Pathogen Inactivation Of Platelet Research Articles

Impact of platelet pathogen inactivation on blood component utilization and patient safety in a large Austrian Regional Medical Centre

In clinical studies, pathogen inactivation (PI) of platelet concentrates (PC) with amotosalen and UVA light did not impact patient risk for haemorrhage but may affect transfusion frequency and component utilization. We evaluated the influence of platelet PI on PC, red cell concentrate (RCC) and plasma use and safety in routine practice in a large regional hospital. Comparative effectiveness of conventional vs. PI-treated PC was analysed during two 21-month periods, before and after PI implementation. Similar numbers of patients were transfused in the pre-PI (control, 1797) and post-PI (test, 1694) periods with comparable numbers of PC (8611 and 7705, respectively). The mean numbers of PC per patient transfused (4·8 vs. 4·5, P = 0·43) were not different but days of PC support (5·9 vs. 5·0, P < 0·01) decreased. Most patients received RCC (86·8% control vs. 84·8% test, P = 0·90) with similar mean numbers transfused (10·8 vs. 10·2 RCC, P = 0·22), and fewer patients (55·4% control vs. 44·7% test, P < 0·01) received less plasma units (mean 9·9 vs. 7·8, respectively, P < 0·01) in the test period. The frequencies of transfusion-related adverse events (AE) were comparable (1·3% vs. 1·4%, P = 0·95). Analysis of haematology-oncology (522 control, 452 test), cardiac surgery (739 control, 711 test), paediatric (157 control, 130 test) and neonate (23 control, 20 test) patients revealed no increase in PC, plasma and RCC utilization, or AE. Component utilization and patient safety were not impacted by adoption of PI for PC. RCC use per patient was comparable, suggestive of no increase in significant bleeding.

Prevention of transfusion‐transmitted Zika virus in French Polynesia, nucleic acid testing versus pathogen inactivation

Background and ObjectivesFrench Polynesia (FP) experienced a large Zika virus (ZIKV) outbreak in 2013–2014. Flavivirus transfusion‐transmission infections (TTIs) had been previously reported. We evaluated several mitigating strategies to prevent ZIKV TTIs in FP.Material and MethodsMitigation strategies consisted of pre/postdonation symptom reporting, donor deferral, importation of plasma units from non‐endemic areas, quarantine of blood components, blood screening using a laboratory‐developed nucleic acid testing (NAT) assay and platelet pathogen inactivation (PI) using the INTERCEPT Blood Systems. The pros and cons of NAT versus PI to prevent ZIKV TTIs were determined.ResultsDonor interview, deferral and component quarantine strategies were not sensitive enough to prevent subsequent detection of ZIKV RNA NAT‐positive donations. A 12‐week delay between the onset of outbreak and NAT implementation allowed for 30 blood products collected from 30 asymptomatic blood donors who retrospectively tested positive for ZIKV RNA by NAT to be transfused while platelet PI which was in routine use since 2010 in FP potentially prevented several cases of ZIKV TTIs.ConclusionNucleic acid testing and PI were used in FP to prevent ZIKV TTIs. NAT was an effective measure once implemented but is not a proactive solution. PI is a proactive solution but with only systems approved for platelets and plasma. Based on the FP experience, there is an urgent need for approved whole blood and/or red blood cell PI systems and to develop multiplex NAT to maintain the availability of the blood supply in remote areas during arbovirus epidemics.

Expired and Pathogen-Inactivated Platelet Concentrates Support Differentiation and Immunomodulation of Mesenchymal Stromal Cells in Culture.

Platelet lysates have been reported as suitable cell culture supplement for cultures of mesenchymal stromal cells (MSCs). The demand for safe and animal-free cultures of MSCs is linked to the potential application of MSCs in clinics. While the use of platelet lysates offers an alternative to animal serum in MSC cultures, obtaining supplies of fresh platelet concentrates for lysate production is challenging and raises concerns due to the already existing shortage of platelet donors. We have previously demonstrated that expired platelet concentrates may represent a good source of platelets for lysate production without competing with blood banks for platelet donors. The INTERCEPT Blood System™ treatment of platelet concentrates allows for prolonged storage up to 7 days, using highly specific technology based on amotosalen and UV-A light. The INTERCEPT system has therefore been implemented in blood processing facilities worldwide. In this study, we evaluated the suitability of INTERCEPT-treated, expired platelet concentrates, processed into platelet lysates, for the culture of MSCs compared to nontreated expired platelets. Bone marrow-derived MSCs were cultured in media supplemented with either platelet lysates from traditionally prepared expired platelet concentrates or in platelet lysates from expired and pathogen-inactivated platelet concentrates. The effects of pathogen inactivation on the ability of the platelets to support MSCs in culture were determined by evaluating MSC immunomodulation, immunophenotype, proliferation, and trilineage differentiation. Platelet lysates prepared from expired and pathogen-inactivated platelet concentrates supported MSC differentiation and immunosuppression better compared to traditionally prepared platelet lysates from expired platelet units. Pathogen inactivation of platelets with the INTERCEPT system prior to use in MSC culture had no negative effects on MSC immunophenotype or proliferation. In conclusion, the use of expired pathogen-inactivated platelet units from blood banks to prepare platelet lysates for the culture of MSCs is desirable and attainable.

