Pathogen Inactivation Technologies Research Articles

Pathogen reduced red blood cells as an alternative to irradiated and washed components with potential for up to 42 days storage.

The urgency of maintaining a safe and adequate blood supply is increasing. One approach to ensure a sufficient supply is to limit the outdating frequency of blood components. Pathogen inactivation technology was developed primarily to increase safety by preventing transmission of infectious diseases. The Intercept Blood System for pathogen reduction of red blood cells (RBC) has additional benefits such as inactivation of leucocytes and removal of plasma and storage debris through centrifugation. Irradiation and automated washing are detrimental to the RBC membrane and often implicate shortened shelf-life. We aimed to assess whether pathogen inactivation can replace RBC irradiation and washing to avoid shelf-life reduction. RBC concentrates (No.=48) were pooled-and-split into four study arms, which underwent pathogen inactivation treatment, irradiation, automated washing or no treatment (reference). RBC quality was evaluated during 42 days by assessment of storage lesion. Washing efficacy was defined by IgA and albumin reduction. Pathogen reduced RBCs had similar membrane preservation to reference RBCs (hemolysis, microvesicles and extracellular potassium ions), whereas the RBCs were negatively impacted by irradiation or automated washing. ATP increased substantially post-pathogen inactivation, while 2,3-DPG decreased. Pathogen inactivation considerably reduced albumin and IgA, though slightly less efficiently than automated washing. RBCs exhibit superior membrane preservation after pathogen inactivation treatment, compared to both irradiation and automated washing. This suggests that replacement is possible, even though the plasma reduction protocol could be further optimised.Replacement of irradiated and washed RBC concentrates with pathogen reduced RBC concentrates storable up to 42 days would be advantageous for both the blood supply and patient safety.

RND Pump-Mediated Efflux of Amotosalen, a Compound Used in Pathogen Inactivation Technology to Enhance Safety of Blood Transfusion Products, May Compromise Its Gram-Negative Anti-Bacterial Activity.

Pathogen inactivation is a strategy to improve the safety of transfusion products. The only pathogen reduction technology for blood products currently approved in the US utilizes a psoralen compound, called amotosalen, in combination with UVA light to inactivate bacteria, viruses, and protozoa. Psoralens have structural similarity to bacterial multidrug efflux pump substrates. As these efflux pumps are often overexpressed in multidrug-resistant pathogens, we tested whether contemporary drug-resistant pathogens might show resistance to amotosalen and other psoralens based on multidrug efflux mechanisms through genetic, biophysical, and molecular modeling analysis. The main efflux systems in Enterobacterales, Acinetobacter baumannii, and Pseudomonas aeruginosa are tripartite resistance-nodulation-cell division (RND) systems, which span the inner and outer membranes of Gram-negative pathogens, and expel antibiotics from the bacterial cytoplasm into the extracellular space. We provide evidence that amotosalen is an efflux substrate for the E. coli AcrAB, Acinetobacter baumannii AdeABC, and P. aeruginosa MexXY RND efflux pumps. Furthermore, we show that the MICs for contemporary Gram-negative bacterial isolates for these species and others in vitro approached and exceeded the concentration of amotosalen used in the approved platelet and plasma inactivation procedures. These findings suggest that otherwise safe and effective inactivation methods should be further studied to identify possible gaps in their ability to inactivate contemporary, multidrug-resistant bacterial pathogens. IMPORTANCE Pathogen inactivation is a strategy to enhance the safety of transfused blood products. We identify the compound, amotosalen, widely used for pathogen inactivation, as a bacterial multidrug efflux substrate. Specifically, experiments suggest that amotosalen is pumped out of bacteria by major efflux pumps in E. coli, Acinetobacter baumannii, and Pseudomonas aeruginosa. Such efflux pumps are often overexpressed in multidrug-resistant pathogens. Importantly, the MICs for contemporary multidrug-resistant Enterobacterales, Acinetobacter baumannii, Pseudomonas aeruginosa, Burkholderia spp., and Stenotrophomonas maltophilia isolates approached or exceeded the amotosalen concentration used in approved platelet and plasma inactivation procedures, potentially as a result of efflux pump activity. Although there are important differences in methodology between our experiments and blood product pathogen inactivation, these findings suggest that otherwise safe and effective inactivation methods should be further studied to identify possible gaps in their ability to inactivate contemporary, multidrug-resistant bacterial pathogens.

