Hemophilia: causes, symptoms, diagnosis, treatment

Hemophilia is usually a congenital disorder caused by deficiency of factors VIII or IX. The severity of the factor deficiency determines the likelihood and severity of bleeding. Bleeding into soft tissue or joints usually occurs within a few hours of injury. The diagnosis is suspected in patients with prolonged partial thromboplastin time, normal prothrombin time, and normal platelet count and is confirmed by measuring individual factors. Treatment consists of replacing the deficient factor if acute bleeding is suspected, confirmed, or likely to occur (e.g., before surgery).

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Causes hemophiliacs

Hemophilia A (factor VIII deficiency), which is diagnosed in 80% of patients, and hemophilia B (factor IX deficiency) have identical clinical manifestations, abnormal screening tests, and an X-linked inheritance pattern. Determination of the content of individual coagulation factors is necessary to differentiate these diseases.

Hemophilia is a congenital disorder that results from mutations, deletions, or inversions of the factor VIII or IX gene. Because these genes are located on the X chromosome, hemophilia affects mainly males. Daughters of men with hemophilia are obligate carriers, but sons are healthy. Each son of a hemophilia gene carrier has a 50% risk of being a hemophiliac, and each daughter has a 50% risk of becoming a carrier of the hemophilia gene.

More than 30% of factors VIII and IX are required to ensure normal hemostasis. Most patients with hemophilia have levels of these factors less than 5%. Carriers usually have factor levels of about 50%; occasionally, random inactivation of the normal X chromosome during early embryonic life results in a carrier having levels of factors VIII and IX less than 30%.

A large number of hemophiliacs treated with plasma concentrates in the early 1980s were infected with HIV due to viral contamination of the factor concentrates. Some patients develop immune thrombocytopenia in the context of HIV infection, which can increase bleeding.

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Symptoms hemophiliacs

Patients with hemophilia experience tissue bleeding (e.g., hemarthrosis, muscle hematomas, retroperitoneal bleeding), the onset of bleeding after injury may be delayed. Pain often accompanies the development of hemorrhage, sometimes preceding the manifestation of any other signs of bleeding. Chronic, recurrent hemarthrosis can lead to the development of synovitis and arthropathy. Even a small blow to the head can cause intracranial hemorrhage. Hemorrhage in the area of the root of the tongue can cause life-threatening compression of the respiratory tract.

Severe hemophilia (factor VIII and IX levels less than 1% of normal) results in severe bleeding throughout life, beginning soon after birth (e.g., a scalp hematoma after childbirth or severe bleeding after circumcision). Moderate hemophilia (factor levels from 1 to 5% of normal) usually results in bleeding after minor trauma. Mild hemophilia (factor levels from 5 to 25%) may result in severe bleeding after surgery or tooth extraction.

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Diagnostics hemophiliacs

Hemophilia is suspected in patients with recurrent bleeding, unexplained hemarthrosis, or prolonged PTT. If hemophilia is suspected, platelet count and factor VIII and IX levels should be measured. Patients with hemophilia have prolonged PTT but normal PT and platelet counts. Factor VIII and IX levels determine the type and severity of hemophilia. Because factor VIII levels may be decreased in von Willebrand disease (VWD), von Willebrand factor (VWF) activity, VWF antigen, and VWF multimer levels should be measured in patients with newly diagnosed hemophilia, especially if the disease is mild and there is a family history of both male and female hemophilia. Factor VIII and IX levels can sometimes be measured to determine whether a woman is a true carrier of the hemophilia A or B gene. PCR analysis of DNA containing the factor VIII gene is available in specialized centers and can be used for the diagnosis of haemophilia A carriage and for prenatal diagnosis of haemophilia A in chorionic villus sampling at 12 weeks or amniocentesis at 16 weeks. The risk of obtaining an erroneous result with this procedure is 0.5 to 1%.

