American Society of Hematology

Preventing Venous Thromboembolic Disease: Defining Biomarkers for Prediction and Diagnosis of Recurrence

Over the last several decades, considerable progress has been made in the field of venous thromboembolic disease (VTE); perhaps the most significant advance is the prevention of VTE recurrence, which can now be reduced by as much as 80 percent.1 Current prophylactic standard-of-care regimens prevent fatal PE that would otherwise occur in at least one of every 200 major operations.2

These improvements have been made possible by enhanced VTE risk assessment, improved diagnosis, and advanced pharmaceutical agents with better safety profiles and routes of administration. Yet despite these advances, VTE remains an enormous health concern worldwide. In the United States alone, the incidence of VTE is estimated at greater than 900,000 cases per year, with annual mortality between 100,000 and 200,000.3 In particular, the rate of unprovoked VTE in the unselected (i.e., low-risk) population has remained unchanged for the last four decades. In the United States, unprovoked VTE accounts for at least 80,000 to 160,000 cases per year, or up to approximately 18 percent of all VTE cases.2

Anticoagulation has been the mainstay of VTE therapy since the 1930s when heparin was first used for this purpose. While newer pharmaceutical agents have helped improve VTE outcomes, nearly all current therapies have the potential to cause bleeding because they inhibit thrombin generation. Thus, the development of therapeutics with novel mechanisms of action is greatly needed. However, the underlying pathophysiology of VTE remains poorly understood (especially the early molecular events), with murine models having been established only within the last several years.

Consequently, an improved understanding of the underlying pathophysiology would help advance the pharmaceutical armamentarium beyond anticoagulation, with the development of multifaceted approaches to prophylaxis and treatment that may reduce or eliminate the risk of bleeding. Not only will this further advance the field, but it will also provide critical insights into hemostatic disorders such as hemophilia and von Willebrand Disease, as well as arterial thrombotic disorders such as ischemic stroke and myocardial infarction, which remain significant public health concerns.

Transforming Care for VTE: Priorities to Pursue New Approaches and Improve Outcomes
To improve upon the state of care for VTE, future research must address unanswered questions about the risk profile of this disease and the accuracy in predicting occurrence and recurrence.


Recent efforts to evaluate biomarkers for VTE occurrence and recurrence have led to the identification of multiple potential candidates, including P-selectin, E-selectin, D-dimer, various microparticles, various inflammatory cytokines, fibrin monomers, free DNA/nucleosomes/histones, coagulation Factor VIII, and thrombin generation time. However, no specific biomarker has yet emerged for routine clinical use for individual VTE risk stratification and personal targeted therapeutics.

1.1Plasma, platelet, and microparticle proteomic studies are needed to identify novel candidate biomarkers distinct from the “conventional” biomarkers. Recently, unbiased proteomic studies have identified several candidates (e.g., ApoAI) that would have otherwise been unlikely for consideration. These biomarkers could be used as predictive tools and may allow earlier diagnosis of VTE, prior to venous damage or life-threatening thrombosis.
1.2Improved animal models will advance the study of VTE pathophysiology, allowing for more accurate evaluation of emerging biomarkers and initial assessments of potential advanced therapeutic interventions.
1.3Prioritizing the identification of novel VTE biomarkers will lead to an improved understanding of the molecular mechanisms underlying VTE, which will shepherd the development of novel mechanisms of therapy beyond anticoagulation.

The VTE field is approaching a new era of therapy in which predictive measures at the primary care level will identify those patients most at risk for VTE, and improved oral anticoagulant agents will allow for safe, easy, and effective prophylaxis. Studies that correlate risk-assessment scores and biomarker research findings will provide more accurate risk prediction and diagnostic value.

2.1Clinical trials targeting prophylaxis to high-risk subgroups based on clinical prediction models are a major priority in this area. It will be critical to accelerate risk-scoring systems that are beginning to incorporate biomarker candidates into the algorithm and/or collecting data for their future use.
2.2Once biomarker candidates are validated in high-risk VTE patient subgroups, further clinical studies will be necessary to combine clinical individual VTE risk-assessment scoring with the most promising biomarker candidates to improve risk prediction in the general patient population.
2.3With the identification of predictive biomarkers for VTE occurrence or existing sub-clinical VTE, efforts will be necessary to develop point-of-care or in-home biomarker testing devices to improve risk-assessment scoring and identification, so that patients could then be treated before progression.

References

  1. Ridker et al. Long-Term, Low-Intensity Warfarin Therapy for the Prevention of Recurrent Venous Thromboembolism. N Engl J Med 2003; 348:1425-1434.
  2. Anderson F, Audet A-M. Best Practices. Preventing Deep Vein Thrombosis and Pulmonary Embolism. University of Massachusetts Medical School, Center for Outcomes Research.
  3. White R. The epidemiology of Venous Thromboembolism. Circulation. 2003;107:1-4-1-8.
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