{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T12:48:45Z","timestamp":1793278125204,"version":"4.5.0"},"reference-count":28,"publisher":"American Society of Hematology","issue":"2","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2024,7,11]]},"abstract":"<jats:sec>\n                  <jats:title>Abstract<\/jats:title>\n                  <jats:p>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\u00a0vivo hemostatic potential under conditions of FX deficiency. We therefore developed a novel model of inducible FX deficiency, generating mice expressing &amp;lt;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\u00a0&amp;lt; .001). Thrombin generation was severely reduced, irrespective of whether tissue factor or factor XIa was used as an initiator. In\u00a0vivo 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\u00a0\u00b1 16 \u03bcL to 590\u00a0\u00b1 335 \u03bcL (P\u00a0&amp;lt; .0001). In the saphenous vein puncture (SVP) model, the number of clots generated was reduced from 19\u00a0\u00b1 5 clots every 30 minutes for f10WT mice to 2\u00a0\u00b1 2 clots every 30 minutes (P\u00a0&amp;lt; .0001) for f10low mice. In both models, bleeding was corrected upon infusion of purified FX. Treatment of f10low mice with fitusiran (2\u00a0\u00d7\u00a010 mg\/kg at 1 week interval) resulted in 17\u00a0\u00b1 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\u00a0\u00b1 6 clots every 30 minutes (P\u00a0= .0029). Altogether, we demonstrate that reduction in antithrombin levels is associated with improved hemostatic activity under conditions of FX deficiency.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1182\/blood.2023023404","type":"journal-article","created":{"date-parts":[[2024,4,15]],"date-time":"2024-04-15T18:12:01Z","timestamp":1713204721000},"page":"227-236","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":11,"title":["Fitusiran reduces bleeding in factor X\u2013deficient mice"],"prefix":"10.1182","volume":"144","author":[{"given":"Sebastien","family":"Verhenne","sequence":"first","affiliation":[{"name":"1Universit\u00e9 Paris-Saclay, INSERM, H\u00e9mostase Inflammation Thrombose HITh U1176, Le Kremlin-Bic\u00eatre, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Genevi\u00e8ve","family":"McCluskey","sequence":"additional","affiliation":[{"name":"1Universit\u00e9 Paris-Saclay, INSERM, H\u00e9mostase Inflammation Thrombose HITh U1176, Le Kremlin-Bic\u00eatre, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-7423-2769","authenticated-orcid":false,"given":"Hortense","family":"Maynadi\u00e9","sequence":"additional","affiliation":[{"name":"1Universit\u00e9 Paris-Saclay, INSERM, H\u00e9mostase Inflammation Thrombose HITh U1176, Le Kremlin-Bic\u00eatre, France"},{"name":"2Centre de R\u00e9f\u00e9rence de l\u2019H\u00e9mophilie et des Maladies H\u00e9morragiques Constitutionnelles rares, H\u00f4pital Bic\u00eatre, Assistance Publique\u2013H\u00f4pitaux de Paris, Universit\u00e9 Paris-Saclay, Le Kremlin-Bic\u00eatre, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6603-2687","authenticated-orcid":false,"given":"Fr\u00e9d\u00e9ric","family":"Adam","sequence":"additional","affiliation":[{"name":"1Universit\u00e9 Paris-Saclay, INSERM, H\u00e9mostase Inflammation Thrombose HITh U1176, Le Kremlin-Bic\u00eatre, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8271-6795","authenticated-orcid":false,"given":"Caterina","family":"Casari","sequence":"additional","affiliation":[{"name":"1Universit\u00e9 Paris-Saclay, INSERM, H\u00e9mostase Inflammation Thrombose HITh U1176, Le Kremlin-Bic\u00eatre, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurence","family":"Panicot-Dubois","sequence":"additional","affiliation":[{"name":"3Aix Marseille Universit\u00e9, Center for Cardiovascular and Nutrition Research, Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement 1260, INSERM U1263, Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lydie","family":"Crescence","sequence":"additional","affiliation":[{"name":"3Aix Marseille Universit\u00e9, Center for Cardiovascular and Nutrition Research, Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement 1260, INSERM U1263, Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2421-6087","authenticated-orcid":false,"given":"Christophe","family":"Dubois","sequence":"additional","affiliation":[{"name":"3Aix Marseille Universit\u00e9, Center for Cardiovascular and Nutrition Research, Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement 1260, INSERM U1263, Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5152-9156","authenticated-orcid":false,"given":"C\u00e9cile V.","family":"Denis","sequence":"additional","affiliation":[{"name":"1Universit\u00e9 Paris-Saclay, INSERM, H\u00e9mostase Inflammation Thrombose HITh U1176, Le Kremlin-Bic\u00eatre, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7937-3429","authenticated-orcid":false,"given":"Peter J.","family":"Lenting","sequence":"additional","affiliation":[{"name":"1Universit\u00e9 Paris-Saclay, INSERM, H\u00e9mostase Inflammation Thrombose HITh U1176, Le