Risk Of Prion Transmission Research Articles

From mad cows to sensible blood transfusion: the risk of prion transmission by labile blood components in the United Kingdom and in France

Transfusion transmission of the prion, the agent of variant Creutzfeldt-Jakob disease (vCJD), is now established. Subjects infected through food may transmit the disease through blood donations. The two nations most affected to date by this threat are the United Kingdom (UK) and France. The first transfusion cases have been observed in the UK over the past 5 years. In France, a few individuals who developed vCJD had a history of blood donation, leading to a risk of transmission to recipients, some of whom could be incubating the disease. In the absence of a large-scale screening test, it is impossible to establish the prevalence of infection in the blood donor population and transfused patients. This lack of a test also prevents specific screening of blood donations. Thus, prevention of transfusion transmission essentially relies at present on deferral of "at-risk" individuals. Because prions are present in both white blood cells and plasma, leukoreduction is probably insufficient to totally eliminate the transfusion risk. In the absence of a screening test for blood donations, recently developed prion-specific filters could be a solution. Furthermore, while the dietary spread of vCJD seems efficiently controlled, uncertainty remains as to the extent of the spread of prions through blood transfusion and other secondary routes.

Reducing the risk of prion transmission in anaesthesia

Reducing the risk of prion transmission in anaesthesia

Removal of Prions by the Manufacturing Process of Haemate® P/Humate-P®.

Prions, the causative agents of Creutzfeldt-Jakob Disease (CJD) and related neurodegenerative disorders in humans including variant CJD (vCJD) have up to now never been demonstrated in human blood although if in UK two probable transmissions of vCJD by blood transfusion were reported (Llewelyn et al., Lancet 2004; 363:417–421 and Peden et al., Lancet 2004; 364:527–529). In order to minimize a theoretical risk of human prion contamination of plasma pools, potential donors at risk of incubating CJD are excluded from donation permanently. Due to the implementation of these precautionary measures, the risk to collect plasma from a donor developing vCJD subsequent to a donation is very low. In addition, the amount of prions present in plasma of a healthy donor (i.e., a donor in the incubation period of (v)CJD) can be considered very low (Comer Risk Assessment of Exposure to vCJD Infectivity in Blood and Blood Products for Department of Health [UK], Revision DE, Det Nordske Veritas, February 2003). Even with this very low risk related to plasma for fractionation, the capacity of selected steps of the manufacturing process of the VWF/FVIII product Haemate® P/Humate-P® to remove prions has been evaluated in prion removal studies. As it has never been possible to isolate infectious prion protein, termed PrPSc, from human blood or plasma, the model prion strain 263K (isolated from brain of deliberately infected hamsters) was spiked to intermediates of scaled-down plasma protein purification processes. As there is no knowledge of the biophysicochemical nature of potential prion contaminants in plasma, we employed two different prion spike preparations in these studies: membrane associated prions in so-called microsomes and purified prion protein PrPSc, an almost native, molecular, non-membrane associated form of prion infectivity. Laboratory studies were performed by spiking either experimental plasma pools or an intermediate at a production stage further downstream with prion preparations and investigating the prion reduction by consecutive scaled-down process steps. These investigational studies resulted in a mean overall prion reduction factor of 5.3 log10 and 6.4 log10, respectively, for the two hamster derived spike preparations.Reduction of prions by selected manufacturing steps for Haemate® P/Humate-P®Manufacturing stagesPrion Reduction Factor [log10]MicrosomesPrPScCombined steps cryoprecipitation, Al(OH)3, glycine and NaCl precipitation3.53.9Combined steps ultracentrifugation/sterile filtration1.82.5Mean Overall Prion Reduction5.36.4Additionally, confirmative data were obtained in studies employing human brain-derived prion preparations (sCJD and vCJD) as spiking material in selected studies of a single manufacturing step. Therefore, it can be concluded that the risk of prion transmission by the VWF/FVIII product Haemate® P/Humate-P® is extremely remote based on complementary safety procedures, i.e., collection of plasma by stringent donor selection and the overall prion reduction factor which clearly exceeds a potential prion load in the manufacturing pool. This high safety margin is confirmed in a probabilistic risk calculation, demonstrating at a probability of 95% a safety factor for each vial of the product of 6.4 log10.

The Use of Factor XI Concentrates (Hemoleven, LFB) in Patients with Congenital Factor XI Deficiency and a Known Bleeding Tendency.

