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Importance Patients undergoing cardiac surgery with cardiopulmonary bypass often require platelet transfusions for bleeding. Platelets are routinely stored at room temperature (20-24 °C) for up to 5 to 7 days; however, cold storage (1-6 °C) may allow for increased storage duration without loss of hemostatic function. Objective To determine the maximum cold-storage duration, up to 21 days, for which cold-stored platelets (CSPs) are noninferior or superior in hemostatic efficacy to room-temperature platelets (RTPs) when transfused in actively bleeding patients undergoing cardiac surgery with cardiopulmonary bypass. Design, Setting, and Participants A phase 3, multicenter, randomized, partially blinded, adaptive, noninferiority, storage duration–ranging trial conducted in pediatric and adult patients undergoing cardiac surgery with planned cardiopulmonary bypass at 27 sites in the US and Australia from December 2021 to March 2025. Statistical analysis was conducted from September 9 to October 3, 2025. Intervention Patients were randomized 2:1 to receive CSPs with a maximum of 21 days of storage vs RTPs with a maximum of 7 days of storage. Main Outcomes and Measures The primary outcome was a hemostatic efficacy score with values ranging from 1 to 5 and higher values indicating greater bleeding. The noninferiority margin was 1 point. The success criterion was met if at least 1 cold-storage duration of 7 days or more had a posterior probability of noninferiority of at least 97.5%. The secondary outcome was 24-hour chest tube output. Results Of the 1000 patients who underwent platelet transfusion, 989 were included in the primary analysis (650 CSPs and 339 RTPs). The cohort had a mean (SD) age of 42.1 (30.1) years and 67.8% were male. CSPs were noninferior to RTPs for the primary outcome, with a probability of greater than 99.9% for all cold-storage durations. Pooled across storage durations, CSPs had a mean difference from RTPs of 0.09 (95% credible interval, −0.06 to 0.23). Median (IQR) chest tube output at 24 hours (8.9 mL/kg [5.2-15.4] for CSPs vs 8.4 mL/kg [5.5-15.9] for RTPs; difference in medians, 0.4 [95% CI, −1.0 to 1.5]) was not statistically different between study groups. In a post hoc analysis, as all storage durations were noninferior, considering the CSPs as a single group, the hemostatic efficacy score was similar between both groups: mean (SD) of 3.08 (1.15) CSPs vs 2.99 (1.10) RTPs. There were no differences in venous or arterial thrombotic events, transfusion-associated adverse events, acute respiratory distress syndrome, kidney failure, septic shock, and mortality between the study groups, except for increased reexploration rates in the CSP group. Conclusions and Relevance For patients undergoing cardiac surgery, CSPs stored up to 21 days are noninferior to RTPs for the control of active surgical bleeding. Use of CSPs may allow for increased availability of platelets by reducing wastage and shortages and may allow for incorporation of platelets into inventory at locations where platelets cannot be maintained due to the 5- to 7-day shelf life of RTPs. Trial Registration ClinicalTrials.gov Identifier: NCT04834414

Abstract Hemorrhagic shock is a common emergency that accounts for more than 10% of global mortality and up to 40% of trauma-related mortality. The Advanced Trauma Life Support (ATLS) guidelines outline resuscitation strategies in patients with massive hemorrhage based on clinical trial and observational data. Early intervention with fluids and/or blood products is recommended during resuscitation as key to maintaining vascular patency, stabilizing a patient’s blood pressure, maintaining tissue oxygenation, and limiting shock. From a transfusion perspective, there is wide heterogeneity in the quality of blood products due to donor and manufacturing variation. The optimal transfusion strategy for massive hemorrhage remains unclear. In silico models of resuscitation may offer a means to evaluate the effectiveness and safety of various resuscitation protocols. Here we describe a stochastic multicompartment model of fluid balance and resuscitation that includes (i) cardiovascular hemodynamics, (ii) body fluid compartments and capillary solute exchange, (iii) the ability to alter hemorrhage, resuscitation, and hemostasis parameters, and (iv) tissue oxygenation and capillary-alveolar gas exchange. Building upon deterministic frameworks, this stochastic model more faithfully reflects the clinical heterogeneity of bleeding patients at a level I trauma center. This allows for a proof of concept in silico trial comparing crystalloids, conventional component therapy (CCT), i.e. red cell, platelet and plasma components, to cold-stored low titer group O whole blood (LTOWB). In an in silico cohort of ATLS class III (>30% and ≤40% blood volume lost) hemorrhage, LTOWB resuscitation reduced the time spent in the critical hemostatic window (platelet count <50x109/L, INR≥2, hemoglobin (Hgb) <8 g/dL and fibrinogen <150 mg/dL) compared with CCT (90.59 vs. 147.62 minutes; p=0.04), with no difference in predicted event-free survival (t = 240 minutes; cardiac < 1.5, fluid overload > 10% or SBP > 150% of the starting SBP, or Hgb < 3.0 g/dL). In a separate cohort of ATLS class IV (>40% blood volume lost) hemorrhage, LTOWB yielded a higher predicted event-free survival (74%) versus the CCT arm (69%, p < 0.01). We demonstrate how this in silico platform can function as a digital twin for hemorrhagic trauma enabling precision transfusion strategies, and in parallel, an operational twin to support blood banks to forecast blood product demand and inform massive transfusion protocols and clinical trial design.

