Venous Thromboembolic Disease: Opportunities to Improve Risk Prediction, Treatment, and Prevention
Venous thrombosis and pulmonary embolism (PE) (collectively venous thromboembolism [ VTE]) is an enormous health concern worldwide. There are approximately 1,000,000 VTE cases per year in both the United States and European Union, with a yearly mortality rate of about 300,000 in each.1-4
VTE risk increases with age, cancer diagnosis, pregnancy, oral contraceptive use, recovery from surgery, bed rest for medical illness (e.g., heart failure, COPD, neurologic disorders, etc.), and in individuals with hereditary thrombophilia stemming from common and uncommon gene mutations (e.g., Factor V Leiden and natural anticoagulant deficiencies, respectively).5 VTE is also a frequent and devastating complication in patients with other hematologic diseases such as sickle cell anemia, thrombotic thrombocytopenia purpura, hemolytic uremic syndrome, and paroxysmal nocturnal hemoglobinuria and autoimmune diseases such as antiphospholipid syndrome.
Enhanced VTE risk assessment and the development of advanced pharmaceutical agents with better safety profiles and routes of administration has led to improved VTE diagnosis and prevention for many patients. As a result, VTE recurrence has been reduced by as much as 98 percent.6 In addition the recent prophylactic regimens for total knee replacement have decreased the incidence of VTE down to one in every 25 operations.7
Notwithstanding the progress in VTE diagnosis and prevention, effective treatment of this disease remains an ongoing challenge. Anticoagulation has been the mainstay of VTE therapy since the 1930s when heparin was introduced. While newer pharmaceutical agents improve VTE outcomes, nearly all current therapies have the potential to cause bleeding. The development of therapeutics with novel mechanisms of action is needed to determine if thrombosis can be prevented and treated with agents that do not cause bleeding. To do so, the underlying pathophysiology of VTE needs to be better understood at genetic, protein, and cellular levels.
Improved understanding of the underlying pathophysiology would help advance assessment tools for predicting VTE risk in the unselected (i.e., low-risk) population and reduce the incidence of primary VTE. Enhanced understanding would also improve the pharmaceutical armamentarium with the development of novel drugs that are effective for prophylaxis and treatment and may reduce or eliminate the risk of bleeding. Such drugs would likely have high impact for treating VTE in patients across a wide spectrum of diseases. Understanding this balance may also provide critical insights into common arterial thrombotic disorders such as myocardial infarction and ischemic stroke, which remain significant public health concerns, and less common hemostatic disorders such as von Willebrand disease and hemophilia A, B and C.
Transforming Care for VTE: Priorities to Pursue New Approaches and Improve Outcomes
To improve upon the state of care for VTE, future research must aim to understand pathophysiologic mechanisms that lead to VTE in different patient populations as well as address unanswered questions about disease risk profiles, and the role of antithrombotics for VTE prevention in different clinical situations.
Recent efforts to evaluate biomarkers for VTE occurrence and recurrence have led to the identification of multiple potential candidates. However, no specific biomarker(s) has emerged for routine clinical use for individual VTE risk stratification or use in personalized anticoagulation strategies. The VTE field needs to focus on developing effective predictive measures that identify patients most at risk of developing the disease. This will allow for improved use of oral anticoagulant agents that provide safe, easy, and effective prophylaxis. Studies that correlate risk-assessment scores and biomarker research will be crucial to the development of more accurate risk prediction and will enhance VTE diagnosis. Areas of VTE research that warrant investigation include:
|1.1||Identifying novel candidate biomarkers through unbiased proteomic and genetic studies of blood vessels and blood components. These new biomarkers could be used for earlier prediction and diagnosis of VTE, prior to venous damage or life-threatening PE.|
|1.2||Assessing new candidate biomarkers in risk-prediction algorithms as well as evaluating of their predictive capability in high-risk VTE patient subgroups. In addition, methods for analyzing promising biomarkers should be standardized to enable their broad application in both research and clinical settings.|
|1.3||Adopting clinical studies that combine individual VTE risk-assessment scoring with the most promising biomarker candidates to improve risk prediction in the general patient population.|
