Factor VIII concentrate

Fig. 6. Share of U.S. market occupied by human albumin/plasma protein fraction, (—) Factor VIII concentrate, (-) intravenous immunoglobulin...

In past years, treatment for patients with hemophilia A has consisted of administration of cryoprecipitates (enriched in factor VIII) prepared from individual donors or lyophilized factor VIII concentrates prepared from plasma pools of up to 5000 donors. It is now possible to prepare factor Vlll by recombinant DNA technology. Such preparations are free of contaminating viruses (eg, hepatitis A, B, G, or HlV-1) found in human plasma but are at present expensive their use may increase if cost of production decreases. 

Type 1 patients unresponsive to desmopressin, patients with types 2 and 3 von Willebrand s disease, and major surgery patients require replacement therapy with plasma-derived intermediate- and high-purity factor VIII virus-inactivated factor VIII concentrates containing von Willebrand factor. 

Factor VIII concentrates Alphanate Plasma Solvent detergent, dry heat Albumin, heparin, vWF... 

FIGURE 64-3. Guidelines for the treatment of von Willebrand disease. aUse factor VIII concentrate for life-threatening bleeding. 6Some patients with type 2 or 3 von Willebrand disease may respond to desmopressin. 

Clinical trials have demonstrated excellent efficacy with recombinant human factor VIII concentrates available as Recombinate and Kogenate. These recombinant factor VIII products are purified from the cell culture of plasmids, not viral DNA-transfected hamster cells and therefore do not express viral sequences. The addition of human serum albumin for stabilization, constitutes the sole possible source for human viral contamination. More recently recombinant factor IX has been genetically engineered by insertion of the human factor IX gene into a Chinese hamster ovary cell line. It has been proved to be safe and effective in the treatment of patients with hemophilia B. 

Von Willebrand Von Willebrand disease 30% Approximately 10 hours Intermediate purity factor VIII concentrates that contain von Willebrand factor. Some patients respond to DDAVP Cryoprecipitate1... 

Smales CM, Pepper DS, James DC (2002), Protein modification during anti-viral heat-treatment bioprocessing of factor VIII concentrates, factor IX concentrates, and model proteins in the presence of sucrose, Biotechnol. Bioeng. 77 37-48. 

Schwarzinger I, Pabinger I, Korninger C, et al. Incidence of inhibitors in patients with severe and moderate hemophilia A treated with factor VIII concentrates. Am J Hematol 1987 24(3) 241-5. 

Peerlinck K, Arnout J, Gilles JG, Saint-Remy JM, Vermylen J. A higher than expected incidence of factor VIII inhibitors in multitransfused haemophilia A patients treated with an intermediate purity pasteurized factor VIII concentrate. Thromb Haemost 1993 69 115-18. 

Scharrer I, Bray GL, Neutzling O. Incidence of inhibitors in haemophilia A patients—a review of recent studies of recombinant and plasma-derived factor VIII concentrates. Haemophilia 1999 5 (3) 145—54. 

In haemophilia A antihaemophilic globulin (factor VIII) concentrate (t) 8-12 h) should be used for bleeding that is more than minor. Administration of each unit of factor VIII per kg body weight raises the plasma level by 2%. Repeat dosing 2-3 times daily is necessary to maintain levels. 

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. 

Arrighi, S. Rossi, R. Borri, M.G. Lesnikov, V. Lesnikova, M. Franco, E. Divizia, M. De Santis, M.E. Bucci, E. In vitro and in animal studies on a double virus-inactivated factor VIII concentrate. Thromb. Hemost. 1995, 74,... 

Hollinger, F.B. Dolana, G. Thomas, W. Gyorkey, F. Reduction in risk of hepatitis transmission by heat treatment of a human factor VIII concentrate. J. Infect. Dis. 

