– Dr. Geeta Sundar

Each year, April 17th is recognised worldwide as the World Hemophilia Day. The essence behind such a day hopes to bring the needed awareness and togetherness to understand the diagnosis better and enhance care to those who don’t have it.
World Haemophilia Day was started in 1989 by the World Federation of Hemophilia (WFH) which chose to bring the community together on April 17 in honour of WFH founder Frank Schnabel’s birthday. Hemophilia A and B make the cut, but vWD is also included under the umbrella of this day.

In fact, women with Hemophilia A, a.k.a the carriers are also at an increased risk of complications. For a brief understanding, Hemophilia A is a bleeding disorder resulting from the partial or complete deficiency of functional factor VIII protein caused by a wide range of heterogeneous mutations in the factor 8(F8) gene. Due to the X-linked recessive inheritance pattern, males are affected, while females, denoted as carriers, transmit the disease. Usually these females do not exhibit a hemophilic phenotype due to the presence of the second X chromosome.
Female carriers are expected to have a plasma concentration of factor VIII corresponding to half the concentration found in healthy individuals, which is generally sufficient for normal hemostasis. However due to the phenomenon of lyonization – a random X chromosome inactivation takes place in an early phase of embryonic development – a wide range in clotting factor levels is found in carriers of hemophilia A from <1 % to >150%.
When a female embryo consists of only a few cells, one of the two X chromosomes inside each cell is inactivated, randomly, as part of a natural process. Normally, about half of each of the X chromosomes will be inactivated, but in some cases more X chromosomes carrying the hemophilia mutation are inactivated. In other females, the majority of “healthy” X chromosomes may be inactivated. Which is why, femlaes typically have a mosaic of affected and unaffected X chromosomes being expressed. Other factors such as ABO blood group, pregnancy, and stress may also influence levels of factor 8.

Clinically, carriers are comparable to mild hemophilia, except that they may have increased bleeding during menstruation and after delivery. While diagnosis and severity classification of Hemophilia A in males is based on factor 8 activity, identification of carriers is more challenging as the majority of Hemophilia A carriers have normal factor 8 activity (>0.40 IU/mL) and there is inconsistent correlation of factor 8 activity to bleeding symptom severity. But, despite normal factor 8 activity (>0.40 IU/mL) the carriers often report an increased bleeding tendency – like epistaxis, easy bruising, menorrhagia, and post-operative surgical and dental bleeding.
The phenotypic expression of the disease in females could result from different mechanisms. What is believed is that a skewed inactivation of the X chromosome leads to predominant expression of the mutated allele as a result of a preferential inactivation of the normal X chromosome. Research also suggests that Hemophilia A phenotype in females can be linked to numerical or structural X chromosomal anomaly as Turner syndrome or translocation respectively.
But, caution is required when diagnosing these rare cases, given that a vWD deficiency can result in decreased factor 8 binding capacity. Measuring the clotting factor levels in all carriers, whether obligatory, proven, or possible carriers should be done routinely and as early as possible. Carriers with levels <60% should be counselled, educated and given factor replacement if required. Carriers with <30% often present with mild haemophilia and require replacement, more so before any medical intervention.

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