The vessel wall, platelets, and the coagulation system are vital to maintain hemostasis after vascular injury. However, their inappropriate activation under certain pathological conditions can result in vessel occlusion in vital organs, leading to heart attack, stroke, and DVT. According to recently published data from World Health Organization (WHO), ischemic heart disease and stroke account for the death of 14.1 million people, or 25.1% of all death around the world in 2012. Contrary to conventional assumption that cardiovascular diseases are predominantly a concern of the western society, the majority of death from heart attack and stroke actually happens in low and middle income countries (WHO, 2014).
The pathogenesis of coronary artery disease is a rather complex interaction of various components of the inflammation process and the immune system, but the direct cause of death in these patients is thrombosis after the rupture of atherosclerotic plaque. Following the breaching of the atherosclerotic plaque, tissue factor and collagen in the lipid core of the plaque and the subendothelial matrix are exposed to the flowing blood. Platelets and the coagulation cascade are subsequently activated to initiate thrombus formation, resulting in occlusion of the vessel and downstream ischemia and infarction of the heart. The main culprit in ischemic stroke is also a vessel occlusive event, either by thrombosis formed directly in atherosclerotic brain vessels or by embolization from thrombi formed elsewhere in the body (e.g. carotid artery, left atrium).
In addition to arterial thrombotic disease, DVT and the main complication of DVT, pulmonary embolism (PE), represent the major life threatening thrombosis event in the venous system. DVT is relatively common in patients with risk factors, such as major surgery, cancer, immobilization, pregnancy, oral contraceptives, etc. However, due to current limitations in patient stratification and risk identification, most DVT patients are undiagnosed and untreated until an acute PE event, at which point the available therapies are far less effective.
The main goal of acute management is to reopen the occluded artery with thrombolytics or angioplasty. Undoubtedly, the development of thrombolytic agents and angioplasty technology, especially the use of drug eluting coronary stents, has greatly expanded our armamentarium against thrombotic diseases. However, when faced with a growing and evolving patient population, the shortcomings of these therapies can significantly limit their effectiveness in certain patient groups. The main issue with thrombolytics is the bleeding risk, which is associated with a bleeding complication rate of approximately 7% for ischemic stroke patients and consequently these bleeding complications significantly increase mortality. Angioplasty is also failing a considerable number of patients. Even with placement of drug eluting stents, restenosis can follow angioplasty in 5% to 15% of patients. Perhaps the far more critical issue is the dilemma faced by physicians in balancing bleeding and thrombotic risks when instilling antiplatelet or anticoagulant therapy for the prevention of arterial or venous thrombosis. The fear of bleeding complications has greatly limited the use of antiplatelet and anticoagulant agents in certain patient populations, depriving them one of the most efficient defense in our armamentarium against cardiovascular disease. To break the bottleneck in the management of thrombosis as well as hemorrhagic disease, we need a better understanding of the mechanisms of thrombosis and hemostasis, especially the factors with different functions in thrombosis and hemostasis.
Cancer patients are known to have a higher rate of venous thromboembolism (VTE) than non-cancer patients with estimates of 4 to 5-fold increased risk for VTE development for patients with cancer versus the general population. One study found a rate of VTE of 12.6% among cancer patients versus 1.4% in non-cancer patients. Further, 18-20% of first time VTE has been found to be associated with active malignancy. Cancer patients who are diagnosed with VTE are at an increased risk of death due to all causes compared with non-VTE patients. VTE in cancer patients also has a significant impact on disease morbidity due to pain, loss of mobility, and interruption of cancer chemotherapy. The absolute incidence of VTE in cancer patients varies by study and has increased over time, in part due to improved diagnostic procedures. In addition, new cancer treatment strategies leading to improved cancer survival and a more aged population of patients with cancer have increased the rate of VTE. Risk of VTE in cancer patients is highest within the first 3 months of cancer diagnosis, decreases but is still high between 3-12 months, and returns to basal levels 10 years after cancer diagnosis.
Risk of cancer-associated thrombosis is known to vary with cancer type. Pancreatic, hematologic, brain, and ovarian cancer are known to have the highest rate of VTE. The reported incidence of VTE in pancreatic cancer patients varies from 59-102 per 1000 person years or 5.3%- 26% depending on the study. Brain cancer patients have a VTE incidence of 48-116 per 1000 person years or 1.6%-26%. VTE incidence in breast cancer patients on the other hand, who are considered low risk for VTE, varies from 5-55 per 1000 person years or 0.4%-8.1%. In general, it has been noted that more aggressive cancers have the highest rates of VTE. Timp and colleagues recently compiled data from 3 different studies which demonstrated a clear negative correlation between cancer type 1-year survival and reported incidence of VTE.