key: cord-0968839-9lrb896o authors: Cushman, Mary; Barnes, Geoffrey D.; Creager, Mark A.; Diaz, Jose A.; Henke, Peter K.; Machlus, Kellie R.; Nieman, Marvin T.; Wolberg, Alisa S. title: Venous thromboembolism research priorities: A scientific statement from the American Heart Association and the International Society on Thrombosis and Haemostasis date: 2020-07-08 journal: Res Pract Thromb Haemost DOI: 10.1002/rth2.12373 sha: 7b2e0aa0ee3e048ca794cd583aca96974a1f4697 doc_id: 968839 cord_uid: 9lrb896o Venous thromboembolism (VTE) is a major cause of morbidity and mortality. The impact of the Surgeon General’s Call to Action in 2008 has been lower than expected given the public health impact of this disease. This scientific statement highlights future research priorities in VTE, developed by experts and a crowdsourcing survey across 16 scientific organizations. At the fundamental research level (T0), researchers need to identify pathobiologic causative mechanisms for the 50% of patients with unprovoked VTE and better understand mechanisms that differentiate hemostasis from thrombosis. At the human level (T1), new methods for diagnosing, treating, and preventing VTE will allow tailoring of diagnostic and therapeutic approaches to individuals. At the patient level (T2), research efforts are required to understand how foundational evidence impacts care of patients (eg, biomarkers). New treatments, such as catheter‐based therapies, require further testing to identify which patients are most likely to experience benefit. At the practice level (T3), translating evidence into practice remains challenging. Areas of overuse and underuse will require evidence‐based tools to improve care delivery. At the community and population level (T4), public awareness campaigns need thorough impact assessment. Large population‐based cohort studies can elucidate the biologic and environmental underpinings of VTE and its complications. To achieve these goals, funding agencies and training programs must support a new generation of scientists and clinicians who work in multidisciplinary teams to solve the pressing public health problem of VTE. across 16 scientific organizations. At the fundamental research level (T0), researchers need to identify pathobiologic causative mechanisms for the 50% of patients with unprovoked VTE and better understand mechanisms that differentiate hemostasis from thrombosis. At the human level (T1), new methods for diagnosing, treating, and preventing VTE will allow tailoring of diagnostic and therapeutic approaches to individuals. At the patient level (T2), research efforts are required to understand how foundational evidence impacts care of patients (eg, biomarkers). New treatments, such as catheter-based therapies, require further testing to identify which patients are most likely to experience benefit. At the practice level (T3), translating evidence into practice remains challenging. Areas of overuse and underuse will require evidence-based tools to improve care delivery. At the community and population level (T4), public awareness campaigns need thorough impact assessment. Large population-based cohort studies can elucidate the biologic and environmental underpinings of VTE and its complications. To achieve these goals, funding agencies and training programs must support a new generation of scientists and clinicians who work in multidisciplinary teams to solve the pressing public health problem of VTE. hemostasis , postthrombotic syndrome , pulmonary embolism, thrombosis, venous thromboembolism, venous thrombosis , research priorities Essentials • The article presents future research priorities in venous thromboembolism. • It was developed by experts and a crowdsourcing survey across 16 scientific organizations. • It covers fundamental (T0), human-level (T1), patient-level (T2), practice-level (T3), and community-and population-level (T4) research. • The authors suggest that multidisciplinary team science approaches be prioritized. Venous thromboembolism (VTE) remains a major cause of morbidity and mortality, affecting up to 1 million Americans and more than 700 000 Europeans annually. 1 Composed of both deep vein thrombosis (DVT) and pulmonary embolism (PE), VTE disproportionately impacts older adults worldwide. 2 An estimated 1-in-12 people will develop VTE after age 45. 3 Thirty-day mortality is as high as 30% for patients with PE. 4 Emerging knowledge suggests that impaired quality of life is common. Up to 50% of patients with DVT will develop postthrombotic syndrome (PTS), which consists of pain, swelling, skin changes, and ulceration; 5%-10% will have severe morbidity with reduced quality of life. 5 In 2008, the US surgeon general issued a call to action to prevent DVT and PE. 6 That document highlighted the unique opportunity for multiple stakeholders to coordinate efforts aimed at (i) increasing public awareness, (ii) supporting development of evidence-based practices, and (iii) carrying out research to address gaps in knowledge. It is unclear how much progress has been made in the decade since that call to action. While some organizations champion patient, provider, and public awareness, efforts in translational and transformative research are not commensurate with the public health impact of VTE. 7 This statement outlines key research priorities to address knowledge gaps in VTE ( Table 1) . As outlined in Supplements S1 and S2, in 2018, members of 16 international organizations, including lead organizations for this project (American Heart Association, American Venous Forum, and ISTH) were invited in a crowdsourcing activity to share their priorities for VTE research through a survey. While attempts were made to include a global perspective, we did not collect participant location, and North