Hepatitis from blood products

In 1983 the move to develop red cell substitutes intensified when it was recognized that the acquired immune deficiency syndrome (AIDS) could be transmitted by the blood-bome human immunodeficiency vims (HIV). Concern for the nation s blood supply followed. Since that time other retrovimses have been identified, efforts to screen blood not only for these agents but also for vimses that cause hepatitis have intensified, the indications for transfusion have been reevaluated, and the use of blood products has become much more efficient. More carehil screening of donors, testing of all donated units, and a general awareness in the donor population have all contributed to a decreased risk from transfusion-contracted AIDS. 

Hepatic reperfusion injury is not a phenomenon connected solely to liver transplantation but also to situations of prolonged hypoperfusion of the host s own liver. Examples of this occurrence are hypovolemic shock and acute cardiovascular injur) (heart attack). As a result of such cessation and then reintroduction of blood flow, the liver is damaged such that centrilobular necrosis occurs and elevated levels of liver enzymes in the serum can be detected. Particularly because of the involvement of other organs, the interpretation of the role of free radicals in ischaemic hepatitis from this clinical data is very difficult. The involvement of free radicals in the overall phenomenon of hypovolemic shock has been discussed recently by Redl et al. (1993). More specifically. Poll (1993) has reported preliminary data on markers of free-radical production during ischaemic hepatitis. These markers mostly concerned indices of lipid peroxidation in the serum and also in the erythrocytes of affected subjects, and a correlation was seen with the extent of liver injury. The mechanisms of free-radical damage in this model will be difficult to determine in the clinical setting, but the similarity to the situation with transplanted liver surest that the above discussion of the role of XO activation, Kupffer cell activation and induction of an acute inflammatory response would be also relevant here. It will be important to establish whether oxidative stress is important in the pathogenesis of ischaemic hepatitis and in the problems of liver transplantation discussed above, since it would surest that antioxidant therapy could be of real benefit. 

It overcomes problems of product safety. Direct extraction of product from some native biological sources has, in the past, led to the unwitting transmission of disease. Examples include the transmission of blood-borne pathogens such as hepatitis B and C and human immunodeficiency virus (HIV) via infected blood products and the transmission of Creutzfeldt-Jakob disease to persons receiving human growth hormone (GH) preparations derived from human pituitaries. 

Biopharmaceutical products are also subjected to screening for the presence of viral particles prior to final product release. Although viruses could be introduced, for example, via infected personnel during downstream processing, proper implementation of GMP minimizes such risk. Any viral particles found in the finished product are most likely derived from raw material sources. Examples could include HIV or hepatitis viruses present in blood used in the manufacture of blood products. Such raw materials must be screened before processing for the presence of likely viral contaminants. 

Native factor VIII is traditionally purified from blood donations first screened for evidence of the presence of viruses such as hepatitis B and HIV. A variety of fractionation procedures (initially mainly precipitation procedures) have been used to produce a factor VIII product. The final product is filter-sterilized and filled into its finished product containers. The product is then freeze-dried and the containers are subsequently sealed under vacuum, or are flushed with an inert gas (e.g. N2) before sealing. No preservative is added. The freeze-dried product is then stored below 8 °C until shortly before its use. 

Better methods for preparing clotting factors from blood and the development of recombinant clotting factors provided the solutions. Methods of detecting, inactivating, and removing viruses were improved, and none of the hemophilia replacement products— conventional or recombinant—has transmitted either HIV or hepatitis since 1987. As an alternative, recombinant clotting factors 8 and 9, produced in animal cells, were approved in 1992 and 1997, without the risk associated with human blood products. 

Biological products were developed traditionally, before recombinant proteins, as extracts or derivatives of the actual protein from the human body or nature. This approach continues today and Table 15 lists 18 such products, mostly blood derivatives for therapeutic use. Albumin is obtained for cardiovascular volume conditions. A fish protein is harvested for osteoporosis. Igs extracted from blood are available for immunodeficiency conditions, viral infections (hepatitis-B and vaccinia), hemolytic anemia in newborns, and idiopathic thrombocytopenic purpurea. Antihemophilic products are still derived from blood. An antiglobulin is produced for kidney transplant rejection. A collagen product and two botulinum toxin products are used for various facial wrinkle problems and cervical dystonia. A bacterial antigen is formulated to enhance immunity to treat a cancer. 

In order to increase the sensitivity of screening, so as to minimize the so-called window period during which serological markers will not detect the infectivity marker, methods of detecting nucleic acids from, for example, the virus particle have been developed. Hepatitis C virus nucleic acid testing is obligatory in Europe, the USA, and Japan, and in many countries nucleic acid testing for other viruses has also been implemented. There is nevertheless no doubt that in future PCR-based methods will further increase the safety of blood and blood products. 

Most of this of work has been devoted to make blood products free from viral infection like human immunodeficiency virus (HIV) or the hepatitis viruses B and... 

More recently, a recombinant non-infec-tious subunit viral vaccine derived from the hepatitis B surface antigen (Recombi-vax HB) has been developed. The antigen is produced in fermentation cultures of Saccharomyces cerevisiae, and is therefore free from human blood products. Hepatitis B is an inflammation of the liver caused by the hepatitis B virus, and can be very serious or even fatal. The virus is usually spread by contact with infected blood, though an infection can be prevented by vaccination. The vaccine is highly immunogenic, well-tolerated, and possesses an excellent protective efficacy that leads to immunity for 10 years. 

Chiron Corp., Emeryville, California, founded in 1978 by William J. Rutter, pursued, unlike other start-ups, a wide menu of pharmaceuticals, including vaccines, diagnostics, and therapeutics. Hepatitis Delta (HDV) was cloned and characterized in Michael Houghtons laboratory in 1986 and in 1989 also Hepatitis C virus (HCV) [72, 83]. This latter along with PCR-based diagnostics allowed much-improved (1000-fold increased sensitivity also for HIV) safety for products still derived from blood serum, for example, for serum albumen used to stabilize other rDNA products used intravenously. 

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