A third methodology for eliminating virus from concentrate involves affinity chromatography using a murine monoclonal antibody to either von Willebrand factor or factor VIII. MLID88264483 67 Cryoprecipitate is used as the starting material. A much higher purity factor VIII concentrate results (specific activity >3,000 U/mg protein before addition of albumin stabilizer). HIV titers are reduced significantly by this process. The product is either pasteurized in the final stage (Monoclate-P, Rorer) or is initially treated with tri-n-butyl phosphate (TNBP)/Triton X-100 (Hemophil M, Hyland). A summary of these methods and specific concentrates is given in Table 106-2 Table 106-2.
Alloantigens in Factor Concentrate
In addition to viral contamination of factor concentrates, it has been shown (beginning in the early 1980s) that intermediate purity concentrate itself may cause immune aberrations in hemophiliacs, perhaps secondary to the presence of multiple foreign proteins. MLID84244712 68 Factor concentrate in vitro may down-regulate Fc receptors on the macrophage MLID87158064 69 or may inhibit the mixed lymphocyte culture reaction MLID88264484 70 or interleukin-2 production by monocytes. MLID89194118 71 Since detailed immunologic studies were not done routinely on the hemophilia population before infection of patients with HIV, information regarding the effect of concentrate on patients is sporadic. In Scotland, in a group of HIV-seronegative hemophiliacs receiving locally produced factor concentrate not contaminated by HIV, approximately 50% demonstrated mildly decreased helper/suppressor T-lymphocyte ratios secondary to depressed CD4 cell levels. MLID84244712 68 These abnormalities appeared to be related to intensity of treatment. Others researchers have also shown that in a group of HIV-seronegative hemophiliacs, CD4 cell levels are mildly reduced when compared with normal controls. 72 Thus, frequent infusions of intermediate purity factor concentrates may lead to mild immune suppression.
Additional Complications
Other complications of treatment with concentrate include urticaria, temperature elevations, and very rarely anaphylaxis. Urticaria and bronchospasm are more commonly seen with infusions of cryoprecipitate. When cryoprecipitate is used, some centers order type-specific products.
Factor concentrates may also contain measurable titers of isoagglutinins (anti-A or anti-B). When concentrate is administered in large amounts, such as postoperatively, to patients with A and B blood types, significant hemolysis may occur. MLID72211952 73 If the patient with this complication requires blood transfusions, type O should be given. Factor concentrate with low isoagglutinin titer can subsequently be obtained from specific manufacturers. Rarer complications of factor concentrate include a syndrome of primary pulmonary hypertension described in five patients with severe hemophilia A who used large amounts of concentrate. MLID88220869 74 The mechanism has not been elaborated but may be due to particulate matter or immune complexes being deposited in the lungs. A summary of infectious implications associated with therapy is given in Table 106-3 Table 106-3.
Choice of Concentrate
Selection of a factor concentrate depends on efficacy, safety concerning virally transmitted diseases, purity, and cost. Demonstrating that a concentrate is free of harmful viruses is difficult since reliable animal models, especially for HCV, are not available. Human clinical trials are necessary to prove that new factor concentrates are safe. To demonstrate whether a specific concentrate is free of HBV, HCV, or HIV, studies using previously nontransfused patients, primarily newly diagnosed hemophiliac infants, are undertaken. Serologic studies of antiviral antibodies and liver function may be positive if patients are exposed to specific viruses.
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