{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T18:13:43Z","timestamp":1778523223586,"version":"3.51.4"},"reference-count":39,"publisher":"Springer Science and Business Media LLC","issue":"4","license":[{"start":{"date-parts":[[2025,5,24]],"date-time":"2025-05-24T00:00:00Z","timestamp":1748044800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"},{"start":{"date-parts":[[2025,5,24]],"date-time":"2025-05-24T00:00:00Z","timestamp":1748044800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Gene Ther"],"published-print":{"date-parts":[[2025,7]]},"DOI":"10.1038\/s41434-025-00541-w","type":"journal-article","created":{"date-parts":[[2025,5,24]],"date-time":"2025-05-24T05:58:58Z","timestamp":1748066338000},"page":"398-409","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["RNAi targeting heparin cofactor II promotes hemostasis in a canine model of acquired hemophilia A"],"prefix":"10.1038","volume":"32","author":[{"given":"Yuyang","family":"Zhang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tingting","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haiming","family":"Kou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huafang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2815-4568","authenticated-orcid":false,"given":"Yu","family":"Hu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3253-0220","authenticated-orcid":false,"given":"Liang V.","family":"Tang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,5,24]]},"reference":[{"key":"541_CR1","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1016\/S0140-6736(15)01123-X","volume":"388","author":"F Peyvandi","year":"2016","unstructured":"Peyvandi F, Garagiola I, Young G. The past and future of haemophilia: diagnosis, treatments, and its complications. Lancet. 2016;388:187\u201397.","journal-title":"Lancet"},{"key":"541_CR2","doi-asserted-by":"publisher","first-page":"1702","DOI":"10.3324\/haematol.2019.221093","volume":"104","author":"G Castaman","year":"2019","unstructured":"Castaman G, Matino D. Hemophilia A and B: molecular and clinical similarities and differences. Haematologica. 2019;104:1702\u20139.","journal-title":"Haematologica"},{"key":"541_CR3","doi-asserted-by":"publisher","first-page":"e51","DOI":"10.1111\/hae.14217","volume":"27","author":"X Song","year":"2021","unstructured":"Song X, Zhong J, Xue F, Chen L, Li H, Yuan D, et al. An overview of patients with haemophilia A in China: epidemiology, disease severity and treatment strategies. Haemophilia. 2021;27:e51\u2013e59.","journal-title":"Haemophilia"},{"key":"541_CR4","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1111\/hae.14553","volume":"28","author":"C Escuriola Ettingshausen","year":"2022","unstructured":"Escuriola Ettingshausen C, Yang R, Wu W, Meeks SL. Inhibitors: diagnostic challenges, unknowns of inhibitor development, treatment of bleeding and surgery, and insights into diagnosis and treatment in China. Haemophilia. 2022;28:111\u2013118.","journal-title":"Haemophilia"},{"key":"541_CR5","doi-asserted-by":"publisher","first-page":"1335","DOI":"10.1182\/blood-2011-08-369132","volume":"119","author":"CR Hay","year":"2012","unstructured":"Hay CR, DiMichele DM. International Immune Tolerance Study. The principal results of the International Immune Tolerance Study: a randomized dose comparison. Blood. 2012;119:1335\u201344.","journal-title":"Blood"},{"key":"541_CR6","doi-asserted-by":"publisher","first-page":"2629","DOI":"10.1016\/j.jtha.2024.05.026","volume":"22","author":"SM Rezende","year":"2024","unstructured":"Rezende SM, Neumann I, Angchaisuksiri P, Awodu O, Boban A, Cuker A, et al. International Society on Thrombosis and Haemostasis clinical practice guideline for treatment of congenital hemophilia A and B based on the Grading of Recommendations Assessment, Development, and Evaluation methodology. J Thromb Haemost. 2024;22:2629\u201352.","journal-title":"J Thromb Haemost"},{"key":"541_CR7","doi-asserted-by":"publisher","first-page":"1443","DOI":"10.1161\/CIRCRESAHA.115.307015","volume":"118","author":"LL Swystun","year":"2016","unstructured":"Swystun LL, Lillicrap D. Gene therapy for coagulation disorders. Circ Res. 2016;118:1443\u201352.","journal-title":"Circ Res"},{"key":"541_CR8","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1111\/hae.14080","volume":"27","author":"UM Reiss","year":"2021","unstructured":"Reiss UM, Zhang L, Ohmori T. Hemophilia gene therapy-new country initiatives. Haemophilia. 