http://www.priondata.org/data/A_blood.html
Blood Transfusion
It is now (2004) clear that there is a risk from the transmission of vCJD through blood transfusion. The reason for this is not completely clear in that attempts to demonstrate infectivity in blood by inoculation into the brains of animals has show no transfer. However the sheer quantity of blood involved in a blood transfusion from a human must mean that the risk is much greater than can be seen with any animal methods.
Index:
- Introduction
- British Medical Journal: Assessing the rights of CJD risk from transfusion (now that it has been assumed to be taking place). References
- Significant media announcements
- Statistical Assessments of Blood Transfusion and Tissue Transplantation
- Discussion of the risks from blood and blood products
- Prophylaxis against vCJD transmission in blood: Pentosan polysulphate, or Others.
- Removal of CJD infectivity in blood products: this is commercial data and should be investigated through that link: A_codiag.html
- Tests of blood and blood products for prions and CJD
- Useful Scientific References.
Introduction
For a long period it was unclear if CJD was transferred through blood transfusion or not. Initially attempts were made by comparing the difference between transfusion prevalence between those that developed CJD and those that were controls. Unfortunately the number of CJD cases needed to tell the difference would have needed to be several thousands and hence this study was unhelpful. Later much greater numbers of cases were compared using international studies and with sCJD there did not indeed seem to be any increased likelyhood of having received a transfusion in the CJD cases. Meantime it was clear that infectivity was present in the blood of scrapie cases in various species (mice, hamsters etc) and in 2003 it was shown that if sheep were bled, before they were symptomatic with scrapie, then their blood would transfer the disease to other sheep by transfusion. From this it was no longer surprising when a patient that developed vCJD (with exactly the same symptoms as a usual patient with the disease) was found to have received the blood donation from another case of the disease before that person had vCJD symptoms.
It must now be assumed that vCJD is present in blood and that it is infective in transfusions. How to remove it or test for it is now unclear but technologies are being developed currently for this purpose. In March 2004 in UK all blood donation by someone that has already received blood as a transfusion may not be accepted.
British Medical Journal Editorial: defining rights from CJD risk from transfusion
17.1.4 British Medical Journal (Editorial)
Recipients of blood or blood products "at vCJD risk" We need to define their rights and responsibilities and those of others http://bmj.bmjjournals.com/cgi/content/full/328/7432/118
(this is copied directly from the BMJ, which carries a much better copy on its web site)
In December 2003 the health secretary, John Reid, told parliament of the death of the first probable victim of variant Creutzfeldt-Jakob disease (vCJD) after being transfused blood in 1996 from a donor who had been incubating vCJD.1
The disease manifested in the donor in 1999, who died from it. This is the first probable case of transmission of vCJD following blood transfusion. The incubation period of under seven years in the recipient was notably short—consistent with human to human transmission.2 We now need to take steps to define the rights and responsibilities of recipients of "at vCJD risk" blood and blood products and also those of the rest of the population. These steps promise to be expensive and intrusive and have enormous implications for those at risk.3
The issues faced are more parlous than for HIV, against which the blood supply is protected by HIV testing and surgical instruments by autoclaving.4-6 As yet we have no blood test for vCJD and no cure, and surgical instruments used on patients with vCJD have to be destroyed. People who have received blood or blood products that are highly at risk for vCJD will now need to be managed as if vCJD had been diagnosed. This means surgical instruments (including dental) used on these patients cannot be reused. They would also be ineligible for occupations that entail procedures that may expose others to risk of vCJD.4 7
These recipients will also have concerns about the unquantified potential for possible maternal or sexual transmission, if any, of vCJD, as will the children or consorts of patients who have developed vCJD.7 The risk of vCJD transmission may vary considerably by blood, surgical instruments, maternally, occupationally, or sexually and according to age group,2 incubation period, route of exposure, inoculum, and genetics of donor or recipient. All those who have received at vCJD risk blood or
blood products, or are caught up in the "surgical web" spun out from them, or anyone who has suffered percutaneous injury involving blood at risk must refrain from blood or tissue donation and may have to accept restrictions on what they can do.