New ultraviolet C light-based method for pathogen inactivation of red blood cell units.

Pathogen inactivation (PI) technologies for platelet concentrates and plasma are steadily becoming more established, but new PI treatment options for red blood cells (RBCs), the most commonly used blood component, still need to be developed. We present a novel approach to inactivating pathogens in RBC units employing ultraviolet C (UVC) light. Whole blood-derived leukoreduced RBCs suspended in PAGGS-C, a third generation additive solution, served as test samples, and RBCs in PAGGS-C or SAG-M as controls. Vigorous agitation and hematocrit reduction by diluting the RBCs with additional additive solution during illumination ensured that UVC light penetrated and inactivated the nine bacteria and eight virus species tested. Bacterial and viral infectivity assays and in vitro analyses were performed to evaluate the system's PI capacity and to measure the RBC quality, metabolic, functional, and blood group serological parameters of UVC-treated versus untreated RBCs during 36-day storage. UVC treatment of RBCs in the PAGGS-C additive solution did not alter RBC antigen expression, but significantly influenced some in vitro parameters. Compared to controls, hemolysis was higher in UVC-treated RBC units, but was still below 0.8% at 36 days of storage. Extracellular potassium increased early after PI treatment and reached ≤70 mmol/L by the end of storage. UVC-treated RBC units had higher glucose and 2,3-diphosphoglycerate levels than controls. As UVC irradiation efficiently reduces the infectivity of relevant bacteria and viruses while maintaining the quality of RBCs, the proposed method offers a new approach for PI of RBC concentrates.

Residual risks of bacterial contamination for pathogen-reduced platelet components.

Platelet components are commonly transfused to patients for a variety of indications, including patients with low platelet counts or patients with platelet dysfunction who are bleeding or at high risk of bleeding. Although the risk of pathogen contamination of platelet components has declined significantly over the last 40 years, it remains a concern for the patients, for blood banks and for physicians. Pathogen inactivation (PI) technologies have been developed to mitigate this risk. This review focuses on the residual risks of transfusion-transmitted bacterial infections by platelet transfusion after PI. We describe and assess the relationship between the bacterial load and the timing and capacity of reduction of the different PI technologies, as well as the risks that could represent spore-forming microorganisms and the possible introduction of microorganisms after PI.

A comparative study of pathogen inactivation technologies in human platelet lysate and its optimal efficiency in human placenta-derived stem cells culture

BackgroundPathogen inactivation (PI) is necessary for the pooled components derived from a biological source. Recently, the use of human platelet lysate (hPL) has increased in the cell manufacturing process as a xeno-free substitute for Fetal Bovine Serum (FBS). Therefore, an effective PI process to produce a pathogen-free hPL with the optimal efficiency in the manufacturing of cell therapy products is a vital requirement. Study design and methodsTo evaluate the efficacy of gamma irradiation and riboflavin/ultraviolet light (RB/UV) as PI methods for hPL, the reduction factor (RF) of titer of model viruses and bacteria were examined. Furthermore, the effect of different PI methods on the hPL performance was evaluated by the in vitro expansion of human placenta-derived mesenchymal stem cells (PLMSCs). To compare different study groups, the growth kinetic, immunophenotype, colony formation, and differentiation capacity (osteogenic and adipogenic) of PLMSCs were examined. In addition, the concentration of growth factors was assayed in each study group. ResultsAchievement to the RF more than 5 log10 for all pathogens, showed the effectiveness of two PI methods. In comparison with the other study groups, the dose of 45 kGy gamma irradiation considerably decreased the growth factor level of the hPL. It also showed a significant adverse effect on PLMSCs growth kinetics. The dose of 30 KGy gamma irradiation and RB/UV demonstrated a favorable effect on different assays of the in vitro expanded PLMSCs. ConclusionThe 30 KGy gamma irradiation and RB/UV were effective in the RF of the viral and bacterial models of the contaminated hPL. The efficacy of these PI-hPLs for PLMSCs expansion was preserved. To increase the safety of cell therapy products, PI methods should be considered for the hPL preparations.

