Hemophilia A (factor VIII deficiency), which affects about 80% of hemophiliacs, and hemophilia B (factor IX deficiency) have identical clinical manifestations, screening test abnormalities, and X-linked genetic transmission. Specific factor assays are required to distinguish the two.
Hemophilia may result from gene mutations: point mutations involving a single nucleotide, deletions of all or parts of the gene, and mutations affecting gene regulation. About 50% of cases of severe hemophilia A result from a major inversion of a section of the tip of the long arm of the X chromosome. Because factor VIII and factor IX genes located on the X chromosome, hemophilia affects males almost exclusively. Daughters of hemophiliacs will be obligatory carriers, but sons will be normal. Each son of a carrier has a 50% chance of being a hemophiliac, and each daughter has a 50% chance of being a carrier. Rarely, random inactivation of one of the two X chromosomes in early embryonic life will result in a carrier’s having a low enough factor VIII or IX level to experience abnormal bleeding.
A patient with a factor VIII or IX level < 1% of normal has severe bleeding episodes throughout life. The first episode usually occurs before age of 18 months. Minor trauma can result in extensive tissue hemorrhages end hemarthroses, which, if improperly managed, can result in crippling musculoskeletal deformities. Bleeding into the base of the tongue, causing airway compression, may be life threatening and requires prompt, vigorous replacement therapy. Even a trivial blow to the head requires replacement therapy to prevent intracranial bleeding.
Patients with factor VIII or IX levels about 5% of normal have mild hemophilia. They rarely have spontaneous hemorrhages; however, they will bleed severely (even fatally) after surgery if not managed correctly. Occasional patients have even milder hemophilia with a factor VIII or IX level in the 10% to 30% of normal range. Such patients may also bleed excessively after surgery or dental extraction.
By measuring the factor VIII level and comparing it with the level of von Wiellebrand factor antigen, it is often possible to determine whether a female is a true carrier of hemophilia A. Similarly, measuring the factor IX level often identifies a carrier of hemophilia B. Polymerase chain reaction analysis of DNA in the factor VIII gene amplified from lymphocytes allows identification of the hemophilia A carrier, either directly by recognition of a known specific genomic defect in the pedigree, or indirectly through study of restriction fragment length polymorphisms linked to the factor VIII gene. These techniques have also been applied to the diagnosis of hemophilia A by chorionic villus sampling in the 8 to 11 weeks fetus.
Typical findings in hemophilia are a prolonged PTT, a normal PT, and a normal bleeding time. Factor VIII and IX assays determine the type and severity of the hemophilia. Because factor VIII levels may also be reduced in Von Wiellebrand’s disease, von Wiellebrand factor antigen should be measured in patients with newly diagnosed hemophilia A, particularly if the disease is mild and a family history cannot be obtained. Some patients have an abnormal von Wiellebrand factor that binds abnormally to factor VIII, which in turn is catabolized more rapidly.
After transfusion therapy, about 15% of patients with hemophilia A develop factor VIII antibodies that inhibit the coagulant activity of further factor VIII given to the patients. Patients should be screened for factor VIII anticoagulant activity, especially before an elective procedure that requires replacement therapy.
Patients with hemophilia should avoid using aspirin. In some patients, disabling pain from musculoskeletal complications may require judicious use of other NSAIDs, which have a lesser, more transient effect than aspirin on platelet function. Regular dental care is essential to avoid tooth extractions and other dental surgery. All drugs should be given orally or intravenously, because intramuscular injections can cause large hematomas. Patients who are newly diagnosed with hemophilia should be vaccinated against hepatitis B.
Fresh frozen plasma contains factors VIII and IX. However, unless plasma exchange is performed, sufficient whole plasma cannot be given to patients with severe hemophilia to raise factor VIII or IX concentrations to levels that effectively prevent or control bleeding. For hemophilia A, the treatment of choice is viral inactivated or recombinant factor VIII concentrate. For hemophilia B, the treatment of choice is a highly purified viral inactivated factor IX concentrate.
In hemophilia A, the factor VIII level should be raised transiently to about 0,3 U (30%) to prevent bleeding after dental extraction or to abort a beginning joint hemorrhage; to 0.5 U (50%) if major joint bleeding is already evident and 1.0 U (100%) if bleeding is life threatening or before major surgery.
In hemophilia B, the dose of factor IX is given as purified factor IX. The plasma factor IX level rises to only half that expected from the units of factor IX listed on the bottle.