American participation may be overrepresented. Informed by these results, invited experts presented their vision at the 2018 American Heart Association Vascular Discovery conference (San Francisco, CA), and the audience provided input. At that meeting, a writing group was formed to develop this scientific statement based on survey results. The final manuscript outlines key areas for future research across the spectrum of translational research (bench-to-bedside-to-population; Figure 1 ). As this article was going to production, the rapid realization of a new coagulopathy with marked VTE risk related to coronavirus disease 2019 has led to pressing need for basic, translational, and clinical research, including on antithrombotic treatments in these patients. Most of the time, the coagulation system remains well balanced to respond to vascular injury without clotting within the vessels (hemostasis). However, when clot formation does occur within blood vessels (thrombosis), the effects are life threatening. Mechanisms that differentiate clot formation occurring in the setting of hemostasis versus those that promote thrombosis remain poorly understood. The fact that up to half of VTE cases lack an identifiable provoking trigger highlights a critical knowledge gap regarding the mechanisms that drive pathological thrombus formation. In VTE, as in any thrombotic disease, pathological cross-talk between the vessel wall and blood components is considered a driver of thrombosis. This complex scenario is difficult to reproduce in a laboratory setting. Over the years, the scientific community has recognized the importance of both in vitro (eg, cell coculture, microfluidic, and computational models) and in vivo (eg, vena cava ligation, FeCl 3 injury) preclinical models to understand thrombosis and evaluate potential treatments. All current VTE preclinical models have pros and cons. Understanding these strengths and limitations is imperative when choosing models in the context of a given research question. Given the strength that in vivo models can simultaneously incorporate all 3 arms of Virchow's triad, animal research has become an essential tool in efforts to define pathophysiologic mechanisms in VTE and has significantly advanced understanding of cellular and biochemical mechanisms. However, live models have their limitations based on species, size, and life span. These differences can limit their application to the human experience of VTE. For example, most PE models do not replicate the human experience where a DVT embolizes from the deep veins to the lungs. Instead, they commonly rely on protein infusion locally to incite thrombosis. Developing new models that more closely mimic human pathobiology (including embolism) is a high priority given PErelated mortality and differences in DVT-and PE-specific risk factors. 10 Significant advances in diagnosing, treating, and preventing VTE depends on translating fundamental and discovery-based research findings to humans (T1 research). A high priority in diagnosis of VTE is elucidating thrombus chronicity or embolic potential with imaging that incorporates information on thrombus pathophysiology. This might improve diagnostic accuracy and influence treatment decisions. For example, a lower-extremity thrombus with imaging characteristics that suggest low embolic potential may be safely treated with shorter courses of anticoagulation, while one with higher embolic potential may warrant longer courses of anticoagulation or the placement of an inferior vena cava filter if anticoagulation is contraindicated. The emergence of direct oral anticoagulants (DOACs) has transformed VTE treatment; however, the search continues for even safer treatments. 11 Recent epidemiological studies and animal models show relationships between a number of cloting factors (eg, factors XIa, XII, and IX) and VTE suscepibility. For example, factor XIa inhibition is emerging as a promising therapeutic strategy with the potential of limited bleeding complications. 12 While various factor inhibitor agents move through the clinical trials pipeline, carefully designed studies should concurrently identify optimal treatment strategies based on patient and VTE Independent of therapy choice, identifying patients at greatest risk for recurrent VTE, who might benefit from long-term secondary TA B L E 1 Some research priorities in venous thromboembolism across the spectrum of translational research • Uncover mechanistic differences between hemostasis and thrombosis • Specify individual and interacting roles for cellular, biochemical, and biophysical (flow) functions and thrombogenesis • Explore effects of vascular wall dysfunction and blood flow on thrombus formation • Develop robust animal models of PE that mimic human disease • Understand limitations and appropriate use of specific VTE preclinical models • Distinguish mechanisms of in situ thrombosis versus embolization • Develop imaging tools for diagnosis that characterize thrombus chronicity and embolic potential • Identify new targets for anticoagulant therapies • Combine imaging findings with biomarkers (circulating factors, genomics, etc) to identify populations most likely to benefit from VTE prophylaxis or treatment • Identify the role of novel biomarkers to predict VTE recurrence risk • Explore the efficacy of VTE treatment strategies based on thrombus characteristics instead of duration Other avenues to pursue include genetic screening, which is complicated by epigenetic factors that also contribute to disease. 16 Unbiased "omics" approaches that measure circulating microRNAs has identified candidates that are associated with VTE recurrence. 