Effects of the factor V G1691A mutation and the factor II G20210A variant on the clinical expression of severe hemophilia A in children – results of a multicenter study

Hemophilia A (HA) is an X-linked genetic hemorrhagic disorder resulting from a deficiency of blood coagulation factor VIII. The mutation type within the factor VIII gene may influence the clinical severity of hemophilia. It has also recently been suggested that the clinical phenotype of HA is influenced by co-inheritance of the factor V G1691A mutation or the factor II G20210A variant. This clinical observation in patients has been supported by findings that the clinical phenotype of severe hemophilia in mice was influenced by the factor V Leiden genotype. Furthermore, data of an invitro study have demonstrated a 3-7 fold increase in thrombin generation when factor VIII-depleted plasma was supplemented with different concentrations of factor V Leiden plasma. The aim of the present multicenter cohort study was to investigate the role of the factor V (FV) G1691A mutation and the factor II (FII) G20210A variant, co-inherited with severe HA, with respect to the clinical expression of the disease, i.e. the annual bleeding frequency (ABF), the occurrence and severity of image-proven hemophilic target joints, and the development of synovitis. Design and Methods Ethics The present retrospective review of consecutively recruited pediatric patients with HA was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and was approved by the Medical Ethics Committee of the University of Münster, Germany. With regard to the data presented here, the ethics committee has specifically approved the investigation of established prothrombotic risk factors (PR) possibly co-inherited in pediatric patients with HA. Inclusion criteria Previously untreated and undiagnosed Caucasian infants and children (PUP) with severe HA (F VIII activity < 0.01U/mL), aged neonate to 16 years, who had been admitted to the University Children's Hospitals of Frankfurt, Halle, Munich, and Münster, Germany, for the first symptomatic and spontaneous onset of the disease were included in the study. Exclusion criteria Pre-treated pediatric patients and children with hemophilia A and inhibitor development (n=23) were not included in the present review.