Phenotypic Heterogeneity in Severe Hemophilia

Large heterogeneity in bleeding pattern and arthropathy is observed among patients with severe hemophilia. Studies have reported a large variability in bleeding pattern among patients with severe hemophilia. Of special interest are some 10% of the patients with severe hemophilia who only rarely bleed and don't need prophylactic therapy. Prothrombotic risk factors seem to influence phenotype but they can account for only a small part of the heterogeneity. Half-lives for factor VIII (FVIII) range between 7 and 20 h; a significantly shorter half-life has been reported in patients with blood group O and a low von Willebrand antigen level. In addition, thrombin generation tests have been used to differentiate between mild and more severe phenotypes. As the advanced forms of these tests also measure the effects of platelets, it has been argued that they are more sensitive to differentiate phenotypes. We conclude that the origin of the large heterogeneity of phenotypes in severe hemophilia is multifactorial. As they produce no FVIII, patients with severe hemophilia and an intron 22 inversion are ideal candidates to study further bleeding variability. Until other parameters have been identified, the heterogeneity of the clinical phenotype may best be predicted by the first onset of the clinical features. At the moment, age at first joint bleed seems to be the most reliable factor to differentiate between phenotypes.