Component pathogen inactivation: a critical review

Pathogen inactivation (PI)-treated plasma and platelets are increasingly becoming the products of choice, where licensed. This review summarizes the clinical evidence available for licensed component PI technologies and red cell PI under development. Available literature on licensed technologies was reviewed. For the plasma and platelets technologies available, evidence for the inactivation of most pathogens is good, except for certain nonenveloped viruses. Clinical trials and haemovigilance programmes suggest the observed loss of potency is of little clinical significance, with some technology-specific exceptions. Concerns over adverse toxicological effects or neoantigen formation have not been confirmed for currently licensed products. While platelet PI has been adopted to reduce bacterial contamination, the ability of PI methods to replace testing for emerging bloodborne infections, or as a substitute for selective pathogen testing, gamma-irradiation or even leucodepletion, make adoption of PI for components increasingly attractive.

Pathogen inactivation of platelets using ultraviolet C light: effect on in vitro function and recovery and survival of platelets

We evaluated the effect of treating platelets (PLTs) using ultraviolet (UV)C light without the addition of any photosensitizing chemicals on PLT function in vitro and PLT recovery and survival in an autologous radiolabeled volunteer study. For in vitro studies, pooled or single buffy coat-derived PLT concentrates (PCs) were pooled and split to obtain identical PCs that were either treated with UVC or untreated (n = 6 each) and stored for 7 days. PLT recovery and survival were determined in a two-arm parallel autologous study in healthy volunteers performed according to BEST guidelines. UVC-treated or untreated PCs (n = 6 each) were stored for 5 days and were compared to fresh PLTs from the same donor. There were no significant differences on Day 7 of storage between paired UVC-treated and control PC units for pH, adenosine triphosphate, lactate dehydrogenase, CD62P, CD63, PLT microparticles, and JC-1 binding, but annexin V binding, lactate accumulation, and expression of CD41/61 were significantly higher in treated units (p < 0.05). Compared with control units, the recovery and survival of UVC-treated PC were reduced after 5 days of storage (p < 0.05) and when expressed as a percentage of fresh values, survival was reduced by 20% (p = 0.005) and recovery by 17% (p = 0.088). UVC-treated PLTs stored for 5 days showed marginal changes in PLT metabolism and activation in vitro and were associated with a degree of reduction in recovery and survival similar to other pathogen inactivation systems that are licensed and in use.

Inactivation/réduction des pathogènes des concentrés de plaquettes : conséquences sur l’organisation de la transfusion plaquettaire

In the past few years, pathogen reduction technologies for labile blood products have been part of the enhancement of global transfusion safety regarding residual risks of transmitting infectious pathogens. Having carried out a feasibility study for the implementation of pathogen inactivation of platelet concentrates by means of the amotosalen/HCl/UVA (Intercept™) technology, and participated to a reinforced haemovigilance study, we took the opportunity to analyze the organization consequences for platelet concentrates inventory and distribution. This impact study first indicated that those novel needs forced the blood donation service, as well as the labile blood product preparation laboratory, to review and improve practices; secondly, it showed that the routine implementation has little (no major) consequence in the overall organization, independently of the economic consequences (not covered here).

The Pathogen Inactivation of Platelets: Studies of the Possible Mechanisms of the Platelet Dysfunction Seen Following Photochemical Treatment.

Background: The platelet mitochondrial genome has many similarities to bacterial and viral genomes. These include the lack of DNA redundancy, the lack of introns, no protective histone proteins, and inefficient DNA repair mechanisms; all of which are important characteristics that likely contribute to the increased rate of mutations occurring with mitochondrial DNA (mtDNA) compared to that seen with nuclear genomic DNA. Recent studies have shown that the use of pathogen inactivation involving UVA phototherapy using the combination of ultraviolet A (UVA) light and either the photoactive psoralen 4′-aminomethyltrioxsalen hydrocholoride (AMT/UVA, known to induce cross-linking of DNA) or the B-vitamin riboflavin (RF/UVA, known to produce the oxidized guanine moiety 8-OH-dG) are effective approaches to reduce and/or inactivate the bacterial and viral contaminants often present in human blood products. Such treatments however have been shown to be associated with impaired in vivo platelet recovery, survival and hemostatic function.Methods and Results: In the current study, rabbit and human platelets were treated with the two photochemical pathogen inactivation methods, (AMT/UVA or RF/UVA), using various UVA exposure, and the resultant platelets compared to control platelets with regard to their in vivo recovery, survival, and hemostatic function, as well as evaluating evidence of damage to platelet mtDNA. Rabbit platelets treated with UVA (1 to 5 joules/cm2) alone, RF alone, or AMT alone, showed minimal or no effect on in vivo platelet function; without evidence of damage to mtDNA. In contrast, the photochemical treatment of rabbit platelets with either AMT/UVA or RF/UVA showed a UVA-dose-dependent effect on in vivo platelet function as well as on mtDNA damage. Platelets treated with AMT/UVA(1 to 5 joules/cm2) revealed a 10–30% UVA-dose-dependent reduction in platelet recovery, survival, and hemostatic function, as well as a widespread but a non-specific effect upon platelet mtDNA structure. The treatment of rabbit platelets with RF/UVA(1 to 5 joules/cm2) showed considerably greater impact on platelet recovery, survival, and hemostatic function than that seen with AMT/UVA, at equivalent UVA doses. This was associated with a reproducible impairment of the amplification of a 3.8kb fragment within the platelet mtDNA genome. This mtDNA fragment is specifically associated with the coding for the NADH dehydrogenase subunit 1. A threshold dose of 1.0 joule/cm2 was noted for RF/UVA treatment, below which damage to mtDNA was found to be UVA-dose-dependent. Using HPLC to determine the concentration of 8-OH-dG within photochemically treated human platelets resulted in the demonstration of a UVA-dose-dependent increase of 8-OH-dG production for RF/UVA treated platelets. Control (no treatment), UVA alone, or AMT/UVA treated platelets produced no increase in 8-OHdG levels, even at UVA doses of 5 joules/cm2.Conclusions: These results indicate that the reproducible focal damage of platelet mtDNA by RF/UVA may have a considerably greater effect upon platelet in vivo circulatory and hemostatic functions than does the introduction of random mtDNA cross-linking produced by AMT/UVA treatment, possibly because of the discrete reproducible defect caused by the RF/UVA on the platelet mtDNA. These data nonetheless support the hypothesis that platelet mtDNA damage produced by pathogen inactivation methodology is associated with and may affect subsequent in vivo platelet function following platelet transfusion to a recipient.

