Targeting factor XI to prevent thrombosis.

T he finding that humans with hereditary factor XI deficiency have relatively mild bleeding tendencies—yet are significantly protected against certain thrombotic diseases— has sparked considerable interest in factor XI/XIa as a target for novel antithrombotic treatments. In the classic waterfall description of blood coagulation, there are 2 ways to trigger the plasma clotting system: the tissue factor (or extrinsic) pathway and the contact (or intrinsic) pathway. 1 Extensive studies in knockout mice have demonstrated that the triggering of blood clotting via the tissue factor/ factor VIIa complex (TF:VIIa) is essential for normal hemo-stasis. 2 In contrast, humans and mice that completely lack the proteins that trigger the contact pathway (factor XII, prekalli-krein, or high molecular weight kininogen) exhibit no bleeding tendencies, indicating that the triggers of the classical contact/ intrinsic pathway are dispensable for normal hemostasis. Although factor XI is activated by factor XIIa in the classic waterfall description of blood clotting, in stark contrast to the phenotype with factor XII deficiency, humans with severe factor XI deficiencies do exhibit bleeding diatheses. 4 Patients with factor XI deficiency tend to have relatively mild bleeding tendencies and generally do not bleed spontaneously (other than menorrhagia). Rather, when these patients bleed, it is typically after injury or surgery, especially in tissues with a high thrombolytic potential, such as the oral cavity or urinary tract. Heterozygous humans with factor XI deficiency bleed less frequently than do homozygous patients. 4 Knockout mice lacking factor XI have no detectable deficiency in hemostasis, although bleeding has not specifically been tested in tissues with high thrombolytic capacity in these animals. 5 The very different bleeding phenotypes between severe factor XI and factor XII deficiencies in man suggested that, in normal hemostasis, factor XI must be activated by a protease other than factor XIIa. In 1991, 2 groups reported that thrombin can feed back to activate factor XI, 6,7 which could allow sustained throm-bin generation and possibly also inhibition of fibrinolysis via thrombin-activatable fibrinolysis inhibitor. 8 These reports were initially criticized on the basis that the kinetics of factor XI activation by thrombin are very slow, and that plasma contains such a high concentration of competing thrombin substrates that physiological levels of factor XI activation by thrombin were unlikely (reviewed by Löwenberg et al 5). However, subsequent studies directly demonstrated factor XI activation in plasma that was independent of factor XII. Our laboratory recently showed that polyphosphate secreted …