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Hemophilias
are common hereditary bleeding disorders caused by deficiencies
of either clotting factor VIII or IX. The extent of factor deficiency determines
the probability and severity of bleeding. Bleeding into deep tissues
or joints usually develops within hours of trauma. The diagnosis
is suspected in a patient with an elevated PTT and normal PT and
platelet count; it is confirmed by specific factor assays. Treatment
includes replacement of the deficient factor if acute bleeding is
suspected, confirmed, or likely to develop (eg, before surgery).
Hemophilia A (factor VIII deficiency), which affects about 80% of hemophilic patients, 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 is an inherited disorder that results from mutations, deletions, or inversions affecting a factor VIII or IX gene. Because these genes are located on the X chromosome, hemophilia affects males almost exclusively. Daughters of hemophilic males are obligate carriers, but sons are normal. Each son of a carrier has a 50% chance of having hemophilia, and each daughter has a 50% chance of being a carrier.
Normal hemostasis requires > 30% of normal factor VIII and IX levels. Most hemophilia patients have levels < 5%. Carriers usually have levels of about 50%; rarely, random inactivation of their normal X chromosome in early embryonic life results in a carrier having factor VIII or IX levels of < 30%.
Most hemophilia patients who were treated with plasma concentrates in the early 1980s were infected with HIV due to contaminated factor concentrates. An occasional patient develops immune thrombocytopenia secondary to HIV infection, which can exacerbate bleeding.
Symptoms and Signs
Patients with hemophilia bleed into tissues (eg, hemarthroses, muscle hematomas, retroperitoneal hemorrhage), and the bleeding may be delayed after trauma. Pain often occurs as bleeding commences, sometimes before other signs of bleeding develop. Chronic or recurrent hemarthroses can lead to synovitis and arthropathy. Even a trivial blow to the head can cause intracranial bleeding. Bleeding into the base of the tongue can cause life-threatening airway compression.
Severe hemophilia (factor VIII or IX level < 1% of normal) causes severe bleeding throughout life, usually beginning soon after birth (eg, scalp hematoma after delivery or excessive bleeding after circumcision). Moderate hemophilia (factor levels 1 to 5% of normal) usually causes bleeding after minimal trauma. In mild hemophilia (factor levels 5 to 25% of normal), excessive bleeding may occur after surgery or dental extraction.
Diagnosis
Hemophilia is suspected in patients with recurrent bleeding, unexplained hemarthroses, or a prolongation of the PTT. If hemophilia is suspected, PTT, PT, platelet count, and factor VIII and IX assays are obtained. In hemophilia, the PTT is prolonged, but the PT and platelet count are normal. Factor VIII and IX assays determine the type and severity of the hemophilia. Because factor VIII levels may also be reduced in von Willebrand's disease (VWD), von Willebrand's factor (VWF) activity, antigen, and multimer composition are measured in patients with newly diagnosed hemophilia A, particularly if the disease is mild and a family history indicates that both male and female family members are affected. Determining if a female is a true carrier of hemophilia A is sometimes possible by measuring the factor VIII level. Similarly, measuring the factor IX level often identifies a carrier of hemophilia B. PCR analysis of DNA that comprises the factor VIII gene, available at specialized centers, can be used for diagnosis of the hemophilia A carrier state and for prenatal diagnosis of hemophilia A by chorionic villus sampling at 12 wk or amniocentesis at 16 wk. These procedures carry a 0.5 to 1% risk of miscarriage.
After repeated exposure to factor VIII replacement, about 15 to 35% of patients with hemophilia A develop factor VIII isoantibodies (alloantibodies) that inhibit the coagulant activity of any additional factor VIII infused. Patients should be screened for isoantibodies (eg, by measuring the degree of PTT shortening immediately after mixing the patient's plasma with an equal volume of normal plasma, and then by repeating the measurement after incubation for 1 h), especially before an elective procedure that requires replacement therapy. If isoantibodies are present, their titers can be measured by determining the extent of factor VIII inhibition by serial dilutions of patient plasma.
Prevention
and Treatment
Hemophilia patients should avoid aspirin and NSAIDs that suppress platelet function more transiently than aspirin . The newer COX-2 inhibitors have little antiplatelet activity, may produce fewer GI erosions than aspirin or other NSAIDs, and can be used with caution in hemophilia. Regular dental care is essential so that tooth extractions and other dental surgery can be avoided. Drugs should be given orally or IV; IM injections can cause hematomas. Hemophilia patients should be vaccinated against hepatitis B.
If symptoms suggest bleeding, treatment should begin immediately, even before diagnostic tests are completed. For example, treatment for headache that might indicate intracranial hemorrhage should begin before a CT scan is completed.
Replacement of the deficient factor is the primary treatment. In hemophilia A, the factor VIII level should be raised transiently to about 30% of normal to prevent bleeding after dental extraction or to abort an incipient joint hemorrhage; to 50% if major joint or IM bleeding is already evident; and to 100% before major surgery or if bleeding is intracranial, intracardiac, or otherwise life threatening. Repeated infusions at 50% of the initial calculated dose should then be given q 8 to 12 h to keep trough levels above 50% for 7 to 10 days after major surgery or life-threatening hemorrhage. Each unit/kg of factor VIII increases the factor VIII level by about 2%. Thus, to increase the level from 0% to 50%, about 25 units/kg are required.
Factor VIII can be given as purified factor VIII concentrate, which is derived from multiple donors. It undergoes viral inactivation, but this may not eliminate parvovirus or hepatitis A. Recombinant factor VIII is free of viruses but is expensive and may confer a greater risk of inducing isoantibodies. It is usually preferred unless the patient is already seropositive for HIV or for hepatitis B or C virus.
In hemophilia B, factor IX can be given as a purified or recombinant viral-inactivated product q 24 h. The target levels of factor correction are the same as in hemophilia A; however, to achieve these levels, the dose must be higher than in hemophilia A because factor IX is smaller than factor VIII and, in contrast to VIII, has an extensive extravascular distribution.
Fresh frozen plasma contains factors VIII and IX. However, unless plasma exchange is performed, sufficient whole plasma usually cannot be given to patients with severe hemophilia to raise factor VIII or IX concentrations to levels that prevent or control bleeding. Fresh frozen plasma should, therefore, be used only if rapid replacement therapy is necessary in the circumstance that factor concentrate is unavailable or the patient has a coagulopathy that is not yet defined precisely.
In hemophiliacs who develop a factor VIII inhibitor, treatment is best accomplished using recombinant factor VIIa in repeated high doses (eg, 90 μg/kg).
Adjunctive therapies may include desmopressin or an antifibrinolytic drug. As described for VWD (see Thrombocytopenia and Platelet Dysfunction: Treatment), desmopressin may temporarily raise factor VIII levels. The patient's response should be tested before desmopressin is used therapeutically. Its use after minor trauma or before elective dental surgery may obviate replacement therapy. Desmopressin should be used only for patients with mild hemophilia A (basal factor VIII levels ≥ 5%) who have demonstrated responsiveness.
An antifibrinolytic agent (ε- aminocaproic acid 2.5 to 4 g po qid for 1 wk or tranexamic acid 1.0 to 1.5 g po tid or qid for 1 wk) should be given to prevent late bleeding after dental extraction or other oropharyngeal mucosal trauma (eg, tongue laceration).
Last full review/revision November 2005
Content last modified November 2005
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