Examining downstream effects of concizumab in hemophilia A with a mathematical modeling approach.

Autor:	Miyazawa K; Quantitative Biosciences and Engineering Program, Colorado School of Mines, Golden, Colorado, USA., Mast AE; Thrombosis and Hemostasis Program, Versiti Blood Research Institute, Milwaukee, Wisconsin, USA., Wufsus AR; Rare Disease, Novo Nordisk, Inc., Plainsboro, NJ, USA., Dockal M; Rare Blood Disorders, Novo Nordisk A/S, Novo Nordisk Park, Maaloev, Denmark., Kjalke M; Rare Blood Disorders, Novo Nordisk A/S, Novo Nordisk Park, Maaloev, Denmark., Leiderman K; Department of Mathematics, University of North Carolina at Chapel Hill, Chapel Hill, NC; Computational Medicine Program, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. Electronic address: karin.leiderman@unc.edu.
Jazyk:	angličtina
Zdroj:	Journal of thrombosis and haemostasis : JTH [J Thromb Haemost] 2024 Nov 12. Date of Electronic Publication: 2024 Nov 12.
DOI:	10.1016/j.jtha.2024.10.028
Abstrakt:	Background: Tissue 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 is a monoclonal antibody that blocks FXa inhibition by TFPI and reduces bleeding in hemophilia. Objectives: To examine how concizumab impacts various reactions of TFPI to restore thrombin generation in hemophilia A using mathematical models. Methods: A compartment model was used to estimate plasma concentrations of free concizumab and its complexes with TFPIα and TFPIβ. Concizumab 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 concizumab'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. Results: Concizumab improved simulated thrombin generation in hemophilia A by simultaneously altering all 3 mechanisms of the TFPI anticoagulant blockade examined. Concizumab sequestered ∼75% of plasma TFPIα through the formation of ternary TFPIα-concizumab-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. Conclusion: The effectiveness of concizumab is mediated through the blockade of TFPI anticoagulant activities in plasma and on multiple physiological surfaces. An important and previously unrecognized function of concizumab was the sequestration of plasma TFPIα to the endothelium. Competing Interests: Declaration of competing interests A.E.M. receives research funding from Novo Nordisk and Pharmacosmos and has received honoraria for serving on Novo Nordisk Advisory Boards. A.R.W., M.D., and M.K. are employees of Novo Nordisk. M.K. is a minor shareholder of Novo Nordisk. K.M. and K.L. received research funding from Novo Nordisk. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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