Age‐dependent increase of FVIII:C in mild haemophilia A

Abstract

Variability of FVIII:C levels in healthy individuals and age-dependent increase are a known phenomenon. In haemophilia, increasing FVIII:C levels with age have not been described yet. In our study, we evaluated this issue retrospectively in a cohort older than 45 years of 29 patients with mild haemophilia and 14 patients with moderate or severe haemophilia at last visit at the haemophilia centre Frankfurt. The median duration of observation evaluated in this study was 17 years (range 5-28). Results show a significant correlation of increasing FVIII:C levels with age in mild haemophilia (P = 0.000041) and a non-significant tendency to a higher increase in higher age (P = 0.085652). The median difference of FVIII:C level between the first and last measurement was 8% of normal plasma concentration (range -3% to +35%). Median FVIII:C level increase of patients younger than 62 years was 7.5% (range -3 to 22), median increase in older patients was 12% (range 0-35). This tendency could not be correlated to decreased number of bleedings, but FVIII substitution dosage should be adapted to changing plasma levels at higher age to prevent overdosing or thrombotic risks. Possible causes and contributing factors for increasing FVIII:C levels are discussed. Statistical significance remains to be confirmed in larger prospective studies also including younger patients.

Response to desmopressin in patients with mild hemophilia A caused by the F8 c.1910A>G, p.Asn637Ser mutation

“…Seary et al [9] found, in their study of 74 boys with 38 different mutations causing moderate or mild hemophilia, that age and FVIII level were strong predictors of response to desmopressin. The stronger effect of desmopressin in older patients in our study may reflect the increase in baseline FVIII levels with age, as previously described by Miesbach et al [10], but our model does not completely explain the variation in the effect of DDAVP. Larger groups of patients are needed to better evaluate the effects of VWF:Ag, blood group and age on baseline FVIII levels and in relation to test results.…”

“…While both the plasma-and platelet-derived molecules can form a functional complex, several studies demonstrate that the two cofactor pools are physically and functionally distinct [2][3][4][5][6][7]. Despite these differences, the entire platelet-derived pool of the procofactor, FV, is endocytosed from the plasma by megakaryocytes [4,8] via a two-receptor system consisting of a specific, unknown FV receptor and low density lipoprotein (LDL) receptor-related protein-1 (LRP-1) [9], an endocytic receptor belonging to a superfamily of proteins related to the LDL receptor [10]. Flow cytometric analyses and fluorescence microscopy indicate that all megakaryocytes express LRP-1 [9,11].…”

Changes in von Willebrand factor level and von Willebrand activity with age in type 1 von Willebrand disease

“…In hemophilia A, FVIII levels increase with age, particularly in mild disease. (14) The clinical significance of this change has not been determined. In one retrospective cohort study, the authors describe increased bleeding in HA patients with increased age.…”

Association between phenotype and genotype in carriers of haemophilia A

“…Underlying predispositions of the carriers like type of mutation or severity of haemophilia A in the male relatives might have an influence on bleeding tendency. Contributing factors to FVIII:C levels might be age and comorbidities [5] or type of blood group [6]. Notably, the wide range of FVIII:C levels found in carriers does not always show a clear correlation between bleeding tendency and factor level in carriers, which might in part be explained by other factors as thrombophilic genotypes.…”