Pathogen reduction of platelets: experience of a single blood bank
Review Article

Pathogen reduction of platelets: experience of a single blood bank

Teresa Jimenez-Marco1,2

1Fundació Banc de Sang i Teixits de les Illes Balears, Majorca, Spain; 2Institut d’Investigació Sanitària Illes Balears (IdISBa), Majorca, Spain

Correspondence to: Dr. Teresa Jimenez-Marco. Fundació Banc de Sang i Teixits de les Illes Balears, C/ Rosselló i Caçador, 20. 07004. Palma de Mallorca, Balearic Islands, Spain. Email: tjimenez@fbstib.org; matejimenez@hotmail.com.

Abstract: Pathogen reduction technology (PRT) has the potential to prevent pathogen transfusion transmission from blood donor to patient by impeding the replication of bacteria, viruses and parasites in blood components. Additionally, PRT can help to guarantee blood safety in challenging situations for blood supply, as in the Ebola or Chikungunya epidemics, or in a scenario full of uncertainties such as the current SARS-CoV-2 pandemic. The Balearic Islands Blood Bank (BIBB) is one of the few blood establishments worldwide with more than 10 years of experience in the routine use of amotosalen/UVA (Intercept Blood System) and riboflavin/UVA-UVB (Mirasol PRT system) for platelets (PLTs), the use of riboflavin/UVA-UVB for plasma and with research experience in riboflavin/UVA-UVB applied to whole blood. Over the years, we have had the opportunity to evaluate PRT from different perspectives, such as clinical and hemovigilance research in adults and children, in vitro studies on PRT effects on PLTs and assessing the financial impact of PRT implementation. PRT methods offer remarkable benefits but also have certain limitations, which are important to bear in mind during the decision-making process for PRT implementation. The purpose of this study is to review the current knowledge on PRT for PLTs drawing on our experience acquired over the last decade.

Keywords: Pathogen reduction technology (PRT); platelets; blood safety


Received: 26 November 2020; Accepted: 28 December 2020; Published: 30 June 2021.

doi: 10.21037/aob-2020-pt-03


Introduction

Despite increasingly strict donor selection criteria, advances in laboratory testing and procedures for preventing bacterial contamination, such as donor skin disinfection, diversion of the first milliliters of collected blood and bacterial culture, a small risk of bacterial (1,2), viral (3,4) and parasite (5-9) contamination of platelet (PLT) concentrates still remains. There is also a permanent threat of emerging and novel pathogens entering the blood supply, as demonstrated in the recent epidemics caused by the West Nile virus (WNV), Chikungunya virus (CHIKV), Zika and Ebola virus (10-13).

Pathogen reduction technology (PRT) for PLTs has the potential to prevent pathogen transmission from donor to patient during PLT transfusion (14). In addition to improving blood safety by preventing the replication of bacteria, viruses and parasites, PRT has other benefits: (I) elimination of the risk of transfusion-transmitted graft-versus-host disease by substituting gamma irradiation with white blood cell inactivation (15); (II) the potential reduction of alloimmunization, which has been described in animal models (16) but still needs to be confirmed by evidence from clinical practice (17); (III) fewer PLT transfusion reactions (18,19); and (IV) the improvement of PLT supply by extending the storage time from 5 to 7 days, which results in a substantial reduction in PLT outdating (20,21).


Our experience in pathogen reduction technologies

The Balearic Islands Blood Bank (BIBB) is responsible for supplying blood to 22 hospitals located in the Balearic Islands, a Mediterranean archipelago in Spain. These hospitals provide a total of 3,675 beds for a population of around one million inhabitants. The BIBB collects around 40,000 whole blood and 5,700 PLT components per year for transfusion therapy in hematology, oncology, and surgery patients, among others, including those requiring cardiovascular surgery and bone marrow transplant.