The responsibilities of recipients include to avoid transmission to others of vCJD and to contribute key data7 so that uncertainty for them and others about the size of risks is resolved as quickly as possible. But we also need to take steps to protect their rights and the rights of the public (box 1).
Box 1: Steps to protect the rights of recipients and of the public
- Develop a national protocol for vCJD counselling
- Develop a national standard for categorising vCJD risk
- Define actions to minimise vCJD transmission and say which of them are mandatory—these would depend on the category of the individual's risk4
- Clarify criminal justice liabilities for reckless and culpable transmission of vCJD6
- Make a national provision of the insurance and mortgage terms for which individuals would have been eligible had they not been caught up with at vCJD risk blood or blood products
- Provide information about clinical or public health research studies for which they are eligible or to which it is their responsibility to contribute in the national public health interest
- Provide meaningful redress against intrusion by the press
- Express national gratitude that they take up such exceptional burdens to protect others from a condition that they may not even have but may be at risk of having
To prevent further human to human transmission, the steps that need to be taken for every patient who is suspected of having any type of CJD are listed in box 2.
This case has implications for the national prospective collection of tonsils to be tested anonymously for detectable PrPSC, which is to begin in 2004.8 9 We do not know for certain that a child whose tonsillar tissue tests positive for abnormal PrPSC will develop vCJD. However, the unknown child is at risk of vCJD, and the
transmission of vCJD through blood or blood products may now mean that any test positive specimen will have to be identifiable, so that the person can be managed in accordance with rights and responsibilities that fall to recipients of blood that is at risk of vCJD Would parents permit testing of tonsillar tissue if it were not to
remain anonymous? Can the United Kingdom's chief medical officers and ministers of health risk the responsibility of allowing the destruction of operative tissue, when testing that material8 9 could otherwise prevent possible transfusion, surgical, and dental risks to other citizens? Similar testing could be done in postmortems.
Box 2: Steps to prevent further human to human transmission
Every patient suspected of having any form of CJD needs to be immediately notified to the national CJD surveillance unit and cross checked against the list of identified recipients of blood potentially contaminated with vCJD—to check for human to human transmission
Blood transfusion services must stop immediately the use of any blood or tissue that a patient suspected of having CJD may have donated—to safeguard blood supply
Recipients of potentially vCJD contaminated blood transfusion or products should be alerted immediately without waiting for a definitive diagnosis to be made—to prevent surgical and other transmission
We need to identify recipients of potentially vCJD contaminated blood who have subsequently undergone surgery—to check the extended network of those at risk of vCJD
Counsel individuals in the risk network to alert them about the categorisation of their own risk, the mandatory actions they need to take to reduce risk to others, and the data requested from them for better calibration of risk. Until more is known about bloodborne vCJD transmission we must hope for the best and protect against the worst. Thus we need to collate key data about other recipients of blood and blood products derived from the vCJD donors, which are necessary to calibrate risk (see box on bmj.com). The network of those at risk extends further—to immediate family7 and, if recipients undergo surgery, possibly to patients on whom their instrument set was next used. We also need to seek agreement from recipients in life for various investigations to be performed after death, especially on their tonsils and brains, so that key data are not lost. Many are likely to be caught up in this web spun out from the recipients of at vCJD risk blood and blood products. Public, press, and professions must have much respect for individuals who have been unwillingly (and so far unknowingly) caught up in this web, the danger of which is now real but poorly quantified. These individuals shoulder immense responsibility for the good of us all.
Sheila M Bird, senior statistician MRC Biostatistics Unit, Cambridge CB2 2SR
References
1.Department of Health. Blood transfusion incident involving vCJD.
www.info.doh.gov.uk/doh/embroadcast.nsf/vwDiscussionAll/0301ECC6DF485EF880256DFF004DA063 (accessed 9 Jan 2004).
2.Cooper JD, Bird SM. Predicting incidence of variant Creutzfeldt-Jakob disease from UK dietary exposure to bovine spongiform encephalopathy for the
1940 to 1969 and post-1969 birth cohorts. Int J Epidemiol 2003;32: 784-91.[Abstract/Free Full Text]
3.Ferguson NM, Donnelly CA. Assessment of the risk posed by bovine spongiform encephalopathy in cattle in Great Britain and the impact of potential
changes to current control measures. Proc R Soc London, Series B 2003; 03PB0529.1.
