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

Autor: de Laat-Kremers RMW; Department of Data Analysis and Artificial Intelligence, Synapse Research Institute, Pastoor Habetsstraat 50, 6217 KM, Maastricht, The Netherlands. r.delaat@thrombin.com.; Department of Functional Coagulation, Synapse Research Institute, Maastricht, The Netherlands. r.delaat@thrombin.com., Ninivaggi M; Department of Functional Coagulation, Synapse Research Institute, Maastricht, The Netherlands., van Moort I; Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands., de Maat M; Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands., de Laat B; Department of Data Analysis and Artificial Intelligence, Synapse Research Institute, Pastoor Habetsstraat 50, 6217 KM, Maastricht, The Netherlands.; Department of Functional Coagulation, Synapse Research Institute, Maastricht, The Netherlands.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2021 Jul 30; Vol. 11 (1), pp. 15572. Date of Electronic Publication: 2021 Jul 30.
DOI: 10.1038/s41598-021-95066-8
Abstrakt: 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.
(© 2021. The Author(s).)
Databáze: MEDLINE
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