Tailoring the effect of antithrombin-targeting therapy in haemophilia A using in silico thrombin generation

Abstract Factor (F) VIII deficiency causes bleeding in haemophilia A patients because of the reduced formation of procoagulant enzyme thrombin, which is needed to make the blood clot. We measured the dynamics of coagulation in haemophilia A patients by measuring thrombin generation (TG). Additionall...

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Autores principales:	Romy M. W. de Laat-Kremers, Marisa Ninivaggi, Iris van Moort, Moniek de Maat, Bas de Laat
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/7b708bf173ce43118f2e527cc850cad9
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spelling	oai:doaj.org-article:7b708bf173ce43118f2e527cc850cad92021-12-02T16:06:45ZTailoring the effect of antithrombin-targeting therapy in haemophilia A using in silico thrombin generation10.1038/s41598-021-95066-82045-2322https://doaj.org/article/7b708bf173ce43118f2e527cc850cad92021-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-95066-8https://doaj.org/toc/2045-2322Abstract Factor (F) VIII deficiency causes bleeding in haemophilia A patients because of the reduced formation of procoagulant enzyme thrombin, which is needed to make the blood clot. We measured the dynamics of coagulation in haemophilia A patients by measuring thrombin generation (TG). Additionally, we quantified the procoagulant process of prothrombin conversion and anticoagulant process of thrombin inhibitor complex formation. In haemophilia A, prothrombin conversion is severely reduced, causing TG to be low. Nevertheless, the thrombin inactivation capacity of these patients is comparable to that in healthy subjects, leading to a severe imbalance between procoagulant and anticoagulant processes and a subsequent increased bleeding risk. A novel therapy in haemophilia A is the targeting of anticoagulant pathway, e.g. thrombin inhibitor antithrombin (AT), to restore the haemostatic balance. We simulated the effect of AT reduction on TG in silico. Lowering AT levels restored TG dose-dependently and an AT reduction of 90–95% led to almost normal TG in most patients . However, the variation in response to AT reduction was large between patients, indicating that this approach should be tailored to each individual patients. Ideally, TG and thrombin dynamics simulation could in the future contribute to the management of patients undergoing AT targeting therapy.Romy M. W. de Laat-KremersMarisa NinivaggiIris van MoortMoniek de MaatBas de LaatNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Romy M. W. de Laat-Kremers Marisa Ninivaggi Iris van Moort Moniek de Maat Bas de Laat Tailoring the effect of antithrombin-targeting therapy in haemophilia A using in silico thrombin generation
description	Abstract Factor (F) VIII deficiency causes bleeding in haemophilia A patients because of the reduced formation of procoagulant enzyme thrombin, which is needed to make the blood clot. We measured the dynamics of coagulation in haemophilia A patients by measuring thrombin generation (TG). Additionally, we quantified the procoagulant process of prothrombin conversion and anticoagulant process of thrombin inhibitor complex formation. In haemophilia A, prothrombin conversion is severely reduced, causing TG to be low. Nevertheless, the thrombin inactivation capacity of these patients is comparable to that in healthy subjects, leading to a severe imbalance between procoagulant and anticoagulant processes and a subsequent increased bleeding risk. A novel therapy in haemophilia A is the targeting of anticoagulant pathway, e.g. thrombin inhibitor antithrombin (AT), to restore the haemostatic balance. We simulated the effect of AT reduction on TG in silico. Lowering AT levels restored TG dose-dependently and an AT reduction of 90–95% led to almost normal TG in most patients . However, the variation in response to AT reduction was large between patients, indicating that this approach should be tailored to each individual patients. Ideally, TG and thrombin dynamics simulation could in the future contribute to the management of patients undergoing AT targeting therapy.
format	article
author	Romy M. W. de Laat-Kremers Marisa Ninivaggi Iris van Moort Moniek de Maat Bas de Laat
author_facet	Romy M. W. de Laat-Kremers Marisa Ninivaggi Iris van Moort Moniek de Maat Bas de Laat
author_sort	Romy M. W. de Laat-Kremers
title	Tailoring the effect of antithrombin-targeting therapy in haemophilia A using in silico thrombin generation
title_short	Tailoring the effect of antithrombin-targeting therapy in haemophilia A using in silico thrombin generation
title_full	Tailoring the effect of antithrombin-targeting therapy in haemophilia A using in silico thrombin generation
title_fullStr	Tailoring the effect of antithrombin-targeting therapy in haemophilia A using in silico thrombin generation
title_full_unstemmed	Tailoring the effect of antithrombin-targeting therapy in haemophilia A using in silico thrombin generation
title_sort	tailoring the effect of antithrombin-targeting therapy in haemophilia a using in silico thrombin generation
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/7b708bf173ce43118f2e527cc850cad9
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Tailoring the effect of antithrombin-targeting therapy in haemophilia A using in silico thrombin generation

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