piperidines and Hemophilia-A

Hemophilia A is a rare hemorrhagic disorder caused by the lack of functional pro-coagulant factor VIII. Factor VIII replacement therapy in patients with severe hemophilia A results in the development of inhibitory anti-factor VIII IgG in up to 30% of cases. To date, immune tolerance induction, with daily injection of large amounts of factor VIII, is the only strategy to eradicate factor VIII inhibitors. This strategy is, however, efficient in only 60-80% of patients. We investigated whether blocking B-cell receptor signaling upon inhibition of Bruton tyrosine kinase prevents anti-factor VIII immune responses in a mouse model of severe hemophilia A. Factor VIII-naïve and factor VIII-sensitized factor VIII-deficient mice were fed with the selective inhibitor of Bruton tyrosine kinase, (R)-5-amino-1-(1-cyanopiperidin-3-yl)-3-(4-[2,4-difluorophenoxyl] phenyl)-1H pyrazole-4-carboxamide (PF-06250112), to inhibit B-cell receptor signaling prior to challenge with exogenous factor VIII. The consequences on the anti-factor VIII immune response were studied. Inhibition of Bruton tyrosine kinase during the primary anti-factor VIII immune response in factor VIII-naïve mice did not prevent the development of inhibitory anti-factor VIII IgG. In contrast, the anti-factor VIII memory B-cell response was consistently reduced upon treatment of factor VIII-sensitized mice with the Bruton tyrosine kinase inhibitor. The Bruton tyrosine kinase inhibitor reduced the differentiation of memory B cells

Topics: Agammaglobulinaemia Tyrosine Kinase; Animals; Antibody Formation; B-Lymphocytes; Disease Models, Animal; Factor VIII; Hemophilia A; Immune Tolerance; Immunoglobulin G; Immunologic Memory; Mice; Mice, Inbred C57BL; Mice, Knockout; Piperidines; Pyrazoles

Women who are carriers for hemophilia are usually considered as safe carriers. However, they can present hemorragic symptoms associated with low factor VIII or IX levels. During pregancy, factor VIII increases whereas factor IX does not. The peripartum period is at risk of increased bleeding in these women. Here are presented reports of clinical data concerning two hemophilia carriers with low factor VIII or IX (30-40%) during the peripartum period. They received remifentanil and ketamine for labor pain management because of contraindication of epidural and spinal analgesia. Delivery occured quickly but they presented immediate moderate postpartum haemorrage. They did not necessitate blood transfusion. The one with hemophilia A received desmopressin just after delivery and the other one received factor IX when she arrived in delivery room. Blood factor VIII or IX has to be assessed in these women with familial history of hemophilia and bleeding. During pregnancy, factor VIII increases and can be assessed many times during pregnancy expecting a level over 50%. Factor IX does not really increase during pregancy and hemorrage can occur. Epidural and spinal anesthesia seem to be contraindicated as far as recommandations are concerned. Coagulation factor substitution is a mean of increasing factor level before these anaesthesias and can be discussed for each case.

Topics: Adult; Analgesia, Patient-Controlled; Anesthesia, Obstetrical; Anesthetics, Dissociative; Anesthetics, Intravenous; Coagulants; Factor IX; Factor VIII; Female; Hemophilia A; Heterozygote; Humans; Ketamine; Peripartum Period; Piperidines; Pregnancy; Remifentanil

Topics: Alanine; Amidines; Benzamidines; Dextrans; Enzyme Activation; Factor X; Factor Xa; Factor XII Deficiency; Hemophilia A; Heparin; Humans; Kallikreins; Oligopeptides; Phenprocoumon; Phosphatidylethanolamines; Piperidines; Protease Inhibitors; Thrombin; Viper Venoms