Blood transfusion service in Poland in 2020

Background: The aim of this study was to present the basic aspects of the activity of Polish blood transfusion service (hereinafter referred to as Centers) in 2020, taking into account the conditions related to the ongoing COVID-19 pandemic. Materials and methods: Analysis of data forwarded to the Institute by the Polish Blood Transfusion Centers (Centers). Results: In 2020, 23 Centers and 136 local collection sites operated in Poland. Blood and blood components were also collected during 10,432 mobile collections. The overall number of blood donors was estimated at 569,914, the majority of which were non-remunerated donors (569,566, including 50,012 responders to donation appeals) as well as 25 remunerated donors and 323 autologous donors. Most frequent were whole blood collections (1,105,434) and the least frequent — granulocyte concentrate collections (82) and RBC collections by apheresis (16). Whole blood was collected mostly in local collection sites (46.84%), less frequently in Centers (30.62%) and mobile collection sites (22.54%). The most frequently prepared blood components were RBCs (1,089,978 units) and FFP (1,264,654 units). COVID-19 convalescent plasma was also collected (57 708 units). In 2020, a total of 77,485 units of PCs pooled from whole blood and 52,030 units of PCs from apheresis were prepared. Additional processing methods (leukocyte depletion, irradiation) were more frequently applied to PCs (55.47% leukodepleted, 44.53% both leuko-depleted and irradiated), than to RBC (21.03% leukodepleted, 9.85% both leukodepleted and irradiated, 0.06% irradiated). Pathogen inactivation technologies were applied to 14.21% of FFP units issued for clinical use and 11.01% of PCs. For various reasons the following amounts of blood components were wasted in 2020: 11,430 units of whole blood, 29,530 units of RBCs, 53,946 units of FFP, 1,691 units of apheresis PCs, 5,455 units of pooled PCs and 1,381 units of cryoprecipitate. As compared to the previous years, in 2020 almost all the indicators of the activity of the blood transfusion service in Poland have markedly decreased. Conclusions: The data presented in this study point to the significant impact that the COVID- 19 pandemic had on blood donation in Poland in 2020. The data may serve as a starting point for the analysis of issues related to the activity of organizational units of the Polish blood transfusion service and contribute to practical benchmarking. This in turn may prove beneficial to the transfusion community as a whole.

Research Advance on Preparation Technology and Application of Virus-inactivated Lyophilized Plasma---Review

Lyophilized plasma has a certain advantage in emergency situation, such as war wound treatment. However, lyophilized plasma has two major problems, plasma pathogen pollution and mass loss after lyophilized. Studies have shown that plasma pathogen inactivation technology targeting pathogen envelope or nucleic acid can ensure its safety, and adding citric acid and glycine to plasma can effectively maintain pH and protein activity of plasma after reconstitution. At present, there are three kinds of lyophilized plasma products on the market abroad, but none for China. Therefore, understanding the research progress of lyophilized plasma may contribute to the development of similar products in China.

Pathogen reduction of whole blood: Supplementing fibrinogen partly corrects clot formation in a massive transfusion model.

The use of whole blood (WB) to treat trauma patients is becoming more common. Similar to the treatment of individual components, pathogen inactivation (PI) technologies are available to treat WB. The impact of PI on WB function is not well understood. This study investigated the impact of PI of WB with riboflavin/ultraviolet (UV) light on its hemostatic function by modeling transfusion scenarios for trauma patients and assessing transfusion efficacy by rotational thromboelastometry (ROTEM). As fibrinogen is affected by PI of WB, the effect of fibrinogen supplementation commonly used in trauma patients was also analyzed in this model. Trauma transfusion scenarios were simulated by mixing untreated WB or WB treated with the Mirasol PI technology (riboflavin/UV) in different ratios with hemodiluted blood, and the thromboelasticity was monitored by ROTEM. The impact of supplementation with the fibrinogen concentrate RiaSTAP was investigated in this model. Pathogen-inactivated WB (PI-WB) showed decreased activity in the hemostatic profile compared to the untreated control. Hemodiluted blood at a hematocrit (hct) of 20%, which was reconstituted with PI-WB or untreated WB, exhibited increased alpha values, maximum clot firmness, and clot formation time. Simulating transfusion scenarios by blood replacement with PI-WB resulted in a significant difference in ROTEM parameters between reconstituted PI-treated and -untreated WB (p≥ .05). The effect of PI treatment waned when PI-WB was enriched with fibrinogen. ROTEM investigations suggest that PI treatment has a negative impact on WB clot formation unless fibrinogen supplementation is used.