2021;27:132\u2013141.","journal-title":"Haemophilia"},{"key":"541_CR9","doi-asserted-by":"publisher","first-page":"5957","DOI":"10.1182\/bloodadvances.2024014111","volume":"8","author":"SR Deshpande","year":"2024","unstructured":"Deshpande SR, Joseph K, Tong J, Chen Y, Pishko A, Cuker A. Adeno-associated virus-based gene therapy for hemophilia A and B: a systematic review and meta-analysis. Blood Adv. 2024;8:5957\u201374.","journal-title":"Blood Adv"},{"key":"541_CR10","doi-asserted-by":"publisher","first-page":"1148","DOI":"10.1161\/ATVBAHA.120.312919","volume":"40","author":"K Yada","year":"2020","unstructured":"Yada K, Nogami K. Novel insights and new developments regarding coagulation revealed by studies of the anti-factor IXa (Activated Factor IX)\/Factor X bispecific antibody, emicizumab. Arterioscler Thromb Vasc Biol. 2020;40:1148\u201354.","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"541_CR11","doi-asserted-by":"publisher","first-page":"959","DOI":"10.1111\/hae.15062","volume":"30","author":"Y Xu","year":"2024","unstructured":"Xu Y, Wang Y, Wu R, Zheng C, Zhang L, Xu W, et al. Reduced doses of emicizumab achieve good efficacy: results from a national-wide multicentre real-world study in China. Haemophilia. 2024;30:959\u201369.","journal-title":"Haemophilia"},{"key":"541_CR12","doi-asserted-by":"publisher","first-page":"1427","DOI":"10.1016\/S0140-6736(23)00284-2","volume":"401","author":"G Young","year":"2023","unstructured":"Young G, Srivastava A, Kavakli K, Ross C, Sathar J, You CW, et al. Efficacy and safety of fitusiran prophylaxis in people with haemophilia A or haemophilia B with inhibitors (ATLAS-INH): a multicentre, open-label, randomised phase 3 trial. Lancet. 2023;401:1427\u201337.","journal-title":"Lancet"},{"key":"541_CR13","doi-asserted-by":"publisher","DOI":"10.1016\/j.rpth.2023.100179","volume":"7","author":"G Young","year":"2023","unstructured":"Young G, Lenting PJ, Croteau SE, Nolan B, Srivastava A. Antithrombin lowering in hemophilia: a closer look at fitusiran. Res Pr Thromb Haemost. 2023;7:100179.","journal-title":"Res Pr Thromb Haemost"},{"key":"541_CR14","doi-asserted-by":"publisher","first-page":"1360","DOI":"10.1182\/blood-2017-09-800326","volume":"131","author":"R Prince","year":"2018","unstructured":"Prince R, Bologna L, Manetti M, Melchiorre D, Rosa I, Dewarrat N, et al. Targeting anticoagulant protein S to improve hemostasis in hemophilia. Blood. 2018;131:1360\u201371.","journal-title":"Blood"},{"key":"541_CR15","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1182\/blood-2016-05-718635","volume":"129","author":"SG Polderdijk","year":"2017","unstructured":"Polderdijk SG, Adams TE, Ivanciu L, Camire RM, Baglin TP, Huntington JA. Design and characterization of an APC-specific serpin for the treatment of hemophilia. Blood. 2017;129:105\u201313.","journal-title":"Blood"},{"key":"541_CR16","doi-asserted-by":"publisher","first-page":"6777","DOI":"10.1021\/bi00345a008","volume":"24","author":"MJ Griffith","year":"1985","unstructured":"Griffith MJ, Noyes CM, Tyndall JA, Church FC. Structural evidence for leucine at the reactive site of heparin cofactor II. Biochemistry. 1985;24:6777\u201382.","journal-title":"Biochemistry"},{"key":"541_CR17","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1016\/S0140-6736(85)92736-9","volume":"2","author":"TH Tran","year":"1985","unstructured":"Tran TH, Marbet GA, Duckert F. Association of hereditary heparin co-factor II deficiency with thrombosis. Lancet. 1985;2:413\u20134.","journal-title":"Lancet"},{"key":"541_CR18","doi-asserted-by":"publisher","first-page":"414","DOI":"10.1016\/S0140-6736(85)92737-0","volume":"2","author":"P Sie","year":"1985","unstructured":"Sie P, Dupouy D, Pichon J, Boneu B. Constitutional heparin co-factor II deficiency associated with recurrent thrombosis. Lancet. 1985;2:414\u20136.","journal-title":"Lancet"},{"key":"541_CR19","first-page":"109","volume":"48","author":"S Lopaciuk","year":"1996","unstructured":"Lopaciuk S, Bykowska K, Kope\u0107 M. Prevalence of heparin cofactor II deficiency in patients with a history of venous thrombosis. Pol J Pharm. 1996;48:109\u201311.","journal-title":"Pol J Pharm"},{"key":"541_CR20","doi-asserted-by":"publisher","first-page":"1613","DOI":"10.1182\/blood.2022018661","volume":"142","author":"MV Ragni","year":"2023","unstructured":"Ragni MV, Chan SY. Innovations in RNA therapy for hemophilia. Blood. 