Joint bleeds increase the inhibitor response to human factor VIII in a rat model of severe haemophilia A
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Joint bleeds increase the inhibitor response to human factor VIII in a rat model of severe haemophilia A. / Löfgren, Karin Maria; Søndergaard, H.; Skov, Søren; Wiinberg, B.
In: Haemophilia, Vol. 22, No. 5, 09.2016, p. 772-779.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Joint bleeds increase the inhibitor response to human factor VIII in a rat model of severe haemophilia A
AU - Löfgren, Karin Maria
AU - Søndergaard, H.
AU - Skov, Søren
AU - Wiinberg, B.
PY - 2016/9
Y1 - 2016/9
N2 - IntroductionThe most serious complication in haemophilia A (HA) replacement therapy with coagulation factor VIII (FVIII) 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 FVIII in on-demand treatment, increasing the inhibitor risk.AimTo compare the antibody response to treatment with recombinant human FVIII (rhFVIII) in relation to induced knee joint bleeds and treatment without concurrent bleeds in a HA rat model.MethodHA rats were divided into two groups: one group (n = 10) receiving three needle induced knee joint bleeds 14 days apart and a control group (n = 9) receiving three sham procedures. Three hours after each injury/sham 50 IU kg−1 rhFVIII was administrated intravenously. Subsequently, both groups continued rhFVIII treatment for another 9 weeks. Binding antibodies were analysed using an enzyme-linked immunosorbent assay and neutralizing antibodies using a Bethesda-like assay.ResultsRats in the knee-bleed group developed a significantly faster inhibitor response and reached significantly higher inhibitor levels. In the knee-bleed group, 80% developed inhibitors vs. 33% in the control group, demonstrating a 2.4 times higher inhibitor risk when treating concurrent with bleeds.ConclusionFVIII treatment in relation to a bleed potentiates inhibitor development compared to FVIII treatment alone in this HA rat, indicating that bleeding is a potential danger signal. Our results support the theory that FVIII 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.
AB - IntroductionThe most serious complication in haemophilia A (HA) replacement therapy with coagulation factor VIII (FVIII) 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 FVIII in on-demand treatment, increasing the inhibitor risk.AimTo compare the antibody response to treatment with recombinant human FVIII (rhFVIII) in relation to induced knee joint bleeds and treatment without concurrent bleeds in a HA rat model.MethodHA rats were divided into two groups: one group (n = 10) receiving three needle induced knee joint bleeds 14 days apart and a control group (n = 9) receiving three sham procedures. Three hours after each injury/sham 50 IU kg−1 rhFVIII was administrated intravenously. Subsequently, both groups continued rhFVIII treatment for another 9 weeks. Binding antibodies were analysed using an enzyme-linked immunosorbent assay and neutralizing antibodies using a Bethesda-like assay.ResultsRats in the knee-bleed group developed a significantly faster inhibitor response and reached significantly higher inhibitor levels. In the knee-bleed group, 80% developed inhibitors vs. 33% in the control group, demonstrating a 2.4 times higher inhibitor risk when treating concurrent with bleeds.ConclusionFVIII treatment in relation to a bleed potentiates inhibitor development compared to FVIII treatment alone in this HA rat, indicating that bleeding is a potential danger signal. Our results support the theory that FVIII 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.
KW - animal model
KW - factor VIII
KW - haemarthrosis
KW - haemophilia A
KW - inhibitors
KW - rats
U2 - 10.1111/hae.13014
DO - 10.1111/hae.13014
M3 - Journal article
C2 - 27439658
VL - 22
SP - 772
EP - 779
JO - Haemophilia, Supplement
JF - Haemophilia, Supplement
SN - 1355-0691
IS - 5
ER -
ID: 169438118