In Focus
Cold-stored platelets
An adjunctive, indication-specific transfusion product
Platelets are essential mediators of hemostasis and play a critical role in the prevention and control of bleeding.
Platelet transfusion are administered in severe bleeding and prophylactically in thrombocytopenic patients, where maintaining an adequate and sustained post-transfusion platelet count is a key therapeutic objective. To preserve platelet viability and circulation time, platelet concentrates (PCs) are conventionally stored at room temperature (RT, +20-24°C) under continuous agitation for up to 5-7 days depending on national regulations. However, these storage conditions increase the risk of bacterial proliferation, necessitating the implementation of mitigation strategies such as pathogen reduction technologies, including the INTERCEPT™ Blood System, in many countries. Cold storage of platelets at 2-6 °C, which was widely used until the 1970s, was largely abandoned due to the rapid post-transfusion clearance of chilled platelets1. Nevertheless, interest in cold-stored platelets (CSPs) has re-emerged in recent years as a potential alternative to standard RT storage. Accumulating evidence suggests that CSPs may exhibit enhanced hemostatic properties despite reduced circulatory lifespan, making them particularly suitable for the management of active bleeding, where rapid clot formation is critical. Cold stored platelets up to day 14 are approved in the USA and Norway for actively bleeding patients when conventional platelets are unavailable. This short review aims to synthesize current knowledge on the biochemical effects of platelet cold storage, their functional aspects, and the main clinical implications.
Biochemical and hemostatic effects of cold-stored platelets
Platelet counts remain relatively stable during storage at 2-6 °C for up to 21 days.2,3 Metabolic activity is reduced, as reflected by decreased glucose consumption and lactate production, with a gradual decline in pH that generally remains above the 6.40 threshold specified by regulatory authorities.4-6 Surface receptor expression is differentially affected by cold storage: GPIIb and GPVI remain relatively stable, whereas GPIbα progressively decreases.5,6 Cold-stored platelet concentrates exhibit a heightened basal activation state, characterized by increased P-selectin exposure reflecting α-granule release,3,5 phosphatidylserine externalization indicating enhanced procoagulant potential, and activation of the αIIbβ3 integrin associated with aggregation.4-7 Mitochondrial integrity and function remain incompletely understood, with studies reporting either preservation2 or early alterations after exposure to +4°C.7 The combined assessment of these various activation markers reveals a progressive emergence of procoagulant and apoptotic platelet subpopulations by day 7, whereas senescent platelets become more prominent by day 14. In contrast, RT-stored platelets for up to 7 days largely retain a resting phenotype.8
Regarding functionality of cold-stored platelets, platelet aggregation is better preserved at 2-6°C compared with 20-24°C (room temperature; RT) when assessed at equivalent storage durations.3-6 However, aggregation capacity remains lower than that observed in platelets stored for shorter periods at room temperature (e.g., day 7 at RT).3
Accordingly, under flow conditions on collagen-coated surfaces, CSPs exhibited reduced aggregate formation by day 7, but retain the ability to adhere and form smaller aggregates covering a broader surface area for at least day 148 (Figure 1). Cold-stored platelets demonstrate increased thrombin generation and shortened clot formation time.3,9 Clot firmness, measured as maximal clot amplitude (MA in mm) in thromboelastography, has been reported to be both increased10, or reduced6 compared with RT-stored platelets. Caution is warranted in interpreting these findings, because clot amplitude is not a direct measurement of elasticity, and relationship between clot amplitude and clot elasticity is nonlinear. Cold storage is also associated with enhanced release of extracellular vesicles (EVs)3,4, which may further contribute to hemostatic activity. In addition, specific platelet subpopulations/EVs may contribute to inflammation and immune signaling; however, these potential roles remain to be fully elucidated.
The Haemovigilance Working Party of the International Society of Blood Transfusion (ISBT) has established a comprehensive set of standardized definitions, underscoring the temporal correlation between transfusion and adverse reactions. These definitions encompass five primary imputability categories: definite (certain), probable (likely), possible, unlikely (doubtful), and excluded.5
Regulatory bodies such as the UK Serious Hazards of Transfusion (SHOT), the US National Healthcare Safety Network (NHSN), and the Haemovigilance Program of India (HvPI), have implemented robust reporting systems that rely on imputability assessment for effective haemovigilance.6 Imputability assessments also carry legal liability, as numerous healthcare institutions are subject to growing scrutiny regarding adverse reactions in transfusion recipients and blood donors.
Product heterogeneity and standardisation challenges
It is important to consider the substantial heterogeneity of cold-stored platelet products, which arises from differences in processing procedures and storage conditions across blood transfusion centers. Studies have included apheresis- and buffy coat–derived platelets, units stored in plasma or platelet additive solutions, pathogen-reduced components, and products subjected to varying refrigeration initiation protocols and storage durations. These various parameters may affect platelet metabolic activity, activation status, and the emergence of distinct platelet subpopulations with differing functional properties and clinical efficacy, either independently or in combination, underscoring the need for greater standardisation of product definitions and storage conditions.