2023;142:1613\u201321.","journal-title":"Blood"},{"key":"541_CR21","doi-asserted-by":"publisher","first-page":"1394","DOI":"10.5858\/2002-126-1394-HCID","volume":"126","author":"DM Tollefsen","year":"2002","unstructured":"Tollefsen DM. Heparin cofactor II deficiency. Arch Pathol Lab Med. 2002;126:1394\u20131400.","journal-title":"Arch Pathol Lab Med"},{"key":"541_CR22","doi-asserted-by":"publisher","first-page":"1011","DOI":"10.1055\/s-0037-1614320","volume":"82","author":"P Villa","year":"1999","unstructured":"Villa P, Aznar J, Vaya A, Espa\u00f1a F, Ferrando F, Mira Y, et al. Hereditary homozygous heparin cofactor II deficiency and the risk of developing venous thrombosis. Thromb Haemost. 1999;82:1011\u20134.","journal-title":"Thromb Haemost"},{"key":"541_CR23","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1055\/s-0038-1650612","volume":"76","author":"F Bernardi","year":"1996","unstructured":"Bernardi F, Legnani C, Micheletti F, Lunghi B, Ferraresi P, Palareti G, et al. A heparin cofactor II mutation (HCII Rimini) combined with factor V Leiden or type I protein C deficiency in two unrelated thrombophilic subjects. Thromb Haemost. 1996;76:505\u20139.","journal-title":"Thromb Haemost"},{"key":"541_CR24","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1172\/JCI0213432","volume":"109","author":"L He","year":"2002","unstructured":"He L, Vicente CP, Westrick RJ, Eitzman DT, Tollefsen DM. Heparin cofactor II inhibits arterial thrombosis after endothelial injury. J Clin Investig. 2002;109:213\u20139.","journal-title":"J Clin Investig"},{"key":"541_CR25","doi-asserted-by":"publisher","first-page":"658","DOI":"10.1016\/j.omtn.2021.03.022","volume":"24","author":"WY Lin","year":"2021","unstructured":"Lin WY, Zhu R, Zhang Z, Lu X, Wang H, He W, et al. RNAi targeting heparin cofactor II promotes hemostasis in hemophilia A. Mol Ther Nucleic Acids. 2021;24:658\u201368.","journal-title":"Mol Ther Nucleic Acids"},{"key":"541_CR26","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1160\/TH04-10-0706","volume":"93","author":"Y Dargaud","year":"2005","unstructured":"Dargaud Y, B\u00e9guin S, Lienhart A, Al Dieri R, Trzeciak C, Bordet JC, et al. Evaluation of thrombin generating capacity in plasma from patients with haemophilia A and B. Thromb Haemost. 2005;93:475\u201380.","journal-title":"Thromb Haemost"},{"key":"541_CR27","doi-asserted-by":"publisher","first-page":"3165","DOI":"10.1182\/blood-2014-07-585737","volume":"124","author":"A Muto","year":"2014","unstructured":"Muto A, Yoshihashi K, Takeda M, Kitazawa T, Soeda T, Igawa T, et al. Anti-factor IXa\/X bispecific antibody ACE910 prevents joint bleeds in a long-term primate model of acquired hemophilia A. Blood. 2014;124:3165\u201371.","journal-title":"Blood"},{"key":"541_CR28","doi-asserted-by":"publisher","first-page":"541","DOI":"10.1111\/j.1365-2141.2007.06693.x","volume":"138","author":"S Shetty","year":"2007","unstructured":"Shetty S, Vora S, Kulkarni B, Mota L, Vijapurkar M, Quadros L, et al. Contribution of natural anticoagulant and fibrinolytic factors in modulating the clinical severity of haemophilia patients. Br J Haematol. 2007;138:541\u20134.","journal-title":"Br J Haematol"},{"key":"541_CR29","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1111\/j.1365-2516.2004.00906.x","volume":"10","author":"Y Dargaud","year":"2004","unstructured":"Dargaud Y, Meunier S, Negrier C. Haemophilia and thrombophilia: an unexpected association! Haemophilia. 2004;10:319\u201326.","journal-title":"Haemophilia"},{"key":"541_CR30","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1038\/s41587-020-0741-7","volume":"39","author":"GN Nguyen","year":"2021","unstructured":"Nguyen GN, Everett JK, Kafle S, Roche AM, Raymond HE, Leiby J, et al. A long-term study of AAV gene therapy in dogs with hemophilia A identifies clonal expansions of transduced liver cells. Nat Biotechnol. 2021;39:47\u201355.","journal-title":"Nat Biotechnol"},{"key":"541_CR31","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1055\/s-2004-825634","volume":"30","author":"FE Rawle","year":"2004","unstructured":"Rawle FE, Lillicrap D. Preclinical animal models for hemophilia gene therapy: predictive value and limitations. Semin Thromb Hemost. 