title: Tailoring hemostatic therapies to lower inhibitor development in previously untreated patients with severe hemophilia A.
abstract: After technological progress provided safer therapeutic products for patients with hemophilia A, the development of alloantibodies (inhibitors) neutralizing the coagulant activity of infused factor VIII (FVIII) remains the most serious complication of replacement therapy, predisposing patients to greater morbidity and causing higher treatment costs. The pathogenesis of inhibitors, which develop at a high rate in previously untreated children with severe hemophilia A, is multifactorial, resulting from complex interactions between genetic and environmental factors. Among non-genetic determinants, a key role is played by treatment-related factors, including the source of FVIII product (i.e., plasma derived or recombinant) and the mode of replacement therapy delivery (i.e., intensity, prophylaxis vs. on demand). We review the potential interventions on these modifiable factors that may help to lower the rate of inhibitor development. In addition, interest is currently directed toward the potential for lesser immunogenicity of novel hemostatic agents designed to decrease the dosing frequency or avoid/delay the need of FVIII replacement therapy.
authors.affiliation: Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico and University of Milan, Milan, Italy.
authors.forename: P M
authors.initials: PM
authors.lastname: Mannucci
authors.affiliation: Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico and University of Milan, Milan, Italy.
authors.forename: M E
authors.initials: ME
authors.lastname: Mancuso
authors.affiliation: Department of Transfusion Medicine and Hematology, Carlo Poma Hospital, Mantova, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Franchini
mesh_terms: D001777:Blood Coagulation; D002648:Child; D005169:Factor VIII / Q000276:immunology; D059647:Gene-Environment Interaction; D015316:Genetic Therapy; D006467:Hemophilia A / Q000097:blood* / Q000628:therapy*; D006487:Hemostasis; D006490:Hemostatics / Q000627:therapeutic use; D006801:Humans; D007518:Isoantibodies / Q000276:immunology*; D011994:Recombinant Proteins / Q000737:chemistry; D012307:Risk Factors; D016896:Treatment Outcome
chemical_list: D006490:Hemostatics; D007518:Isoantibodies; D011994:Recombinant Proteins; C078147:F8 protein, human; D005169:Factor VIII
keywords: factor VIII; inhibitors; prevention; prophylaxis; therapy