4.Bird AG, Gore SM. Revised guidelines for HIV infected health care workers. We need data not dogma. BMJ 1993;306: 1013-4.[ISI][Medline]
5.European Partner Notification Study Group. Recently diagnosed sexually HIV-infected patients: seroconversion interval, partner notification period and yield
of HIV diagnoses among partners. Q J Med 2001;94: 379-90.[ISI]
6.Bird SM, Leigh Brown AJ. Criminalisation of HIV transmission: implications for public health in Scotland. BMJ 2001;323: 1174-7.[Free Full Text]
7.Gore SM. Bovine Creutzfeldt-Jakob disease? Failures of epidemiology need to be remedied. BMJ 1996;312: 791-2.[Free Full Text]
8.Hilton DA, Ghani AC, Conyers L, Edwards P, McCardle L, Penney M, et al. Accumulation of prion protein in tonsil and appendix: review of tissue samples.
BMJ 2002;325: 633-4.[Free Full Text]
9.Hilton DA, Fathers E, Edwards P, Ironside J, Zajicek J. Prion immunoreactivity in appendix before clinical onset of variant Creutzfeldt-Jakob disease. Lancet
1998;352: 703-4.[CrossRef][ISI][Medline]
Significant announcements and media publications
18.3.4
FURTHER PRECAUTIONS TO PROTECT BLOOD SUPPLY
Recipients of blood transfusions are to be excluded from donating blood
in the future as a further precautionary measure against the possible
risk of transmission of variant Creutzfeldt Jakob Disease (vCJD), Health
Secretary John Reid announced today.
This follows the government announcement in December last year of the
first report of a possible transmission of vCJD from person to person
via blood. This remains a possibility and not a proven causal connection.
The new precautionary measure to change the eligibility for blood
donation will be implemented from April 5th this year. It will exclude
people who confirm they have received a transfusion after 1 January 1980
because it is generally accepted that there will have been no exposure
to BSE in the UK before than date.
Health Secretary John Reid said:
"I must stress that the risk attached to this group of blood donors is
of course uncertain but we are taking these measures as a precaution, as
the risk may be slightly higher than for the population as a whole.
"Excluding these donors will inevitably lead to a reduction in the
supply of blood available for transfusions. Whilst the National Blood
Service estimates a loss of 52,000 donors, I am pleased to report that
they have put in place measures to help conpensate for these losses and
hospitals are being encouraged to make best possible use of blood."
Mr Reid also announced that Chief Medical Officer Sir Liam Donaldson is
to draw up a strategy to ensure more appropriate and effective use of
blood in the NHS. This strategy will build on the current "Better Blood
Transfusion - More Appropriate Use" initiative, securing further
improvments in conserving blood stocks through better use of blood in
hospitals.
The Health Secretary said:
"We are following a highly precautionary approach. Although people may
have concerns about the implications of this announcement, I would
emphasise again that this action is being taken because of an uncertain
but slight risk. People should, indeed, continue to have a blood
transfusion when it is really necessary. Any slight risk associated with
receiving blood must be balanced against the significant risk of not
receiving that blood when it is most needed.
"People who can should continue to give blood. Blood donation is a safe
procedure and people should continue to donate blood regularly. We place
great value on those who already donate and would welcome new donors."
http://www.wired-gov.net/NWC8394A7F/WGLaunch.aspx?ARTCL=23316
16.1.4 Financial Times
Warning over vCJD blood infection http://news.ft.com/servlet/ContentServer?pagename=FT.com/StoryFT/FullStory&c=StoryFT&cid=1073281075945
Tough and costly action is needed following the first potential case of someone developing vCJD from a blood transfusion, a government adviser said yesterday.
