Factor VIII source

Estimates for a number of economic aspects of plasma fractionation can be made (200—206). The world capacity for plasma fractionation exceeded 20,000 t of plasma in 1990 and has increased by about 75% since 1980, with strong growth in the not-for-profit sector (Fig. 4). The quantity of plasma processed in 1993 was about 17,000 t/yr the commercial sector accounts for about 70% of this, with over 8000 t/yr in the form of source plasma from paid donors (Fig. 5). Plant capacities and throughput are usually quoted in terms of principal products, such as albumin and Factor VIII. These figures may not encompass manufacture of other products. 

Production of recombinant factor VIII (Table 12.2) has ended dependence on blood as the only source of this product, and eliminated the possibility of transmitting blood-borne diseases specifically derived from infected blood. In the past, over 60 per cent of haemophiliacs were likely to be accidentally infected via contaminated products at some stage of their life. 

Some patients, particularly those suffering from severe haemophilia A (i.e. those naturally producing little or no VIII C), will mount an immune response against injected factor VIII C whatever its source. 

Owing to the frequency of product administration, the purification procedure for recombinant factor VIII C must be particularly stringent. Unlike the situation pertaining when the product is purified from human blood, any contaminant present in the final product will be non-human and, hence, immunogenic. Sources of such contaminants would include ... 

Natural source may carry risk of infection. Recombinant Factor VIII used to treat hemophilia A has helped reduce the incidence of HIV infection in hemophiliacs. Recombinant HbsAg is now used to immunize against hepatitis B, eliminating the risk of introducing a viral infection during vaccination. 

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. 

The functions of the above three classes of proteins are directly related to the protein-bound copper ions. In those cases where functions have been unequivocally established, they are either electron storage and transfer or redox catalysis. Representative proteins from each of the above-mentioned classes have been purified directly from their natural sources and extensively characterized both structurally and biophysically. In addition, there are well-established protocols for their expression and purification from different heterologous systems. [Factor VIII is a special case for which blue copper binding has not been experimentally demonstrated, although at least two such sites can be identified in its amino acid sequence (Section VIII).]... 

Plasma-derived therapeutic proteins are parenteral biologies that are purified on an industrial scale. All biologies derived from human sources, such as plasma, carry the risk of viral contamination. Thus, in order to market a medicinal product derived from human plasma, manufacturers must assure the absence of specific viral contamination. Virus validation studies are performed to evaluate the capacity of a manufacturing process to remove viral contaminants. Virus clearance across three different terminal inactivation steps, low pH incubation of immunoglobulins (IgG), pasteurization of albumin, and freeze dry/dry heat treatment of plasma-derived products (Factor VIII and Protein G), is discussed in this article. The data show that, like all other upstream virus reduction steps, the methods used for terminal inactivation are process and product dependent, and that the reduction factors for an individual step may be overestimated or underestimated due to inherent limitations or inadequate designs of viral validation studies. 

Advances in recombinant technology alleviated the problem of protein production and its purity. Through the process of recombinant DNA technology and use of nonhuman cell lines, human proteins can be manufactured free of viral contamination. This process enables production of large quantities of proteins previously difficult to obtain from human sources. Further isolation of protein from human sources is associated with a high risk of viral contamination. One such example, plasma derived clotting factor VIII isolated from human blood, resulted in transmission of viral diseases such as hepatitis and AIDS [1,2]. 

Mancuso ME, Mannucci PM, Rocino A, Garagiola I, Taghaferri A, Santagostino E. Source and purity of factor VIII products as risk factors for inhibitor development in patients with hemophUia A. J Thromb Haemost 2012 10(5) 781-90. 

It is less forbidding than it looks. The first three lines are the linearized Boltzmann operator acting on the factor u(rin the factorial cumulant the next three lines are the same operator acting on the factor u(r2,p2) lines seven and eight represent the sources of the fluctuations and on the last line the flow terms have been added for both factors. The equation has therefore the general form (VIII.6.8), when A is identified with the linearized Boltzmann operator including the streaming term. 

Other factors of importance in atmospheric corrosion of zinc are (i) the distance from the ground (ii) orientation of the samples (iii) wind or rain shielding (iv) distance to the local contaminant sources (v) wind, radiation (vi) condensation and drying rate (vii) amount of contaminants and nature of corrosion products and (viii) seasonal variation of factors also should be considered. This shows the complexity of the problem of determining the atmospheric corrosion rates to a high degree of certainty. This uncertainty is exemplified by the observed corrosion rate of 0.6-3.8 pm/yr at 26 sites in rural area in Spain.95 The corrosion rate of 8.5 pm/yr observed on the zinc coating in an under-vehicle situation is comparable to severe marine atmospheric conditions.96... 

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