Hemophilia Transfusion

In the early 1980s, the development of HIV/AIDS in young blood transfusion patients was a powerful incentive to find other sources for the blood-derived proteins used to treat hemophilia, a group of inherited disorders affecting the clotting of blood. Hemophilia has... 

When hemophilia is due to a deficiency in factor IX (FIX), it is designated hemophilia B. In the same way as hemophilia A, the alternative to treatment based on blood transfusion or plasma-derived products is the use of recombinant FIX, which was approved for commercialization in 1997 with the name of BeneFix. ... 

Graham JB,Buckwalter JA, Hartley LJ, Brinkhous KM. Canine hemophilia. Observations of the course, the clotting anomaly, and the effects of blood transfusions. J Exp Med 1949 90 97-111. 

In the past, hemophiliacs were treated with transfusions of a concentrated plasma fraction containing factor VIII. This therapy carried the risk of infection. Indeed, many hemophiliacs contracted hepatitis and AIDS. A safer preparation of factor VIII was urgently needed. With the use of biochemical purification and recombinant DNA techniques, the gene for factor VIII was isolated and expressed in cells grown in culture. Recombinant factor VIII purified from these cells has largely replaced plasma concentrates in treating hemophilia. 

Schimpf, K. Mannucci, P.M. Kreuz, W. Brackmann, H.H. Auerswald, G. Ciavarella, N. Moesseler, J. De Rosa, V. Kraus, M.D. Brueckman, C.H. Mancuso, G. Mittler, V. Haschke, F. Morfini, M. Absence of hepatitis after treatment with a pasteurized factor VIII concentrate in patients with hemophilia and no previous transfusions. N. Engl. J. Med. 1987, 316, 918-922. 

Up to 1987,4% of all reported patients with AIDS in 28 European countries were likely to have been infected by blood transfusion. In these countries the percentages of patients with hemophilia or other coagulation disorders that develop AIDS were similar up to 1987 (178). 

Van der Planken MG, Schroyens W, Vertessen F, Michiels JJ, Berneman ZN. Distal deep venous thrombosis in a hemophilia A patient with inhibitor and severe infectious disease, 18 days after recombinant activated factor VII transfusion. Blood Coagul Fibrinolysis 2002 13(4) 367-70. 

Classical studies of the recessive, sex-linked disorder hemophilia provided evidence that a gene concerned with the synthesis of factor VIII must be situated on the X-chromosome. When it was discovered that a reduction in factor VIII was commonly present also in von WUlebrand s disease, with a somatic dominant inheritance, it became clear that another gene, on an autosome, must also be involved. Cross-transfusion experiments between patients suffering from hemophilia and von Willebrand s disease show-ed that hemophilic blood would stimulate factor VIII synthesis in von Willebrand s disease, but not vice versa. These data have made it possible to construct a number of alternative genetic models now being submitted to critical experimentation. 

The simplest explanation of the results of cross-transfusion experiments seems to be to suppose that factor VIII is synthesized in two stages that the von-Willebrand genes normally create an intermediate product which the hemophilia gene then converts to the final product, factor VIII. This may be written... 

Richardson LC, Evatt BL. Risk of hepatitis A infection in persons with hemophilia receiving plasma-derived products. Transfus Med Rev 2000 14 64-73. 

More complex proteins have been produced in mammalian cell culture using recombinant DNA techniques. The gene for Factor VIII, a protein involved in blood clotting, is defective in individuals with hemophilia. Before genetically engineered Factor VIII became available, a number of hemophiliac patients died of AIDS or hepatitis that they contracted from transfusions of contaminated blood or from Factor VIII isolated from contaminated blood. 

These drugs find clinical utility in settings such as prevention of rebleeding in intracranial hemorrhages, as adjunctive therapy in hemophilia, and of course, in treatment of bleeding associated with fibrinolytic therapy. In most bleeding conditions, however, -aminocaproic acid therapy has not been shown to be of definitive benefit. In recent trials, tranexamic acid was found to reduce red cell transfusion better than -aminocaproic acid or placebo in patients undergoing liver transplantation (136). 

Prion diseases In the 1990s, four patients were infected with variant Creutzfeldt-Jakob disease (vCJD) after transfusions of non-leukodepleted blood. The incubation periods in the recipients were 6.5-8.3 years after transfusion. Leukocytes are now removed from blood used for transfusion [60, 96, 9T]. Plasma products carry a low risk of transmission of transmissible spongiform encephalopathies because of production processes [96 ]. The estimated risk depends on the prion load. Of plasma products, vCJD-implicated batches of clotting factor concentrates were categorized as likely to transmit prion diseases [9T]. In the UK, and before the exclusion of the use of British plasma, the risk of prion transmission by blood was estimated to be 7-14 per 10000 patients with hemophilia, assuming a vCJD population prevalence of 1 in 10000... 

Protein replacement has long been used in the therapy of hemophilia and hemorrhage. A direct enzyme replacement has been successful in animals where it has been possible to correct UDP-glucuronyl transferase deficiencies in mice or rats but in humans, enzyme administration has met with little success. Enzymes can also be administered by transfusion of leukocytes or by bone marrow grafts, which have been particularly successful in some cases of agammaglobulinemia. 

McFarland was the first to report the development of hemophilia in a 45-year-old patient who had received repeated transfusions. Several case reports have appeared. At first it was believed that the hemorrhagic diathesis resulted from the accumulation of coagulation inhibitors heparin was often incriminated. Only in the 1950 s was the immunological pathogenesis of the disease accepted. Inhibitors of factors VIII (hemophilia A) and IX (hemophilia B) have been reported. The acquired inhibitors to factor VIII have been studied most extensively. In fact, the inhibitors have been purified. They are believed to be y-globulins with a sedimentation constant of 7 S. 

Repeated small transfusions of fresh blood constitute the most efficient form of therapy in classical hemophilia. Unfortunately, the patient often becomes refactory to transfusion, probably because of the development of neutralizing antibodies. For these reasons it is sometimes postulated that small amounts of the antihemophilic factor are present in the blood, and that the primary deficiency is in the inhibition or excessive breakdown of that factor. 

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