Determinants of factor VIII plasma levels in carriers of haemophilia A and in control women

Abstract

Factor VIII (FVIII) levels show a considerable variability in female carriers of haemophilia A. Presently, the reasons for this are poorly understood. The aim of the study was to elucidate the influence of genetic and non-genetic parameters on FVIII plasma levels in carriers (n = 42). Results were compared with age-matched healthy women without carriership of haemophilia A (n = 42). Each carrier was tested for the family-specific mutation, ABO blood group, FVIII level, von Willebrand factor (VWF) antigen and activity and C-reactive protein (CRP). FVIII levels were lower in carriers compared to non-carriers [74% (51-103) vs. 142% (109-169), P < 0.001]. No statistically significant differences were observed between the two groups with respect to VWF activity, prothrombin-time, hs-CRP, fibrinogen, body mass index (BMI), age and smoking status as well as the distribution of ABO blood groups. In non-carriers, FVIII was statistically significantly correlated with BMI, activated partial thromboplastin time (APTT), VWF antigen, hs-CRP and fibrinogen. In carriers, significant correlations between FVIII and APTT, VWF antigen and activity were found, whereas BMI, hs-CRP or fibrinogen did not correlate with FVIII. In non-carriers, the association of FVIII with ABO blood groups was statistically significant (P = 0.006), but not in carriers of haemophilia A (P = 0.234). The type of FVIII gene mutation did not influence FVIII levels. Carrier status is the major determinant of a carrier;s FVIII plasma level. Factors known to influence FVIII levels in the general population do not significantly affect FVIII activity in carriers, neither does the type of mutation influence FVIII levels.

Factor levels in carriers of haemophilia are associated with familial severity: a Danish single centre study

“…Factor levels according to familial severity were not reported. A possible influence on the observed factor levels cannot be ruled out, though the median FVIII level in this study is concordant with former studies [1][2][3]7]. In the Swedish study by Knobe and Ljung [6], there was no association between severity and FIX levels in 67 HB carriers.…”

“…In one larger Dutch study, Plug et al [1] reported median factor levels of 60 IU mL À1 in a similar cohort of 274 carriers of HA and HB. Concerning carriers of HA, von Willebrand factor activity and antigen levels influence the FVIII level [7], but were not routinely assessed in this cohort. Miesbach et al [2] did not find a difference in factor levels between severity groups in 46 HA carriers, median FVIII 0.55%.…”

Thrombin generation in patients with a bleeding tendency of unknown origin

“…The measurement of factor VIII and factor IX was performed according to routine laboratory methods and as described previously [13,14].…”

Influence of Imprinting of an X Chromosome and of the Methylene Tetrahydrofolate Reductase (MTHFR) 677C>T Polymorphism on FVIII Activity

“…VWF levels and polymorphisms in the VWF gene are known to have a major impact on FVIII:C [4][5][6][7][8][9][10]. In addition, AB0 blood groups influence FVIII:C. Individuals with blood group 0 have significantly lower FVIII:C than those with blood group A, B or AB [1,[4][5][6][7][8][9][10][11]. Genes involved in FVIII synthesis and degradation have also been reported to be associated with FVIII activity [8,[11][12][13][14][15].…”

“…Genes involved in FVIII synthesis and degradation have also been reported to be associated with FVIII activity [8,[11][12][13][14][15]. Moreover, factors like age, sex, hormone levels and inflammatory processes have been found to contribute to the high variability of FVIII:C [1,3,4,10,11,[16][17][18]. However, all these factors do not fully explain the variability of FVIII, and it is likely that other mechanisms play a role.…”