Hemophilia A is the inherited bleeding disorder most often associated with severe morbidity, frequently requiring hospitalization. It is due to deficiency of factor VIII. When activated, factor VIII forms a complex with activated factor IX, enabling the efficient proteolytic activation of factor X (see bottom of sidebar and Chapter 13 for more information about factor VIII). Hemophilia A occurs in about 1 in 5000 male births. The gene encoding factor VIII is located near the tip of the long arm of the X chromosome. Thus, hemophilia A is inherited in an X-linked manner, with female heterozygous carriers passing the disease on to half of their sons. The royal families depicted in Figure 15-1 comprise a typical kindred demonstrating X-linked transmission. About 30% of patients have no family history of abnormal bleeding. Most of these cases are due to spontaneous mutations. Although hemophilia A can occur in homozygous females, often owing to consanguinity, most females who bleed abnormally are heterozygous carriers of the hemophilia gene. Although the mechanism for their low factor VIII levels is not known, skewed X-inactivation (lyonization) has been hypothesized.
Patients with hemophilia A tend to have deep bleeding into joints (hemarthroses) or muscle beds, rather than bleeding from mucosal surfaces. Patients with repeated joint hemorrhage develop chronic disability due to swelling, deformity, severe pain, limitation of motion, and contractures that can be corrected only by joint replacement. Less often patients have bouts of gastrointestinal or genitourinary bleeding and, rarely, intracerebral hemorrhage—a catastrophic event. Patients are assigned to one of three levels of severity according to plasma levels of factor VIII. These levels generally predict the phenotype of the patient. Those with 1% or less factor VIII (severe hemophilia) have an average of 20 to 30 episodes per year of either spontaneous bleeding or excessive bleeding after minor trauma. Patients with 1% to 4% factor VIII levels have moderate hemophilia, whereas individuals with greater than 4% factor VIII levels generally have bleeding episodes only after trauma or surgery.
As might be surmised from the range of phenotypes, hemophilia A is a genetically heterogeneous disease. A wide variety of mutations of the factor VIII gene have been identified in hemophilia patients, including missense mutations, nonsense mutations leading to premature termination of translation, frame shifts, deletions, and rearrangements. The most commonly encountered mutation, depicted in Figure 15-2A, is an inversion that reverses the orientation of the 3' end of the gene relative to the 5' promoter and transcriptional start site. Alleles bearing this rearrangement, observed in about 50% of severe hemophilia A patients, make no factor VIII. As shown in Figure 15-2B, the great majority of mutations in patients with severe hemophilia A have either inversions, large deletions, nonsense mutations, or frame shifts, all of which preclude synthesis of full-length factor VIII. In contrast, those with moderate or mild hemophilia A usually have missense mutations in which full-length protein is produced but has impaired stability or function.
Mutations of factor VIII gene in hemophilia A. A) Inversion responsible for most cases of severe hemophilia A. B) Distribution of mutations in severe versus mild to moderate hemophilia A. (Modified with permission from Kaufman RJ and Antonarakis SE. Structure, biology and genetics of factor VIII. In Hoffman R, Benz EJ, Shattil SJ, et al, eds. Hematology: Basic Principles and Practice, 3rd Edition. New York, USA, Churchill Livingstone, 2001: 1858-1859.)
Because factor VIII is part of the intrinsic pathway of coagulation, the partial thromboplastin time in a patient with hemophilia A is prolonged, whereas the prothrombin time is normal. Moreover, there are no abnormalities in the platelet count or in tests of platelet function such as the bleeding time. Assay of factor VIII coagulant activity is used not only in establishing the diagnosis but also in monitoring patients with hemophilia A and assessing their need for therapy. This test entails measurement of the clotting time after the patient's plasma is mixed with factor VIII–deficient plasma. Molecular genetic testing is now available to diagnose hemophilia A during early fetal life for purposes of genetic counseling.
