{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T17:30:02Z","timestamp":1787160602566,"version":"build-2736575974"},"reference-count":36,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2018,5,31]],"date-time":"2018-05-31T00:00:00Z","timestamp":1527724800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100004326","name":"Bayer","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004326","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004702","name":"Baxter International","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004702","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009431","name":"Baxalta","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009431","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004191","name":"Novo Nordisk","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004191","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008322","name":"CSL Behring","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008322","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004319","name":"Pfizer","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004319","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Haemophilia"],"published-print":{"date-parts":[[2018,7]]},"abstract":"\n Introduction<\/jats:title>\n \n For individuals with haemophilia A, prophylaxis with factor\n VIII<\/jats:styled-content>\n (\n FVIII<\/jats:styled-content>\n ) is typically directed towards trough activity >1\u00a0\n IU<\/jats:styled-content>\n \/\n dL<\/jats:styled-content>\n ; however, some patients still experience spontaneous bleeding events (\n sBE<\/jats:styled-content>\n s).\n <\/jats:p>\n <\/jats:sec>\n \n Aim<\/jats:title>\n \n Aims were to evaluate relationships of endogenous thrombin potential (\n ETP<\/jats:styled-content>\n ) and\n FVIII<\/jats:styled-content>\n :C with occurrence of clinical bleeding.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n GENA<\/jats:styled-content>\n \u201021 was a prospective, open\u2010label, phase\n III<\/jats:styled-content>\n b study investigating the safety and efficacy of Nuwiq\n \u00ae<\/jats:sup>\n (human\u2010cl rh\n FVIII<\/jats:styled-content>\n ) in previously treated adults with severe haemophilia A. The study included a 72\u2010hour pharmacokinetic (\n PK<\/jats:styled-content>\n ) evaluation phase and a 6\u2010month personalized prophylaxis phase in which treatment was guided by\n PK<\/jats:styled-content>\n parameters. This subanalysis assessed\n FVIII<\/jats:styled-content>\n :C by one\u2010stage assay and\n ETP<\/jats:styled-content>\n by thrombin generation assay in blood samples.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Baseline mean\n ETP<\/jats:styled-content>\n was lower in the 7 patients who experienced\n sBE<\/jats:styled-content>\n s during personalized prophylaxis versus 25 who did not (n\u00a0=\u00a032 with data from\n PK<\/jats:styled-content>\n phase and prophylaxis phase;\n P<\/jats:italic>\n \u00a0=\u00a0.0002). During personalized prophylaxis (n\u00a0=\u00a049), only patients with lower median trough\n ETP<\/jats:styled-content>\n experienced\n sBE<\/jats:styled-content>\n s (8\/49 patients;\n ROC AUC<\/jats:styled-content>\n \u00a0=\u00a00.9421;\n P<\/jats:italic>\n \u00a0<\u00a0.0001); there was no significant relationship for\n FVIII<\/jats:styled-content>\n :C in predicting\n sBE<\/jats:styled-content>\n s (\n ROC<\/jats:styled-content>\n AUC\u00a0=\u00a00.5838;\n P<\/jats:italic>\n \u00a0=\u00a0.4750). Directly following infusion of human\u2010cl rh\n FVIII<\/jats:styled-content>\n ,\n ETP<\/jats:styled-content>\n was lower in patients who experienced\n sBE<\/jats:styled-content>\n s versus those who did not (\n P<\/jats:italic>\n \u00a0=\u00a0.0002), whereas\n FVIII<\/jats:styled-content>\n :C did not differ significantly between these groups.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n In adults with severe haemophilia A and reduced thrombin generation, increased frequency of spontaneous bleeding was observed irrespective of trough\n FVIII<\/jats:styled-content>\n levels. Thus, personalized prophylaxis should take into account variables other than\n FVIII<\/jats:styled-content>\n :C. Large prospective trials are needed to verify\n ETP<\/jats:styled-content>\n as a marker for spontaneous bleeding.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1111\/hae.13493","type":"journal-article","created":{"date-parts":[[2018,5,31]],"date-time":"2018-05-31T23:15:07Z","timestamp":1527808507000},"page":"619-627","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Individual thrombin generation and spontaneous bleeding rate during personalized prophylaxis with Nuwiq\n \u00ae<\/sup>\n (human\u2010cl rh\n FVIII<\/scp>\n ) in previously treated patients with severe haemophilia A"],"prefix":"10.1111","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4888-1463","authenticated-orcid":false,"given":"Y.","family":"Dargaud","sequence":"first","affiliation":[{"name":"Hopital Cardiologique Louis Pradel University of Lyon Lyon France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"Negrier","sequence":"additional","affiliation":[{"name":"Hopital Cardiologique Louis Pradel University of Lyon Lyon France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L.","family":"Rusen","sequence":"additional","affiliation":[{"name":"Sanador SRL Bucharest Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7877-4784","authenticated-orcid":false,"given":"J.","family":"Windyga","sequence":"additional","affiliation":[{"name":"Department of Disorders of Haemostasis and Internal Medicine Institute of Haematology and Transfusion Medicine Warsaw Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P.","family":"Georgiev","sequence":"additional","affiliation":[{"name":"Clinic of Haematology University Multiprofile Hospital