Fast track — Research LettersEffectiveness of leucoreduction for removal of infectivity of transmissible spongiform encephalopathies from blood
Summary
In 1999, the UK implemented universal leucoreduction as a precaution against transmission of variant Creutzfeldt-Jakob disease by transfusion of domestic blood or red blood cells. We aimed to assess how effectively leucoreduction reduced infectivity of transmissible spongiform encephalopathies (TSEs) in blood. 450 mL of whole blood collected and pooled from scrapie-infected hamsters was leucoreduced with a commercial filter. Blood cell concentrations were quantified, and infectivity titres measured. Blood cell recovery and white blood cell removal complied with American Association of Blood Banks standards. Leucofiltration removed 42% (SD 12) of the total TSE infectivity in endogenously infected blood. Leucoreduction is necessary for the removal of white-cell-associated TSE infectivity from blood; however, it is not, by itself, sufficient to remove all blood-borne TSE infectivity.
References (7)
- CA Llewelyn et al.
Possible transmission of variant Creutzfeldt-Jakob disease by blood transfusion
Lancet
(2004) - ML Williamson
Leucocyte depletion of blood supply—how will patients benefit?
Br J Haematol
(2000) - P Brown et al.
The distribution of infectivity in blood components and plasma derivatives in experimental models of transmissible spongiform encephalopathy
Transfusion
(1998)
Cited by (179)
Transmission of Variant Creutzfeldt-Jakob Disease Through Blood Transfusion and Plasma-Derived Products: A Narrative Review of Observed and Modeled Risks
2023, Transfusion Medicine ReviewsSecondary transmission of variant Creutzfeldt-Jakob disease (vCJD) can occur through blood transfusion or receipt of plasma-derived products. However, published reviews on this topic are outdated, focused on a single country or product type, or did not comprehensively review modeling studies on the risk of transfusion-transmission. We reviewed existing data on observed and modeled risks of transfusion-transmission of vCJD. To date, five patients are suspected to have acquired clinical vCJD or a vCJD infection after receiving a blood or plasma-derived product from a donor who later developed clinical vCJD. All of these cases received a nonleukodepleted blood-derived product in the United Kingdom between 1994 and 1999. Thus, all transfusion-associated cases occurred before the adoption of universal leukodepletion in 1999, which supports the preferential tropism of vCJD for leukocytes. In descriptive cohort studies, no cases of clinical vCJD were observed over ∼13 years of follow-up. In modeling studies, the risk of collecting a contaminated donation was generally <23 per million donations, that of infection was generally <10 per million transfusions or doses, and that of clinical vCJD was generally <2 per million transfusions or doses. These low risk estimates and the two-decade long absence of new cases of transfusion-associated vCJD suggest vCJD poses minimal risks to the safety of the blood supply. Furthermore, despite concerns of a second wave driven by individuals harboring a non-MM genotype at codon 129 of PRNP, there has been only 1 autopsy-confirmed case of clinical vCJD in an MV individual in 2016. The current trend to reassess or (in some countries) fully withdraw the blood donation criteria related to vCJD therefore seems justified, safe, and may significantly expand the donor base.
