{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T23:59:33Z","timestamp":1766102373668,"version":"3.40.5"},"reference-count":42,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2022,12,19]],"date-time":"2022-12-19T00:00:00Z","timestamp":1671408000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Haemophilia"],"published-print":{"date-parts":[[2023,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Introduction<\/jats:title><jats:p>Gene variation in receptors for circulating factor VIII (FVIII) is candidate to explain the large inter\u2010patient variability of infused FVIII pharmacokinetics (PK) in haemophilia A (HA).<\/jats:p><\/jats:sec><jats:sec><jats:title>Aim<\/jats:title><jats:p>To compare in an Italian HA cohort (<jats:italic>n<\/jats:italic>\u00a0=\u00a026) the influence on FVIII PK of genetic components in four von Willebrand factor (VWF)\/FVIII receptors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Genotypes of low\u2010density lipoprotein receptor (<jats:italic>LDLR<\/jats:italic>), asialoglycoprotein receptor minor subunit (<jats:italic>ASGR2<\/jats:italic>), family 4 member M (<jats:italic>CLEC4M<\/jats:italic>), stabilin2 (<jats:italic>STAB2<\/jats:italic>) and <jats:italic>ABO<\/jats:italic> blood\u2010group, and VWF:Ag levels were included as independent variables in linear regression analyses of two\u2010compartment model (TCM) \u2013 standard half\u2010life (SHL) FVIII PK parameters.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In the initial FVIII distribution phase, the <jats:italic>STAB2<\/jats:italic> rs4981022 AA, <jats:italic>ASGR2<\/jats:italic> rs2289645 TT and <jats:italic>LDLR<\/jats:italic> rs688 TT genotypes may contribute to increase <jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub>, and prolong or shorten AlphaHL. In the elimination phase, a shorter BetaHL was associated with the <jats:italic>CLEC4M<\/jats:italic> rs868875 GG (beta\u2010coefficient .366, <jats:italic>p<\/jats:italic>\u00a0=\u00a0.025) and <jats:italic>ASGR2<\/jats:italic> rs2289645 TC (beta\u2010coefficient .456, <jats:italic>p<\/jats:italic>\u00a0=\u00a0.006) genotypes, which also showed shorter mean residence time (MRT) than TT genotypes (<jats:italic>p<\/jats:italic>\u00a0=\u00a0.021). The alpha and beta phase effects were independent of <jats:italic>ABO<\/jats:italic> and VWF:Ag levels at baseline. The association of the <jats:italic>LDLR<\/jats:italic> rs2228671 genotypes with clearance was independent of <jats:italic>ABO<\/jats:italic> (beta\u2010coefficient \u2212.363, <jats:italic>p<\/jats:italic>\u00a0=\u00a0.035) but not of other receptors or VWF:Ag, which may point out multiple and competing interactions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>With the limitation of the small number of HA patients, these observations highlight multiple genetic components acting in distinct phases of FVIII PK and contributing to explain FVIII PK variability. This analysis provides candidates for genotype\u2010based, individual tailoring of FVIII substitutive treatment.<\/jats:p><\/jats:sec>","DOI":"10.1111\/hae.14722","type":"journal-article","created":{"date-parts":[[2022,12,19]],"date-time":"2022-12-19T12:50:09Z","timestamp":1671454209000},"page":"479-487","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Modulation of factor VIII pharmacokinetics by genetic components in factor VIII receptors"],"prefix":"10.1111","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1517-4762","authenticated-orcid":false,"given":"Barbara","family":"Lunghi","sequence":"first","affiliation":[{"name":"Department of Life Sciences and Biotechnology University of Ferrara  Ferrara Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6565-4943","authenticated-orcid":false,"given":"Massimo","family":"Morfini","sequence":"additional","affiliation":[{"name":"Italian Association of Hemophilia Centers (AICE)  Naples Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6465-5119","authenticated-orcid":false,"given":"Nicola","family":"Martinelli","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Verona  Verona Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6113-2694","authenticated-orcid":false,"given":"Alessio","family":"Branchini","sequence":"additional","affiliation":[{"name":"Department of Life Sciences and Biotechnology University of Ferrara  Ferrara Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5849-7377","authenticated-orcid":false,"given":"Silvia","family":"Linari","sequence":"additional","affiliation":[{"name":"Center for Bleeding Disorders Department of Oncology Careggi University Hospital  Florence Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4973-1317","authenticated-orcid":false,"given":"Giancarlo","family":"Castaman","sequence":"additional","affiliation":[{"name":"Center for Bleeding Disorders Department of Oncology Careggi University Hospital  Florence Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0305-2212","authenticated-orcid":false,"given":"Francesco","family":"Bernardi","sequence":"additional","affiliation":[{"name":"Department of Life Sciences and Biotechnology University of Ferrara  Ferrara 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