Hemophilia A is the most common hereditary disease with serious bleeding. It is caused by a reduction in the amount or activity of factor VIII. This protein serves as a cofactor for the activation of factor X in the coagulation cascade. Hemophilia A is inherited as an X- linked recessive trait, and thus it occurs in males and in homozygous females. However, excessive bleeding has been described in heterozygous females, presumably caused by extremely ? unfavorable lyonization? (inactivation of the normal X chromosome in most of the cells) Approximately 30% of the patients have no family history; their disease is presumably caused by new mutations.

Hemophilia A exhibits a wide range of clinical severity that correlates well with the level of factor VIII activity. Those with less than 1% of normal activity develop severe disease; levels between 2% and 5% of normal are associated with moderate disease and patients with 6% to 50% of activity develop mild disease. The variable degrees of dificiency in the level of factor VIII procoagulant are related to the type of mutation in the factor VIII gene. As with ?-thalassemias, several genetic lesions ( deletions, nonsense mutations that create stop condon, splicing errors) have been documented. Most of the severely affected patients have an unusual mutation in which a large sequence of DNA becomes inverted thus preventing ay synthesis of factor VIII. In a minority of patients, the mutations do not affect the synthesis of factor VIII, but the functional domains are altered. In such cases , there is a tendency toward easy bruising and massive hemorrhage after trauma or operative procedures. In addition, ? spontaneous? hemorrhages are frequently encountered in regions of the body normally subject to trauma, particularly the joints, where they are known as hemarthroses. Recurrent bleeding into the joints leads to progressive deformities that may be crippling Petechiae are characteristically absent.

Patients with hemophilia A typically have normal bleeding time and platelet counts, with prolonged PTT and normal PT. These tests point to an abnormality of intrinsic coagulation pathway. Factor VIII assays are required for diagnosis. Visit for

Treatment of hemophilia A involves infusion of factor VIII, currently derived from human plasma. Approximately 15% of severely affected patients with low or absent factor VIII develop antibodies against factor VIII that can complicate replacement therapy as well, the most serious of which is the risk of transmission of viral disease.

Hemophilia B (Christmas disease, factor IX deficiency)

Severe factor IX deficiency is a disorder that is clinically indistinguishable from hemophilia A. With the exception of DNA inversion , the spectrum of mutations found in hemophilia B is similar to that seen in hemophilia A. Moreover, it is also inherited as an X-linked recessive trait and may occur asymptomatically or with associated hemorrhage. In about 14% of these patients, factor IX is present but non functional. As with hemophilia A. PTT is prolonged and PT is normal , as is bleeding time. Identification of Christmas disease ( named after the first patient with this condition and not the holiday) is possible only by assay of the factor levels.