Platelet concentrates safety: a focus on the challenging pathogen Staphylococcus aureus—a narrative review

Introduction

Donated blood can be separated into three unique components; red blood cell concentrates (RBCCs), plasma, and platelet concentrates (PCs), which are therapeutic for treating bleeding disorders and patients suffering from platelet dysfunction (1). Blood banks and healthcare centers play a mediating role between blood donors and blood recipients ensuring the safety of donated blood from collection to transfusion (2). Although mitigation measures employed by blood centers around the globe to prevent septic transfusion reactions might differ slightly, they have the same overall goal and are implemented at every step of the vein-to-vein chain (2). Before blood collections, donors are screened for eligibility via an extensive health check questionnaire and requested to report any symptoms of infection. Additionally, prior to blood collection, the donor’s arm at the venipuncture area is disinfected and the first aliquot of collected blood is diverted and not transfused. Finally, PCs are either screened for bacterial contamination with automated culture or rapid methods or treated with pathogen reduction (PR) technologies (PRTs) (3,4). Once blood components are produced, they are stored under conditions that ensure their integrity following Good Manufacturing Practices (5). Once produced, PCs suspended in either 100% plasma or a mix of plasma and platelet additive solution are stored in gas-permeable bags at 22±2 ℃ under agitation for up to seven days to maintain in vitro quality and platelet functionality; unfortunately, these conditions are amenable for the growth of common PC bacterial contaminants that could be introduced during blood collection (3,4).

Inconsistent PC screening algorithms make it difficult to compare rates of bacterial contamination within blood suppliers. While some testing sites sample PCs at 24 h post-blood collection, others have implemented a large volume delayed sampling (LVDS) protocol with PC sampling performed at >36 h post-blood collection and inoculation of at least two culture bottles (aerobic and anaerobic) (3). Considering these differences, White et al. conducted a meta-analysis of 22 published studies with results of PC culture screening data (5). The studies included testing results of over 4 million apheresis and whole blood derived PC products. Their analysis revealed an overall mean rate of bacterial contamination of approximately 1 per 2,000 PCs (5).

PCs are contaminated mainly with skin, or mucosa flora bacteria introduced into donated blood during venipuncture (3). One of the predominant PC contaminants is the pathogenic Gram-positive coccus Staphylococcus aureus (S. aureus). This bacterium has not only been missed during routine screening of PCs with optimal LVDS algorithms (6,7) but unexpectedly, it has also been shown to resist PR treatment (8). Therefore, this narrative review is aimed at uncovering and discussing the molecular mechanisms that could be modulated in the unique storage environment of S. aureus-contaminated PCs leading to missed detection of this bacterium during screening with culture methods or resistance to PR treatment. We present this article in accordance with the Narrative Review reporting checklist (available at https://aob.amegroups.com/article/view/10.21037/aob-24-31/rc).

Methods

The literature search strategy for this narrative review is summarized in Table 1 with an example of the detailed search strategy in PubMed [National Institutes of Health (NIH), National Library of Medicine, National Center for Biotechnology Information] summarized in Table S1. In addition to the literature search, this narrative review includes published (9,10) and unpublished transcriptome data from transcriptome studies of S. aureus grown in PCs compared to S. aureus cultured in trypticase soy broth (TSB).

Results

Bacterial spectrum of PC contaminants

Bacteria can be introduced during blood collection, but occasionally contamination occurs during blood component production or storage due to sterility breaches (11). Most PC contaminants originate from the donor’s normal skin flora, but donors may also present asymptomatic or transient bacteremia resulting in contaminated products. A wide variety of bacterial species have been isolated from contaminated PCs, including Gram-positive species such as Cutibacterium and Staphylococcus spp. as well as Gram-negative organisms (3,4).