Kremlin-Bic\u00eatre, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9080-6336","authenticated-orcid":false,"given":"Olivier D.","family":"Christophe","sequence":"additional","affiliation":[{"name":"1Universit\u00e9 Paris-Saclay, INSERM, H\u00e9mostase Inflammation Thrombose HITh U1176, Le Kremlin-Bic\u00eatre, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","reference":[{"issue":"1","key":"2024071115205941000_bib1","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1152\/physrev.00016.2011","article-title":"New fundamentals in hemostasis","volume":"93","author":"Versteeg","year":"2013","journal-title":"Physiol Rev"},{"issue":"2","key":"2024071115205941000_bib2","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1054\/blre.2002.0191","article-title":"Factor X deficiency","volume":"16","author":"Uprichard","year":"2002","journal-title":"Blood Rev"},{"issue":"4","key":"2024071115205941000_bib3","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1055\/s-0029-1225763","article-title":"Factor X deficiency","volume":"35","author":"Menegatti","year":"2009","journal-title":"Semin Thromb Hemost"},{"issue":"4","key":"2024071115205941000_bib4","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1111\/j.1538-7836.2012.04653.x","article-title":"Coagulation factor activity and clinical bleeding severity in rare bleeding disorders: results from the European Network of Rare Bleeding Disorders","volume":"10","author":"Peyvandi","year":"2012","journal-title":"J\u00a0Thromb Haemost"},{"issue":"2","key":"2024071115205941000_bib5","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1046\/j.1365-2141.1998.00806.x","article-title":"Congenital factor X deficiency: spectrum of bleeding symptoms in 32 Iranian patients","volume":"102","author":"Peyvandi","year":"1998","journal-title":"Br J Haematol"},{"issue":"6","key":"2024071115205941000_bib6","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1111\/j.1365-2516.2008.01856.x","article-title":"Diagnosis and treatment of inherited factor X deficiency","volume":"14","author":"Brown","year":"2008","journal-title":"Haemophilia"},{"issue":"4","key":"2024071115205941000_bib7","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1111\/hae.14570","article-title":"A\u00a0review of the pharmacokinetics, efficacy and safety of high-purity factor X for the prophylactic treatment of hereditary factor X deficiency","volume":"28","author":"Payne","year":"2022","journal-title":"Haemophilia"},{"issue":"9","key":"2024071115205941000_bib8","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1056\/NEJMoa1616569","article-title":"Targeting of antithrombin in hemophilia A or B with RNAi therapy","volume":"377","author":"Pasi","year":"2017","journal-title":"N\u00a0Engl J Med"},{"issue":"5","key":"2024071115205941000_bib9","doi-asserted-by":"crossref","first-page":"e322","DOI":"10.1016\/S2352-3026(23)00037-6","article-title":"Fitusiran prophylaxis in people with severe hemophilia A or hemophilia B without inhibitors (ATLAS-A\/B): a multicenter, open-label, randomized, phase 3 trial","volume":"10","author":"Srivastava","year":"2023","journal-title":"Lancet Haematol"},{"issue":"10386","key":"2024071115205941000_bib10","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.1016\/S0140-6736(23)00284-2","article-title":"Efficacy and safety of fitusiran prophylaxis in people with hemophilia A or hemophilia B with inhibitors (ATLAS-INH): a multicenter, open-label, randomized phase 3 trial","volume":"401","author":"Young","year":"2023","journal-title":"Lancet"},{"issue":"4","key":"2024071115205941000_bib11","doi-asserted-by":"crossref","first-page":"100179","DOI":"10.1016\/j.rpth.2023.100179","article-title":"Antithrombin lowering in hemophilia: a closer look at fitusiran","volume":"7","author":"Young","year":"2023","journal-title":"Res Pract Thromb Haemost"},{"issue":"22","key":"2024071115205941000_bib12","doi-asserted-by":"crossref","first-page":"2256","DOI":"10.1182\/blood.2023021864","article-title":"Fitusiran prophylaxis in people with hemophilia A or B who switched from prior BPA\/CFC prophylaxis (ATLAS-PPX)","volume":"143","author":"Kenet","year":"2024","journal-title":"Blood"},{"issue":"3","key":"2024071115205941000_bib13","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1172\/JCI1240","article-title":"Inducible inactivation of hepatic LRP gene by cre-mediated recombination confirms role of LRP in clearance of chylomicron remnants","volume":"101","author":"Rohlmann","year":"1998","journal-title":"J\u00a0Clin Invest"},{"issue":"39","key":"2024071115205941000_bib14","doi-asserted-by":"crossref","first-page":"eaaw8405","DOI":"10.1126\/sciimmunol.aaw8405","article-title":"Myeloid cell-synthesized coagulation factor X dampens antitumor immunity","volume":"4","author":"Graf","year":"2019","journal-title":"Sci Immunol"},{"issue":"5","key":"2024071115205941000_bib15","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1038\/nm.3847","article-title":"An RNAi therapeutic targeting antithrombin to rebalance the coagulation system and promote hemostasis in hemophilia","volume":"21","author":"Sehgal","year":"2015","journal-title":"Nat