Blood coagulation is an important part of the host defense mechanism required for repair and maintenance of the circulatory system. This complex and multifactorial process has been described to contain two parallel but distinct pathways; hemostasis and thrombosis. Hemostasis is initiated in response to trauma to the vascular system and is termed the “extrinsic or contact pathway”. Thrombosis is initiated by intravascular injury, and is described as the “intrinsic pathway”. These pathways merge to form the “common pathway” that leads to fibrin formation and/or platelet aggregation (Figure 1).
Adapted from: Schumacher et al (2010) Inhibition of Factor XIa as a New Approach to Anticoagulation. Arterioscler Thromb Vasc Biol 30:388-392.
Activation of the intrinsic pathway induces thrombi that can result in vessel occlusion causing ischemia. Furthermore, clot fragments can break off from a thrombus and travel downstream resulting in circulation blockage (embolization) in other locations. Anticoagulants used to treat or prevent thromboembolism are some of the most commonly prescribed drugs in the clinic. However, the currently available anti-thrombotics have limited discrimination between the intrinsic and extrinsic pathways, resulting in undesired impairment of normal hemostasis. These anticoagulants can cause abnormal clot formation that could lead to bleeding and delay vessel repair putting patients on anticoagulants at significant risk of serious bleeding.
Though Factor XIa appears to play a relatively minor role in hemostasis, recent epidemiological data and work with animal models suggest that Factor XIa could play a more significant role in thrombosis than in hemostasis. In one study, patients with plasma Factor XI levels in the top 10% of the normal range were nearly twice as likely to develop venous thromboembolism as everyone else in the study population (1). Later studies associated high plasma Factor XI levels with increased incidences of myocardial infarction and stroke (2,3). In contrast, Factor XI deficient individuals exhibited remarkable antithrombosis activity with an eight-fold reduction in ischemic stroke and reduction in venous thrombosis (4, 5). Importantly, these patients presented little or no bleeding liabilities in spite of their deficiency.
The science presented above supports eXIthera’s efforts to develop drugs to inhibit Factor XIa with the objective of preventing thrombosis without causing bleeding. As previously noted, new anti-thrombotic drugs have been developed to replace older blood thinning drugs such as warfarin and heparin. These products, though, are limited due to unpredictable, and difficult to manage, serious bleeding adverse events within the efficacious clotting dose range. There is still, therefore, an unmet need for an effective anticoagulant without serious bleeding side effects. eXIthera’s lead compounds are being developed to meet this need.
- Meijers JC et al. (2000) High levels of coagulation factor XI as a risk factor for venous thrombosis. N. Eng. J. Med. 342: 696-701.
- Doggen CJ et al. (2006) Levels of intrinsic coagulation factors and the risk of myocardial infarction among men: opposite and synergistic effects of factors XI and XII. Blood 108: 4045-4051.
- Yang DT et al. (2006) Elevated factor XI activity levels are associated with an increased odds ratio for cerebrovascular events. Am J. Clin. Pathol. 126: 411-415.
- Salomon O et al. (2008) Reduced incidence of ischemic stroke in patients with severe factor XI deficiency. Blood 111:4113-4117.
- Salomon O et al. (2011) Patients with severe factor XI deficiency have a reduced incidence of deep-vein thrombosis. Thromb. Haemost. 105: 269-273.