Factor XI Inhibition to Uncouple Thrombosis From Hemostasis: JACC Review Topic of the Week

Abstract

Hemostasis and thrombosis are believed to be so intricately linked that any strategies that reduce thrombosis will have an inevitable impact on hemostasis. Consequently, bleeding is viewed as an unavoidable side effect of anticoagulant therapy. Emerging evidence suggests that factor XI is important for thrombosis but has a minor role in hemostasis. This information raises the possibility that anticoagulants that target factor XI will be safer than currently available agents. The authors provide a visual representation of the coagulation pathways that distinguishes between the steps involved in thrombosis and hemostasis to explain why factor XI inhibitors may serve as hemostasis-sparing anticoagulants. A safer class of anticoagulants would provide opportunities for treatment of a wider range of patients, including those at high risk for bleeding. Ongoing clinical studies will determine the extent to which factor XI inhibitors attenuate thrombosis without disruption of hemostasis.

Keywords: anticoagulation; factor XI; hemostasis; thrombosis.

FIGURE 1. Schematic Representation of Processes Required for Hemostasis

Hemostasis is initiated when FVII or FVIIa in blood binds to extravascular TF exposed at the site of injury (left). The FVIIa/TF complex converts FX to FXa leading to formation of sufficient thrombin to convert fibrinogen to fibrin and to form an unstable hemostatic plug. The FVIIa/TF complex also activates FIX (center), which amplifies and sustains FXa and thrombin generation. This additional thrombin strengthens the clot and maintains its stability over time. In some patients and in certain situations, conversion of FXI to FXIa is required to consolidate the hemostatic plug (right). FXI is thought to be activated by thrombin generated early in hemostasis, and contributes to sustained thrombin generation by activating FIX in addition to the FIX activated by the FVIIa/TF complex. Italics indicate cofactors. TF = tissue factor.

FIGURE 2. Schematic Representation of Processes That Contribute to Thrombosis

Tissue factor (TF) on the luminal surface of blood vessels initiates thrombin generation by forming a complex with FVII/FVIIa (left). However, thrombus growth away from the vessel wall depends on activation of FXI to amplify the process (center). In most cases, FXI is likely to be activated by thrombin, but in some situations, particularly those in which blood is exposed to artificial surfaces (right), FXIIa may be the major activator of FXI. Italics indicate cofactors. NETs = neutrophil extracellular traps; PP = polyphosphate.

FIGURE 3. Impact of Various Anticoagulants on Hemostasis Versus Thrombosis

Current anticoagulants inhibit either FXa or thrombin (IIa) (DOACs), or both (heparins), or reduce synthesis of their precursors (VKAs). This will attenuate thrombosis but also compromise hemostasis. The greater role of FXI in thrombosis relative to hemostasis provides a potential target for hemostasis-sparing anticoagulation. Cross-sectional view of vessels shown with hemostasis in red and thrombosis in purple. DOACs = direct oral anticoagulants; VKA = vitamin K antagonist.

CENTRAL ILLUSTRATION. Hemostasis and Thrombosis

Schematic representation of the key differences between hemostasis and thrombosis showing coagulation factor activation pathways and cross sections of a blood vessel. Two related but distinct processes of coagulation are represented, one characterized by clot formation to seal off a vessel wall injury (hemostasis) and the other by intraluminal clot formation resulting in obstruction of blood flow (thrombosis). Tissue factor initiates both processes but, whereas FXI plays a subsidiary role in hemostasis, in thrombosis FXI is required for thrombus growth within the vessel lumen. The predicted relative importance of the pathway components is denoted by the intensity of shading. Italics denote cofactors. NETs = neutrophil extracellular traps; PP = polyphosphate; TF = tissue factor.