In 2008, the BIBB initiated the implementation of PRT for PLTs based on amotosalen plus ultra violet (UV) A light (Intercept System, Cerus Corporation, Concord, CA) (20). In 2012, PRT using UVA and UVB light in the presence of riboflavin (Mirasol System, Terumo BCT, Lakewood, CO) was introduced for treating plasma (22). A year later, in order to treat plasma and PLTs with the same PRT, the BIBB adopted the universal routine use of riboflavin plus UVA and UVB light–treated PLTs for transfusion support in adults (21) and children (23) with thrombocytopenia. In 2017, our blood establishment investigated the effectiveness of riboflavin plus UVA and UVB light in eliminating T. cruzi from whole blood units (24). The BIBB is one of the few blood establishments worldwide with more than 10 years of routine application of Intercept and Mirasol PRT for PLTs, the only two commercial PRT systems for PLTs currently available. We also have experience in the routine use of Mirasol PRT for plasma, and in its experimental use for whole blood. Although our research group has previously published papers on the use of these technologies (20-24), the aim of this article is to review current developments in PRT for PLTs drawing on more than a decade of experience in the field.


Pathogen reduction technologies

The three PRT systems developed to date for producing pathogen-reduced PLT concentrates are based on UV light in the absence or presence of a photosensitizer.

The Intercept system (Intercept System, Cerus Corporation, Concord, CA) utilizes approximately 150 µM amotosalen, the synthetic psoralen S-59, as a photosensitizer in combination with UVA light (320–400 nm) at dose of 3.9 J/cm2. After UV illumination for 3–4 min, the photoexcited amotosalen forms covalent bonds with thymidine bases. This reaction inhibits DNA replication and RNA transcription, which in turn prevents replication of leukocytes and pathogens. After PLT treatment, amotosalen and its photoproducts need to be removed by an in-line compound adsorption device for 6–24 h (25,26).

The Mirasol system (Mirasol System, Terumo BCT, Lakewood, CO) uses on average 50 µM of riboflavin (vitamin B2) as a photosensitizer along with UVA and UVB light (270–360 nm) at a dose of 6.2 J/mL. Upon UV illumination over 4–10 min, the oxygen free radicals generated by riboflavin cause irreversible damage to nucleic acids, which inhibits the replication of pathogens and leukocytes. After illumination, the removal of riboflavin is unnecessary, as this common and essential water-soluble vitamin is considered to be safe (27,28).

The Theraflex-UV PLT system (MacoPharma, Tourcoing, France) uses UVC light (254 nm) at a dose of 0.2 J/cm2 for 30–60 seconds without the addition of a photosensitizer. Light penetration is achieved by strong agitation and the generated pyrimidine dimers prevent replication of nucleic acids and pathogen proliferation (29,30).

The Theraflex-UV system requires PLT concentrates diluted in a PLT additive solution (PAS), whereas in the Intercept and Mirasol systems PLTs can be diluted either in PAS or plasma. As described in recent reviews, all three PRT systems effectively reduce bacteria and other nucleic acid-containing infectious agents found in PLTs (31-33).


Impact of PRT on PLT functionality

PLT functionality is apparently unaltered by PRT, which only targets dividing life forms. Nevertheless, some researchers have shown that PLTs can be damaged by interactions with the photosensitizer and UV light. It has been demonstrated that PRT treatment can induce deterioration of mitochondrial function, increased metabolism, and spontaneous PLT aggregation and activation, resulting in altered PLT function and quality (34-37). Approaches to studying the impact of PRT on PLTs have gradually changed over the years. In addition to the classical PLT in vitro tests, other methodologies such as proteomic (38) and biomolecular (39) profiling are being progressively incorporated into the research field of PRT effects on PLTs.

Most studies using classical tests for evaluating PLT functionality, i.e., swirling, glucose consumption and lactate formation, pH, hypotonic shock response, adhesion assays, aggregation induced by different agonists and flow cytometry detection of PLT membrane markers of activation (CD63, CD62p, CD40L) and apoptosis (annexin V), report a low to moderate loss of PLT in vitro function compared to conventional PLTs, which occurs gradually during the 5 to 7 days of PLT storage (34-37). Although in general in vitro PLT function assessed by the classical methods has no or scarce correlation with in vivo PLT recovery, survival and hemostatic activity (40), some of the in vitro tests correspond with in vivo parameters. For example, lactate production and pH correlate reasonably well with PLT recovery and survival time in human subjects, i.e., the lower the pH and the higher the lactate production, the lower the PLT survival and recovery in vivo (41). Moreover, PLTs showing swirling as an indicator of discoid shape retention in vitro are expected to be functional in vivo at transfusion (42).

