

  • Joel Bennett, M.D., University of Pennsylvania
  • Lawrence Brass, M.D., Ph.D., University of Pennsylvania
  • Shaun Coughlin, M.D., Ph.D., University of California San Francisco
  • Stephen Davis, M.D., Vanderbilt University
  • Jane Freedman, M.D., Boston University
  • David Ginsburg, M.D., University of Michigan
  • Andra James, M.D., Duke University
  • Thomas McIntyre, Ph.D., Cleveland Clinic
  • Robert Montgomery, M.D., Medical College of Wisconsin
  • Diane Nugent, M.D., Children’s Hospital Orange County, CA
  • John Oates, M.D., Vanderbilt University
  • David R. Phillips, Ph.D., Portola Pharmaceuticals
  • Samuel Santoro, M.D., Vanderbilt University
  • Roy Silverstein, M.D., Cleveland Clinic

NHLBI Staff Members:

  • Keith Hoots, M.D.
  • Mary Joyce, RN, MSN, MBA
  • Andrei Kindzelski, M.D., Ph.D.
  • Rebecca Link, Ph.D.
  • Harvey Luksenburg, M.D.

NHLBI Contact:
Rebecca Link, Ph.D., DBDR, NHLBI, NIH
linkr@nhlbi.nih.gov; 301-435-0050

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