Among bacterial contaminants of PCs, Cutibacterium acnes is the most isolated followed by coagulase negative staphylococci (12,13). However, S. aureus is the organism most frequently involved in septic transfusion reactions, in some cases resulting in fatal outcomes (6,7,14-20). S. aureus is occasionally missed during PC screening principally due to delayed growth and formation of surface-attached aggregates known as biofilms during PCs storage (10,21). The slow growth dynamics of S. aureus in PCs can result from low initial inocula [typically 1–30 colony forming units (CFU)/PC bag] leading to prolonged lag growth phase with average doubling time of 8 hours (3,22-25). However, with high inocula, the lag time is drastically reduced as bacteria take less time to enter log phase (9,10). During the log phase of S. aureus growth in PCs, the median doubling time is 2 h and can take 2.1 days on average to reach clinically significant bacterial loads (10⁵ CFU/mL) (3), producing virulence factors in PCs that pose high safety risks to transfusion patients (9,10,22). By days 3 to 5 of PC storage, S. aureus can attain high loads in PCs, and if not identified by visual inspection, swirling or rapid tests, it can result in transfusion sepsis in PC recipients (6,7). Additionally, expression of S. aureus virulence factors such as exotoxins in PCs (10), and bacterial stasis/killing by platelet antimicrobial factors affect S. aureus growth and biofilm production (3). In recent years, there have been multiple reports of failed detection of S. aureus during PC screening, resulting in septic transfusion reactions (6,7,14,16-20). Furthermore, a recent report also showed that S. aureus can resist treatment with the PRT INTERCEPT (8). Table 2 summarizes reported cases of S. aureus involved in septic transfusion reactions or near-misses between 2014 and 2024 (6,7,14,16,17,19,26-30).

S. aureus: a challenging PC contaminant

The phenotypic and genotypic contents of S. aureus, including the ability to express virulent determinants and adopt alternative metabolic pathways in harsh niches (31,32) make it a threat in transfusion medicine. The PC storage environment creates a unique and challenging environment for S. aureus due to a combination of physiological stressors, host defenses, and limited nutrient availability. Platelets can sense the presence of bacteria in their environment and coordinate defense mechanisms (33,34), engaging platelet receptors-mediated signaling cascades, antimicrobial peptides (AMPs), oxidative stressors among others (35), which may be relevant in the PC milieu. These mechanisms together with PC storage factors, which are discussed below, can enhance platelet-mediated entrapment, damage to cell membrane and immune clearance of S. aureus (36).

Unfortunately, S. aureus has developed sophisticated strategies to interfere with platelet elements, manipulate immune responses, and evade clearance (37). These mechanisms enable S. aureus to compromise platelet activation and aggregation, neutralize toxic systems, counteract emerging environmental challenges and bypass nutrients limitations (33,38), which could otherwise foster elimination of the pathogen. The interactions between platelets and S. aureus in stored PCs can be complex and raise significant concerns regarding not only the safety of transfusion patients but also changes in platelet quality and functionality. Discussed below are key strategies that S. aureus may employ to undermine platelet immune defenses, escape detection during PCs screening, enhance its survival, thrive during storage and potentially infect PC recipients.

Manipulation of immune defenses in the PC milieu

S. aureus employs several resistance mechanisms against immune stressors including surface modification, resistance to opsonization, degradation of platelets and AMPs, and biofilm formation as illustrated in Figure 1.

Figure 1 S aureus resistance mechanisms against immune stressors in PCs. In S. aureus-contaminated PCs, the bacterium employs the following defense mechanisms to evade immune response. (A) Modification of its cell wall, (B) binding platelet surface receptor targets non-conventionally, (C) degradation of platelets and AMPs, and (D) formation of biofilms to shield from external attacks. The proteins involved are either in parentheses or noted beside each S. aureus defense mechanism. This image was created using BioRender (https://BioRender.com/x85e055). AMPs, antimicrobial peptides; Hla, α-hemolysin or alpha toxin; PCs, platelet concentrates; PVL, Panton-Valentine leucocidin; S. aureus, Staphylococcus aureus; vWbp, von Willebrand binding proteins; vWF, von Willebrand factor.

Resistance to AMPs via cell surface modification

Platelets secrete AMPs like thrombocidins, defencins and chemokines upon activation, which have bactericidal effects on S. aureus by disrupting the bacterial cell membranes, leading to death of the pathogen (34,39). The platelet factor 4 (PF4/CXCL4) released during platelet degranulation, and thrombocidins have direct bactericidal effects against S. aureus by binding to the bacterial surfaces and disrupting their membranes (34). Defensins exert their role by integrating into the microbial membranes, creating pores that lead to leakage of cellular contents and ultimately causing bacterial lysis (40). Interleukin-1β (IL-1β) and RANTES (CCL5), which promote inflammation and recruitment of immune cells to help eliminate S. aureus, are released by platelets (41).