Abstract Background Substituting group A whole blood (GAWB) might relieve some of the burden on the low titer group O whole blood (LTOWB) inventory. This simulation examined the effect of implementing GAWB at a large trauma hospital. Study Design and Methods A civilian trauma center with LTOWB and GAWB par levels set to 22 and 10 units, respectively, was modeled as the baseline. The average daily number of WB recipients was 0.5 who received an average of four WB units per patient. LTOWB was issued in packages of five and all had to be consumed before a group A patient could be switched to GAWB. Several variations on the baseline simulation were also modeled. Results In the baseline simulation, there was a median (interquartile range, IQR) of 1 (0–2) GAWB and 16 (13–19) LTOWB recipients per month. The median (IQR) GAWB and LTOWB units transfused per month was 2 (0–9) and 56 (42–72), respectively. Fourteen percent of group A patients received any quantity of GAWB. The variations that had the most impact on GAWB usage included increasing the number of WB recipients to 2.5 per day where the median (IQR) monthly number of GAWB recipients and units transfused increased to 4 (3–5) recipients and 21 (12–29) units, respectively, and when the average WB requirements increased to eight units per patient resulting in transfusing a median (IQR) of 10 (5–15) GAWB units per month to 3 (1–4) recipients. Discussion Under routine civilian hospital circumstances, implementing GAWB will have a modest impact on LTOWB inventory.

Abstract Artificial intelligence (AI) and machine learning (ML) are beginning to enhance key workflows across blood banking (BB) and transfusion medicine (TM), including donor engagement, inventory forecasting, immunohaematology interpretation, haemovigilance and clinical decision support. These tools can extract signals from large, diverse datasets to improve efficiency, consistency and timeliness of care while enabling more proactive patient blood management. At the same time, TM is uniquely sensitive to safety and trust, so the field must pair innovation with disciplined validation and governance. This review surveys emerging applications and distils a balanced ethics and oversight framework tailored to TM and BB practice. Core elements include outcome‐focused validation and continuous monitoring; targeted fairness testing where biological or scientific plausibility suggests subgroup differences; layered transparency that distinguishes transparency, interpretability and explainability; and privacy by design with proportionate consent. We emphasize human oversight at every step: clinicians and laboratorians evaluate, monitor and troubleshoot models, perform tasks AI cannot, integrate multiple inputs to make decisions and interact with AI through guardrails such as intended‐use statements, confidence thresholds and clear override pathways. Accountability is shared across users, service directors, institutions and regulators. When implemented with these safeguards, AI can reduce preventable errors, improve resource allocation and support more equitable access to safe transfusion. The goal is principled pragmatism that protects patients and donors while enabling timely adoption of well‐validated tools.

AbstractBackgroundAs low titer group O whole blood (LTOWB) increases in popularity, blood centers are finding innovative ways of maintaining the supply. One potential way is collecting LTOWB from parous female donors without testing for HLA antibodies. This in silico simulation predicted the risk of an LTOWB unit containing an HLA antibody and the subsequent risk for an HLA‐incompatible transfusion.MethodsAn LTOWB blood bank with 1 million units was simulated consisting of male, nulliparous, and parous female donors. The proportion of each donor type was modeled after the sex distribution at US blood centers. The parity of female donors was calculated based on the average number of live births per female depending on her age. HLA‐alloimmunization risk was determined by her parity status. The HLA haplotypes of the simulated recipients were derived from the 100 most common HLA haplotypes in the US National Marrow Registry Program database. The proportion of different race/ethnic groups in the US was used to simulate 100,000 LTOWB recipients to whom between 1 and 10 units were administered.ResultsOverall, the risk of an LTOWB unit containing at least one HLA antibody was 12.2% and the rate of receiving an HLA‐incompatible unit was 21.3%. The risk of receiving an HLA‐incompatible unit rose from 4.8% after receipt of one unit to 36.5% after 10 units.ConclusionBlood collectors and hospitals should evaluate the potential TRALI risk against the benefit of a potentially expanded inventory of LTOWB before collecting plasma‐containing products from non‐HLA‐tested parous female donors.

AbstractBackgroundUsing low titer group O whole blood (LTOWB) is increasingly popular for resuscitating trauma patients. LTOWB is often RhD‐positive, which might cause D‐alloimmunization and hemolytic disease of the fetus and newborn (HDFN) if transfused to RhD‐negative females of childbearing potential (FCP). This simulation determined the number of life years gained by the FCP and her future children if she was resuscitated with LTOWB compared with conventional component therapy (CCT).MethodsThe model simulated 500,000 injured FCPs of each age between 0 and 49 years with LTOWB mortality relative reductions (MRRs) compared with components between 0.1% and 25%. For each surviving FCP, number of life years gained was calculated using her age at injury and average life expectancy for American women. The number of expected future pregnancies for FCPs that did not survive was also based on her age at injury; each future child was assigned the maximum lifespan unless they suffered perinatal mortality or serious neurological events from HDFN.ResultsThe LTOWB group with an MRR 25% compared with CCT had the largest total life years gained. The point of equivalence for RhD‐positive LTOWB compared to CCT, where life years lost due to severe HDFN was equivalent to life years gained due to FCP survival/future childbearing, occurred at an MRR of approximately 0.1%.ConclusionIn this model, RhD‐positive LTOWB resulted in substantial gains in maternal and child life years compared with CCT. A >0.1% relative mortality reduction from LTOWB offset the life years lost to HDFN mortality and severe neurological events.