Recent clinical trials show that the oral anti-factor Xa and antithrombin agents are some of the best characterized pharmaceutical agents approved for medical care. These agents have equivalent antithrombotic effects as warfarin or low-molecular-weight heparins, but reduced bleeding risk. However, additional clinical trials are needed to determine if these agents are effective and safe for preventing primary and recurrent VTE in high-risk patient populations such as children, and in patients with anti-phospholipid antibody syndrome, hereditary thrombophilias, cancer, central venous catheters, and other pathologies. Such clinical trials will help inform the development of evidence-based guidelines that are needed to improve clinical care and outcomes in these and other high-risk groups. To accomplish this, the following research areas must be addressed:
|2.1||Clinical trials focused on the efficacy and safety of new oral anticoagulants especially in situations in which primary VTE risk is high and practice guidelines are lacking. Patients with stroke or those undergoing neurosurgical procedures, elective back surgery, and other procedures have increased VTE risk; however, few guidelines are available to standardize clinical care. Studies aimed at evaluating prophylaxis (based on clinical prediction models) and optimizing clinical anticoagulation protocols in high-risk subgroups would further decrease both VTE incidence and post-surgical bleeding risk.|
|2.2||Clinical studies that identify optimal therapies for difficult-to-treat groups including children, pregnant women, and patients with liver disease and neurologic conditions. Since concerns stemming from the particularly unique hemostatic balance in these individuals, as well as unknown risks from fetal exposure, have limited the use of the newer anticoagulants in these populations, additional studies are needed in these underserved patient groups to help inform the development of future evidence-based guidelines.|
At present, about a dozen intravenous and oral agents are used to prevent VTE. All are directed to factors Xa and thrombin – major enzymes in the hemostatic cascade. The trade-off of these agents is that they all cause bleeding, limiting their use in certain situations and patient populations. Identification of novel contributors to thrombotic pathways and development of agents that target these pathways may lead to new drugs that limit thrombosis without increasing bleeding risk. Such agents would address an unmet need for antithrombotics in populations where thrombosis risk is high, but anticoagulation use is avoided due to bleeding risks. Critical near-term priorities in this area include:
|3.1||Evaluating new mechanistic targets as well as pathways in vitro and in vivo that determine their role in VTE prevention. Discovery-based research studies have begun to identify new mechanistic targets that may be clues to therapeutic molecules that could reduce thrombosis without interfering with hemostasis. Potential targets include both newly-recognized and previously-characterized plasma proteins and molecules on blood and vascular cells that contribute to VTE pathophysiology. In addition, inflammatory pathways may also increase risk of VTE. Fundamental research studies evaluating these targets and their respective pathways in vitro and in vivo will be vital to VTE prevention. Furthermore, libraries of potential targets must be screened to identify specific and selective molecules that may be advanced into clinical trials.|
|3.2||Improving in vitro and in vivo animal models of VTE are needed to advance understanding of VTE pathophysiology. Models that recapitulate the pathophysiology of VTE, including mechanisms leading to spontaneous embolism, may expose new cellular or molecular targets for specific therapeutic interventions. Improved methods for imaging venous thrombi and pulmonary emboli in small animal models would enhance discovery-based research of the early triggers of VTE. Advances in these areas would facilitate drug screens for novel potential antithrombotics, accelerate preclinical evaluation of candidate therapeutic interventions, and advance promising molecules into clinical trials.|
|3.3||Evaluating the role of pharmacogenomic data in the assessment of novel and established antithrombotic agents. An improved understanding of how genetic variants affect the use of antithrombotic agents, particularly with respect to pharmacogenomic markers that modulate potential toxicities and therapeutic efficacy of novel antithrombotic agents. This is important to both the discovery of new genetic factors that affect therapy for VTE and the clinical implementation of biomarker screening in the clinic for patients with VTE.|
- Centers for Disease Control and Prevention. Venous Thromboembolism. Retrieved October 13, 2017
- Heit JA, Spencer FA, White RH. The epidemiology of venous thromboembolism. J. Thromb Thrombolysis. 2016;41:3–14
- Cohen AT, Agnelli G, Anderson FA, et al. Venous thromboembolism (VTE) in Europe - The number of VTE events and associated morbidity and mortality. Thrombosis and Haemostasis. 2007; 98:756-764.
- Wendelboe AM, Raskob GE. Global Burden of Thrombosis: Epidemiologic Aspects. Circulation Research. 2016; 118:1340-1347
- Wolberg AS, Rosendaal FR, Weitz JI, et al. Venous Thrombosis. Nat Rev Dis Primers. 2015; 1:15006.
- Weitz JI, Lensing AWA, Prins MH, et al. Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism. N Engl J Med. 2017; 376:1211-1222.
- Büller HR, Bethune C, Bhanot S, et al. Factor XI Antisense Oligonucleotide for Prevention of Venous Thrombosis. N Engl J Med. 2015; 372:232-40