Large Cohort of Symptomatic Female Carriers of Hemophilia in an Extended Native American Family

Hemophilia A is an X-linked recessive genetic bleeding disorder resulting in a lack of clotting factor VIII. Although this disorder primarily affects males, a female who inherits one affected X chromosome from a parent becomes a carrier of hemophilia. While it is widely believed that carriers are asymptomatic, some of these women have mild hemophilia, defined by ISTH as a circulating factor VIII level > 0.5 to 0.40 IU/ml or 5 - 40 % of normal. (White et al Thromb Haemost 2001)

Data demonstrates hemophilia A carriers have the same risk for bleeding as a male with mild hemophilia A at the corresponding factor level. Carriers report significantly more bleeding events than non-carriers from small wounds and after invasive procedures, and their bleeding tendency is inversely correlated to their factor level. (Plug et al Blood 2006) Carriers have been shown to demonstrate decreased joint range of motion, soft tissue and osteochondral changes on MRI, consistent with subclinical joint bleeds leading to structural abnormalities in their joints. (Gilbert et al Haemophilia 2014). Additionally, carriers have been shown to report higher scores on pictorial blood assessment charts, a semi-quantitative measure of menstrual blood loss. (Kadir et al Haemophilia 1999)

We report here a unique patient population from our Owyhee Indian Health Hemophilia Treatment Center Outreach Clinic on the Duck Valley Indian Reservation in Owyhee, NV. On this reservation, a German Immigrant with hemophilia A married 2 women of the Shoshone Indian Tribe, and they had 14 children (8 females and 6 males). The family tree reveals after four generations there are currently 162 descendants with the same hemophilia A gene mutation, which has been identified. Factor VIII levels in the female family members range from 7% to 50%. The male hemophilia A patients are treated on demand with plasma-derived factor VIII products, currently Koate-DVI, for traumatic events, and prophylactically for medical or dental procedures, or surgery. Approximately 20-25% of the female carriers in this population have been treated with plasma-derived FVIII concentrates, currently Koate-DVI, for childbirth and surgeries. Additionally, all female carriers from teenage years to age 30 are treated with desmopressin acetate nasal spray (Stimate) for menorrhagia and are treated with oral aminocaproic acid (Amicar) for nose bleeds and soft tissue bleeds.

Carriers of hemophilia A with factor VIII levels in the range observed in this family, particularly when symptomatic, should receive the diagnosis of "mild hemophilia". Their propensity for developing subclinical as well as clinical bleeding needs to be recognized to assure the receive treatment appropriate to their symptomatology. The low levels of FVIII observed in this family are likely due to extreme lyonization associated with their particular gene mutation. Familial low levels of FVIII can also be seen in some forms of type 2 von Willebrand Disease secondary to poor FVIII binding and a shortened half-life. However, since VWD is inherited in an autosomal recessive pattern, males would not selectively have the severity observed here. Optimal diagnostic and therapeutic strategies as well as many other aspects concerning mild hemophilia remain to be clarified. Additional studies to define these findings are underway.