Abstract
BackgroundTissue factor (TF) pathway inhibitor (TFPI) is an anticoagulant protein that inhibits factor (F)Xa, the TF-FVIIa-FXa complex, and early forms of the prothrombinase complex. Concizumab (C) is a monoclonal antibody that blocks FXa inhibition by TFPI and reduces bleeding in hemophilia. ObjectivesTo examine how C impacts various reactions of TFPI to restore thrombin generation in hemophilia A using mathematical models. MethodsA compartment model was used to estimate plasma concentrations of free C and its complexes with TFPIα and TFPIβ. C was integrated into a flow-mediated mathematical model of coagulation, and a small injury was simulated under hemophilia A conditions. Simulations were then analyzed to determine how C’s blockade of TFPI anticoagulant activities, specifically the inhibition of FXa in plasma and on platelets, inhibition of TF:FVIIa at the subendothelium, and prior sequestration of plasma TFPIα to the endothelium via TFPIβ, altered thrombin generation. ResultsC improved simulated thrombin generation in hemophilia A by simultaneously altering all 3 mechanisms of the TFPI anticoagulant blockade examined. C sequestered ∼75% of plasma TFPIα through the formation of ternary TFPIα-C-TFPIβ-complexes. For all TF levels, reducing the TFPIα plasma concentration had the largest impact on the lag time, followed by blocking TFPIα inhibition of TF:FVIIa:FXa and subsequently by blocking TFPIα inhibition of FXa in plasma and on the platelet surface. ConclusionThe effectiveness of C is mediated through the blockade of TFPI anticoagulant activities in plasma and on multiple physiological surfaces. An important and previously unrecognized function of C was the sequestration of plasma TFPIα to the endothelium.
Published Version
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