S. aureus employs several strategies to overcome and defeat AMPs, effectively evading their activities. These include modification of cell surface, formation of capsule and AMP degradation.

Alteration of surface component and membrane charge

By altering its cell membrane charge or composition, S. aureus becomes less susceptible to the membrane-disrupting effects of AMPs. For example, S. aureus can modify its teichoic acids with D-alanine, reducing the negative charge on its cell wall (42) (Figure 1A). This helps resisting the action of cationic AMPs like defensins, which are attracted to negatively charged bacterial surfaces. The expression of genes such as femAB, pbpA, wecC, tagAE, murAB, and dltX, involved in cell wall modification were upregulated in S. aureus-contaminated PCs compared to regular laboratory media (Table 3).

Capsule formation

S. aureus can adapt and thrive in harsh environments (e.g., PC) by forming capsular structures that encase the bacteria masking its surface molecules that platelets would normally bind to, such as peptidoglycan or teichoic acids (43,44). Capsules shield S. aureus from AMP activity and other immune cells from efficiently engulfing and killing the bacteria. Genes involved in capsular polysaccharide biosynthesis were among the most highly expressed genes in S. aureus from PCs (9,10) (Table 3).

Degradation of AMPs and platelets

Platelet-derived AMPs can be degraded or neutralized by secreted S. aureus proteins. For example, Staphopains proteases can degrade PF4, defensins, and thrombocidins, reducing their bactericidal activity (45) (Figure 1C). Likewise, S. aureus secretes anti-immune enzymes like staphylokinase (Sak), which can degrade AMPs and block the formation of platelet-leukocyte aggregates (46,47). Furthermore, the cytotoxins, hemolysins [e.g., α-hemolysin or alpha toxin (Hla)] and bi-component Panton-Valentine leucocidin (PVL) known to lyse red blood cells and other host cells (48) can directly damage platelets by forming pores in their membranes, which can compromise antimicrobial functions (49). Likewise, S. aureus proteases and lipases, respectively break down proteins and lipids involved in the platelet immune response, releasing trapped S. aureus and facilitating escape from platelet defenses (50). Our RNA-seq-based analysis revealed increased expression of genes encoding for Hla, HlgBC, SspAP, and SplBCF in some of the tested S. aureus strains (9,10) (Table 3).

Inhibition of opsonization by binding platelet receptor targets

Platelets interact directly with S. aureus via Toll-like receptor 2 (TLR2), which recognizes components of the bacterial cell wall, such as peptidoglycan and lipoteichoic acid, leading to activation of downstream immune responses (34). By modifying the structure of lipoteichoic acid and peptidoglycan in the cell wall, S. aureus make complement-opsonized bacteria less recognizable to TLR2, thereby diminishing platelet’s ability to detect the pathogen (51,52). As mentioned above, cell wall modification genes were upregulated in S. aureus-contaminated PCs compared to regular laboratory media, in an RNA-seq-based study (Table 3).

When exposed to S. aureus, platelet surface receptors glycoproteins Ib alpha (GPIbα) and GPIIb/IIIa (αIIbβ3) mediate the platelet coagulation cascades responsible for platelet aggregation and adhesion (34,37). PCs contain plasma protein von Willebrand factor (vWF) that binds GPIbα enabling its interaction between platelets and S. aureus (53). Furthermore, the binding of fibrinogen to GPIIb/IIIa promotes platelet aggregation that helps entrap S. aureus within platelet clumps (35). This physical barrier aids bacterial containment and limits its dissemination preventing proliferation within PCs and making it more accessible to immune cells for clearance.

To overcome platelet aggregation traps, S. aureus expresses the adhesins clumping factors A and B (ClfA and ClfB), von Willebrand binding proteins (vWbp), extracellular adherence protein (Eap) (35,54), and superantigen-like proteins (SSL5 and SSL10), that interfere with platelets clumping (46). ClfA/B and Eap can bind fibrinogen, which is the target of GPIIb/IIIa (35) (Figure 1B), thereby inhibiting platelet aggregation mediated via this pathway. The formed fibrin-clot is advantageous to S. aureus as the bacteria is masked within the clot preventing proper platelet recognition. Transcriptome analysis showed upregulation of genes coding for ssl10, vwbp, clfA, clfB and spa in PCs compared to TSB media (9,10) (Table 3).