Human transmissible spongiform encephalopathies: historic view
2018, Handbook of Clinical NeurologyThe first of several pivotal moments leading to current understanding of human transmissible spongiform encephalopathies (TSEs) occurred in 1959 when veterinary pathologist W.J. Hadlow first recognized several similarities between scrapie—a slow infection of sheep caused by an unusual infectious agent—and kuru, a fatal exotic neurodegenerative disease affecting only people of a single language group in the remote mountainous interior of New Guinea, described two years earlier by D.C. Gajdusek and V. Zigas. Based on the knowledge of scrapie, Gajdusek, C.J. Gibbs, Jr., and M.P. Alpers soon initiated efforts to transmit kuru by inoculating kuru brain tissue into non-human primates, that—although requiring several years—ultimately proved successful. In the same year that Hadlow first proposed that kuru and scrapie might have similar etiology, I. Klatzo noted that kuru's histopathology resembled that of Creutzfeldt-Jakob disease (CJD), another progressive fatal neurodegenerative disease of unknown etiology that A.M. Jakob had first described in 1921. Gajdusek and colleagues went on to demonstrate that not only the more common sporadic form of CJD but also familial CJD and a generally similar familial brain disease (Gerstmann-Sträussler-Scheinker syndrome) were also transmissible, first to non-human primates and later to other animals. (Other investigators later transmitted an even rarer brain disease, fatal familial insomnia, to animals.) Iatrogenic CJD (spread by human pituitary-derived hormones and tissue grafts) was also transmitted to animals. Much later, in 1996, a new variant of CJD was attributed to human infection with the agent of bovine spongiform encephalopathy; vCJD itself caused an iatrogenic TSE spread by blood transfusion (and probably by a human-plasma-derived clotting factor). Starting in the 1930s, the scrapie agent was found to have a unique constellation of physical properties (marked resistance to inactivation by chemicals, heat and radiation), eventually interpreted as suggesting that it might be an unconventional self-replicating pathogen based on protein and containing no nucleic acid. The work of S.B. Prusiner led to the recognition in the early 1980s that a misfolded form of a ubiquitous normal host protein was usually if not always detectable in tissues containing TSE agents, greatly facilitating the diagnosis and TSEs and understanding their pathogenesis. Prusiner proposed that the TSE agent was likely to be composed partly if not entirely of the abnormal protein, for which he coined the term “prion” protein and “prion” for the agent. Expression of the prion protein by animals—while not essential for life—was later found to be obligatory to infect them with TSEs, and a variety of mutations in the protein clearly tracked with TSEs in families, explaining the autosomal dominant pattern of disease and confirming a central role for the protein in pathogenesis. Prusiner's terminology and the prion hypothesis came to be widely though not universally accepted. A popular corollary proposal, that prions arise by spontaneous misfolding of normal prion protein leading to sporadic cases of CJD, BSE, and scrapie, is more problematic and may serve to discourage continued search for environmental sources of exposure to TSE agents.
Safety of blood, blood derivatives, and plasma-derived products
2018, Handbook of Clinical NeurologyThere has been concern for several decades around the possibility that prion diseases may be transmissible by blood components and / or plasma products. Whilst the evidence in respect of transmission of sporadic Creutzfeldt–Jakob disease (CJD) is largely circumstantial, the identification of variant CJD gave rise to increased concern due to the evidence of prion accumulation in peripheral lymphoid tissue at the time of clinical disease. A series of studies of appendix tissues in the United Kingdom revealed prion accumulation in around 1 / 2000 of the individuals tested and raised further concern that there may be a significant proportion of the healthy population with subclinical infection posing an increased risk of transmission by substances of human origin (blood, plasma, tissues, organs) and interventional medical and surgical procedures. The former risk was realized with transmission of variant CJD infection to four individuals becoming evident between 2004 and 2006. These concerns precipitated significant changes to donor selection criteria internationally, to blood processing in the United Kingdom with the introduction of universal leucodepletion, and to the use of UK plasma for fractionation to plasma products. Considerable effort has also been invested in the development of peripheral blood assays for subclinical variant CJD and of prion reduction filters for blood components, though to date these technologies have not achieved routine clinical implementation. Whilst the variant CJD outbreak appears to be receding, continued vigilance is required in respect of the risks posed by all prion diseases to blood safety.
