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To clot or not: Anticoagulation without bleeding
Current drugs designed to prevent blood clots, heart attack, or stroke also increase the risk of hazardous bleeding. Toward testing whether selective block of one branch of the coagulation cascade might inhibit clotting without causing bleeding, David et al. developed an antibody that occupies and blocks the active site of a critical protein called FXIa. This antibody inhibited clotting of human blood and prevented blood vessel block in animal models but did not cause bleeding. So that the antibody can be used safely in people, the authors also developed a second antibody that can reverse the action of the first.
Abstract
Thrombosis is a major cause of morbidity and mortality. Current antithrombotic drugs are not ideal in that they must balance prevention of thrombosis against bleeding risk. Inhibition of coagulation factor XI (FXI) may offer an improvement over existing antithrombotic strategies by preventing some forms of thrombosis with lower bleeding risk. To permit exploration of this hypothesis in humans, we generated and characterized a series of human immunoglobulin Gs (IgGs) that blocked FXIa active-site function but did not bind FXI zymogen or other coagulation proteases. The most potent of these IgGs, C24 and DEF, inhibited clotting in whole human blood and prevented FeCl3-induced carotid artery occlusion in FXI-deficient mice reconstituted with human FXI and in thread-induced venous thrombosis in rabbits at clinically relevant doses. At doses substantially higher than those required for inhibition of intravascular thrombus formation in these models, DEF did not increase cuticle bleeding in rabbits or cause spontaneous bleeding in macaques over a 2-week study. Anticipating the desirability of a reversal agent, we also generated a human IgG that rapidly reversed DEF activity ex vivo in human plasma and in vivo in rabbits. Thus, an active site–directed FXIa-specific antibody can block thrombosis in animal models and, together with the reversal agent, may facilitate exploration of the roles of FXIa in human disease.
- Copyright © 2016, American Association for the Advancement of Science