Enhanced biofilm formation in PCs

In addition to S. aureus ability to bind platelet receptors and escape entrapment by platelets, this pathogen can also evade immune recognition by forming biofilms in PCs (9,10). Our RNA-seq-based investigations revealed increased expression of cflB, fnbpA as well as other genes associated with collagen-fibrinogen and protein-eDNA biofilm pathways in PCs compared to regular media (9,10). Biofilms serve as a physical barrier that protects S. aureus from immune clearance by blocking interactions between the bacteria and platelet receptors, effectively hiding the bacteria from platelet-released AMPs and reactive oxygen species (ROS) (55,56). While in biofilm state, the multiplication of S. aureus is slow and detection of the pathogen during PCs screening could be impacted (4).

Manipulation of platelet activation via S. aureus toxins

S. aureus produces a wide array of exotoxins, including exfoliative toxins, hemolysins, leukocidins, and superantigens [staphylococcal enterotoxins (SEs), superantigen-like toxins (Ssl) and toxic shock syndrome toxin-1 (TSST-1)] (50).

Hyperactivation of platelets by SEs

SEs can bind platelet receptors non-specifically causing overstimulation leading to excessive activation of platelets (57). This renders the dysregulation of the normal activation pathways. The unconventional binding to platelet receptors promotes massive release of platelet factors like pro-inflammatory molecules and growth factors (33,49), which may exacerbate infection or cause adverse reactions leading to sepsis in transfusion patients (6,58). We have recently demonstrated that SEs in PCs can repress S. aureus growth and enhanced biofilm formation heightening the chances of S. aureus evading detection (10).

Metabolic adaptation and survival strategies in the PC storage environment

Neutralization of oxidative stress

In S. aureus-contaminated PCs, oxidative stress is a key environmental challenge that can inhibit bacterial growth and survival. This stress results primarily from ROS and reactive nitrogen species (RNS) generated by platelets, residual immune cells, and the storage conditions within platelet bags (59-61). Oxidative stress can damage bacterial DNA, proteins, lipids, and overall cellular integrity, contributing to direct bacterial killing (62), even within PCs, potentially limiting bacterial contamination or infections post-transfusion. Nonetheless, S. aureus uses a multifaceted approach to mitigate oxidative stress and survive in such conditions, including antioxidant systems, redox maintenance and DNA/protein repair mechanisms.

Antioxidant enzyme systems

S. aureus expresses oxidative stress neutralizing enzymes like superoxide dismutases (SodA and SodM), catalase (KatA), Nitric oxide reductase (Nor) and hydroperoxide reductase (AhpC) (63) (Figure 2A). SodA is critical for detoxifying superoxide by catalyzing the conversion of superoxide anions (O₂⁻) into hydrogen peroxide (H₂O₂) (64), while KatA and AhpC catalyze the breakdown of this byproduct into water (H₂O) and oxygen (O₂), helping to defend S. aureus from oxidative damage in PC. Moreover, S. aureus cell membrane is coated with staphyloxanthin (encoded by the crtMNOPQ operon), a golden pigment that provides antioxidant properties, protecting the bacteria from ROS (65) and contributing to the bacterium’s ability to survive in oxidative environments like PCs. Likewise, the nitric oxide reductase system (encoded by the nreABC regulon), and flavohemoglobin (Hmp) reduce nitric oxide (NO) to nitrogen gas (N₂) and nitrate (NO₃⁻) or nitrous oxide (N₂O), respectively (66,67). Through the nitrite reductase pathway, the enzyme complex NirBD (nitrite reductase) detoxify nitrite (NO₂⁻), a reactive nitrogen intermediate, to ammonia or other less toxic compounds (68).

Figure 2 Stress response and adaptation mechanisms of S. aureus in PCs. In S. aureus-contaminated PCs, the bacterium expresses genes that counteract (A) environmental stresses like oxidative, acidic, and osmotic stresses, and (B) nutrient uptake pathways. The proteins involved are in parentheses below each S. aureus defense mechanism. This image was created using BioRender (https://BioRender.com/x85e055). PCs, platelet concentrates; RNS, reactive nitrogen species; ROS, reactive oxygen species; S. aureus, Staphylococcus aureus.