17 Metabolic screening has also shown potential to identify new biomarkers that influence VTE. 18 26 Harnessing a multicenter consortium to pool standardized anatomic, therapeutic, and demographic data with long-term follow-up may further define the clinical course of VTE in children. VTE in pregnancy is a highly morbid complication. While low-molecular-weight heparin is standard of care for prophylaxis in high-risk women, major gaps remain in assessing the absolute VTE risk, selecting dose, and determining duration of prophylaxis, 27, 28 and in optimal treatment when VTE occurs in pregnant women. at extremes of weight, those with reduced absorption due to gastrointestinal surgery, those with autoimmune diseases, and those who have had venous stenting procedures. 34, 35 High-quality efficacy and safety data for DOAC use in cerebral and portal venous thrombosis is also lacking. Since it is impractical to conduct randomized trials in each of these patient groups, observational studies are needed to further assess safety and efficacy. Finally, many inherited and acquired thrombophilias can be diagnosed in patients with VTE, and some increase risk of recurrence after a first event. However, only D-dimer has been adequately studied for guiding management decisions, and little is known on the overall health impact and economics of thrombophilia testing, in both patients and their relatives. More work is needed to understand the benefits and harms of genetic and nongenetic thrombophilia testing and how best to integrate that information into management and prevention. Across a range of treatment modalities, better equipping physicians and health care systems to translate evidence into practice is needed. This includes identifying subpopulations most likely to benefit from therapies, exploring therapeutic benefits in populations not typically included in randomized trials, and understanding the impact of diagnostic testing on care at the practice and population levels for patients with VTE. Public awareness and public health efforts to address VTE prevention and treatment have a limited evidence base (T4 research). Despite VTE being a common disease, few in the public are aware of its signs, symptoms, and risk factors. 36 Campaigns such as World Thrombosis Day, initiatives from the American Heart Association, and other efforts may increase awareness, but more studies are needed to gauge improvement in public knowledge based on these programs. Analogous to research efforts in atherosclerosis, large popula- The VTE research field needs answers, and the answers cannot come from one single research tool. Collaboration among experts in each preclinical and clinical area will provide optimal insight to the field and to the patients, the ultimately beneficiary of our daily efforts. We propose multidisciplinary approaches that integrate epide- Devices permiting control of fluid mechanics may enable more controlled studies of the contribution of blood flow than is possible in mice. Studies using biologically engineered "blood vessels" with innovative designs may expose vascular responses to changes in flow, as well as interactions between blood cells and proteins with the vessel wall during DVT. 47 Similarly, integrating approaches in genomics and epidemiology with functional analysis of molecular mechanisms may define additional pathways that contribute to VTE. This kind of integrated approach may alleviate confounding "noise" in genetic analysis and provide specific and focused hypotheses to guide biological and biochemical studies in new directions. Pathways identified and characterized through these collaborations may provide robust new therapeutic targets and translate genetic discovery to practical applications in the clinic. Facilitating multidisciplinary science teams via specific funding mechanisms is a major priority for advancing in VTE research. To solve the problems outlined above, we need to bring together scientists and clinicians from disparate disciplines, including those not traditionally involved in VTE research. For example, at the intersection of rehabilitation science, epidemiology, clinical investigation, health services research, and big data sits an opportunity to explore the prevalence, impact, and potential therapies of the post-PE syndrome. While progress is being made in prevention and treatment of cancer-associated VTE, many questions across the translational spectrum remain. These include mechanistic, preventative, and therapeutic questions about this high-mortality condition. Multidisciplinary teams may employ different approaches to better understand the etiology, prevention, and treatment of cancer-associated VTE as a distinct entity from non-cancer-associated VTE. The broad adoption of electronic health records presents an opportunity to gather large quantities of data for retrospective analysis and to screen for patient enrollment in research studies. However, without improvements in quality and availability of natural language processing in electronic health records, much of the data stored is not easily searchable, presenting a major barrier to innovation. Additionally, challenges with interoperability between health systems and electronic health record platforms stifles potential largescale studies and collaborative efforts. As a leading cause of death and disability, efforts to improve the prevention, diagnosis, and management of VTE are vitally important. Across the spectrum of translational research, opportunities exist to transform the care of patients with VTE. New scientists who become invigorated to explore these high-need areas will have a tremenous impact on the population's health. It is imperative that funding agencies and training programs support the next generation of scientists who will solve many of these pressing public health problems. 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