Viability and function of 8‐day‐stored apheresis platelets

Methods of bacterial detection and pathogen inactivation of platelets (PLTs) may allow extended storage of PLTs as long as PLT quality is maintained. Twenty normal volunteers had their PLTs collected with an apheresis machine (Haemonetics Corp.). A variety of in vitro PLT function and metabolic assays were performed both on Day 0 and after 8 days of storage. On Day 8, a small blood sample was drawn from each donor to obtain fresh PLTs. The fresh and stored autologous PLTs were labeled with either (51)Cr or (111)In, and the radiolabeled PLTs were transfused. Posttransfusion serial blood samples were drawn to determine the relative posttransfusion recoveries and survivals of the fresh versus the stored PLTs. Although the in vitro assays showed some differences between the two trial sites, the results were generally within the ranges expected for fresh and stored PLTs. Overall, PLT recoveries averaged 66 +/- 16 percent versus 53 +/- 20 percent and survivals averaged 8.5 +/- 1.6 days versus 5.6 +/- 1.6 days, respectively, for fresh compared to 8-day-stored PLTs. There were no significant differences in the in vivo PLT data between the trial sites or based on the radiolabel used for the measurements. After 8 days of storage, the in vivo posttransfusion recovery and survival of autologous Haemonetics apheresis PLTs meet the proposed standards for poststorage PLT quality.

Pathogen inactivation of platelets with a photochemical treatment with amotosalen HCl and ultraviolet light: process used in the SPRINT trial

A photochemical treatment (PCT) system has been developed to inactivate a broad spectrum of pathogens and white blood cells in platelet (PLT) products. The system comprises PLT additive solution (PAS III), amotosalen HCl, a compound adsorption device (CAD), a microprocessor-controlled ultraviolet A light source, and a commercially assembled system of interconnected plastic containers. A clinical prototype of the PCT system was used in a large, randomized, controlled, double-blind, Phase III clinical trial (SPRINT) that compared the efficacy and safety of PCT apheresis PLTs to untreated apheresis PLTs. The ability of multiple users was assessed in a blood center setting to perform the PCT and meet target process specifications. Each parameter was evaluated for 2237 to 2855 PCT PLT products. PCT requirements with respect to mean PLT dose, volume, and plasma content were met. Transfused PCT PLT products contained a mean of 3.6 x 10(11) +/- 0.7 x 10(11) PLTs. The clinical process, which included trial-specific samples, resulted in a mean PLT loss of 0.8 x 10(11) +/- 0.6 x 10(11) PLTs per product. CAD treatment effectively reduced the amotosalen concentration from a mean of 31.9 +/- 5.3 micromol per L after illumination to a mean of 0.41 +/- 0.56 micromol per L after CAD. In general, there was little variation between sites for any parameter. The PCT process was successfully implemented by 12 blood centers in the United States to produce PCT PLTs used in a prospective, randomized trial where therapeutic efficacy of PCT PLTs was demonstrated. Process control was achieved under blood bank operating conditions.

Pathogen inactivation of platelet concentrates and fresh frozen plasma

Transfusion of blood products carries the risk of pathogen transmission, despite careful donor selection and screening tests. This is due to viral transmission from window-period donations, the emergence of new pathogens such as variant Creutzfeldt-Jakob disease, for which routine screening tests are not yet available, and to bacterial contamination. Techniques have been developed to inactivate pathogens in both fresh frozen plasma and platelet concentrates. The relative benefits to the recipient, and the ease of incorporation into blood component processing are considered for the technologies currently available.