DNA and protein repair mechanisms

Our comparative transcriptome analysis revealed upregulation of S. aureus genes associated with the different oxidative stress resistance mechanisms in PCs compared to regular laboratory media (Table 3). Damage to S. aureus DNA caused by oxidative stress can be fixed via the bacterial base excision and recombinant repair pathways (69). The former uses DNA glycosylases (MutY, MutT, MutM, etc.) to remove nitrosatively damaged bases, preventing mutations and maintaining genomic stability, while the recombination system activates error-prone DNA polymerases to allow replication, ensures double-strand breaks in DNAs. RecA plays a key role in this process, enabling homologous recombination repair, protecting against genotoxic effects from RNS exposure. Likewise, S. aureus expresses the protease chaperones complex, ClpCPX that repairs misfolded or ROS damaged proteins ensuring stability and functionality (70). These repair systems help maintain DNA and protein integrity under stress conditions like in PCs, ensuring survival of S. aureus.

Resistance to acid and osmotic stresses

Comparative RNA-seq data of S. aureus grown in PCs and lab media showed increased expression of genes associated with acid and osmotic stress resistance mechanisms in PCs (9) (Table 3). Platelets and S. aureus can metabolize glucose anaerobically, accumulating lactic acid as a byproduct (71,72) which could potentially lower the pH and increase the overall solute concentration in the PC bag during storage. Additionally, carbon dioxide released from the process can dissolve in the storage media forming carbonic acid which further dissociates into acidic compounds creating a hypertonic environment. Moreover, as platelets age or undergo spontaneous activation, they release acidic metabolites and inflammatory mediators (73) contributing to the overall reduction in pH and osmotic imbalance within the PC. This increased acidity and osmotic stress create a hostile environment for S. aureus, that could challenge its ability to regulate internal pH by disrupting enzyme function, damaging cellular structures, and impairing metabolic processes (74). To combat these conditions, S. aureus uses several mechanisms to maintain intracellular pH homeostasis, stabilize its proteins, protect its membrane integrity, and adapt to low-pH conditions. These mechanisms include amino acid decarboxylation, proton/ion pumps and transporter systems, and compatible solute synthesis and uptake (75-77).

Nutrient acquisition to overcome growth limitation

PC is a nutrient-rich niche, but in the presence of contaminating bacteria, a phenomenon known as “nutritional immunity” can occur where plasma proteins sequester essential elements like iron, amino acids, metal ions and other growth factors, restricting availability to S. aureus, thereby inhibiting bacterial proliferation (78). To overcome this challenge, S. aureus relies on specialized pathways and transport systems to scavenge essential nutrients from its environment, utilize alternative metabolic pathways, and regulate resource use, effectively ensuring continued growth and survival (74). Key pathways that may play a role in S. aureus survival in the PC storage environment include those involved in heme-iron and metal ions acquisition, amino acids and peptides scavenging and utilization, and carbohydrate and phosphate uptake and utilization (Figure 2B) (79-83). Genes associated with heme-iron uptake (isdABCDEHI, sfaA, sbnAB), amino acids (ssctC, brnQ, gltD), carbohydrates/carbon (ptsABC, pyrAB) and phosphate (glpDQ) were upregulated in PCs in all studied S. aureus isolates (Table 3). Furthermore, our data show increased expression of pore forming toxins, proteases and lipases in PC (Table 3). These bacterial components can damage platelets and release nutrients, aiding bacterial growth during storage. This adds to the reasons for significant S. aureus growth in PCs environment vs. normal lab media (9,10).

Regulation of virulence and metabolic pathways in the PC storage milieu

The expression of genes involved in virulence, AMP resistance and stress response employed by S. aureus to manipulate, interfere with and escape platelet immune stressors, is enhanced via a communication network system controlled by global transcription as well as auxiliary regulators (9,10,55) (Figure 3). The expression of the accessory gene regulator (agr), staphylococcal accessory regulator A (sarA), alternative sigma factor B (sigB), control of D-glutamine metabolism Y (codY), staphylococcal accessory element regulatory system (saeRS), autolysis regulator locus regulatory system (arlS), among others, is influenced by the bacterial density and changes in environment signals, such as nutrient availability, temperature, and host components (55,84). While Agr, a quorum sensing regulator controls the expression of many virulence genes responsible for cell density (85), SigB typically regulates genes involved in stress response (86), and CodY activates the expression of genes associated with nutrient-sensing (87). This could allow S. aureus to regulate the expression of virulence factors and adapt to the immune defenses present in PCs. For instance, SigB can increase the production of enzymes that degrade host immune factors or enhance biofilm formation under stress conditions (84). The following S. aureus transcription regulators and pathways were upregulated in contaminated PCs compared to media; lytRS, graF and walR (regulate cell wall modification), sarVRX (principal regulator of biofilm and virulence), mgrA (modulates capsule formation), sigB, srrB, arlS and spx (controls expression of stress response genes), rpiAR (pentose pathways regulator), ctsR (controls expression of chaperones and proteases), and cadC and zntR (metal ion import) (9,10) (Table 4).