Currently, patients with hemophilia A are treated with infusions of either recombinant factor VIII or highly purified plasma-derived factor VIII prepared from human donor plasma. Both are equally effective and free of viral pathogens. The recombinant product costs 2 to 3 times as much as the plasma concentrates. Factor VIII has a plasma half-life of 8 to 12 hours. Thus, twice daily infusions are required to maintain levels adequate for hemostasis in patients with serious active bleeding (eg, intracranial, intraperitoneal, and gastrointestinal bleeds) or facing major surgery. Isolated joint hemorrhage is usually successfully treated with a single infusion sufficient to raise the plasma level of factor VIII to over 30%. Many children in the United States and in other developed countries are treated with prophylactic self-infusions of factor VIII three times a week in order to prevent damage to joints. Raising the factor VIII level from a baseline of 1% or less to 3% to 4% alters the phenotype of the patient dramatically. In the absence of human immunodeficiency virus (HIV) infection, patients with severe hemophilia treated with factor replacement have a life expectancy of about 65 years, whereas life expectancy in those with mild or moderate disease is near normal. The limiting factor is cost. Prophylactic treatment of children with factor VIII deficiency costs over $100,000 per year. In less developed countries, the high cost of factor VIII precludes most patients from being adequately treated, and many suffer a life of severe pain and disability. In patients with mild or moderate hemophilia A who produce some factor VIII, treatment with desmopressin releases von Willebrand -factor (vWF) from stores in endothelial cells and results in a significant increase in plasma levels of factor VIII, due to the ability of vWF to bind and stabilize factor VIII. As a general rule, desmopressin infusion raises factor VIII levels 3-fold to 4-fold when given daily for up to 3 days.
Patients with hemophilia A are ideal candidates for gene therapy. Hemophilia A is a monogenetic disease that, in contrast to sickle cell disease, is not significantly confounded by concurrent genetic modifiers. Moreover, tight regulation of factor VIII gene expression is not necessary for safe and effective treatment of hemophilia A, because factor VIII levels from 10% to 150% of normal are adequate to achieve hemostasis and carry no apparent risk of thrombosis on the high end of the range. Contrast this with the situation in sickle cell anemia and thalassemia, in which erythroid-specific, precisely balanced and controlled globin gene expression is critical. Despite these inherent advantages, progress in this endeavor has been disappointing to date.
In addition to the consequences of repetitive hemarthroses mentioned earlier, two other major problems threaten the well-being and life expectancy of patients with hemophilia A. Prior to 1990, patients were treated with concentrates of pooled plasma that were contaminated with pathogenic viruses—in particular, hepatitis B and C as well as HIV. As a result, nearly all patients with hemophilia A severe enough to require infusions became infected with hepatitis B or C, and of these, nearly 20% developed hepatic cirrhosis. About two-thirds of these patients were also infected with HIV. The development of AIDS in hemophilia patients enormously complicates their management and for the last two decades has been the leading cause of death among adult patients with severe disease.
A second major complication is the development of antibodies that neutralize factor VIII. These inhibitors arise primarily in about 10% to 15% of severe hemophiliacs who lack the ability to produce even small amounts of endogenous factor VIII. The immune system in these patients sees the exogenously administered protein as "foreign" and mounts an antibody response. In some patients, inhibitor titers remain low enough to be overridden by infusion of large amounts of factor VIII. Moreover, the titer of low-level inhibitors generally does not rise with factor VIII infusions (non-inducible). Unfortunately, in others the titer of anti-factor VIII antibodies builds up to extremely high levels—enough to neutralize the total amount of factor VIII normally present in the circulation and all of the exogenous factor VIII that can reasonably be infused. Moreover, infusions of factor VIII in such patients usually result in an anamnestic antibody response. These patients are at very high risk of catastrophic bleeding. If there is minimal cross-reactivity between the anti-factor VIII antibody and porcine factor VIII, an effective therapeutic option is to switch to porcine factor VIII infusions. Alternatively, patients with high-titer inhibitors that neutralize porcine factor VIII can be treated with recombinant activated factor VII or by preparations that bypass the intrinsic pathway and directly trigger the activation of factor X to factor Xa.