Indications for transfusion of blood components

Indications for transfusion of blood components

Human babesiosis: recent advances and future challenges.

As human babesiosis caused by apicomplexan parasites of the Babesia genus is associated with transfusion-transmitted illness and relapsing disease in immunosuppressed populations, it is important to report novel findings relating to parasite biology that may be responsible for such pathology. Blood screening tools recently licensed by the FDA are also described to allow understanding of their impact on keeping the blood supply well tolerated. Reports of tick-borne cases within new geographical regions such as the Pacific Northwest of the USA, through Eastern Europe and into China are also on the rise. Novel features of the parasite lifecycle that underlie the basis of parasite persistence have recently been characterized. These merit consideration in deployment of both detection, treatment and mitigation tools such as pathogen inactivation technology. The impact of new blood donor screening tests in reducing transfusion transmitted babesiosis is discussed. New Babesia species have been identified globally, suggesting that the epidemiology of this disease is rapidly changing, making it clear that human babesiosis is a serious public health concern that requires close monitoring and effective intervention measures. Unlike other erythrocytic parasites, Babesia exploits unconventional lifecycle strategies that permit host cycles of different lengths to ensure survival in hostile environments. With the licensure of new blood screening tests, incidence of transfusion transmission babesiosis has decreased.

Apoptosis as an underlying mechanism in lymphocytes induced by riboflavin and ultraviolet light

Riboflavin plus UV light pathogen reduction technology (RF-PRT) is an effective method for inactivating donor-derived leukocytes (DDLs) in blood components. Literature data have shown that reactive oxygen species (ROS) increased in lymphocytes after RF-PRT treatment. Sustained high levels of ROS may abolish the endogenous antioxidant system, leading to damage to proteins, lipids, and nucleic acids, resulting in cell apoptosis. Nevertheless, whether riboflavin plus UV light can trigger leukocyte apoptosis remains obscure. In this study, a pool-and-split design, ABO/D-matched lymphocytes treated with RF-PRT or UV light or left untreated. After treatment, the level of ROS and intracellular calcium were measured in samples. Changes in the protein expression of cleaved PARP, Bax, and Bcl-2 and the activities of caspase-3 and caspase-9 were determined by immunoblot analysis or luminometer, respectively. Cell apoptosis was evaluated by flow cytometry. The effect of ROS on apoptosis was assessed. The RF-PRT treatment significantly augmented ROS production, intracellular calcium concentration. The pro-apoptotic proteins expression levels of Bax, but did not the anti-apoptotic protein Bcl-2, were markedly increased after the RF-PRT treatment.Furthermore, the percentage of apoptotic cells was increased in RF-PRT-treated lymphocytes compared to UV-treated cells or untreated cells. Moreover, the inhibition of ROS generation partially neutralized the apoptosis effects of riboflavin plus UV treatment. These findings revealed that RF-PRT-treated lymphocytes significantly increase the proportion of apoptotic cells by promoting ROS generation delineation of the biochemical processes influenced by RF-PRT are a necessary step to provide novel insights into the riboflavin pathogen inactivation technology.

The Plasma Mobile, 'A gift from heaven': The impact of health technology transfer on trial perceptions and expectations during the Ebola-Tx Trial, Conakry.