Proteomic analysis is a very useful approach for studying the quality and function of PRT-treated PLTs, as PLTs have a limited capacity to translate messenger RNA to substitute PRT-modified cellular proteins. Interestingly, proteomic studies have demonstrated that the different PRT systems have different impacts on PLT functionality. Thus, Intercept affects proteins involved in the mechanism of PLT activation and aggregation pathways, Mirasol mainly acts on proteins related to actin polymerization, cytoskeleton organization, adhesion, granule secretion and PLT shape, whereas Theraflex influences proteins associated with changes in PLT shape and aggregation (38).

Studies on the effect of PRT on PLTs at the biomolecular level show that Intercept damages nucleic acids such as RNA, mitochondrial DNA and lipid molecules, resulting in altered membrane packing and defects in PLT signal transduction. The Mirasol system changes proteins by oxidative mechanisms and increases PLT metabolism, leading to an increment in lactic acid and a lower pH. Theraflex also increases metabolism and induces conformational changes in PLT integrin (39).

A long-debated issue is whether the PRT-induced reduction in cell viability only affects a proportion of the treated PLTs (43,44) or results in an overall functional deterioration (45,46). PRT damage (affecting a percentage of PLTs or all of them) can result in increased cellular metabolism, reduced clot strength, and lower PLT increments post-transfusion compared with conventional PLTs. However, patients transfused with PRT-treated PLTs do not necessarily suffer more bleeding events (47).

Our research group has investigated the metabolic activity and hemostatic function of buffy coat PLT concentrates treated with riboflavin and UVA and UVB light. We found that this PRT system accelerates and augments PLT storage lesion, producing glucose depletion, lactate accumulation, PLT acidification and discoid shape loss. Additionally, the clots generated by conventional PLTs at day 14 measured by thrombelastography were still remarkably strong, whereas those produced by PRT-treated PLTs at day 7 were weaker. To confirm these results, clinical trials studying the efficacy of PRT-treated PLTs transfused at the end of the storage period (day 7), when the in vitro clot strength seems weaker, are needed (37).


Clinical studies on PRT-treated PLT transfusion

Autologous transfusion studies have found lower PLT recovery and survival in PRT-treated versus conventional PLTs: Mirasol (−25% and −27%) (48), Theraflex (−26% and 29%) (49) and Intercept (−16% and −20%) (50).

The efficacy of PRT-treated PLTs has also been investigated through observational studies, such as those carried out by our research group (20,21). Randomized clinical trials (RCTs) have compared PRT-treated and conventional PLTs in hematology patients: 8 RCTs used Intercept (51-58) and 3 used Mirasol (57,59,60) (Table S1).

Most of these studies found that the transfusion of PLTs treated with PRT resulted in lower post-transfusion PLT count increments, which is consistent with the reduced PLT recovery and survival previously observed in autologous transfusion studies with healthy subjects (48-50). Consequently, to achieve the necessary PLT increment, the use of PRT-treated PLTs implied a higher transfusion frequency (52,58,60).

A meta-analysis of RCTs that evaluated hematology and oncology patients found moderate-quality evidence that PRT-treated PLT transfusion was not associated with statistically significant increments of clinically relevant bleeding and high-quality evidence that it increases PLT requirements (47).

Three RCTs have assessed whether PLTs treated with PRT are non-inferior to conventional PLTs, using as the primary outcome the prevention of WHO grade 2 or higher bleeding in thrombocytopenic patients with hematological disorders. The Italian Platelet Technology Assessment Study (IPTAS) was not able to prove non-inferiority of PRT-treated PLTs due to low statistical power (57). The Evaluation of the Efficacy of Platelets Treated with Pathogen Inactivation Process (EFFIPAP) study found that PLTs treated with Intercept are non-inferior when stored in PAS, but non-inferiority was not demonstrated when they were suspended in plasma (58). The Pathogen Reduction Evaluation and Predictive Analytical Score (PREPAReS) study evaluated the efficacy of PLTs treated with Mirasol compared to conventional PLTs in plasma obtained from whole blood by the buffy coat method, proving non-inferiority in the intention-to-treat analysis, but not in the per-protocol analysis (60).

