Factor VIII is a large glycoprotein cofactor (320 kilodaltons) that is produced mainly in hepatocytes, but also to some extent by liver macrophages, megakaryocytes, and endothelial cells.6,10 Factor VIII circulates in the plasma bound to von Willebrand factor (vWF) at a concentration of approximately 0.1 mg/mL.10 The plasma half-life of factor VIII is short at about 8 to 10 hours.10 Factor VIII deficiency should be suspected when a patient with excessive bleeding has a normal protime (PT) and an extended activated partial thromboplastin time (aPTT).
Hemophilia A, or classic hemophilia, occurs as the result of congenital deficiency of factor VIII.6,11 Clinical features of hemophilia A are the same as for hemophilia B which is caused by factor IX deficiency (see Factor IX Activity [086298]). Hemophilia A is the second most common inherited bleeding abnormality (second only to von Willebrand disease), occurring in approximately 1 of every 5000 live male births.6,11 Hemophilia A accounts for approximately 85% of all hemophilia cases.11 This condition is transmitted as an X chromosome-linked hereditary disorder.11 The majority of cases occur in men whose mothers are carriers of the genetic defect. About 30% of factor VIII deficiencies arise in men as spontaneous mutations.6,11 The prevalence of hemophilia A is equal in all ethnic groups.6,11 Female carriers of hemophilia A may rarely present with excessive bleeding.6 Hemophilia symptoms can also occur in female carriers who have a high degree of lyonization of the factor VIII alleles.11 Females with Turner syndrome karyotype XO, can also be symptomatic.11
The severity of hemophilia A can be defined by the level of factor VIII activity.7,11 Severe hemophilia, which represents approximately half the cases, is associated with a factor VIII level <1%. About 10% of cases are moderate with factor VIII levels of 1% to 5% and the remaining 30% to 40% of hemophiliacs have the mild condition with factor VIII levels above >5%.
Approximately 45% of cases of severe hemophilia A occur as the result of a genetic inversion of intron 22 of the factor VIII gene locus.7,11,12 This genetic mutation results in the production of a protein that has no functional or immunologic factor VIII activity.11 Numerous deletions, point mutations, and missense mutations have also been implicated in hemophilia A.7,11 Family studies combined with genetic testing can determine if at-risk women are carriers for a hemophilia A mutation.11 Factor VIII activity levels should not be used as the method of determining carrier status because a number of clinical conditions including pregnancy, infection, or inflammation can affect activity levels.11
Patients with hemophilia A can present with any number of bleeding manifestations.6,11 Often, infants with severe hemophilia are first diagnosed during the neonatal period because of excessive bleeding after circumcision or due to cord necrosis.11 Hemophilic infants also frequently suffer from intracranial hemorrhage or scalp hematomas. Spontaneous hemarthroses, a common symptom of hemophilias, typically do not occur until the child starts walking.7,11 Hematomas can often be observed at the sites of intramuscular injections for vaccination or medication. The most common sites of spontaneous bleeding in patients with severe hemophilia involve the joints and muscles. Recurrent bleeding leads to chronic muscle injury and degeneration of the joint tissue.6,11 Gastrointestinal bleeding can occur in approximately 10% of hemophiliacs.11 Males with mild-to-moderate hemophilia and female carries may have an increased bleeding tendency, especially following surgery or trauma.7
Most individuals with von Willebrand disease will have decreased factor VIII levels because the von Willebrand factor (vWF) is the carrier protein for factor VIII in plasma.6,11 Individuals with von Willebrand disease type 2 Normandy will have normal to slightly low vWF ristocetin cofactor activity and von Willebrand factor antigen and low factor VIII levels due to defective binding of factor VIII to the variant vWF molecule.11
Factor VIII levels are elevated at birth and increase during pregnancy.6 Factor VIII is an acute phase reactant with levels that rise during periods of acute stress, following surgery, and in inflammatory conditions.6 Levels can also increase as the result of strenuous exercise or the administration of several drugs including epinephrine, DDAVP, or estrogen (for birth control or hormone replacement therapy). Factor VIII levels can be elevated in a number of clinical conditions including carcinoma, leukemia, liver disease, renal disease, hemolytic anemia, diabetes mellitus, deep vein thrombosis, and myocardial infarction.6
Persistent elevation of factor VIII above 150% is associated with an increased risk for venous thrombosis of more than fivefold.10,13 Elevated factor VIII is also associated with an increased risk for recurrence of venous thromboembolism. Risk is graded such that the higher the factor VIII activity, the higher the risk.14 The basis for this increased risk is not well understood as genetic studies of the factor VIII and von Willebrand factor genes failed to identify a genetic basis for this increased risk.10 Values >150% are observed in 20% to 25% of individuals with venous thrombosis or thromboembolism in the absence of other known causes of factor VIII elevation.13
A syndrome of combined factor VIII and V deficiencies has been described in over 60 families in and around the Mediterranean basin.15
Hemophilia A patients receiving replacement products can develop inhibitors to factor VIII due to the production of alloantibodies.6,8 Acquired hemophilia caused by the development of autoantibodies to factor VIII can also occur.9 This rare condition (1 in 1,000,000 individuals) can following pregnancy and in elderly individual with autoimmune disorders. In this life-threatening condition, patients have bleeding symptoms similar to those seen in severe congenital hemophilia A.