John Reid, the health secretary, told parliament last month of the first probable case of someone dying from the human equivalent of mad cow disease following a blood transfusion. Although it could not be proved that it was the source of infection, it was the first "probable" case of human to human transmission, said Sheila Bird, a senior statistician with the Medical Research Council. Mr Reid has asked an expert advisory committee to report urgently on what measures need to be taken. But Ms Bird, who sits on a Department of Health committee that advises on studies in the area, said that the necessary measures "promise to be expensive and intrusive and have enormous implications for those at risk".
22.12.3
First UK case of variant CJD from blood. http://www.nature.com/nsu/031215/031215-14.html
A patient who died from the human form of mad cow disease may have caught the illness from a blood transfusion. Policies governing blood donation may require a rethink as a result. It is not possible to tell whether the patient caught the fatal disease - called variant Creutzfeldt-Jakob disease (vCJD) - from the transfusion or contracted it by eating infected meat. But the incident is the first case of "possible transmission" through transfusion - something that scientists have long known to be a possibility.
Britain's Department of Health and the National Blood Service have since contacted 15 other patients who also received blood from donors who later died from vCJD. The patients have been offered counselling.
There is no blood test for vCJD, so blood banks cannot check their stocks for signs of the disease. But precautions are in place to minimize the risk of transmission. US and Canadian blood banks refuse donations from British citizens or those who have spent a significant amount of time in the country. In Britain itself, transfusions are stripped of white blood cells, which are thought to aid disease transmission.
3.8.2 Guardian
Tests reveal CJD blood riskhttp://www.guardian.co.uk/bse/article/0,2763,768641,00.html
Scientists say there is "an appreciable risk" of people catching the human form of BSE through blood transfusions, a significant upgrading of the threat posed by the inevitably fatal disease. The results from tests on sheep, seen by the Guardian, suggest the danger is far more serious than first suspected. Previously the risk has been described by the government as "theoretical". One in six animals given blood from infected sheep appear to have caught the disease so far. The experiments by scientists at the Institute of Animal Health indicate that more blood components than previously thought might carry the killer agents of BSE and variant CJD, and the blood might be infective long before animals, and by extension humans, show outward signs of the long-incubating diseases.
The findings, circulated to blood specialists, are regarded as enormously significant. They have prompted urgen consideration of new measures to protect the public and orders to hospitals to drastically reduce their use of blood, including using technology that allows the recycling of patients' own blood.
22.8.1 BBC News
Scientists say tests on animals suggest there may be a risk of people catching the human form of BSE through blood transfusions, according to reports.
http://news.bbc.co.uk/2/hi/health/2169663.stm
Tests at the UK's Institute of Animal Health indicated that one in six animals given blood from infected sheep appeared to develop the illness, the Guardian newspaper says. The study suggests red cells and plasma may have infectivity for vCJD - the human form of BSE which destroys brain tissues - but the full version of the research is not published until November. Scientists have previously demonstrated transmission of BSE in animals, but in animals fed infected brain.
The National Blood Service said the research was valuable, but stressed there was no risk of contracting the disease by giving blood.
17.1.2-
The Redcross announced to the Spongiform Encephalopathy Committee of the FDA that it fully supports extending the UK Blood ban to below 6 months and extending it to include donors from, or who have traveled to, NOT JUST FRANCE, BUT ALL OF WESTERN EUROPE. Read their entire statement (1 page).
Most recently, the American Red Cross is urged in a Science (March 9, 2001) article that a "Broad U.S. Response is Required," an incredible turn around for an agency which had been saying up till recently that there was "no proof" that prion disease could be acquired via blood products. Starting in September 2001 the ARC will ban all donors who have spent a mere 3 months in the UK and 6 months anywhere else in Europe. Only Red Cross blood
will have this increased protection - not blood from other blood agencies. (The ARC collects only ~1/2 of the blood in the US) The FDA has set a much lower bar for prevention of nvCJD in the US that is ridiculously lacking: 3 months in the UK and 10 years in France, Portugal and Ireland (no, it is not a joke, but the FDA is certainly vying for that description).
