{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T02:34:04Z","timestamp":1791686044328,"version":"4.3.4"},"reference-count":39,"publisher":"Elsevier BV","issue":"12","license":[{"start":{"date-parts":[[2023,12,1]],"date-time":"2023-12-01T00:00:00Z","timestamp":1701388800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2023,12,1]],"date-time":"2023-12-01T00:00:00Z","timestamp":1701388800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2024,12,1]],"date-time":"2024-12-01T00:00:00Z","timestamp":1733011200000},"content-version":"vor","delay-in-days":366,"URL":"http:\/\/www.elsevier.com\/open-access\/userlicense\/1.0\/"}],"content-domain":{"domain":["jthjournal.org","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Journal of Thrombosis and Haemostasis"],"published-print":{"date-parts":[[2023,12]]},"DOI":"10.1016\/j.jtha.2023.08.030","type":"journal-article","created":{"date-parts":[[2023,9,6]],"date-time":"2023-09-06T10:17:06Z","timestamp":1693995426000},"page":"3287-3291","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":2,"title":["Crippling down factor IX for therapeutic gain"],"prefix":"10.1016","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1530-0818","authenticated-orcid":false,"given":"Viola J.F.","family":"Strijbis","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5161-5863","authenticated-orcid":false,"given":"Jafar","family":"Vatandoost","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8164-817X","authenticated-orcid":false,"given":"Mettine H.A.","family":"Bos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.jtha.2023.08.030_bib1","doi-asserted-by":"crossref","first-page":"4501","DOI":"10.1021\/cr000033x","article-title":"Serine protease mechanism and specificity","volume":"102","author":"Hedstrom","year":"2002","journal-title":"Chem Rev"},{"key":"10.1016\/j.jtha.2023.08.030_bib2","doi-asserted-by":"crossref","first-page":"D624","DOI":"10.1093\/nar\/gkx1134","article-title":"The Merops database of proteolytic enzymes, their substrates and inhibitors in 2017 and a comparison with peptidases in the PANTHER database","volume":"46","author":"Rawlings","year":"2018","journal-title":"Nucleic Acids Res"},{"key":"10.1016\/j.jtha.2023.08.030_bib3","doi-asserted-by":"crossref","first-page":"3467","DOI":"10.1002\/j.1460-2075.1989.tb08511.x","article-title":"The refined 1.9 A crystal structure of human alpha-thrombin: interaction with D-Phe-Pro-Arg chloromethylketone and significance of the Tyr-Pro-Trp insertion segment","volume":"8","author":"Bode","year":"1989","journal-title":"EMBO J"},{"key":"10.1016\/j.jtha.2023.08.030_bib4","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1021\/ar50123a006","article-title":"Structural basis of the activation and action of trypsin","volume":"11","author":"Huber","year":"1978","journal-title":"Acc Chem Res"},{"key":"10.1016\/j.jtha.2023.08.030_bib5","doi-asserted-by":"crossref","first-page":"4797","DOI":"10.1093\/emboj\/16.16.4797","article-title":"Lysine 156 promotes the anomalous proenzyme activity of tPA: x-ray crystal structure of single-chain human tPA","volume":"16","author":"Renatus","year":"1997","journal-title":"EMBO J"},{"key":"10.1016\/j.jtha.2023.08.030_bib6","doi-asserted-by":"crossref","first-page":"1527","DOI":"10.1182\/blood-2016-10-744110","article-title":"Proteolytic properties of single-chain factor XII: a mechanism for triggering contact activation","volume":"129","author":"Ivanov","year":"2017","journal-title":"Blood"},{"key":"10.1016\/j.jtha.2023.08.030_bib7","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1182\/blood.2019002224","article-title":"Protease activity in single-chain