Unfortunately, the question explored in these studies remains unresolved, especially if we take into account that the non-inferiority trials had insufficient statistical power to establish a significant difference between WHO grade 2 and 4 bleeding, owing to the infrequency of the more severe events. On the other hand, most studies assessing the safety and efficacy of PRP-treated PLTs have focused on adult hematology and oncology patients.

Insufficient research has been carried out in other patient populations, such as those undergoing massive transfusion in the setting of organ transplantation, surgery or trauma.

Moreover, very few reports have been published about the safety and use of PRT-treated PLTs for transfusion in pediatric patients. A retrospective study in which 240 children received 1,072 Intercept-treated PLTs and 860 conventional PLTs over 21 months found no safety issues and red blood cell utilization patterns were similar. Only febrile nonhemolytic and allergic transfusion reactions were reported over the study period, with the number and type of transfusion reactions similar in both groups. However, there was an increased utilization of PLTs in pediatric recipients aged 1–18 years after the transfusion of Intercept–treated PLTs (61). In another retrospective study, 51 children with a mean age of 11 years were transfused with 141 Mirasol–treated PLTs and showed lower post-transfusion PLT counts compared with 86 children receiving 291 standard PLTs. However, the incidence of bleeding episodes and transfusion-related adverse events was similar in both groups (62). Our research group evaluated PLT use in 379 children up to the age of 15 years, who received 4,236 PLTs treated with Mirasol between 2013 and 2017. While all adverse events in children were mild, we found a significant increase in PLT transfusions in 132 neonates receiving 458 Mirasol-treated PLTs compared with 99 neonates transfused with 176 standard PLTs. We concluded that additional studies are required to assess the efficacy and safety of PRP-treated PLTs in pediatric patients, especially those requiring chronic transfusion therapy (23).


Hemovigilance and PRT-treated blood components

Intercept, which was granted the CE mark in 2002, is commercially available in many European countries (63). According to national hemovigilance systems, there have been no confirmed septic transfusion reactions after the transfusion of 227,797, 167,200 and 214,293 PLT concentrates treated with the Intercept system in Belgium, Switzerland and France, respectively (64). Additionally, a study in Switzerland showed no cases of bacterial infection associated with the transfusion of 205,574 Intercept-treated PLT concentrates (65). There is a potential risk that UV exposure and/or residual photo-products may cause short- or long-term side effects (66,67), especially that residual psoralen may trigger skin rashes in newborns receiving phototherapy for hyperbilirubinemia (68). A retrospective study on transfusion reactions in children failed to find any new rashes after a manual chart review of 11 newborns undergoing phototherapy and receiving Intercept-treated PLTs, although no chart review was done in the control group (61).

In 2014, Intercept PRT was approved for apheresis PLTs diluted in 100% plasma and in 65% PAS-3/35% plasma by the US Food and Drug Administration (FDA) (69). A prospective open label, post-marketing surveillance study following transfusion of Intercept PLT components is currently in progress (PIPER, identifier: NCT02549222) (70). This trial has been designed to detect acute respiratory distress syndrome (ARDS), as Intercept carries a warning to monitor patients for symptoms and signs of ARDS, after a recipient of Intercept-treated PLTs in the SPRINT trial exhibited an increased incidence of the syndrome (1.6% vs. 0%) (52).

Mirasol, which obtained CE approval in 2007, is currently in use in some European countries (63), as well as in Russia and the Middle East. A European hemovigilance report, in which our blood establishment participated, described no septic transfusion reactions, virus transmission or any other severe adverse effects after the transfusion of 91,954 Mirasol-treated PLT concentrates in Poland, Spain, Lithuania, Greece, Austria, Luxembourg and Belgium (19). Presently, Mirasol PRT is being assessed in the US in a phase III randomized clinical trial named Efficacy of Mirasol-treated Apheresis Platelets in Patients with Hypoproliferative Thrombocytopenia (MIPLATE, identifier: NCT02964325) (71).