After frequent factor VIII replacement therapy, 15–35% of patients with hemophilia A develop isoantibodies (alloantibodies) to factor VIII, which inhibit the activity of additional factor VIII infusions. Patients should be screened for the presence of isoantibodies (e.g., by determining the degree of shortening of the ART immediately after mixing equal volumes of the patient's plasma and normal plasma and then repeating the test after 1 hour of incubation of the mixture), especially before procedures requiring replacement therapy. If isoantibodies are present, their titer should be determined by measuring the degree of inhibition of factor VIII in serial dilutions of the patient's plasma.

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Treatment hemophiliacs

If bleeding symptoms are present, treatment should be started immediately, even before diagnostic tests are completed. For example, if a person has a headache, which may indicate intracranial hemorrhage, treatment should be started before a CT scan is performed.

Replacement of the deficient factor is the mainstay of therapy. In hemophilia A, the factor VIII level should be increased to 30% to prevent bleeding during tooth extraction or to stop incipient intra-articular hemorrhage; to 50% if there are signs of hemorrhage into a large joint or intramuscular hemorrhage; to 100% before major surgery or in the case of intracranial, intracardiac, or life-threatening hemorrhage.

Repeat transfusions of 50% of the initial dose should be given 8 to 12 hours apart to maintain factor levels above 50% for 7 to 10 days after major surgery or life-threatening bleeding. Each unit/kg of factor VIII given increases the blood level of factor VIII by approximately 2%. Thus, approximately 25 units/kg of factor VIII must be given to increase the level from 0 to 50%.

Factor VIII can be administered as a purified factor VIII concentrate, which is prepared from the blood of many donors. The preparation undergoes viral inactivation, but may not eliminate parvovirus or hepatitis A virus. Recombinant factor VIII is virus-free, but it is expensive and has an increased tendency to induce isoantibody formation. It is usually preferred until the patient is seropositive for HIV or hepatitis B or C viruses.

In hemophilia B, factor IX may be given as purified or recombinant virus-inactivated product every 24 hours. The initial and maintenance levels required are similar to those in hemophilia A; however, to achieve the same levels, the dose of factor IX must be higher than in hemophilia A because factor IX is smaller than factor VIII and, unlike factor VIII, it has extensive extravascular distribution.

Fresh frozen plasma contains factors VIII and IX. However, unless plasma exchange is necessary, whole plasma is not routinely given to patients with severe hemophilia to increase factor VIII and IX levels to control bleeding. Fresh frozen plasma should be given when immediate replacement therapy is needed when concentrated factor is not available or when the cause of the coagulopathy is uncertain.

If a factor VIII inhibitor develops, it is better to use recombinant factor VIII for treatment in subsequent administrations (90 mcg/kg).

Desmopressin or antifibrinolytic drugs may be used for treatment. As described for von Willebrand disease, desmopressin may temporarily increase factor VIII levels. For therapeutic use, the patient's response to desmopressin should be assessed before use. The drug is used after minor trauma or before certain types of dental care when replacement therapy can be avoided. Desmopressin should be used only in patients with hemophilia A (baseline factor VIII > 5%) who have had a good response to the drug.

Antifibrinolytic drugs (e-aminocaproic acid 2.5 to 4 g orally 4 times a day for 1 week or tranexamic acid 1.0 to 1.5 g 3 or 4 times a day for 1 week) are prescribed to prevent bleeding after tooth extraction or trauma to the mucous membrane of the oropharyngeal zone (for example, a ruptured tongue).

Prevention

Patients with hemophilia should avoid aspirin and nonsteroidal anti-inflammatory drugs that inhibit platelet function for a shorter period than aspirin. The newer COX-2 inhibitors have little antiplatelet activity and cause less gastrointestinal erosion than aspirin and other nonsteroidal anti-inflammatory drugs and can be used with caution in hemophilia. Regular dental examinations are necessary, since it is desirable to avoid tooth extractions and other dental surgeries. Medications should be administered orally or intravenously, since intramuscular injections may cause hematomas. Patients with hemophilia should be vaccinated against hepatitis B.

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