prekallikrein","volume":"135","author":"Ivanov","year":"2020","journal-title":"Blood"},{"key":"10.1016\/j.jtha.2023.08.030_bib8","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1182\/blood.2019004339","article-title":"Plasma kallikrein\u2019s low gear","volume":"135","author":"Emsley","year":"2020","journal-title":"Blood"},{"key":"10.1016\/j.jtha.2023.08.030_bib9","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/0014-5793(76)80443-7","article-title":"Induction of the bovine trypsinogen-trypsin transition by peptides sequentially similar to the N-terminus of trypsin","volume":"68","author":"Bode","year":"1976","journal-title":"FEBS Lett"},{"key":"10.1016\/j.jtha.2023.08.030_bib10","doi-asserted-by":"crossref","first-page":"26084","DOI":"10.1074\/jbc.M101966200","article-title":"Streptokinase triggers conformational activation of plasminogen through specific interactions of the amino-terminal sequence and stabilizes the active zymogen conformation","volume":"276","author":"Boxrud","year":"2001","journal-title":"J\u00a0Biol Chem"},{"key":"10.1016\/j.jtha.2023.08.030_bib11","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1038\/nature01962","article-title":"Staphylocoagulase is a prototype for the mechanism of cofactor-induced zymogen activation","volume":"425","author":"Friedrich","year":"2003","journal-title":"Nature"},{"key":"10.1016\/j.jtha.2023.08.030_bib12","doi-asserted-by":"crossref","first-page":"11601","DOI":"10.1074\/jbc.M113.451542","article-title":"Autoactivation of thrombin precursors","volume":"288","author":"Pozzi","year":"2013","journal-title":"J\u00a0Biol Chem"},{"key":"10.1016\/j.jtha.2023.08.030_bib13","doi-asserted-by":"crossref","first-page":"20441","DOI":"10.1074\/jbc.R800064200","article-title":"Exosite determinants of serpin specificity","volume":"284","author":"Gettins","year":"2009","journal-title":"J\u00a0Biol Chem"},{"key":"10.1016\/j.jtha.2023.08.030_bib14","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/S0006-291X(67)80055-X","article-title":"On the size of the active site in proteases","volume":"27","author":"Schechter","year":"1967","journal-title":"I.\u00a0Papain. Biochem Biophys Res Commun"},{"key":"10.1016\/j.jtha.2023.08.030_bib15","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1111\/j.1538-7836.2011.04360.x","article-title":"Serpin structure, function and dysfunction","volume":"9","author":"Huntington","year":"2011","journal-title":"J\u00a0Thromb Haemost"},{"key":"10.1016\/j.jtha.2023.08.030_bib16","doi-asserted-by":"crossref","first-page":"25","DOI":"10.3389\/fmed.2019.00025","article-title":"Serpins-from trap to treatment","volume":"6","author":"Sanrattana","year":"2019","journal-title":"Front Med (Lausanne)"},{"key":"10.1016\/j.jtha.2023.08.030_bib17","doi-asserted-by":"crossref","DOI":"10.3389\/fcvm.2022.878199","article-title":"Anticoagulant serpins: endogenous regulators of hemostasis and thrombosis","volume":"9","author":"Grover","year":"2022","journal-title":"Front Cardiovasc Med"},{"key":"10.1016\/j.jtha.2023.08.030_bib18","doi-asserted-by":"crossref","first-page":"18627","DOI":"10.1074\/jbc.M802205200","article-title":"The conformational switch from the factor X zymogen to protease state mediates exosite expression and prothrombinase assembly","volume":"283","author":"Toso","year":"2008","journal-title":"J\u00a0Biol Chem"},{"key":"10.1016\/j.jtha.2023.08.030_bib19","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1182\/blood-2010-08-300756","article-title":"Zymogen-like factor Xa variants restore thrombin generation and effectively bypass the intrinsic pathway in\u00a0vitro","volume":"117","author":"Bunce","year":"2011","journal-title":"Blood"},{"key":"10.1016\/j.jtha.2023.08.030_bib20","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.1038\/nbt.1995","article-title":"A\u00a0zymogen-like factor Xa variant corrects the coagulation