{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T05:38:25Z","timestamp":1790314705996,"version":"4.1.0"},"reference-count":20,"publisher":"Ferrata Storti Foundation (Haematologica)","issue":"7","license":[{"start":{"date-parts":[[2020,4,23]],"date-time":"2020-04-23T00:00:00Z","timestamp":1587600000000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/legalcode"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["haematol"],"abstract":"<jats:p>During factor VIII prophylaxis for severe hemophilia A, bleeding risk increases with time when factor VIII activity is below 1%. Maintaining trough activity above 1% does not protect all patients from bleeding. The relationship between factor VIII activity during prophylaxis and bleeding risk has not been thoroughly studied. We investigated factor VIII activity and annualized bleeding rate for spontaneous bleeds during prophylaxis. A population pharmacokinetic model derived from three clinical trials was combined with dosing data and bleed information from patient diaries. Each patients' time on prophylaxis was divided into five categories of predicted activity (0-1%, &gt;1-5%, &gt;5-15%, &gt;15-50%, and &gt;50%). Exposure time, mean factor VIII activity, and bleed number (from patient diaries) were calculated for each activity category, and annualized bleeding rates estimated using negative binomial regression and a parametric model. Relationships between these bleeding rates and factor VIII activity were evaluated by trial phase (pivotal vs. extension) and age (adults\/adolescents [\u226512 years] vs. children [0-&lt;12 years]). In total (N=187; 815 patient-years' exposure), factor VIII activity was predicted to reach &gt;1% for 85.64% of the time. Annualized bleeding rate decreased as factor VIII activity increased in each trial phase and age group. However, for a given activity level, bleeding rate differed substantially by trial phase, and age. This suggests that bleeding risk can change over time and is influenced by factors independent of factor VIII pharmacokinetics and trough levels. Target trough and prophylactic regimen should consider patient age, joint disease activity, and other bleeding risk determinants.<\/jats:p>","DOI":"10.3324\/haematol.2019.241554","type":"journal-article","created":{"date-parts":[[2020,4,23]],"date-time":"2020-04-23T20:05:28Z","timestamp":1587672328000},"page":"1902-1909","source":"Crossref","is-referenced-by-count":19,"title":["Factor VIII activity and bleeding risk during prophylaxis for severe hemophilia A: a population pharmacokinetic model"],"prefix":"10.3324","volume":"106","author":[{"family":"Andreas Tiede","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Faraizah Abdul Karim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Victor Jim\u00e9nez-Yuste","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Robert Klamroth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Sandra Lejniece","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Takashi Suzuki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Andreas Groth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Elena Santagostino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1856","published-online":{"date-parts":[[2020,4,23]]},"reference":[{"key":"27211","unstructured":"Biggs R, MacFarlane RG. 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Haemophilia. 2013; 19(5):691-697."},{"key":"27220","unstructured":"Kulkarni R, Karim FA, Glamocanin S. Results from a large multinational clinical trial (guardianTM 3) using prophylactic treatment with turoctocog alfa in paediatric patients with severe haemophilia A: safety, efficacy and pharmacokinetics. Haemophilia. 2013; 19(5):698-705."},{"key":"27221","unstructured":"Lentz SR, Janic D, Kavakli K. Longterm safety and efficacy of turoctocog alfa in prophylaxis and treatment of bleeding episodes in severe haemophilia A: final results from the guardian 2 extension trial. Haemophilia. 2018; 24(6):e391-e394."},{"key":"27222","unstructured":"Jimenez-Yuste V, Lejniece S, Klamroth R. The pharmacokinetics of a B-domain truncated recombinant factor VIII, turoctocog alfa (NovoEight\u00ae), in patients with hemophilia A. J Thromb Haemost. 2015; 13(3):370-379."},{"key":"27223","unstructured":"Ozelo M, Misgav M, Abdul KF. 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Association of peak factor VIII levels and area under the curve with bleeding in patients with haemophilia A on every third day pharmacokinetic-guided prophylaxis. Haemophilia. 2016; 22(4):514-520."},{"key":"27227","unstructured":"Bjorkman S, Oh M, Spotts G. Population pharmacokinetics of recombinant factor VIII: the relationships of pharmacokinetics to age and body weight. Blood. 2012; 119(2):612-618."},{"key":"27228","unstructured":"Ahn JE, Karlsson MO, Dunne A, Ludden TM. Likelihood based approaches to handling data below the quantification limit using NONMEM VI. J Pharmacokinet Pharmacodyn. 2008; 35(4):401-421."},{"key":"27229","unstructured":"Garmann D, McLeay S, Shah A, Vis P, Maas Enriquez M, Ploeger BA. Population pharmacokinetic characterization of BAY 81-8973, a full-length recombinant factor VIII: lessons learned - importance of including samples with factor VIII levels below the quantitation limit. Haemophilia. 2017; 23(4):528-537."},{"key":"27230","unstructured":"Fischer K, Chowdary P, Collins P. Modelling FVIII levels for predictions of zero spontaneous-joint bleeding in a cohort of severe hemophilia A subjects with target joints initiated on tertiary prophylaxis. Blood. 2016; 128(22):2576."}],"container-title":["Haematologica"],"original-title":[],"link":[{"URL":"https:\/\/haematologica.org\/article\/download\/9730\/70811","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/haematologica.org\/article\/download\/9730\/70812","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/haematologica.org\/article\/download\/9730\/70811","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,7,1]],"date-time":"2021-07-01T08:30:53Z","timestamp":1625128253000},"score":1,"resource":{"primary":{"URL":"https:\/\/haematologica.org\/article\/view\/9730"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,4,23]]},"references-count":20,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2021,7,1]]}},"URL":"https:\/\/doi.org\/10.3324\/haematol.2019.241554","relation":{},"ISSN":["1592-8721","0390-6078"],"issn-type":[{"value":"1592-8721","type":"electronic"},{"value":"0390-6078","type":"print"}],"subject":[],"published":{"date-parts":[[2020,4,23]]}}}