Traditional treatment modalities for FXI deficiency (UK prevalence 400 cases) include antifibrinolytics, desmopressin, fresh frozen plasma (FFP) and FXI concentrates but there has been reluctance to use FXI concentrates because of reported incidence rates of thrombosis up to 10%. Concerns over the safety and efficacy of FFP, with additional viral inactivation steps possibly leading to reduced FXI recoveries, have led us to increase our use of FXI concentrates. We aimed to assess the indications, dosage, recovery, efficacy and safety of Hemoleven, a plasma derived, purified and virally inactivated FXI concentrate, which also contains heparin and antithrombin, in patients with congenital factor XI deficiency. A retrospective study was performed using hospital notes and laboratory records of all patients who had received Hemoleven over a 2-year period. Eleven patients (6 male, 5 female) had been treated with a median age of 38 years (range 7–74) and mean baseline FXI:C levels of 25.4U/dl (3–50). All patients received Hemoleven as prophylaxis for surgery or dental work and had all previously had excess bleeding when surgically challenged. One patient died of a condition unrelated to FXI treatment. Pre- and post-FXI:C levels were available for a total of 60 treatment episodes of which 25 were 1000-unit doses and 35 were 2000-unit doses. The mean increase in FXI:C per 1000-unit dose was 25.4 U/dl (12.4–43.9) while the mean increase in FXI:C per 2000-unit dose was 50.5 U/dl (11.8–106.5). This is consistent with the manufacturer's data. Ten minute post infusion FXI:C levels were above the normal range (73–133 U/kg) in 8% of patients given 1000 units and 11% of patients given 2000 units but below the normal range in 24% of patients who received 1000 units and 20% of patients who received 2000 units. 90% of treatment episodes led to FXI:C levels above the usual treatment target of 65 U/dl. Genetic analysis of 9/11 patients showed that 2 were homozygous (one type II and one type III), 6 were heterozygous for other recognised mutations and one had no mutation identified but apparent absence of RNA from one allele demonstrated in a relative by qRT-PCR. No excess bleeding or inhibitor development was recorded even in one patient who had had a poor haemostatic response with FFP. There were no episodes of arterial or venous thrombotic complications within this group and no clinical or laboratory evidence of DIC following treatment. In summary, treatment with factor XI concentrates gave consistent increments in FXI:C at the doses given and achieved good haemostasis with no episodes of thrombosis in this study, even in patients over the age of 60y. While the risk of prion transmission is still unknown, use of FXI concentrates is not associated with the risks of fluid overload and TRALI that are seen with FFP. We acknowledge that the study includes small numbers of patients however the cohort of patients with a bleeding diathesis in this condition is small. We conclude that Hemoleven appears to be an effective and reliable treatment for patients with FXI:C deficiency but should be given in the context of FXI:C level monitoring in order to detect those patients who may develop high levels and possible thrombosis.

Intrathecal Grafting of Porcine Chromaffin Cells Reduces Formalin-Evoked c-Fos Expression in the Rat Spinal Cord

Chromaffin cells from the adrenal gland secrete a combination of neuroactive compounds including catecholamines, opioid peptides, and growth factors that have strong analgesic effects, especially when administered intrathecally. Preclinical studies of intrathecal implantation with xenogeneic bovine chromaffin cells in rats have provided conflicting data with regard to analgesic effects, and recent concern over risk of prion transmission has precluded their use in human clinical trials. We previously developed a new, safer source of adult adrenal chromaffin cells of porcine origin and demonstrated an in vivo antinociceptive effect in the formalin test, a rodent model of tonic pain. The goal of the present study was to confirm porcine chromaffin cell analgesic effects at the molecular level by evaluating neural activity as reflected by spinal cord c-Fos protein expression. To this end, the expression of c-Fos in response to intraplantar formalin injection was evaluated in animals following intrathecal grafting of 10(6) porcine or bovine chromaffin cells. For the two species, adrenal chromaffin cells significantly reduced the tonic phases of the formalin response. Similarly, c-Fos-like immunoreactive neurons were markedly reduced in the dorsal horns of animals that had received injections of xenogeneic chromaffin cells. This reduction was observed in both the superficial (I-II) and deep (V-VI) lamina of the dorsal horn. The present study demonstrates that both xenogeneic porcine and bovine chromaffin cells transplanted into the spinal subarachnoid space of the rat can suppress formalin-evoked c-Fos expression equally, in parallel with suppression of nociceptive behaviors in the tonic phase of the test. These findings confirm previous reports that adrenal chromaffin cells may produce antinociception by inhibiting activation of nociceptive neurons in the spinal dorsal horn. Taken together these results support the concept that porcine chromaffin cells may offer an alternative xenogeneic cell source for transplants delivering pain-reducing neuroactive substances.

Reducing the risk of prion transmission in anaesthesia

Reducing the risk of prion transmission in anaesthesia

Intérêt d’un questionnaire de dépistage du risque de transmission de la maladie de Creutzfeldt-Jacob en consultation d’Ophtalmologie

The risk of prion transmission during an ophthalmic examination concerns all ophthalmologists screening patients at risk, a procedure normally based on collecting past history and clinical data. The authors proposed a shortened version of a questionnaire where the patient provides only the past history by answering three questions, which are then validated by the ophthalmologist. This procedure was proposed to 500 patients. Only five patients answered one of the questions positively, and the ophthalmologist did not use any contact device during their examination. Of these five patients, none was confirmed to be at risk for prion transmission. This questionnaire seems to be a suitable way to compensate the lack of time and reduced staff in ophthalmology, whatever the ophthalmic practice may be.