Needed Research in Cancer-Related Thrombosis

Discussion:

The close relationship between cancer and thrombosis was recorded as early as the 1820’s by Jean Baptiste Bouillard and further developed by Armand Trousseau, who described the clinical correlation between idiopathic venous thromboembolism (VTE) and occult malignancy in 1865.1,2 Today, we know that cancer is associated with a hypercoagulable state and a four- to seven- fold increase in venous thrombosis risk.3 Epidemiologic and population-based studies have provided detailed information on the disease burden of cancer-associated thrombosis and identified VTE risk factors, including those related to the tumor and its treatment (e.g. tumor type, clinical stage, chemotherapy, use of anti-angiogenic drugs or erythropoietic growth factors, surgery, and presence of central venous catheters), and those related to individual patient characteristics (e.g. sex, race, age, previous VTE history, blood cell counts, immobilization, and obesity). As thrombosis is a significant cause of morbidity and mortality in cancer patients, it is important to identify and appropriately treat patients at higher risk, especially prior to chemotherapy or surgery.

The Working Group discussion was organized along the following major topics:

• Cancer-related thrombosis - epidemiology and current standards of care
• Advances in coagulation research and their translation to cancer
• Role of platelet, tumor, and vascular biology in cancer-related thrombosis
• Identification and validation of biomarkers for high/low thrombotic risk cancer patients
• Cancer prevention - use of anticoagulants and NSAIDs  
• Thromboprophylaxis in cancer patients

The Working Group identified the following as major unmet needs in the field of cancer-related thrombosis:

Mechanistic studies of thrombosis in cancer to investigate:

• Platelet and leukocyte contributions to VTE in cancer patients
• Role of coagulation proteins in cancer-associated thrombosis
• Cell-free DNA/circulating tumor cell contribution to thrombosis
• Role of inflammation in triggering pro-thrombotic changes
• Cancer-type specific determinants of thrombosis
• Impact of cancer therapeutics on thrombotic pathways

Identification and validation of improved, actionable biomarkers and risk factors of VTE in cancer patients based upon:

• Unbiased, “omics” approaches
• Biomarker combinations rather than individual biomarkers
• Detection of low abundance blood biomarkers
• Incorporation of findings from mechanistic studies

Prospective cohort studies and intervention trials to investigate:

• Appropriate selection of cancer patients to receive thromboprophylaxis in inpatient and outpatient settings
• Appropriate selection of anticoagulant agent in cancer patients
• Appropriate duration of thromboprophylaxis in cancer patients
• Factors that change VTE risk over time in cancer patients

The Working Group emphasized the urgency and need for collaborative efforts of the NHLBI and NCI to address the clinically significant issue of cancer-related thrombosis.

Publication Plans:

The group intends to prepare a manuscript describing its discussions in more detail for publication in a peer-reviewed journal.

NHLBI Contact:

Andrei L. Kindzelski, M.D., Ph.D
andrei.kindzelski@nih.gov

NCI Contact:

Michelle Berny-Lang, Ph.D.
michelle.berny-lang@nih.gov

Working Group Participants:

Chair:

Nigel Key, M.D., University of North Carolina at Chapel Hill

Discussion Leaders:

Andrew Chan, M.D., M.P.H., Massachusetts General Hospital
Charles Francis, M.D., University of Rochester
Alok Khorana. M.D., Cleveland Clinic
Nigel Mackman, Ph.D., University of North Carolina at Chapel Hill
Owen McCarty, Ph.D., Oregon Health & Science University
Keith McCrae, M.D., Cleveland Clinic
Joseph Palumbo, M.D., Cincinnati Children’s Hospital Medical Center
Gary Raskob, Ph.D., University of Oklahoma  Health Sciences Center
Anil Sood, M.D., University of Texas MD Anderson Cancer Center
Gilbert White II, M.D., Blood Center of Wisconsin

Participants:

Anita Aggarwal, M.D., U.S. Department of Veterans Affairs
Richard Becker, M.D., University of Cincinnati College of Medicine
Wolfgang Bergmeier, Ph.D., University of North Carolina at Chapel Hill
Lisa Faulcon, M.D., U.S. Food and Drug Administration
Brunhilde Felding, Ph.D., The Scripps Research Institute
Aime Franco, Ph.D., University of Arkansas for Medical Science
Margaret Kresge, J.D., Patient Advocate
Nicole Kuderer, M.D., University of Washington
Gary Lyman, M.D., M.P.H., Fred Hutchinson Cancer Research Center
Dalia Mobarek, M.D., U.S. Department of Veterans Affairs
Daniel Myers, D.V.M., M.P.H., University of Michigan
Stephanie Omokaro, M.D., U.S. Food and Drug Administration
David Pinsky, M.D., University of Michigan
Alvin Schmaier, M.D., Case Western Reserve University
David Tarin, M.D., Ph.D., University of California, San Diego
Denisa Wagner, Ph.D., Children's Hospital Boston
Andrew Weyrich, Ph.D., University of Utah
Richard White, M.D., University of California, Davis
Randall Worth, Ph.D., University of Toledo

NHLBI Staff:

Donna DiMichele, M.D.
Keith Hoots, M.D.
Andrei Kindzelski. M.D., Ph.D.
Rebecca Link, Ph.D.
Traci Mondoro, Ph.D.
Ronald Warren, Ph.D.

NCI Staff:

Michelle Berny-Lang, Ph.D.
Emily Greenspan, Ph.D.
Caryn Johnson
Jerry Lee, Ph.D.
Irina Lubensky, M.D.
Hala Makhlouf, M.D., Ph.D.
Larry Nagahara, Ph.D.
Nonniekaye Shelburne, C.R.N.P., M.S., A.O.C.N.
Elizabeth Woodhouse, Ph.D.

References:
¹Bouillard JB et al. De l’Obliteration des veines et de son influence sur la formation des hydropisies partielles:consideration sur la hydropisies passive et general. Archives of General Medicine 1823; 1: 188-204.

²Trousseau A. Phlegmasia alba dolens. Clinique Medicale de l’Hotel-Dieu de Paris (Paris: The Syndenham Society) 1865; 3: 654-712.

³Timp JF et al. Epidemiology of cancer-associated venous thrombosis. Blood 2013; 122: 1712-1723.