Plasma cholesterol level determines in vivo prion propagation
2017, Journal of Lipid ResearchTransmissible spongiform encephalopathies are fatal neurodegenerative diseases with an urgent need for therapeutic and prophylactic strategies. At the time when the blood-mediated transmission of prions was demonstrated, in vitro studies indicated a high binding affinity of the scrapie prion protein (PrPSc) with apoB-containing lipoproteins, i.e., the main carriers of cholesterol in human blood. The aim of the present study was to explore the relationship between circulating cholesterol-containing lipoproteins and the pathogenicity of prions in vivo. We showed that, in mice with a genetically engineered deficiency for the plasma lipid transporter, phospholipid transfer protein (PLTP), abnormally low circulating cholesterol concentrations were associated with a significant prolongation of survival time after intraperitoneal inoculation of the 22L prion strain. Moreover, when circulating cholesterol levels rose after feeding PLTP-deficient mice a lipid-enriched diet, a significant reduction in survival time of mice together with a marked increase in the accumulation rate of PrPSc deposits in their brain were observed. Our results suggest that the circulating cholesterol level is a determinant of prion propagation in vivo and that cholesterol-lowering strategies might be a successful therapeutic approach for patients suffering from prion diseases.
Blood transfusion-the value of Research and Development programs
2015, Presse MedicaleLa transfusion est une discipline composite qui comprend la production de produits sanguins, une composante biologique visant notamment à établir la plus haute compatibilité des caractéristiques immunologiques des produits délivrés et de celles des receveurs, et enfin une importante partie médicale relative à l’efficacité des produits transfusés et l’éviction proactive des complications pour celles qui peuvent être anticipées.
L’ensemble de cette chaîne se déroule avec le souci de l’amélioration continue de la qualité et de la sécurité transfusionnelle, en particulier vis-à-vis des risques immuno-hématologiques et infectieux.
Ces deux principes (qualité/sécurité) ont fait et font encore l’objet de progrès constants applicables à toutes les étapes, et bénéficient de programmes de recherche et de développement (R&D).
La recherche, fondamentale, mais également appliquée et clinique, accompagne de façon inséparable les progrès scientifiques et médicaux en proposant de nouvelles solutions pour lever les verrous actuels et préparer l’avenir.
Transfusion is a mixed discipline which includes the production of blood components, applied biology aiming in particular at establishing the highest compatibility for immunological characteristics between blood components to be delivered to patients and recipients, and, finally translational medicine to evaluate the effectiveness of the transfused products and to proactively avoid hazards, at least those that are preventible and can be anticipated.
The whole chain takes place with the concern of continuous improvement of quality and safety.
These two principles (quality/safety) have been and still are concerns of constant progress applicable to all the transfusion chain steps; they benefit from programs of Research and Development (R&D).
Fundamental research, basic but also applied and clinical research, accompanies, in a constantly joint manner, scientific and medical progresses by providing new solutions to dampen the current problems and to prepare the future.
Preparation, quality criteria, and properties of human blood platelet lysate supplements for ex vivo stem cell expansion
2015, New BiotechnologyMost clinical applications of human multipotent mesenchymal stromal cells (MSCs) for cell therapy, tissue engineering, regenerative medicine, and treatment of immune and inflammatory diseases require a phase of isolation and ex vivo expansion allowing a clinically meaningful cell number to be reached. Conditions used for cell isolation and expansion should meet strict quality and safety requirements. This is particularly true for the growth medium used for MSC isolation and expansion. Basal growth media used for MSC expansion are supplemented with multiple nutrients and growth factors. Fetal bovine serum (FBS) has long been the gold standard medium supplement for laboratory-scale MSC culture. However, FBS has a poorly characterized composition and poses risk factors, as it may be a source of xenogenic antigens and zoonotic infections. FBS has therefore become undesirable as a growth medium supplement for isolating and expanding MSCs for human therapy protocols. In recent years, human blood materials, and most particularly lysates and releasates of platelet concentrates have emerged as efficient medium supplements for isolating and expanding MSCs from various origins. This review analyzes the advantages and limits of using human platelet materials as medium supplements for MSC isolation and expansion. We present the modes of production of allogeneic and autologous platelet concentrates, measures taken to ensure optimal pathogen safety profiles, and methods of preparing PLs for MSC expansion. We also discuss the supply of such blood preparations. Produced under optimal conditions of standardization and safety, human platelet materials can become the future ‘gold standard’ supplement for ex vivo production of MSCs for translational medicine and cell therapy applications.