for Active Treatment \u201cSveti Georgi\u201d and Medical University Plovdiv Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Bichler","sequence":"additional","affiliation":[{"name":"Octapharma AG Lachen Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"Solomon","sequence":"additional","affiliation":[{"name":"Octapharma AG Lachen Switzerland"},{"name":"Department of Anesthesiology Perioperative Care and General Intensive Care Salzburg University Hospital Paracelsus Medical University Salzburg Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"Knaub","sequence":"additional","affiliation":[{"name":"Octapharma AG Lachen Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T.","family":"Lissitchkov","sequence":"additional","affiliation":[{"name":"Department of Clinical Haematology in Haemorrhagic Diathesis and Anaemia Specialized Hospital for Active Treatment \u201cJoan Pavel\u201d Sofia Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R.","family":"Klamroth","sequence":"additional","affiliation":[{"name":"Vivantes Klinikum im Friedrichshain Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,5,31]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2516.2009.02127.x"},{"key":"e_1_2_9_3_1","first-page":"1","volume-title":"GeneReviews\u00ae","author":"Konkle BA"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1136\/mp.55.2.127"},{"key":"e_1_2_9_5_1","doi-asserted-by":"crossref","unstructured":"SrivastavaA BrewerAK Mauser\u2010BunschotenEP et\u00a0al.World Federation of Hemophilia. Guidelines for the management of hemophilia.2nd ed.2012. Available from:http:\/\/www1.wfh.org\/publication\/files\/pdf-1472.pdf. Accessed August 10 2017.","DOI":"10.1111\/j.1365-2516.2012.02909.x"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538-7836.2008.03270.x"},{"key":"e_1_2_9_7_1","first-page":"314","article-title":"Achieving and maintaining an optimal trough level for prophylaxis in haemophilia: the past, the present and the future","volume":"12","author":"Jimenez\u2010Yuste V","year":"2014","journal-title":"Blood Transfus"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538-7836.2004.00528.x"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538-7836.2010.03767.x"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1160\/TH04-10-0706"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538-7836.2007.02861.x"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-08-378935"},{"key":"e_1_2_9_13_1","first-page":"547","article-title":"Thrombin generation assessed as endogenous thrombin potential in patients with hyper\u2010 or hypo\u2010coagulability","volume":"88","author":"Chantarangkul V","year":"2003","journal-title":"Haematologica"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.thromres.2012.09.011"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/hae.13251"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1159\/000071636"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1160\/TH06-03-0179"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-06-291906"},{"key":"e_1_2_9_19_1","first-page":"S83","article-title":"Sensitivity, specificity, receiver\u2010operating characteristic (ROC) curves and likelihood ratios: communicating the performance of diagnostic tests","volume":"29","author":"Florkowski CM","year":"2008","journal-title":"Clin Biochem Rev"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1111\/hae.12905"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2516.2009.02191.x"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2516.2004.01036.x"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/hae.12381"},{"key":"e_1_2_9_24_1","doi-asserted-by":"crossref","first-page":"1514","DOI":"10.1182\/blood.V124.21.1514.1514","article-title":"Thrombin generation and bleeding in hemophilia inhibitor patients during immune tolerance induction","volume":"124","author":"Ragni MV","year":"2014","journal-title":"Blood"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.seminhematol.2008.03.002"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2516.2008.01931.x"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1111\/jth.13743"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2516.2009.02082.x"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinbiochem.2016.08.022"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.thromres.2016.12.022"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.2007.06785.x"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1097\/MBC.0b013e3282f4bb47"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538-7836.2010.04136.x"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1111\/jth.12458"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.2008.07063.x"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2796.1992.tb00546.x"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1111\/hae.13023"}],"container-title":["Haemophilia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fhae.13493","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/hae.13493","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,7]],"date-time":"2024-07-07T02:27:11Z","timestamp":1720319231000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/hae.13493"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,5,31]]},"references-count":36,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2018,7]]}},"alternative-id":["10.1111\/hae.13493"],"URL":"https:\/\/doi.org\/10.1111\/hae.13493","archive":["Portico"],"relation":{},"ISSN":["1351-8216","1365-2516"],"issn-type":[{"value":"1351-8216","type":"print"},{"value":"1365-2516","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,5,31]]},"assertion":[{"value":"2017-12-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-03-19","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-05-31","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}