Figure 3 Interconnection of S. aureus coordinated regulatory network in PCs. In S. aureus-contaminated PCs, the bacterium expresses different gene regulators in response to platelet immune factors, environmental stresses and nutrient limitation. This image was created using BioRender (https://BioRender.com/x85e055). AMPs, antimicrobial peptides; PCs, platelet concentrates; RNS, reactive nitrogen species; ROS, reactive oxygen species; S. aureus, Staphylococcus aureus.

S. aureus switches to a dormant state inside biofilms produced in PCs

S. aureus can adapt to the specific conditions within PCs, such as nutrient depletion and environmental stress by entering a dormant state where it undergoes significant metabolic adjustments to conserve energy, enhance survival, and evade host immune responses (Figure 4), and detection traps during PCs screening. These changes enable the bacterium to persist in a metabolically quiescent state, often contributing to antibiotic tolerance and chronic infections (88). The first probable line of defense of S. aureus in PC is switching to a dormant state by forming biofilms (Figure 1D) which provide a protective niche and limits proliferation (9,10,89), the probable reason why agr operon that controls cell density is downregulated in PCs in all isolates (9,10) (Table 4). Moreover, other global regulators like sigB and mgrA, which repress the expression of agr (55,84), were increased in the PC storage milieu (9,10) (Figure 3, Table 4). Another defense mechanism by S. aureus in PCs, is cell wall modification including thickening of the peptidoglycans layer and changing membrane charge, thus reducing permeability and membrane fluidity protecting against external threats (Figure 1A).

Figure 4 S aureus switches to dormancy inside biofilms in PCs. In this state the pathogen modifies its cell wall to effectively resists AMPs and environmental stresses while utilizing anaerobic energy production processes and extracting nutrients from the PC environment. This image was created using BioRender (https://BioRender.com/x85e055). ADI, arginine deiminase; AMPs, antimicrobial peptides; PCs, platelet concentrates; ROS, reactive oxygen species; S. aureus, Staphylococcus aureus.

In PCs, the global nutrient regulator (codY) is not differentially expressed compared to laboratory media (Table 4). This is probably because S. aureus can downregulate its central carbon metabolisms to conserve energy by reducing glycolysis, tricarboxylic acid (TCA) cycle activities, and ATP-consuming processes, such as ribosome production and DNA replication (90). Upregulation of genes associated with fermentation pathways in PCs (9) (Table 3) suggests that S. aureus turns on this low-energy-yield process that requires less substrate input, producing minimal energy but maintaining essential redox balance (91). S. aureus also enhances amino acid catabolism, especially arginine deiminase (ADI) pathway as alternative energy source (9) (Figure 4, Table 3). The ADI pathway comprises genes that are highly conserved across bacteria and play a role in pH homeostasis (76). Though in dormant state, S. aureus can import essential nutrients such as amino acids, heme-iron, potassium, and other metal ions from the PC environment (Figure 4, Table 3).

S. aureus prioritizes the upregulation of essential stress-response proteins and chaperones such as antioxidant systems (e.g., catalase, superoxide dismutase) and ClpCX (Table 3) that protects the dormant cells from ROS and repair damaged DNAs and proteins, while downregulating respiratory chain activity, further reducing ROS production and energy expenditure. The bacterium can adapt to hypoxic environments, common in biofilms and host tissues (92,93), by switching to anaerobic state using alternate terminal electron acceptors like nitrate (Table 3).

Switching onto a quiescent state and forming biofilms enables S. aureus to survive under harsh PC conditions by minimizing energy expenditure, altering its metabolic pathways, and enhancing its resistance to environmental stresses. These adjustments contribute to its persistence and may complicate culture-based detection and eradication efforts with pathogen reduction techniques, which could further result in sepsis when contaminated units are transfused.

How can the residual safety risk posed by S. aureus to transfusion patients be further decreased?