Med"},{"issue":"5-6","key":"2024071115205941000_bib16","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1159\/000073575","article-title":"The calibrated automated thrombogram (CAT): a universal routine test for hyper- and hypocoagulability","volume":"32","author":"Hemker","year":"2002","journal-title":"Pathophysiol Haemost Thromb"},{"issue":"4","key":"2024071115205941000_bib17","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1172\/JCI30537","article-title":"Thrombin-initiated platelet activation in\u00a0vivo is vWF independent during thrombus formation in a laser injury model","volume":"117","author":"Dubois","year":"2007","journal-title":"J\u00a0Clin Invest"},{"issue":"11","key":"2024071115205941000_bib18","doi-asserted-by":"crossref","first-page":"1193","DOI":"10.1182\/blood-2018-01-829523","article-title":"A\u00a0factor VIII-nanobody fusion protein forming an ultrastable complex with VWF: effect on clearance and antibody formation","volume":"132","author":"Muczynski","year":"2018","journal-title":"Blood"},{"issue":"5","key":"2024071115205941000_bib19","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1111\/j.1365-2516.2012.02780.x","article-title":"A\u00a0sensitive venous bleeding model in hemophilia A mice: effects of two recombinant FVIII products (N8 and Advate((R)))","volume":"18","author":"Pastoft","year":"2012","journal-title":"Haemophilia"},{"issue":"2","key":"2024071115205941000_bib20","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1055\/s-0037-1613783","article-title":"Blood coagulation factor X deficiency causes partial embryonic lethality and fatal neonatal bleeding in mice","volume":"83","author":"Dewerchin","year":"2000","journal-title":"Thromb Haemost"},{"issue":"2","key":"2024071115205941000_bib21","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1111\/j.1538-7836.2008.02849.x","article-title":"A\u00a0viable mouse model of factor X deficiency provides evidence for maternal transfer of factor X","volume":"6","author":"Tai","year":"2008","journal-title":"J\u00a0Thromb Haemost"},{"issue":"1","key":"2024071115205941000_bib22","doi-asserted-by":"crossref","first-page":"2005","DOI":"10.1038\/s41598-020-59058-4","article-title":"Production and control of coagulation proteins for factor X activation in human endothelial cells and fibroblasts","volume":"10","author":"Cohen","year":"2020","journal-title":"Sci Rep"},{"issue":"5229","key":"2024071115205941000_bib23","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.1126\/science.7660125","article-title":"Inducible gene targeting in mice","volume":"269","author":"Kuhn","year":"1995","journal-title":"Science"},{"issue":"1","key":"2024071115205941000_bib24","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1182\/blood.V100.1.153","article-title":"Circulating and binding characteristics of wild-type factor IX and certain Gla domain mutants in\u00a0vivo","volume":"100","author":"Gui","year":"2002","journal-title":"Blood"},{"issue":"5","key":"2024071115205941000_bib25","doi-asserted-by":"crossref","first-page":"e0285735","DOI":"10.1371\/journal.pone.0285735","article-title":"Presence and activity of fibrinogen like protein 2 in platelets","volume":"18","author":"Cherny","year":"2023","journal-title":"PLoS One"},{"issue":"1","key":"2024071115205941000_bib26","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1007\/s10067-012-2089-y","article-title":"Increased circulating fibrinogen-like protein 2 in patients with systemic sclerosis","volume":"32","author":"Yanaba","year":"2013","journal-title":"Clin Rheumatol"},{"issue":"1","key":"2024071115205941000_bib27","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1111\/jth.14648","article-title":"Recommendations for clinical laboratory testing for antithrombin deficiency; communication from the SSC of the ISTH","volume":"18","author":"Van Cott","year":"2020","journal-title":"J\u00a0Thromb Haemost"},{"issue":"6","key":"2024071115205941000_bib28","doi-asserted-by":"crossref","first-page":"1436","DOI":"10.1111\/jth.15270","article-title":"Targeting of antithrombin in hemophilia A or B with investigational siRNA therapeutic fitusiran-results of the phase 1 inhibitor cohort","volume":"19","author":"Pasi","year":"2021","journal-title":"J\u00a0Thromb Haemost"}],"container-title":["Blood"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/144\/2\/227\/2234068\/blood_bld-2023-023404-main.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/144\/2\/227\/2234068\/blood_bld-2023-023404-main.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,11]],"date-time":"2024-07-11T15:46:26Z","timestamp":1720712786000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/blood\/article\/144\/2\/227\/515750\/Fitusiran-reduces-bleeding-in-factor-X-deficient"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,11]]},"references-count":28,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2024,7,11]]}},"URL":"https:\/\/doi.org\/10.1182\/blood.2023023404","relation":{},"ISSN":["0006-4971","1528-0020"],"issn-type":[{"value":"0006-4971","type":"print"},{"value":"1528-0020","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,11]]}}}