Abstract Uncontrolled hemorrhage accounts for up to 40% of trauma related mortality, and approximately 30% of trauma related deaths occur in the hospital within the first 1-4 hours of injury. The Advanced Trauma Life Support (ATLS) guidelines still recommend initial resuscitation with crystalloid fluid as an integral part of maintaining or restoring hemodynamic stability, but are starting to recognize the role of early resuscitation with blood products in patients with evidence of Class III and IV hemorrhage, in line with recent clinical trial and observational data. Although there is a growing body of evidence that early transfusion with blood products may be associated with improved survival compared with crystalloid infusion, the optimal transfusion strategy still remains unclear and is being actively investigated in clinical trials. In silico models of resuscitation offer a means to evaluate the effectiveness and safety of resuscitation protocols, including effects on body fluid compartment volumes, tissue oxygenation, and hemostatic factors. Here we describe our work extending earlier deterministic models of trauma resuscitation to incorporate hemodynamic, hemostatic, resuscitation, biomarker, and tissue-oxygenation domains into a single comprehensive model. Additionally, this model expands upon previous deterministic models to create a stochastic computational model of hemostatic resuscitation that accounts for variations in blood component composition and temporal features of transfusion therapy. Using this stochastic model, an in silico trial was piloted to compare conventional component therapy, i.e. red cell, platelet and plasma components, to cold-stored whole blood using the following starting assumptions: patient weight of 81.3±21.8 kg, hematocrit of 41.8±4.3%, initial bleeding rate between 50 and 150 mL/min, systolic blood pressure of 125±18 mmHg, fibrinogen of 293±88 mg/dL, international normalized ratio of 1.0±0.1 and platelet count of 239±62x109/L, with blood component and whole blood constituent distributions based on laboratory quality control data. This in silico trial demonstrated that resuscitation with whole blood was associated with a 28-minute reduction in the time spent in the critical window defined by platelet count &lt;50x109/L, INR≥2, hemoglobin &lt;9 g/dL and fibrinogen &lt;150 mg/dL compared with conventional component resuscitation over the course of a 4 hour simulation (p&lt;0.001 based on median regression). We demonstrate how stochastic models of hemostatic resuscitation can be used to perform in silico trials of resuscitation strategies. Our work can guide inclusion and exclusion criteria for future clinical trials and facilitate identification of patient subgroups most likely to benefit from certain resuscitation strategies. This work was partially funded by the AABB Foundation (formerly the National Blood Foundation).

Background The use of low-titer group O whole blood is increasing. To reduce wastage, unused units can be converted to packed red blood cells. Supernatant is currently discarded post-conversion; however, it could be a valuable transfusable product. The aim of this study was to evaluate supernatant prepared from late-storage low-titer group O whole blood being converted to red blood cells, hypothesizing it will have higher hemostatic activity compared to fresh never-frozen liquid plasma. Methods Low-titer group O whole blood supernatant (n = 12) prepared on storage day 15 was tested on days 15, 21, and 26 and liquid plasma (n = 12) on 3, 15, 21, and 26. Same-day assays included cell counts, rotational thromboelastometry, and thrombin generation. Centrifuged plasma from units was banked for microparticle characterization, conventional coagulation, clot structure, hemoglobin, and additional thrombin generation assays. Results Low-titer group O whole blood supernatant contained more residual platelets and microparticles compared to liquid plasma. At day 15, low-titer group O whole blood supernatant elicited a faster intrinsic clotting time compared to liquid plasma (257 ± 41 vs . 299 ± 36 s, P = 0.044), and increased clot firmness (49 ± 9 vs . 28 ± 5 mm, P < 0.0001). Low-titer group O whole blood supernatant showed more significant thrombin generation compared to liquid plasma (day 15 endogenous thrombin potential 1,071 ± 315 vs . 285 ± 221 nM·min, P < 0.0001). Flow cytometry demonstrated low-titer group O whole blood supernatant contained significantly more phosphatidylserine and CD41 + microparticles. However, thrombin generation in isolated plasma suggested residual platelets in low-titer group O whole blood supernatant were a greater contributor than microparticles. Additionally, low-titer group O whole blood supernatant and liquid plasma showed no difference in clot structure, despite higher CD61 + microparticle presence. Conclusions Plasma supernatant produced from late-storage low-titer group O whole blood shows comparable, if not enhanced, in vitro hemostatic efficacy to liquid plasma. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New