{"doi":"10.1016/j.jtha.2023.01.013","title":"Heterogeneity in the half-life of factor VIII concentrate in patients with hemophilia A is due to variability in the clearance of endogenous von Willebrand factor","abstract":"BACKGROUND: Previous studies have reported marked interindividual variation in factor VIII (FVIII) clearance in patients with hemophilia (PWH) and proposed a number of factors that influence this heterogeneity. OBJECTIVES: To investigate the importance of the clearance rates of endogenous von Willebrand factor (VWF) compared with those of other FVIII half-life modifiers in adult PWH. METHODS: The half-life of recombinant FVIII was determined in a cohort of 61 adult PWH. A range of reported modifiers of FVIII clearance was assessed (including plasma VWF:antigen and VWF propeptide levels; VWF-FVIII binding capacity; ABO blood group; and nonneutralizing anti-FVIII antibodies). The FVIII-binding region of the VWF gene was sequenced. Finally, the effects of variation in FVIII half-life on clinical phenotype were investigated. RESULTS: We demonstrated that heterogeneity in the clearance of endogenous plasma VWF is a key determinant of variable FVIII half-life in PWH. Both ABO blood group and age significantly impact FVIII clearance. The effect of ABO blood group on FVIII half-life in PWH is modulated entirely through its effect on the clearance rates of endogenous VWF. In contrast, the age-related effect on FVIII clearance is, at least in part, VWF independent. In contrast to previous studies, no major effects of variation in VWF-FVIII binding affinity on FVIII clearance were observed. Although high-titer immunoglobulin G antibodies (≥1:80) were observed in 26% of PWH, these did not impact FVIII half-life. Importantly, the annual FVIII usage (IU/kg/y) was significantly (p = .0035) increased in patients with an FVIII half-life of <12 hours. CONCLUSION: Our data demonstrate that heterogeneity in the half-life of FVIII concentrates in patients with hemophilia A is primarily attributable to variability in the clearance of endogenous VWF.","journal":"Journal of Thrombosis and Haemostasis","year":2023,"id":357298,"datarank":0.3958585994422889,"base_score":2.639057329615259,"endowment":2.639057329615259,"self_citation_contribution":0.3958585994422889,"citation_network_contribution":0.0,"self_endowment_contribution":0.3958585994422889,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":13,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9651,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":381414,"name":"Michelle Lavin","orcid":"0000-0003-2999-4216","position":1,"is_corresponding":false},{"id":1107160,"name":"Lilian Antunes Heck","orcid":null,"position":2,"is_corresponding":false},{"id":1107161,"name":"Niamh Larkin","orcid":null,"position":3,"is_corresponding":false},{"id":1107162,"name":"Brendan Mullaney","orcid":null,"position":4,"is_corresponding":false},{"id":381413,"name":"Dearbhla Doherty","orcid":"0000-0002-9759-062X","position":5,"is_corresponding":false},{"id":1106764,"name":"Megan Kennedy","orcid":"0000-0002-9060-8022","position":6,"is_corresponding":false},{"id":1106765,"name":"Catriona Keenan","orcid":"0009-0007-0160-573X","position":7,"is_corresponding":false},{"id":1107163,"name":"Thomas Guest","orcid":null,"position":8,"is_corresponding":false},{"id":1010836,"name":"Brian O’Mahony","orcid":"0000-0002-1530-0167","position":9,"is_corresponding":false},{"id":713724,"name":"Judicaël Fazavana","orcid":null,"position":10,"is_corresponding":false},{"id":849628,"name":"Padraic G. Fallon","orcid":"0000-0002-8401-7293","position":11,"is_corresponding":false},{"id":681536,"name":"Roger J. S. Preston","orcid":"0000-0003-0108-4077","position":12,"is_corresponding":false},{"id":1077522,"name":"John Gormley","orcid":"0000-0003-4176-4122","position":13,"is_corresponding":false},{"id":937129,"name":"Kevin M. Ryan","orcid":"0000-0002-1059-9681","position":14,"is_corresponding":false},{"id":381415,"name":"Niamh O’Connell","orcid":"0000-0002-7005-5328","position":15,"is_corresponding":false},{"id":1107164,"name":"Evelyn Singleton","orcid":null,"position":16,"is_corresponding":false},{"id":381417,"name":"Mary Byrne","orcid":"0000-0002-0214-1718","position":17,"is_corresponding":false},{"id":1106766,"name":"Mark McGowan","orcid":"0009-0009-8630-9538","position":18,"is_corresponding":false},{"id":1107165,"name":"Sheila Roche","orcid":null,"position":19,"is_corresponding":false},{"id":382298,"name":"Mairead M. 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