During the West African Ebola Virus Disease (EVD) epidemic from 2014 to 2016, a variety of technologies travelled considering the context of the emergency: a highly contagious fast-killing disease outbreak with no known remedy and a rapidly increasing number of cases. The Ebola-Tx clinical trial tested the efficacy of Convalescent Plasma (CP) as a treatment for EVD in Guinea. This paper is based on ethnographic research in the Ebola-Tx trial and focuses on the introduction of a mobile plasma collection centre, referred to as the ‘Plasma Mobile’, equipped with plasmapheresis and pathogen inactivation technologies, as well as how the transfer itself of this technology entailed complex effects on CP donors as trial participants (i.e. providers of the therapeutic product), directly involved staff and more broadly on the trial implementation as a whole. The transfer led to the emergence of a dimension of hope as CP donors hoped that the plasma would cure and, as providers of the therapeutic, hoped it would decrease their stigmatization and the economic impact of the disease. We conclude that, in light of the intricate effects that the transfer of such health technology can entail–in the localization to the specific context, as well as in the consequences they can have on actors involved in the implementation of such technologies–global health technologies should be put at the services of next epidemic and pandemic (preparedness) on condition that they are accompanied by an understanding of the technologies’ own cultural meanings and social understandings.

Haemostatic responsiveness and release of biological response modifiers following cryopreservation of platelets treated with amotosalen and ultraviolet A light.

Due to the risk of replication of contaminating pathogens, platelets have a limited storage time of 5 days, which can be prolonged to 7 days by the use of pathogen inactivation technologies. Cryopreservation (CP) may be an alternative to permit longer storage periods and increased availability. However, the preparation of platelets can result in secretion of biological response modifiers (BRM), which can cause adverse transfusion reactions in the recipient. We investigated the impact of CP on platelet function and release of BRM in untreated (conventional) and pathogen-inactivated (PI) platelet concentrates. Twelve buffy coat-derived platelet units were treated with amotosalen and ultraviolet A light to inactivate pathogens. Twelve untreated units were used as controls. The 24 units were cryopreserved and in vitro variables were analysed before and after CP. The in vitro variables investigated included platelet surface receptors and activation markers by flow cytometry, and coagulation time by viscoelastography. A panel of BRM, including cytokines, was investigated. CP of both conventional and PI platelets resulted in a significant increase of BRM with similar increases of most of the BRM after CP of conventional and PI platelet concentrates. The increase in some of the BRM correlated significantly with shortened coagulation time, increased P-selectin expression, reduced mitochondrial transmembrane potential, and reduced capacity to respond to stimulation with ADP and collagen. Cryopreservation of both conventional and PI platelets results in secretion of BRM. The increase in some of the BRM correlated with changes in platelet function variables and suggests that BRM release is affected, in part, in a similar way by CP as are changes in platelet function variables. PI with amotosalen and ultraviolet A light in combination with CP did not affect the release of immunomodulatory factors more than CP alone did.

Proceedings of the Food and Drug Administration public workshop on pathogen reduction technologies for blood safety 2018 (Commentary, p. 3026).

On November 29, 2018, experts in the field of infectious diseases, pathogen reduction technologies (PRTs) and other participants from blood centers, academia, and industry gathered at the Food and Drug Administration (FDA) White Oak Campus in Silver Spring, Maryland, for a 2‐day public workshop entitled “Pathogen Reduction Technologies for Blood Safety.” The workshop opened with welcome remarks from Dr. Nicole Verdun, Director, Office of Blood Research and Review (OBRR), Center for Biologics Evaluation and Research (CBER), FDA, followed by introductory remarks from Dr. Peter Marks, Director, CBER, FDA. The first day of the workshop focused on blood‐borne infectious agents and their impact on blood safety, experiences of the American Red Cross, and other blood establishments in implementing FDA‐approved pathogen inactivation (PI) technology for plasma and platelets (PLTs) in the United States and novel PRTs under consideration for whole blood (WB) and red blood cells (RBCs). The second day opened with welcome remarks from Dr. Chintamani Atreya, Associate Director for Research, OBRR, CBER, FDA. The focus was on emerging innovations relevant to PRTs and potential alternatives to PRTs. The workshop concluded with remarks on insights for future research and development in this area for blood and blood product safety from infectious agents. A brief introduction of each session by the session moderator followed by a summary of the speaker presentation as submitted by the moderator and speaker are reported here.

Inactivation of yellow fever virus in plasma after treatment with methylene blue and visible light and in platelet concentrates following treatment with ultraviolet C light.