27.2.98
The UK banned all its own blood products, and vaccines made from those blood products, in a step that was unprecedented in world history. This step was thought necessary by scientific advisors to the UK government due to the results of several critical scientific experiments in the fall and winter of 1997 and early 1998. The studies, conducted by respected prionologists on 2 continents, showed that nvCJD (new variant CJD) is carried heavily in the blood and lymph systems. There was great pause, therefore, in the medical/scientific community, that nvCJD may be much more easily transmissable via blood products than conventional CJD. In spite of its unprecedented and newsworthy nature, the ban has never to this day been reported on U.S. news networks, including PBS and NPR, and most Americans, including health care workers, remain totally ignorant of it. In addition, on June 3,1999 the FDA banned blood donors in the US who have spent a cumulative total of 6 months in the UK in the last 20 years (the 6 month cutoff a wholey arbitrary figure arrived at by financial considerations and worries about wiping out the US blood supply). Furthermore, Health Canada is currently implimenting the 6 month cutoff as well; and Hema-Quebec is to ban Quebecois donors who have spent only one month in the UK. Additionally, Canada has just taken the initiative to ban donors who have traveled in or lived in France for a minimum 6 month period cumulatively since 1980 (8/31/2000).
Risks from Transfusion and Transplantation: Statistical Assessments
- Transplantation
- A Code of Practice for Tissue Banks providing tissues of human origin for therapeutic purposes 2001 (UK) http://www.doh.gov.uk/humantissuebanking/tissuebank.pdf
- Guidance on the Microbiological Safety of Human Organs, Tissues and Cells used in Transplantation Advisory Committee on the
- Microbiological Safety of Blood and Tissues for Transplantation MSBT August 2000 (UK) http://www.doh.gov.uk/msbt/msbt.pdfThis particualr committee meets regularly. and all its meetings can be checked by searching through "vCJD and MSBT" in Google.
- Transfusion
- Further precautionary measures on blood products announced [CJD] CEM/CMO/98/5: 26 February 1998 (UK)
- New variant CJD – patients who have received implicated blood products PL(CMO)(98)1: 6 February 1998 (UK)
- WHO Precautionary measures against the risk of transmission of the agent of vCJD by blood transfusion. this is to be found at www.who.int/wer/pdf/2000/wer7547.pdf
- Det Norske Veritas (DNV) 'Assessment of the risk of exposure to variant CJD and infectivity in blood and blood products'. This was a report for SEAC and the DoH in 1999. I am not sure you can get hold of a copy but initially DNV wre not given all the data needed and it was only when they received much more sinister data from elsewhere that their report was not good news. In the end the signs were that blood was a risk but the plasma products may not be depending on the prevalence of the human vCJD in the blood donors.
- Blood Recall/WithdrawalCJD site (an offspring of CJD VOICE but is often difficult to download) (USA)
- The FDA Blood Recall/WithdrawalSite. (USA)
- Department of Health in UK action in 1998 concerning haemophilia products.
- Department of Health. Blood transfusion incident involving vCJD. www.info.doh.gov.uk/doh/embroadcast.nsf/vwDiscussionAll/0301ECC6DF485EF880256DFF004DA063 (accessed 9 Jan 2004).
- Blood safety and manufacture organisations:
- Pharm Web www.pharm.org
Linda Zambenini explains the banning of their own plasma products and vaccines by the UK in 1998. This is a useful site with insite into the worry that is going on in the background.
