Defining severity of hemophilia: more than factor levels.

Patients with severe hemophilia generally exhibit a severe bleeding phenotype with bleeding into joints or muscles at an early age. Although the severity and frequency of bleeding symptoms correlate with the residual factor VIII/IX (FVIII/IX) activity in the plasma, a considerable variability in bleeding pattern, FVIII/IX concentrate utilization, and joint damage has been observed. A subset of 10 to 15% of patients with severe hemophilia A shows a milder disease phenotype with significantly reduced frequencies of spontaneous bleeding and lower requirements for factor concentrate. This mitigated clinical phenotype is determined by the underlying mutations in the F8/F9 genes, genetic alterations and polymorphisms in other genes of the hemostasis system, differences in inflammatory and immune response genes, limitations in laboratory diagnostics, as well as environmental factors. Identification of disease-modifying factors in hemophilia may influence treatment decisions, such as starting and tailoring prophylaxis according to the specific clinical phenotype, rather than just the laboratory-defined degree of severity. This review focuses on the current information of factors mitigating the clinical presentation of hemophilia and contributing to its high phenotypic heterogeneity. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.