{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T17:34:50Z","timestamp":1791308090651,"version":"4.3.1"},"reference-count":25,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2016,7,21]],"date-time":"2016-07-21T00:00:00Z","timestamp":1469059200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Haemophilia"],"published-print":{"date-parts":[[2016,9]]},"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>The most serious complication in haemophilia A (<jats:styled-content style=\"fixed-case\">HA<\/jats:styled-content>) replacement therapy with coagulation factor <jats:styled-content style=\"fixed-case\">VIII<\/jats:styled-content> (<jats:styled-content style=\"fixed-case\">FVIII<\/jats:styled-content>) is neutralizing antibodies, i.e. inhibitors. It has been hypothesized that danger signals generated during a bleed might have an adjuvant effect on the immune response to <jats:styled-content style=\"fixed-case\">FVIII<\/jats:styled-content> in on\u2010demand treatment, increasing the inhibitor risk.<\/jats:p><\/jats:sec><jats:sec><jats:title>Aim<\/jats:title><jats:p>To compare the antibody response to treatment with recombinant human <jats:styled-content style=\"fixed-case\">FVIII<\/jats:styled-content> (rh<jats:styled-content style=\"fixed-case\">FVIII<\/jats:styled-content>) in relation to induced knee joint bleeds and treatment without concurrent bleeds in a <jats:styled-content style=\"fixed-case\">HA<\/jats:styled-content> rat model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Method<\/jats:title><jats:p><jats:styled-content style=\"fixed-case\">HA<\/jats:styled-content> rats were divided into two groups: one group (<jats:italic>n<\/jats:italic> = 10) receiving three needle induced knee joint bleeds 14 days apart and a control group (<jats:italic>n<\/jats:italic> = 9) receiving three sham procedures. Three hours after each injury\/sham 50 IU kg<jats:sup>\u22121<\/jats:sup> rh<jats:styled-content style=\"fixed-case\">FVIII<\/jats:styled-content> was administrated intravenously. Subsequently, both groups continued rh<jats:styled-content style=\"fixed-case\">FVIII<\/jats:styled-content> treatment for another 9 weeks. Binding antibodies were analysed using an enzyme\u2010linked immunosorbent assay and neutralizing antibodies using a Bethesda\u2010like assay.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Rats in the knee\u2010bleed group developed a significantly faster inhibitor response and reached significantly higher inhibitor levels. In the knee\u2010bleed group, 80% developed inhibitors vs. 33% in the control group, demonstrating a 2.4 times higher inhibitor risk when treating concurrent with bleeds.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p><jats:styled-content style=\"fixed-case\">FVIII<\/jats:styled-content> treatment in relation to a bleed potentiates inhibitor development compared to <jats:styled-content style=\"fixed-case\">FVIII<\/jats:styled-content> treatment alone in this <jats:styled-content style=\"fixed-case\">HA<\/jats:styled-content> rat, indicating that bleeding is a potential danger signal. Our results support the theory that <jats:styled-content style=\"fixed-case\">FVIII<\/jats:styled-content> replacement therapy concurrent with a bleeding episode increases the inhibitor risk, which to the best of our knowledge, has not been confirmed in an animal model before.<\/jats:p><\/jats:sec>","DOI":"10.1111\/hae.13014","type":"journal-article","created":{"date-parts":[[2016,7,21]],"date-time":"2016-07-21T05:22:39Z","timestamp":1469078559000},"page":"772-779","source":"Crossref","is-referenced-by-count":11,"title":["Joint bleeds increase the inhibitor response to human factor VIII in a rat model of severe haemophilia A"],"prefix":"10.1111","volume":"22","author":[{"given":"K. 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