2004;30:205\u201313.","journal-title":"Semin Thromb Hemost"},{"key":"541_CR32","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1016\/j.cca.2008.05.003","volume":"395","author":"M Franchini","year":"2008","unstructured":"Franchini M, Targher G, Montagnana M, Lippi G. Laboratory, clinical and therapeutic aspects of acquired hemophilia A. Clin Chim Acta. 2008;395:14\u201318.","journal-title":"Clin Chim Acta"},{"key":"541_CR33","doi-asserted-by":"publisher","first-page":"1622","DOI":"10.1056\/NEJMc2211173","volume":"387","author":"F Xue","year":"2022","unstructured":"Xue F, Wang P, Yuan Z, Shi C, Fang Y, Liu W, et al. Total knee arthroplasty after gene therapy for hemophilia B. N Engl J Med. 2022;387:1622\u20134.","journal-title":"N Engl J Med"},{"key":"541_CR34","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1056\/NEJMoa067659","volume":"357","author":"MJ Manco-Johnson","year":"2007","unstructured":"Manco-Johnson MJ, Abshire TC, Shapiro AD, Riske B, Hacker MR, Kilcoyne R, et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med. 2007;357:535\u201344.","journal-title":"N Engl J Med"},{"key":"541_CR35","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1111\/j.1365-2516.2012.02838.x","volume":"18","author":"PW Collins","year":"2012","unstructured":"Collins PW. Personalized prophylaxis. Haemophilia. 2012;18:131\u2013135.","journal-title":"Haemophilia"},{"key":"541_CR36","doi-asserted-by":"publisher","first-page":"849","DOI":"10.1111\/j.1365-2516.2011.02539.x","volume":"17","author":"IE Den Uijl","year":"2011","unstructured":"Den Uijl IE, Mauser Bunschoten EP, Roosendaal G, Schutgens RE, Biesma DH, Grobbee DE, et al. Clinical severity of haemophilia A: does the classification of the 1950s still stand? Haemophilia. 2011;17:849\u201353.","journal-title":"Haemophilia"},{"key":"541_CR37","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1208\/s12248-021-00590-0","volume":"23","author":"MN Martinez","year":"2021","unstructured":"Martinez MN, Mochel JP, Neuhoff S, Pade D. Comparison of canine and human physiological factors: understanding interspecies differences that impact drug pharmacokinetics. AAPS J. 2021;23:59.","journal-title":"AAPS J"},{"key":"541_CR38","doi-asserted-by":"publisher","first-page":"4396","DOI":"10.1182\/blood-2012-10-464164","volume":"121","author":"JI Siner","year":"2013","unstructured":"Siner JI, Iacobelli NP, Sabatino DE, Ivanciu L, Zhou S, Poncz M, et al. Minimal modification in the factor VIII B-domain sequence ameliorates the murine hemophilia A phenotype. Blood. 2013;121:4396\u2013403.","journal-title":"Blood"},{"key":"541_CR39","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1038\/gt.2016.34","volume":"23","author":"Q Wang","year":"2016","unstructured":"Wang Q, Dong B, Firrman J, Wu W, Roberts S, Moore AR, et al. Evaluation of the biological differences of canine and human factor VIII in gene delivery: implications in human hemophilia treatment. Gene Ther. 2016;23:597\u2013605.","journal-title":"Gene Ther"}],"container-title":["Gene Therapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41434-025-00541-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41434-025-00541-w","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41434-025-00541-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,6]],"date-time":"2025-09-06T15:35:14Z","timestamp":1757172914000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41434-025-00541-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,24]]},"references-count":39,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2025,7]]}},"alternative-id":["541"],"URL":"https:\/\/doi.org\/10.1038\/s41434-025-00541-w","relation":{},"ISSN":["0969-7128","1476-5462"],"issn-type":[{"value":"0969-7128","type":"print"},{"value":"1476-5462","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,24]]},"assertion":[{"value":"4 March 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 April 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 May 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 May 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"We have received informed consent from all subjects. This study was reviewed and approved by the Medical Ethical Committee and the Animal Ethics Committee of Union Hospital, Huazhong University of Science and Technology. [2024] IACUC Number: 4357. All methods were performed in accordance with the relevant guidelines and regulations.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval and consent to participate"}}]}}