defect in hemophilia","volume":"29","author":"Ivanciu","year":"2011","journal-title":"Nat Biotechnol"},{"key":"10.1016\/j.jtha.2023.08.030_bib21","doi-asserted-by":"crossref","first-page":"1694","DOI":"10.1111\/jth.13059","article-title":"Correction of human hemophilia A whole blood abnormalities with a novel bypass agent: zymogen-like FXa(I16L)","volume":"13","author":"George","year":"2015","journal-title":"J\u00a0Thromb Haemost"},{"key":"10.1016\/j.jtha.2023.08.030_bib22","doi-asserted-by":"crossref","first-page":"2022","DOI":"10.1182\/blood.2022018083","article-title":"Factor IXa variants resistant to plasma inhibitors enhance clot formation in\u00a0vivo","volume":"141","author":"Ivanciu","year":"2023","journal-title":"Blood"},{"key":"10.1016\/j.jtha.2023.08.030_bib23","doi-asserted-by":"crossref","first-page":"7398","DOI":"10.1021\/bi992735q","article-title":"Insertion loop 256-268 in coagulation factor IX restricts enzymatic activity in the absence but not in the presence of factor VIII","volume":"39","author":"Kolkman","year":"2000","journal-title":"Biochemistry"},{"key":"10.1016\/j.jtha.2023.08.030_bib24","doi-asserted-by":"crossref","first-page":"4121","DOI":"10.1074\/jbc.M210722200","article-title":"Physiological FIXa activation involves a cooperative conformational rearrangement of the 99-loop","volume":"278","author":"Sichler","year":"2003","journal-title":"J\u00a0Biol Chem"},{"key":"10.1016\/j.jtha.2023.08.030_bib25","doi-asserted-by":"crossref","first-page":"2395","DOI":"10.1042\/BCJ20160336","article-title":"Releasing the brakes in coagulation factor IXa by co-operative maturation of the substrate-binding site","volume":"473","author":"Kristensen","year":"2016","journal-title":"Biochem J"},{"key":"10.1016\/j.jtha.2023.08.030_bib26","doi-asserted-by":"crossref","first-page":"3433","DOI":"10.1016\/S0021-9258(19)69627-4","article-title":"The role of phospholipid and factor VIIIa in the activation of bovine factor X","volume":"256","author":"van Dieijen","year":"1981","journal-title":"J\u00a0Biol Chem"},{"key":"10.1016\/j.jtha.2023.08.030_bib27","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1055\/s-0038-1660091","article-title":"The role of factor VIII in the activation of human blood coagulation factor X by activated factor IX","volume":"54","author":"Mertens","year":"1985","journal-title":"Thromb Haemost"},{"key":"10.1016\/j.jtha.2023.08.030_bib28","doi-asserted-by":"crossref","first-page":"17012","DOI":"10.1016\/S0021-9258(18)41886-8","article-title":"The active site of factor IXa is located far above the membrane surface and its conformation is altered upon association with factor VIIIa. A fluorescence study","volume":"267","author":"Mutucumarana","year":"1992","journal-title":"J\u00a0Biol Chem"},{"key":"10.1016\/j.jtha.2023.08.030_bib29","doi-asserted-by":"crossref","first-page":"1669","DOI":"10.1016\/j.str.2009.10.011","article-title":"Structural basis of the cofactor- and substrate-assisted activation of human coagulation factor IXa","volume":"17","author":"Z\u00f6gg","year":"2009","journal-title":"Structure"},{"key":"10.1016\/j.jtha.2023.08.030_bib30","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1002\/mgg3.30","article-title":"The CDC hemophilia B mutation project mutation list: a new online resource","volume":"1","author":"Li","year":"2013","journal-title":"Mol Genet Genomic Med"},{"key":"10.1016\/j.jtha.2023.08.030_bib31","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1111\/hae.13947","article-title":"The European Association for Haemophilia and Allied Disorders (EAHAD) coagulation factor variant databases: important resources for haemostasis clinicians and