The Theraflex system, which received a CE mark in 2009, is not yet in routine use and is currently under assessment in a phase III clinical trial in Europe (CAPTURE. EudraCT Number: 2015-001035-20) (72).


Limitations of pathogen reduction technologies

PRT has two main limitations. Firstly, despite the broad range of pathogens that can be inactivated by PRT, it is ineffective against some infectious agents. Secondly, the cost of PRT implementation can inhibit its widespread application.

The pathogen inactivation efficacy of the three PRT methods is widely reported in the literature (73-75). It has been demonstrated that PRT can eliminate the residual risk of transmission of hepatitis C, hepatitis B and HIV infection, as well as prevent transfusion transmission of emerging infectious agents containing nucleic acids. However, the resistance of HIV to the Theraflex-UV system (76) could be an important limitation. The risk of transfusion-transmitted HIV has decreased substantially in most countries, but it can still occur despite negative individual-nucleic acid testing due to the window period (77), the suppression of viral load and delayed seroconversion after the administration of ‘on demand’ pre-exposure prophylaxis (PrEP), or when there is poor adherence to PrEP (78).

Additionally, PRT cannot protect against pathogenic agents without nucleic acids, such as prions. Non-enveloped viruses are also resistant to inactivation, due to the icosahedral nucleocapsid that maintains viral integrity under hostile environments and acts as a barrier against the penetration of photochemical agents (79). Additionally, endotoxin pyrogenic cell wall components, biofilm-positive isolates and spore-forming bacteria, while exceedingly rare, remain transfusion-transmission infection risks even after PRT treatment (80).

Lastly, the widespread adoption of PRT has been hampered by its cost, which may be further increased by higher PLT requirements in patients transfused with PRT-treated PLTs. However, as our research group has reported (20), the expense of PRT can be partially offset by the extension of PLT storage time from 5 to 7 days, which is associated with a substantial reduction in PLT loss due to outdating. Additionally, implementing PRT may be considered as cost-effective if it eliminates the need to test for new and emerging infectious agents that could challenge blood safety.


PRT and the coronavirus pandemic

As an example of the inactivation of a novel infectious agent, the three PRT methods—Intercept, Mirasol and Theraflex—have the ability to inactivate the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (81,82), responsible for the current COVID-19 pandemic, and the Middle East respiratory syndrome coronavirus (MERS-CoV) (83-85), which has many clinical, epidemiological, and virological similarities with SARS-CoV-2. It has recently been proved that the stability of SARS-CoV-2 IgG and its overall neutralizing capacity is preserved after Intercept treatment of convalescent plasma from patients who have recovered from COVID-19. Therefore, Intercept PRT, as well as mitigating the transfusion-associated risk of viral transmission, does not alter the potential therapeutic potency of convalescent plasma (86).


Conclusions

Over the last decade, we have had the opportunity to study PRT methods in different settings, such as clinical and hemovigilance research in adults and children, in vitro studies on PRT effects on PLTs and assessment of the financial impact of PRT implementation. PRT methods offer remarkable advantages but also have certain limitations, which are important to bear in mind during the decision-making process for PRT implementation. Undoubtedly, PRT has the potential to guarantee blood safety in situations that could challenge blood supply, as observed in the Ebola or Chikungunya epidemics, or in a scenario full of uncertainties such as the current SARS-CoV-2 pandemic. Overall, PRT methods are more of an ally than a threat to PLT transfusion safety.


Acknowledgments

The author would like to acknowledge blood donors from the Balearic Islands. The author would also like to thank the laboratory technician team for their contribution to the implementation of pathogen reduction technology in our blood establishment. The author also wishes to thank Lucy Brzoska for her invaluable advice on the revision of the manuscript.

Funding: None.


Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editor (Pilar Solves) for the series “Platelet Transfusion” published in Annals of Blood. The article has undergone external peer review.

Peer Review File: Available at http://dx.doi.org/10.21037/aob-2020-pt-03

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/aob-2020-pt-03). The series “Platelet Transfusion” was commissioned by the editorial office without any funding or sponsorship. The author has no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.


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doi: 10.21037/aob-2020-pt-03
Cite this article as: Jimenez-Marco T. Pathogen reduction of platelets: experience of a single blood bank. Ann Blood 2021;6:13.