Yellow fever virus (YFV) is endemic to tropical and subtropical areas in South America and Africa, and is currently a major public health threat in Brazil. Transfusion transmission of the yellow fever vaccine virus has been demonstrated, which is indicative of the potential for viral transfusion transmission. An approach to manage the potential YFV transfusion transmission risk is the use of pathogen inactivation (PI) technology systems, such as THERAFLEX MB-Plasma and THERAFLEX UV-Platelets (Macopharma). We aimed to investigate the efficacy of these PI technology systems to inactivate YFV in plasma or platelet concentrates (PCs). YFV spiked plasma units were treated using THERAFLEX MB-Plasma system (visible light doses: 20, 40, 60, and 120 [standard] J/cm2 ) in the presence of methylene blue (approx. 0.8 μmol/L) and spiked PCs were treated using THERAFLEX UV-Platelets system (ultraviolet C doses: 0.05, 0.10, 0.15, and 0.20 [standard] J/cm2 ). Samples were taken before the first and after each illumination dose and tested for residual virus using a modified plaque assay. YFV infectivity was reduced by an average of 4.77 log or greater in plasma treated with the THERAFLEX MB-Plasma system and by 4.8 log or greater in PCs treated with THERAFLEX UV-Platelets system. Our study suggests the THERAFLEX MB-Plasma and the THERAFLEX UV-Platelets systems can efficiently inactivate YFV in plasma or PCs to a similar degree as that for other arboviruses. Given the reduction levels observed in this study, these PI technology systems could be an effective option for managing YFV transfusion-transmission risk in plasma and PCs.

Irreversible oxidations of platelet proteins after riboflavin-UVB pathogen inactivation.

Pathogen inactivation technologies are known to alter in vitro phenotype and functional properties of platelets. Because pathogen inactivation generates reactive oxygen species, oxidative stress is considered as one of the plausible cause at the origin of the platelet storage lesion acceleration after treatment. To date proteomics has been used to document the protein variations to picture out the impact. Here, platelet concentrates were prepared from buffy-coats in Intersol additive solution, leukoreduced and pathogen inactivated using a riboflavin/UVB treatment. At day 2 of storage the platelet proteomes of control (untreated) and treated platelet concentrates were investigated against the site specific oxidation by liquid chromatography coupled to tandem mass spectrometry in a shotgun experiment. The shotgun approach detected 9350 peptides (and 2534 proteins) of which 1714 were oxidized. Eighteen peptides were found exclusively oxidized in treated platelets whereas 3 peptides were only found oxidized in control. The present data evidenced an interference with several proteins involved in platelet aggregation and platelet shape change (such as talin and vinculin).

In vitro evaluation of pathogen inactivated platelet quality: An 8 year experience of routine use in Galicia, Spain

BackgroundPlatelet concentrates (PCs) treated by the pathogen inactivation technology (PI) using amotosalen and UVA illumination (PI-PCs) can be manufactured in additive solutions (PAS-III and PAS-IIIM) or in 100% Plasma. Quality control (QC) is an integral part of the production. We capitalized on our ongoing QC program to capture 8 years-worth of data on parameters related to the quality of 116,214 PI-PCs produced under different manufacturing methods. Materials and methodsSelected in vitro parameters of metabolism, activation, and storage were analyzed for the different manufacturing periods to compare PI-PCs versus conventional PCs (C-PCs) resuspended in different PAS. Results and discussionAll BC-PCs met quality standards for pH and dose and residual leucocytes. As expected, storage time correlated with increased lactate, LDH, Annexin V, CD62, sCD40 L levels and decreased glucose and pH. With PAS-IIIM, higher levels of glucose were observed toward the end of shelf life (p < 0.0001) with lower platelet activation markers Annexin V (p = 0.038) and CD62 (p = 0.0006). Following PI implementation, a low expire rate of <0.5% was observed. While a 2.3% mean increase in the production of PCs occurred from 2011 to 2015, the distribution of red blood cell concentrates dropped by 4.4%. A mean incidence of 0.14% for transfusion-related adverse reaction was observed while PI-PCs were distributed, similar to the one observed with C-PCs. Overall, PI-PCs prepared in additive solutions consistently met quality standards. Those prepared in PAS-IIIM appeared to have better retention of in vitro characteristics compared to PAS-III though all demonstrated functionality and clinical effectiveness.

