Inhibition of Factor XIa as a New Approach to Anticoagulation

Abstract

Abstract-The dose-limiting issue with available anticoagulant therapies is bleeding. Is there an approach that could provide antithrombotic protection with reduced bleeding? One hypothesis is that targeting proteases upstream from the common pathway provides a reduction in thrombin sufficient to impede occlusive thrombosis yet allows enough thrombin generation to support hemostasis. The impairment of intrinsic coagulation by selective inhibition of factor XI (FXI) leaves the extrinsic and common pathways of coagulation intact, making FXI a drug target. This concept is supported by the observation that human deficiency in FXI results in a mild bleeding disorder compared with other coagulation factor deficiencies, and that elevated levels of FXI are a risk factor for thromboembolic disease. Moreover, FXI knockout mice have reduced thrombosis with little effect on hemostasis. The results from genetic models have been supported by studies using neutralizing antibodies, peptide inhibitors, and small-molecule inhibitors. These agents impede thrombosis without affecting bleeding time in a variety of experimental animals, including primates. Together, these data strongly support FXIa inhibition as a viable method to increase the ratio of benefit to risk in an antithrombotic drug. (Arterioscler Thromb Vasc Biol. 2010;30:388-392.)Key Words: intrinsic pathway Ⅲ coagulation Ⅲ factor XI Ⅲ thrombosis The Need for Improved Anticoagulant TherapyHemostasis is an adaptive process that maintains blood in a fluid state and preserves vasculature integrity. Thrombosis is a maladaptive process of vascular occlusion and remains a primary cause of cardiovascular morbidity and mortality. Antithrombotic therapy is effective for the prevention and treatment of thromboembolic disease. However, the established oral anticoagulant warfarin has numerous limitations, including lack of reversibility, a steep dose response, food and multiple drug-drug interactions, need for monitoring, and a narrow therapeutic index. The availability of newer oral anticoagulants, such as direct and selective inhibitors of factor Xa (FXa) and thrombin, has overcome many of these liabilities; however, dose-dependent bleeding continues to be observed. 1,2 An overlap of antithrombotic benefit and a disruption of hemostasis are not unexpected given that both processes involve interactions between the vessel wall, platelets, blood coagulation, and fibrinolysis. Improving the risk to benefit ratio remains a viable goal for antithrombotic drug See accompanying article on page 369discovery. This requires selecting a molecular target that defines a difference between hemostasis and thrombosis. Selecting such a target derives from the detailed study of human physiology and animal models. A good example is the inhibition of blood coagulation FXIa as a novel mechanism for preventing and treating thromboembolic diseases. Role of FXIa in Blood CoagulationBlood coagulation is the coordinated activation of plasma proteases, their cofactors, and platelets. The end product is the pr...

A role for factor XIIa–mediated factor XI activation in thrombus formation in vivo

“…High plasma fXI levels are associated with increased risks for arterial 42 and venous thrombosis 43 , and incidences of stroke 44 and deep venous thrombosis 45 are reduced in severe fXI deficiency. Inhibition of fIX activation by fXIa produces an antithrombotic effect in several species, 46 including primates, 12,21 supporting an important role for fXIa in thrombus formation in humans. Paradoxically, a link has been suggested between fXII deficiency and thrombosis dating back to the death of the first described fXII-deficient patient from a pulmonary embolism.…”

Desmolaris, a novel factor XIa anticoagulant from the salivary gland of the vampire bat (Desmodus rotundus) inhibits inflammation and thrombosis in vivo

“…This assumption is based on (1) the highest affinity for FXIa vs other coagulation factors, as calculated by SPR, ITC, and kinetics experiments; (2) the prolongation of the aPTT ex vivo without change in the PT; (3) the finding that salivary inhibitors targeting FXa (eg, tick anticoagulant peptide, antistasin, Lufaxin), 26,44 but not FIX(a) (eg, nitrophorin-2), 45 inhibit experimental thrombosis at concentrations that consistently promote bleeding; and (4) the emerging concept that FXIa plays a major role in thrombus formation in vivo but not for hemostasis. 11,46 Accordingly, interference with FXI(a) function through genetic deletion, 43,46 blockade with antibodies 9,10 or small-molecule inhibitors, 47 or by reduction of FXI synthesis with antisense oligonucleotides 48 results in inhibition of thrombosis with no bleeding phenotype. This profile, also observed here with Desmolaris, represents a novel antithrombotic strategy associated with potentially safe anticoagulation.…”

“…This profile, also observed here with Desmolaris, represents a novel antithrombotic strategy associated with potentially safe anticoagulation. 11,47 Nevertheless, Desmolaris may interfere with hemostasis at higher doses (.250 mg/kg), which is compatible with an anticoagulant targeting FXa. In fact, Desmolaris inhibits FXa-triggered paw edema in mice, an inflammatory event associated with PAR2 activation.…”

“…33 Moreover, Desmolaris differs from infestin-4, a Kazal-type inhibitor from insect midgut that inhibits FXIIa and blocks FeCl 3 -induced mesenteric or carotid thrombosis at 20 mg/kg. 50 Other promising alternatives such as antisense oligonucleotide-mediated knockdown of factor XI levels exhibits a relatively slow onset, 47,48 whereas immediate inhibition would be achieved with Desmolaris. Furthermore, plasma or FXI may overcome the anticoagulant activity of Desmolaris, in case of bleeding.…”

Characterization of Binding Mode for Human Coagulation Factor XI (FXI) Inhibitors

“…Inhibition of the cleaved light chain (FXIa) reduces the size of the clot and may lead to fewer bleeding side effects than when other coagulation factor isozymes are targeted. 6,7 In recent years, several studies of human factor XI have been reported on FXIa-specific inhibitors in order to replace the existing therapies. Previous studies have found that the basic P1group, such as benzamidine or guanidine, interacts with Asp189 in the S1 pocket of FXIa.…”