A. Inheritance is x-linked recessive.
B. Incidence is 1 in 5000 live male births.
C. Mechanism - quantitative deficiency in the synthesis of FVIII
1. The FVIII gene is large and appears to undergo frequent mutations.
2. One of the most common mutations in severe hemophilia A is an inversion within the gene.
D. Clinical features
1. Suspect hemophilia in any male who has history of extensive bleeding after trauma or spontaneous bleeding into joints and muscles.
2. Excessive bleeding at time of circumcision
3. Severity of bleeding depends on level of FVIII
E. Lab abnormalities
1. Prolongation of aPTT (variable with degree of hemophilia)
2. Decreased FVIII acitvity
3. Normal vonWillebrand Factor and Ristocetin cofactor
4. Normal bleeding time
F. Management
1. Avoid aspirin
2. Mild hemophilia - prophylaxis with desmopressin (DDAVP) before dental procedures or minor surgery. Desmopressin induces release of stored FVIII and vonWillebrand Factor. If the increase in FVIII activity is not sufficient, administer FVIII concentrates. Antifibrinolytics such as aminocaproic acid may be helpful. For major surgery, give FVIII concentrates perioperatively.
3. Moderate and Severe hemophilia - give FVIII concentrate at the earliest sign of bleeding. Desmopressin will not be helpful because these patients do not have enough stored FVIII.
4. The amount of FVIII to give depends on the severity of the bleed.
5. Available forms of FVIII
6. Cost of FVIII treatment is $60,000-200,000 per year for severe hemophilia and for those patients with hemarthroses.
7. Future - research is being conducted toward gene therapy involving insertion of the FVIII gene into a viral vector. The vector would inject an autologous cell line which could then be implanted or transplanted.
A. Acquired, not inherited
B. They are antibodies that neutralize FVIII and can either be alloantibodies against exogenous FVIII or autoantibodies.
C. They are a serious complication of FVIII treatment in the severe hemophiliac population where the incidence of developing an inhibitor is 15-20%....
D. But the inhibitors can also occur in non-hemophiliac patients, although rare, in the setting of:
1. Idiopathic conditions - i.e. otherwise normal elderly individuals.
2. Autoimmune disorders such as systemic lupus erythematosus, rheumatoid arthritis, etc.
3. Malignancies such as lymphoproliferative disorders, lymphomas, and solid tumors.
4. Drug reactions to penicillin, chloramphenicol, phenytoin, etc.
5. Pregnancy and the postpartum state
E. Risk factors for development of antibodies
1. Severity of hemophilia: Patients with severe hemophilia are at much higher risk because they are exposed to more FVIII therapy.
2. Age of the patient and degree of FVIII exposure: 15 -20% of heavily treated hemophiliac children develop antibodies by the age of 20.
3. Genetic defect that results in the absence of synthesis of FVIII protein: These patients are at greater risk for developing antibodies after treatment with FVIII concentrates.
F. Characteristics of FVIII antibodies
1. The majority of FVIII inhibitors are IgG antibodies, more specifically of the IgG4 subclass.
2. There are two main types of antibodies
3. Antibodies are identified by their ability to neutralize FVIII at 37 degrees Celcius after incubation for 2-3 hours.
G. Diagnosis
1. Clinical suspicion
a. Whenever classic hemophiliacs show a decreased response to FVIII replacement therapy, screen for FVIII inhibitor.
b. Acquired inhibitors should be suspected when non-hemophiliac patients present with spontaneous hematomas with sudden, life-threatening bleeds.
2. Laboratory information
a. aPTT - will be prolonged and will not correct upon mixing patient's plasma with normal plasma. (Normal plasma contains FVIII. Therefore, when mixing plasma with inhibitor with normal plasma with adequate FVIII levels, the antibodies will neutralize this FVIII as well, resulting in prolongation of aPTT.)
b. However, the presence of FVIII inhibitor can be confirmed by adding inhibitor plasma with normal plasma and then assaying all the residual clotting factors in the normal plasma. If a specific FVIII inhibitor is present, then the FVIII levels will be low.
c. Quantification of the inhibitor can be done with the Bethesda Assay
H. Characteristics of patients - Grouped as low responders or high responders
1. Low responders are patients who usually have low titers of inhibitor (less than 10 BU), which does not increase after challenge with FVIII. Therefore, these patients do not show significant anamnestic response with subsequent FVIII treatments.
2. High responders are mostly hemophiliacs who develop a high titer of inhibitor when challenged with FVIII.
I. Management
1. Once an inhibitor is suspected, measure aPTT and quantify with Bethesda Assay
2. Treatment - depends on patient's status as low or high responder and the severity of the bleeding episode.
3. Low responders
a. Mild bleeding episodes - options include:
b. Severe bleeding - options include:
4. High responders
a. Mild bleeding episodes - considerations include:
b. Severe bleeding episodes
5. Alternative therapies
a. Immunosuppressive agents to control antibody production
b. Intravenous gamma globulin - in the hope that some antibodies in this pooled sample may be directed against the inhibitor
c. Induction of immune tolerance to suppress inhibitor formation by administration of FVIII on a continuous basis.
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