PC safety has improved with the implementation of mitigation strategies such as blood donor skin disinfection, first aliquot diversion, and either screening for bacterial contamination or treatment with PRT (4,8). However, hemovigilance data and published reports show that the risk of transfusing bacterially contaminated PCs has not been eliminated (3,5-7). In this review, we have discussed the molecular mechanisms potentially used by S. aureus to resist immune clearance during PC storage. Once growth of this bacterium is established in PCs, it is not always captured during sampling for culture screening, resulting in false negative results. Additionally, we have also shown that S. aureus may have developed mechanisms to resist PR treatment. With these premises, transfusion services and blood centers should focus their attention in maintaining quality control of their mitigation strategies and increase awareness for visual inspection. Near miss cases of S. aureus have been identified by the effect of this bacterium on PC quality (i.e., loss of swirling or aggregate formation) (4,8). Further studies should focus on targeting the potential mechanisms/bacterial factors such exotoxin production or efflux pump expression, which we hypothesize can be involved in missed detection during PC culture or breakthroughs post PR treatment. Future attention could also be focused on alternative methods for detection of S. aureus such as bacteria- or platelet-derived biomarkers.

Strengths and limitations

A key strength of this review is that it discusses how S. aureus growing in PCs can alter the expression of important genes to adapt and survive in the harsh PC storage environment, defile conventional detection with culture screening, and potentially resist PR treatment. The review also explores traditional methods such as scientific literature review, complemented with experimental data, to advance knowledge on platelet-S. aureus interactions tailored towards bacterial adaptations to thrive in PCs. This manuscript has however not addressed in detail aspects related to the quality and functionality of platelets in S. aureus-contaminated PCs, which may also have an impact on transfusion patients and can be the focus of another narrative review.

Conclusions

S. aureus is a challenging pathogen in PCs due to its ability to thrive at room temperature, evade immune responses, form biofilms, and produce toxins. S. aureus expression of virulence factors and slow growth in stored PCs can translate into missed detection during PC screening with culture methods or rarely, in resistance to PR treatment. This pathogen has developed sophisticated strategies to interfere with platelet immunomodulatory factors, manipulate immune response, adapt to harsh conditions, and evade clearance. Additionally, the bacterium can utilize alternative metabolic pathways like anaerobic fermentation and nutrient acquisition, contributing to its persistence, and complicating detection and eradication in contaminated PC units. To our knowledge, our review is the first revealing novel information on factors that may be affecting S. aureus during PC storage, and it shows that further investigation on the molecular modulatory mechanisms of S. aureus is needed to address the safety risk posed by this pathogen to transfusion patients.

Acknowledgments

Dr. Basit Yousuf (University of Ottawa) and Ms. Carina Paredes (Canadian Blood Services) contributed to RNA extraction and initial RNA-seq analysis of previously unpublished data presented in this narrative review. Dr. Carl McDonald (retired from the NHSBT) provided some of the S. aureus strains used in transcriptome analyses.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://aob.amegroups.com/article/view/10.21037/aob-24-31/rc

Peer Review File: Available at https://aob.amegroups.com/article/view/10.21037/aob-24-31/prf

Funding: This work was supported by the Canadian Blood Services Intramural grant IG2019-SR to S.R.A.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://aob.amegroups.com/article/view/10.21037/aob-24-31/coif). S.R.A. serves as an unpaid editorial board member of Annals of Blood from January 2024 to December 2025. S.R.A. reports funding support from the Canadian Blood Services Intramural grant IG2019-SR for this work. S.R.A. also has served as member of the Editorial Board of the peer-reviewed journal Vox Sanguinis since January 2022, member of the Reviewer Editor Board of the peer-reviewed journal Frontiers in Microbiology since February 2023, and co-chair ISBT TTID Working Party, Bacteria Subgroup since 2016. S.I.C. reports post-doctoral fellowship and research funding from Canadian Blood Services from 1 December, 2021 to 30 November, 2024, and travel bursary awarded by Canadian Blood Services for participation at the Canadian Society for Transfusion Medicine Annual Conference and Canadian Blood Services Research Day from 22 May, 2024 to 25 May, 2024. The authors have 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. Transcriptome analyses were done with S. aureus grown in media and PCs, which were manufactured with donor consent and ethical approval granted by the Canadian Blood Services Research Ethical Board (REB 2015.024 and 2017.033).

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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