lzambeni@indiana.edu
Discussion of Risks from Blood and Blood Products
Blood transfusion and blood products. Infectivity has been shown to be present in the blood of patients with CJD by inoculation into animals (229) and the same phenomenon has been repeated for various animals with a TSE (Table 20). Attempts to indicate the level of infectivity in blood have not been carried out but it is expected to be present mainly in the buffy coat. This work has been reviewed (230,231). In hamsters a long term attempt to follow the level of infectivity in blood following inoculation showed it to remain at approximately 101-103 IU/ml throughout the incubation period (232) and a second experiment following hamsters for 40 days after peritoneal inoculation of scrapie showed 5-50 IU/ml (233). The only attempt to calculate the dose required to transfer disease by intravenous infusion has been reported as 9 IU in mice (Table 1). As such it would be expected that 300ml of the blood of a person incubating CJD would be able to transfer the disease by blood transfusion and because of this CJD patients, relatives and persons having received human growth hormone are banned in the UK from donating blood. There have been isolated specific reports of people developing CJD after having received plasma or blood from a person that themselves developed the disease (234). As a result the USA, Canada and some other countries have set up a recall policy to take back the blood or blood products of anyone that had developed CJD. When it is calculated, the number of people expected to develop CJD by this route is very small, in that, for other reasons, most of the people receiving transfusions do not live long enough to incubate the disease. An attempt was made to compare the proportion of people with CJD that have received a blood transfusion with the proportion of controls and no statistical difference was found (n = 200) (235), however the difference by calculation was expected to be 2 and this could not be shown unless the survey was greater. The best report was one of a Danish blood donor who had given blood for many years and then developed CJD. The recipients of the transfusions were found and none of them (one now over 20 years later) had developed CJD (246). However the point at which his blood would start to become infective is not known.
A recent incomplete report has appeared of CJD developing in a 60 year old liver transplant recipient who received albumin derived from the blood of a donor who subsequently developed CJD (237). Currently we must ethically assume that the blood of someone incubating CJD or nv-CJD represents a risk to a recipient of it. This has been born out by the report to the WHO by Paul Brown showing that plasma from mice infected with nv-CJD is infectious (238). WHO has recommended that anyone with an increased risk of CJD should not be accepted as a blood donor. The current prevalence of nv-CJD in pre-symptomatic people in the community is unknown but it may become accepted that UK donors will not be accepted abroad because of the WHO recommendations.
Gamma globulins.
A risk? In the UK mixed g-globulins (MGG) are used generally for the prophylaxis against hepatitis A in visitors travelling abroad. The population is now one of the lowest in the world for having had the disease through oral infection (now less than 40%). As such this passive immunisation is useful but it is gradually being replaced by active vaccination (Haverix, Smith Kline Beecham; 0208 913 4290). As a result the number of people receiving MGG has dropped from around 300,000 per annum to 160,000 in the UK in 1996. Little risk is though to be derived from this due to other viruses due to the method of fractionation that is used (239). Plasma is separated from whole blood and an initial cryoprecipitate is used to
remove factor VIII (239). The supernatant is then split into two specific fractions and a further alcohol cryoprecipitate is used to remove MGG (239). Attempts have been made to find out the effectiveness of the process is at removing specific viruses (240-243). It led to the reduction in hepatitis B surface antigen by greater than or equal to 103, PCR detectable HCV by 10E5 and HIV infectivity by 10E14 (244,245,246) When products have been prepared in this way, there has been some transmission of hepatitis C by i.v. inoculation but nothing else reported (239). However, due to the fact that nv-CJD agent would not be expected to be damaged by alcohol or cold, these results cannot be expected for it and currently no data is available except from attempts by scientists to separate TSE agents from other factors (brain tissue etc); a process that has been shown to be inefficient (91). Depending on the number of people becoming infected with v-CJD due to food it would be possible to estimate the proportion of the plasma that would be derived from them and hence how diluted it would be when mixed with the plasma of non-infected people. If we accept unmixed GG from a nv-CJD donor to be infective by parenteral inoculation (which it may not be) then the rate of dilution is important. As the number of v-CJD patients increases, the rate of dilution of the infective GG drops. If the dilution is not enough then large numbers of people would be effectively at risk and the disease would spread through this. This is shown in Figure 30. American and Canadian response to findings have been to ban the use of any blood or blood products that might contain the blood from someone that they have found to develop CJD. The result of this is that regularly large amounts of these products are thrown away in North America but proof that this is of value is not currently available. In the UK no attempt to find out the amount of infectivity that is likely to be present in g-globulins has been carried out and inadequate consideration seems to have taken place so far (personal contact National Blood Authority).
Tests of blood and blood products
It is clear now that the first company that products a test of blood for CJD is going to have a very large market indeed. So far this is devided into two groups: those that can test non-specifically but ante-natally and those that produce that is specific for the disease but adequately in advance of symptoms that they can be useful for blood transfusion.
