Association between phenotype and genotype in carriers of haemophilia A

Abstract

Female carriers of haemophilia might suffer from increased bleeding tendency therefore the assessment of the bleeding risk is very important for improving care. This single-centre study documents the occurrence of bleedings in 46 carriers of haemophilia A including bleeding after tooth extraction (77%), easy bruising (67%), postsurgical bleeding (61%), menorrhagia (50%) or prolonged postpartum bleeding (43%). The F8 gene mutation of all 46 carriers (median age: 36.5 years, 15-80 years; mean FVIII:C activity: 59 ± 24.45%; normal range: 64-167%) was determined, and family history of haemophilia was recorded. For analysis, the bleeding tendency of the carriers was differentiated by severity into three groups. There was no statistically significant difference of FVIII:C between these groups. However, a correlation was found between the severity of bleeding tendency and the type of F8 gene mutation (P < 0.05) as well as the severity of haemophilia in affected male relatives (P < 0.0005). Results show that even carriers with a FVIII:C activity as high as 50-60% are at increased risk of bleeding. Incidence and intensity of bleeding symptoms of haemophilia A carriers are high and correlated with the phenotype of the male haemophilic relative and the underlying F8 gene mutation.

Both Hemophilia Health Care Providers and Hemophilia A Carriers Report That Carriers Have Excessive Bleeding

“…The bleeding symptoms noted in our survey data are similar to previously published findings of Hemophilia A carriers with similar demographic information and factor activity (2, 3). Our survey as well as the previously reported data are not only consistent, but also emphasize the differences in bleeding tendencies reported when compared to a healthy population.…”

Management of Inherited Bleeding Disorders in Pregnancy

“…0.5 iu/ml, although studies have shown that the median is in fact slightly higher at 0.6 iu/ml. 6,8 Families in which many females are low level carriers are thought to have co-inherited the haemophilia gene and a genetically controlled susceptibility to skewed lyonisation. 9 Other factors, such as ABO blood group, may also influence factor levels.…”

“…73 Clotting factor levels fall from 2 days postpartum and although the mechanism for cessation of bleeding is largely mechanical (through uterine contraction), borderline levels of factor VIII and IX are associated with increased risk of PPH. 6 Thus, haemostatic levels should be maintained in the initial postpartum period. Where treatment has been given, a factor assay should be repeated 6-12 hours later and top-up treatment given if needed, as consumption of factor can be greater during this time.…”

“…The causative mutation in the family influences severity of haemophilia and may also influence the bleeding phenotype in carriers. 6 The most significant complication of haemophilia is the development of antibodies (inhibitors) to the clotting factor preparations used for treatment. This occurs in around 10-40% of treated patients and involves both genetic and nongenetic factors.…”

“…Since carriers may bleed with invasive procedures with levels around 0.5 iu/ml, this should be the absolute minimum tolerated for major procedures, such as lower segment caesarean section. 6 If treatment is required, factor levels of 1.0 iu/ml should be aimed for and not allowed to fall below 0.5 iu/ml.…”