Inhibition of Factor XI: A New Era in the Treatment of Venous Thromboembolism in Cancer Patients?

Abstract

Direct oral anticoagulants against activated factor X and thrombin were the last milestone in thrombosis treatment. Step by step, they replaced antivitamin K and heparins in most of their therapeutic indications. As effective as the previous anticoagulant, the decreased but persistent risk of bleeding while using direct oral anticoagulants has created space for new therapeutics aiming to provide the same efficacy with better safety. On this basis, drug targeting factor XI emerged as an option. In particular, cancer patients might be one of the populations that will most benefit from this technical advance. In this review, after a brief presentation of the different factor IX inhibitors, we explore the potential benefit of this new treatment for cancer patients.

Keywords: FXI inhibitors; cancer-associated thrombosis; catheter-related thrombosis; venous thromboembolism.

Figure 1

Factor XIa in the coagulation cascade. The coagulation cascade is represented as a pyramid where the closer you get to fibrin the higher is the risk of coagulation. In physiological state FXIa does not play a major role in the balance between bleeding and thrombosis. However, in cancer associated thrombosis several conditions activate FXI such as the cancer itself, surgery, catheter and inflammation. Black arrows represent the traditional pathway of coagulation. The red arrows represent the different pathway of activation of thrombosis in cancer associated thrombosis. Indeed, epidemiological data in patients with constitutional FXI deficiencies and experimental data in animals have strongly supported this hypothesis, with few prothrombotic events and almost no increased risk of bleeding in the central nervous system or gastrointestinal tract [12]. Phase II trials seem to confirm the interest in this strategy [13]. Parallel data on the pathophysiology of thrombotic events during cancer appear to support a prominent role of the contact path way via FXI in thrombus formation. Thus, the advent of FXI inhibitors, which have the potential to attenuate the response to prothrombotic stimuli with little or no disruption of hemostasis, could provide a safer anticoagulant [10]; see Figure 2.

Figure 2

FXI inhibitors and other anticoagulants. The coagulation cascade is represented as a pyramid where the closer you get to fibrin the higher is the risk of coagulation. Therefore regarding anticoagulant the inhibition of thrombin is at a higher risk than the inhibition of FXIa. VKA stands for vitamin K antagonist. Black arrows represent the traditional pathway of coagulation.

Figure 3

Randomized controlled trials for thromboprophylaxis treatment and secondary prevention in cancer-associated thrombosis.