researchers","volume":"26","author":"McVey","year":"2020","journal-title":"Haemophilia"},{"key":"10.1016\/j.jtha.2023.08.030_bib32","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1016\/j.jtha.2023.02.005","article-title":"An updated interactive database for 1692 genetic variants in coagulation factor IX provides new insights into haemophilia B","volume":"21","author":"Xu","year":"2023","journal-title":"J\u00a0Thromb Haemost"},{"key":"10.1016\/j.jtha.2023.08.030_bib33","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/s41572-021-00278-x","volume":"7","author":"Berntorp","year":"2021","journal-title":"Haemophilia. Nat Rev Dis Primers"},{"key":"10.1016\/j.jtha.2023.08.030_bib34","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1097\/PAT.0b013e328353443d","article-title":"Spectrum of F9 mutations in Chinese haemophilia B patients: identification of 20 novel mutations","volume":"44","author":"Yu","year":"2012","journal-title":"Pathology"},{"key":"10.1016\/j.jtha.2023.08.030_bib35","doi-asserted-by":"crossref","first-page":"10876","DOI":"10.1016\/S0021-9258(19)38528-X","article-title":"Mutations in hemophilia Bm occur at the Arg180-Val activation site or in the catalytic domain of factor IX","volume":"265","author":"Bertina","year":"1990","journal-title":"J\u00a0Biol Chem"},{"key":"10.1016\/j.jtha.2023.08.030_bib36","doi-asserted-by":"crossref","first-page":"721","DOI":"10.18388\/abp.1999_4144","article-title":"Molecular analysis of hemophilia B in Poland: 12 novel mutations of the factor IX gene","volume":"46","author":"Wulff","year":"1999","journal-title":"Acta Biochim Pol"},{"key":"10.1016\/j.jtha.2023.08.030_bib37","doi-asserted-by":"crossref","first-page":"6146","DOI":"10.1021\/bi00075a005","article-title":"Molecular defect in factor IX Tokyo: substitution of valine-182 by alanine at position P2\u2032 in the second cleavage site by factor XIa resulting in impaired activation","volume":"32","author":"Maekawa","year":"1993","journal-title":"Biochemistry"},{"key":"10.1016\/j.jtha.2023.08.030_bib38","doi-asserted-by":"crossref","first-page":"6324","DOI":"10.1021\/bi00076a004","article-title":"Mutations in the catalytic domain of factor IX that are related to the subclass hemophilia Bm","volume":"32","author":"Hamaguchi","year":"1993","journal-title":"Biochemistry"},{"key":"10.1016\/j.jtha.2023.08.030_bib39","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.thromres.2020.11.023","article-title":"Elevated anti-human factor Xa activity in rabbit and rodent plasma: implications for preclinical assessment of human factor X in animal models of hemostasis","volume":"198","author":"Verhoef","year":"2021","journal-title":"Thromb Res"}],"container-title":["Journal of Thrombosis and Haemostasis"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S1538783623006591?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S1538783623006591?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T03:38:42Z","timestamp":1761536322000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S1538783623006591"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12]]},"references-count":39,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2023,12]]}},"alternative-id":["S1538783623006591"],"URL":"https:\/\/doi.org\/10.1016\/j.jtha.2023.08.030","relation":{},"ISSN":["1538-7836"],"issn-type":[{"value":"1538-7836","type":"print"}],"subject":[],"published":{"date-parts":[[2023,12]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Crippling down factor IX for therapeutic gain","name":"articletitle","label":"Article Title"},{"value":"Journal of Thrombosis and Haemostasis","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.jtha.2023.08.030","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"simple-article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc.","name":"copyright","label":"Copyright"}]}}