Pulmonary Embolic Disease and CTEPH Research
Deep vein thrombosis (DVT) and pulmonary embolism (PE), known collectively as venous thromboembolism (VTE), affect an approximate 900,000 people in the U.S. annually, resulting in several hundred thousand hospitalizations with an estimated mortality ranging from 100,000 - 300,000 deaths per year; the mortality from VTE is greater than deaths from motor vehicle accidents, breast cancer, and HIV combined. Patients who die from acute PE are most commonly not diagnosed, or even suspected until they are already dead. The major cause of death in acute PE is RV failure. VTE also carries a substantial public health burden, due to the current necessity for life-long clinical management. Despite therapy, a complication of VTE is chronic thromboembolic pulmonary hypertension (CTEPH), for which limited medical management options exist. There are clear clinical risk factors for acute PE, such as immobilization, trauma, surgery, malignancy, and others and obviously these are risk factors for CTEPH. However, the risk factors and pathogenetic events leading to the subsequent development of CTEPH after acute PE are much less clear.
The Division of Lung Diseases (DLD), National Heart, Lung, and Blood Institute convened a workshop in July 2011 to discuss the current state-of-the art in PE and CTEPH research. Multidisciplinary experts discussed the current concepts in VTE etiology and clinical management, identified gaps in our knowledge of CTEPH pathogenesis, and prioritized emerging opportunities to advance pulmonary coagulopathic disease research. Participants evaluated several risk factor conditions associated with VTE, including obesity, COPD, and trauma, in order to identify commonalities and specificities for coagulopathic disease development in co-morbid settings. Specific discussions of acute PE research opportunities included potential novel diagnostics for detecting disease, current and emerging anticoagulation approaches to clinical management of disease, appropriate use of inferior vena cava filters (IVCF), and early surgical intervention for severe acute PE resolution. The panel discussed research in CTEPH, covering basic science knowledge and gaps, translational research, and clinical practices and studies. Pathogenesis research using advanced technology and state-of-the-art techniques was heavily discussed. Topics included: 1) better understanding the interaction between blood cellular elements and the pulmonary vasculature (such as the role for mesenchymal progenitor cells and the fibrin microenvironment in disease development and progression, impact of reduced flow shear in pulmonary vascular remodeling, and effects of platelets and leukocytes in pulmonary vascular biology and pathobiology); and 2) integration of soluble factors and signaling in the pulmonary vasculature to produce vascular remodeling (such as thrombin-mediated endothelial barrier dysfunction, structural changes in fibrinogen against genetic backgrounds, and re-activation of developmental pathways such as Notch signaling in the lung vascular wall). Group discussion of the spectrum of topics from acute PE to CTEPH and the key issues and concerns that emerged led to specific research recommendations presented in this report.
- Increase efforts to understand the relationship between genetics, clinical phenotypes, co-morbidities, and development of VTE for the purposes of determining a "personalized medicine" approach to therapy. This includes the need to predict which patients require more aggressive therapy to improve functional outcome (rather than imaging outcomes and/or mortality alone), such as with massive and sub-massive PE.
- Establish a world-wide registry for PE and CTEPH
- Foster clinical studies which address a number of unanswered diagnostic, therapeutic and prophylactic questions regarding VTE; e.g. more data are needed on the use of ancillary testing and how it should affect therapeutic aggressiveness, when to use thrombolytics, duration of anticoagulation and prophylaxis, and consideration for non-treatment in select VTE, given new anticoagulants will change the approach to VTE.
- Conduct basic and translational research to further our understanding of whether lung coagulopathic disease can occur in the lung vasculature de novo, as compared to disease known to result from antecedent systemic vascular coagulopathy. Studies are needed to address clinical significance of small or asymptomatic PE in the absence of DVT.
- Conduct basic and translational research to identify new pathogenic pathways and new therapeutic targets for developing novel therapy for CTEPH patients with poor post-operative outcome.
- Improve the data available regarding the risks and benefits of IVCF placement in the era of retrievable filter implementation.
- Encourage collaborative and consortium approaches to conducting basic and translational studies in CTEPH.
- Conduct clinical studies to identify the subgroup of PE patients who have high susceptibility for developing CTEPH.
- Identify biomarkers, molecular markers, or disease signature gene expression profiles for diagnosis of CTEPH and prediction of postoperative outcomes of CTEPH using advanced techniques of genetics/genomics and systems biology approach.
- Develop animal models of PE and CTEPH to study the disease pathogenesis and the pharmacologic/toxicological effects of new drugs
- Jason X.-J. Yuan, M.D., Ph.D., University of Illinois, Chicago
- Victor F. Tapson, M.D., Duke University
- Joe G.N. "Skip" Garcia, M.D., University of Illinois, Chicago
- Gregory Piazza, M.D., Brigham and Women’s Hospital, Boston, MA
- Michael H. Kroll, M.D.. University of Texas M.D. Anderson Cancer Center, Houston
- Aron B. Fisher, Ph.D., University of Pennsylvania
- Asrar B. Malik, Ph.D., University of Illinois, Chicago
- Timothy A. Morris, M.D., University of California, San Diego
- Patricia A. Thistlethwaite, M.D., Ph.D., University of California, San Diego
- Michael M. Madani, M.D. University of California, San Diego
- Irene Lang, M.D., Medical University of Vienna, Austria
- George Velmahos, M.D. Harvard University
- Paul D. Stein, M.D., St. Mary Mercy Hospital, Livonia, MI
- D. Mark Courtney, M.D., Northwestern University
- Donald M. Yealy M.D., University of Pittsburgh
- Jose Pablo Morales, M.D. U.S. Food and Drug Administration (FDA)
- Timothy M. Moore, M.D., Ph.D., Division of Lung Diseases
- Dorothy Gail, Ph.D., Division of Lung Diseases
- Jim Kiley, Ph.D., Division of Lung Diseases
- Marc Charette, Ph.D., Division of Cardiovascular Sciences
- Andrei Kindzelski, M.D., Ph.D, Division of Blood Diseases and Resources
Last Updated December 2011