Platelet transfusion associated risks and improvement of platelet transfusion safety with Amotosalen/UVA pathogen inactivation technology

Despite the introduction of multiple measures to minimize the risk of transfusion-transmitted infections, there is still a residual risk of platelet transfusions, especially but not only for bacterial sepsis. Recently, the importance of a reliable hemovigilance system has been underlined and an up to 10-fold difference in the reporting of bacterial transmissions between active and passive reporting has been demonstrated. Another reason for a misjudging of the blood safety may derive from the fact that some pathogens cause obvious damage to critically ill and/or immunocompromised patients only and asymptomatic infections in immuno-competent recipients and thus are not being reported. Pathogen inactivation for platelets, a proactive approach not only broadly inactivating pathogens, but also white blood cells, could minimize the risk of transfusion transmitted infections and graft versus host disease due to residual leukocytes. Only the INTERCEPT technology has received approvals from the regulatory agencies in France, Germany and Switzerland, United States and Canada. That technology utilizes photoactive methods to modify nucleic acids. Long-term routine clinical experience, also with children and neonates, shows the safety and efficacy of INTERCEPT platelet transfusions. The national hemovigilance data of Switzerland, France and Belgium as well as single-center routine use studies show an improved clinical outcome in the acute as well as in the prophylactic setting with a significant decrease in septic and other non-hemolytic transfusion reactions, as well as prevention of graft-versus-host disease.

Pathogen inactivation/reduction technologies for platelet transfusion: Where do we stand?

Pathogen inactivation or reduction technologies for platelet components have been proposed to secure the microbial safety of this component, and particularly the microbial contamination. Transfusion-transmitted bacterial infections were substantially reduced by additive steps applied at different levels of the transfusion chain, but still killed one recipient each year or every other year in a country like France. Besides, pathogen inactivation and reduction stand for eliminating most viral and protozoa infections persisting in the separated blood component. In addition, because those processes attack nucleic acids, they also aim at substantially alleviating the risk of Transfusion Associates Graft versus Host Disease, as they attack lymphocytes still comprises within the component. Meanwhile, pathogen inactivation or reduction may inflict some damages to the platelet components, that are shown to be additive to the “natural” storage lesions linked to ageing. While it is in general assumed that such processes do not expose transfused patients to an over-risk of bleeding, and are safe, this does not mean that there are no detrimental consequences in the patients, even if not ascribed to as serious. Two such effects are now discussed or debated: the first one is the possible increase in the demand of platelet component, and the other one could be a possible risk of alloimmunisation especially when treated platelets are aged (over 5 days). Three processes have been made available by the industry, that differ in their chemical and physical (ultraviolet light illumination) characteristics. Two processes are largely used (one nationwide in two European countries) and the third one is still under clinical evaluation. This short review endeavored to critically present the main features of the processes and of their implementation.

Ultraviolet-Based Pathogen Inactivation Systems: Untangling the Molecular Targets Activated in Platelets.

Transfusions of platelets are an important cornerstone of medicine; however, recipients may be subject to risk of adverse events associated with the potential transmission of pathogens, especially bacteria. Pathogen inactivation (PI) technologies based on ultraviolet illumination have been developed in the last decades to mitigate this risk. This review discusses studies of platelet concentrates treated with the current generation of PI technologies to assess their impact on quality, PI capacity, safety, and clinical efficacy. Improved safety seems to come with the cost of reduced platelet functionality, and hence transfusion efficacy. In order to understand these negative impacts in more detail, several molecular analyses have identified signaling pathways linked to platelet function that are altered by PI. Because some of these biochemical alterations are similar to those seen arising in the context of routine platelet storage lesion development occurring during blood bank storage, we lack a complete picture of the contribution of PI treatment to impaired platelet functionality. A model generated using data from currently available publications places the signaling protein kinase p38 as a central player regulating a variety of mechanisms triggered in platelets by PI systems.