Fitusiran reduces bleeding in factor X-deficient mice.

Autor:	Verhenne S; Université Paris-Saclay, INSERM, Hémostase Inflammation Thrombose HITh U1176, Le Kremlin-Bicêtre, France., McCluskey G; Université Paris-Saclay, INSERM, Hémostase Inflammation Thrombose HITh U1176, Le Kremlin-Bicêtre, France., Maynadié H; Université Paris-Saclay, INSERM, Hémostase Inflammation Thrombose HITh U1176, Le Kremlin-Bicêtre, France.; Centre de Référence de l'Hémophilie et des Maladies Hémorragiques Constitutionnelles rares, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, Université Paris-Saclay, Le Kremlin-Bicêtre, France., Adam F; Université Paris-Saclay, INSERM, Hémostase Inflammation Thrombose HITh U1176, Le Kremlin-Bicêtre, France., Casari C; Université Paris-Saclay, INSERM, Hémostase Inflammation Thrombose HITh U1176, Le Kremlin-Bicêtre, France., Panicot-Dubois L; Aix Marseille Université, Center for Cardiovascular and Nutrition Research, Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement 1260, INSERM U1263, Marseille, France., Crescence L; Aix Marseille Université, Center for Cardiovascular and Nutrition Research, Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement 1260, INSERM U1263, Marseille, France., Dubois C; Aix Marseille Université, Center for Cardiovascular and Nutrition Research, Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement 1260, INSERM U1263, Marseille, France., Denis CV; Université Paris-Saclay, INSERM, Hémostase Inflammation Thrombose HITh U1176, Le Kremlin-Bicêtre, France., Lenting PJ; Université Paris-Saclay, INSERM, Hémostase Inflammation Thrombose HITh U1176, Le Kremlin-Bicêtre, France., Christophe OD; Université Paris-Saclay, INSERM, Hémostase Inflammation Thrombose HITh U1176, Le Kremlin-Bicêtre, France.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2024 Jul 11; Vol. 144 (2), pp. 227-236.
DOI:	10.1182/blood.2023023404
Abstrakt:	Abstract: Factor X (FX) deficiency is a rare bleeding disorder manifesting a bleeding tendency caused by low FX activity levels. We aim to explore the use of fitusiran (an investigational small interfering RNA that silences antithrombin expression) to increase thrombin generation and the in vivo hemostatic potential under conditions of FX deficiency. We therefore developed a novel model of inducible FX deficiency, generating mice expressing <1% FX activity and antigen (f10low mice). Compared with control f10WT mice, f10low mice had sixfold and fourfold prolonged clotting times in prothrombin time and activated partial prothrombin time assays, respectively (P < .001). Thrombin generation was severely reduced, irrespective of whether tissue factor or factor XIa was used as an initiator. In vivo analysis revealed near-absent thrombus formation in a laser-induced vessel injury model. Furthermore, in 2 distinct bleeding models, f10low mice displayed an increased bleeding tendency compared with f10WT mice. In the tail-clip assay, blood loss was increased from 12 ± 16 μL to 590 ± 335 μL (P < .0001). In the saphenous vein puncture (SVP) model, the number of clots generated was reduced from 19 ± 5 clots every 30 minutes for f10WT mice to 2 ± 2 clots every 30 minutes (P < .0001) for f10low mice. In both models, bleeding was corrected upon infusion of purified FX. Treatment of f10low mice with fitusiran (2 × 10 mg/kg at 1 week interval) resulted in 17 ± 6% residual antithrombin activity and increased thrombin generation (fourfold and twofold to threefold increase in endogenous thrombin potential and thrombin peak, respectively). In the SVP model, the number of clots was increased to 8 ± 6 clots every 30 minutes (P = .0029). Altogether, we demonstrate that reduction in antithrombin levels is associated with improved hemostatic activity under conditions of FX deficiency. (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)
Databáze:	MEDLINE
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