Rouzioux, C. Chamaret, S. Montagnier, L. Camelli, V. Rolland, G. Mannucci, P.M. Absence of antibodies to AIDS virus in hemophiliacs treated with heat-treated factor VIII concentrate. Lancet 1985,1, 211-212. 

Colombo, M. Mannucci, P.M. Carnelli, V. Savidge, G.F. Gazengel, C. Schimpf, K. Transmission of non-A, Non-B hepatitis by heat-treated factor VIII concentrate. Lancet... 

Roberts, P.L. Hart, H. Comparison of the inactivation of canine and bovine parvovirus by freeze-drying and dry-heat treatment in two high purity factor VIII concentrates. Biologicals 2000, 28, 185-188. 

Hepatitis A virns (HAV) Only a few reports on hepatitis A virus transmission have appeared (153,154). In 1992 an outbreak of icteric hepatitis A involving at least 83 patients with hemophilia A in Italy, Belginm, Ireland, and Germany was docnmented aU had been treated with a high purity factor VIII concentrate prodnced by one manufacturer (157,158) there was icterus in 93% and a diagnosis of hepatitis A was based on the presence of IgM anti-HA. The original sonrce of contamination was not definitively estabhshed, bnt it is possible that the virus did not originate from the plasma donors. 

Recombinant and high-purity coagulation factor products appear to have a greater tendency to induce inhibitors than human-derived concentrates of intermediate or low purity (7). These intermediate-purity or low-purity human-derived concentrates are probably more suitable for inducing immune tolerance in patients with hemophilia with inhibitors. It has been suggested that for immune tolerance a high content of Von Willebrand factor in factor VIII concentrates is required, although direct comparisons of different products have not been made (8). 

Plasma-derived factor VIII concentrates have been implicated in the transmission of the non-enveloped hepatitis A and parvovirus B19 (28). The virus-inactivating procedures now in use (chemical inactivation, wet-heat treatment, and nanofiltration) should provide coagulation factors without risk of transmitting HIV and with a very high safety for hepatitis virus. Nevertheless, recombinant factor VIII is considered a safer alternative. 

Parvovirus B19 transmission occurred in a child who had received vapor heat-treated prothrombin complex concentrate (60° C for 10 hours and 80° C for 1 hour) and in another child who received dry-heated factor VIII concentrate (80° C for 72 hours). Both children had severe hemophiha A and were treated for factor VIII inhibitors (52). 

Brettler DB, Forsberg AD, Levine PH, Aledort LM, Hilgartner MW, Kasper CK, Lusher JM, McMillan C, Roberts H. The use of porcine factor VIII concentrate (Hyate C) in the treatment of patients with inhibitor antibodies to factor VIII. A multicenter US experience. Arch Intern Med 1989 149(6) 1381-5. 

Mannhalter JW, Ahmad R, Leibl H, Gottlicher J, Wolf HM, Eibl MM. Comparable modulation of human monocyte functions by commercial factor VIII concentrates of varying purity. Blood 1988 71(6) 1662-8. 

Thorpe R, Dilger P, Dawson NJ, Barrowcliffe TW. Inhibition of interleukin-2 secretion by factor VIII concentrates a possible cause of immunosuppression in haemophiliacs. Br J Haematol 1989 71(3) 387-91. 

Prowse CV, Griffin B, Pepper DS, et al. Changes in factor VIII complex activities during the production of a clinical intermediate purity factor VIII concentrate. Thromb Haemost 1981 46 597-... 

Figure 3.4.2 Culture of DON cells showing asparagine and recombinant factor VIII concentrations.

Azzi A, De Santis R, Morfini M, Zakrzewska K, Musso R, Santagostino E, et al. TT virus contaminates first-generation recombinant factor VIII concentrates. Blood 2001 98 2571-73. 

Rubinstein, A., "Heat treatment of lyophilized blood clotting factor VIII concentrate" U.S. patent, 4,456,590. 1984. 

Investigations into the Nature of the Acute Rise in Factor VIII Concentration. 211... 

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