Clinical implications
Available data indicate that CSPs are functionally distinct from RT-stored platelets and may be particularly suited for actively bleeding patients, where immediate hemostatic efficacy outweighs platelet survival. In addition, cold storage has practical and logistical advantages, including extended shelf life of up to 21 days and simplified storage requirements without continuous agitation, which may be especially valuable in remote or resource-limited settings. However, the current clinical evidence remains heterogeneous and warrants cautious interpretation. Large phase II randomized trials in trauma-associated hemorrhagic shock (CriSP-HS) and traumatic brain injury (CriSP-TBI) failed to evidence any benefit of prehospital CSP transfusion.
Furthermore, a post-hoc analysis of TBI patients on antiplatelet therapy showed no improvement in platelet function assessed by TEG-PM, despite a reduction in neurosurgical events. In cardiac surgery, results from the phase III CHIPS trial (CHIlled Platelet Study) are awaited. A pilot randomized study including 25 patients per arm found no difference in ICU drain blood loss. Similarly, a retrospective cohort study comparing delayed CSPs and RT-stored platelets reported increased postoperative transfusion requirement without differences in clinical outcomes.
Overall, these studies support safety of CSPs, with no clear signal for increased thrombotic risk. Ongoing trials, including the randomized CoVeRTS-HM study in patients with hematologic malignancy, are expected to provide further insight. Future studies should be adequately powered to detect uncommon adverse events, including venous or arterial thrombosis.
Figure 1: Thrombus formation on collagen under flow. Whole blood was reconstituted by mixing packed, washed red blood cells (+ hirudin 100 U/mL) with buffy-coat platelet concentrates (50% v/v), stored at +22°C for 7 days, or +4°C for up to 14 days. The mixture was perfused through microfluidic channels coated with type I collagen (200 µg/mL) at a wall shear rate of 1,500 s-1 for 2 min. Aggregation of DIOC6-labeled platelets was monitored in real time under an inverted fluorescence microscope. Representative confocal images of thrombus volume; scale bar: 50 μm.
Conclusion
Cold-stored platelets offer improved hemostatic properties, albeit with reduced post-transfusion circulation relative to RT-stored platelets. Their main clinical value is likely to lie in settings where rapid hemostatic support is required, including active bleeding, trauma, massive hemorrhage, and selected surgical contexts. Accordingly, cold-stored platelets should be regarded as an adjunctive, indication-specific transfusion product. Ongoing large-scale randomized clinical trials will soon tell us their efficacy, safety, optimal storage protocols, and precise clinical indications.
References
1. Murphy S, Gardner FH. Platelet Preservation — Effect of Storage Temperature on Maintenance of Platelet Viability — Deleterious Effect of Refrigerated Storage. N Engl J Med. 1969. 2. Reddoch-Cardenas KM, Peltier GC, Chance TC, Nair PM, Meledeo MA, Ramasubramanian AK, et al. Cold storage of platelets in platelet additive solution maintains mitochondrial integrity by limiting initiation of apoptosis-mediated pathways. Transfusion. 2021. 3. Shea SM, Reisz JA, Mihalko EP, Rahn KC, Rassam RMG, Chitrakar A, et al. Cold-stored platelet hemostatic capacity is maintained for three weeks of storage and associated with taurine metabolism. J Thromb Haemost. 2024. 4. Reddoch-Cardenas KM, Sharma U, Salgado CL, Montgomery, RK, Cantu C, Cingoz N, et al. An in vitro pilot study of apheresis platelets collected on Trima Accel system and stored in T-PAS+ solution at refrigeration temperature (1-6°C). Transfusion. 2019. 5. Johnson L, Vekariya S, Wood B, Tan S, Roan C, Marks DC. Refrigeration of apheresis platelets in platelet additive solution (PAS-E) supports in vitro platelet quality to maximize the shelf-life. Transfusion. 2021. 6. Zhao HW, Serrano K, Stefanoni D, D’Alessandro A, Devine DV. In Vitro Characterization and Metabolomic Analysis of Cold-Stored Platelets. J. Proteome Res. 2021. 7. Hegde S, Wellendorf AM, Zheng Y, Cancelas JA. Antioxidant prevents clearance of hemostatically competent platelets after long-term cold storage. Transfusion. 2021. 8. Brouard N, Mouriaux C, Rudwill F, Magnenat S, Jung C, Galvanin A, et al. Emergence of various platelet subpopulations with specific hemostatic properties in cold-stored amotosalen-UVA pathogen-reduced platelet concentrates. AABB2025, San Diego (CA, USA), October 25-28 2025, P-CB-12. Transfusion. 2025. 9. Six KR, Devloo R, Compernolle V, Feys HB. Impact of cold storage on platelets treated with Intercept pathogen inactivation. Transfusion 2019. 10. Braathen H, Sivertsen J, Felli Lunde TH, Kristoffersen EK, Assmus J, Hervig TA, et al. In vitro quality and platelet function of cold and delayed cold storage of apheresis platelet concentrates in platelet additive solution for 21 days. Transfusion 2019.