The companies that are doing this are not releasing all of their data but one from Israel suggests that they can test urine for PrP showing that it is present in patients that are infected with CJD. Other groups have not been able to repeat this.
One group from North America have indicated that they can look in blood using high voltage electrophoresis...and again this has not been repeated adequately to be useful.
A third have produced a method that seems to work in sheep and so far in humans (
Microsens Biotechnology) but they need to test a lot more samples before they can justify their claim.
Links
Useful Scientific References
229. Manuelidis EE, Kim JIl, Mericangas JR, Manuelidis L. Tansmission to animals of Creutzfeldt-Jakob disease from human blood. Lancet 1985;ii:896-7.
230. Dealler SF. A matter for debate: the risk of bovine spongiform encephalopathy to humans posed by blood transfiision in the UK. Transfiision Medicine 1996;6:217-22.
231 Flannagan P, Barbara JA. Prion disease and blood transfbsion. Transfiision Medicine
1996;6:213-5.
232. Casaccia P, Ladogana A, xi YG, Pocchiari M. Levels of infectivity in the blood throughout the incubation period of hamsters peripherally injected with scrapie. Archives of Virology 1989;108:145-9
233. Diringer H. Sustained viremia in experimental hamster scrapie. Archives of Virology.
1984;82: 105-9.
234. Klein R, Dumble U. Transmission of Creutzfeldt-Jakob disease by blood transtusion. Lancet 1993;341 :768.
235. Esmonde TFG, Will RG, Slattery JM, Knight R, Harries-Jones R, DeSilva R, Matthews WB. Cretuzfeldt-Jakob disease and blood transfosion. Lancet 1993;341:205-7.
236. Heye N, Hensen S, Muller N. Cretuzfeldt-Jakob disease and blood transfiision. Lancet
1 994;343 :298-9.
237. Creange A, Gray F, Cesaro P, Degos J-D. Pooled plasma derivatives and Creutzfeldt-Jakob disease. Lancet 1 996;347:482.
238. News report. Plasma of mice inoculated with nv-CJD becomes infectious. Lancet. 3 April 1997.
239. Roberts P. Virus safety of plasma products. Reviews in Medical Virology.
1996;6:25-38.
240. Henin Y, Marechal V, Barre-Sinoussi F, Chermann JC, Mongenthaler JJ. Inactivation and partition of human immunodeficiency virus durtng Kistler and Nitschmann fractionation of human blood plasma. Vox Sang. 1988;54:78-83
241 Committee for Proprietary Medicinal Products: Ad Hoc Working Party on Biotechnology/Pharmacy (1992). Guidelines for medicinal products derived from human blood and plasma. Biologicals 1992;20: 159-64.
242. Minor PD. Meeting on the acceptance criteria for virus validation studies. Biologicals
1995;23:107-1 10.
243. Committee for Proprietary Medicinal Products: Ad Hoc Working Party on Biotechnology/Pharmacy (1991). Validation of virus removal and inactivation procedures. Biologicals 1991; 19:247-51.
244 Morgenthaler JJ, Omar A. Partitioning and inactivation of viruses during isolation of albumin and immunoglobulins by cold ethanol fractionation. In: Virological Safety Aspects of Plasma Derivatatives. Dev. Biol. Stand. 1993 Vol 81 Eds; F. Brown, Karger, Basel. p.185-90.
245. Yei S, Yu MW, Tankersley DL. Partitioning of hepatitis C virus during Cohn-Oncley fractionation of plasma. Tanstution 1 992;32: 824-8.
246. Morgenthaler JJ. Effect of ethanol on viruses. In: Virus Inactivation in Plasma Products. Current Studies in Hematology. Blood Transtusion. 1989 Vol 56. Ed: JJ Morgenthaler. Karger, Basel. pp 109-21.
247. Wickham EA. Potential transmission of BSE via medicinal products. BMJ
1996;3 12:988-9.
248. Bird.
Recipients of blood or blood products "at vCJD risk" We need to define their rights and responsibilities and those of others http://bmj.bmjjournals.com/cgi/content/full/328/7432/118 BMJ 2004;328:118-9
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