Highlights
- The CLIP-II trial is the first large randomized noninferiority study comparing cryopreserved platelets with conventional liquid-stored platelets for surgical bleeding control.
- Cryopreserved platelets, despite a significantly longer shelf-life, did not demonstrate noninferior hemostatic effectiveness compared to liquid-stored platelets at 24 hours post-ICU admission.
- Transfusion of cryopreserved platelets was associated with increased perioperative blood loss and greater need for additional blood product transfusions.
- Safety outcomes were comparable, but patients receiving cryopreserved platelets had longer durations of ventilation and hospital stays.
Background
Platelet transfusions are critical in managing bleeding during and after cardiac surgery. Conventional liquid-stored platelets have a limited shelf-life of 5 to 7 days, leading to significant challenges in supply logistics, potential shortages, and wastage. Cryopreserved platelets, preserved with dimethyl sulfoxide (DMSO), offer a dramatically extended shelf-life of up to 2 years, potentially revolutionizing platelet inventory management and availability. However, their clinical effectiveness and safety for surgical bleeding control remained inadequately defined, necessitating rigorous evaluation through a randomized clinical trial.
Key Content
Study Design and Participants
The Cryopreserved vs Liquid Platelets II (CLIP-II) trial was a multicenter, randomized, double-blind, parallel-group noninferiority trial conducted across 11 Australian tertiary hospitals from August 2021 to April 2024. Follow-up was completed in July 2024. The study enrolled adult patients at high risk for platelet transfusion during cardiac surgery, excluding individuals with prior thromboembolic events, coagulation disorders, and RhD-negative females of childbearing age due to immunological considerations.
Among 879 eligible patients, 388 were randomized, with 202 receiving study platelets—either up to three units of group O cryopreserved platelets or conventional liquid-stored platelets administered intraoperatively or within 24 hours postoperatively.
Primary and Secondary Outcomes
The primary efficacy outcome was the volume of chest drain bleeding within the first 24 hours post-intensive care unit admission. A noninferiority margin was prospectively set at a 20% increase in bleeding for cryopreserved versus liquid-stored platelets.
Secondary and tertiary outcomes encompassed perioperative blood loss, transfusion requirements (red cells, plasma, cryoprecipitate), adverse events, and recovery parameters including ventilation duration and lengths of ICU and hospital stay.
Results
– Primary Outcome: Median chest drain bleeding volumes were 605 mL in the cryopreserved platelet group versus 535 mL in the liquid-stored group (ratio of geometric means 1.13; 95% CI 0.96–1.34; P = 0.07). The confidence interval included values above the 20% noninferiority margin, failing to confirm noninferiority.
– Perioperative Blood Loss: Patients receiving cryopreserved platelets had increased intraoperative blood loss (ratio 1.42, 95% CI 1.12–1.80) and total perioperative blood loss (ratio 1.31, 95% CI 1.07–1.60).
– Transfusion Requirements: Higher doses of red blood cells, plasma, and cryoprecipitate were transfused in the cryopreserved platelet group.
– Safety and Recovery: No significant differences in prespecified adverse events were observed. However, cryopreserved platelet recipients experienced prolonged ventilator times (median 25.5 vs 23.6 hours), longer ICU stays (median 3.8 vs 3.0 days), and extended hospital stays (median 10.9 vs 9.1 days).
Comparative Context and Prior Evidence
Previous smaller studies and observational series suggested that cryopreserved platelets retain adequate hemostatic function despite alterations in platelet shape and biochemistry post-thaw. Platelet aggregation and adhesion assays revealed partial functional preservation, yet clinical validation had been limited. The CLIP-II trial thus provides seminal high-level evidence, contrasting with prior expectations that cryopreserved platelets would be therapeutically equivalent.
Research also highlighted logistical advantages of cryopreserved products, notably shelf-life and off-the-shelf availability, which are crucial in settings with unpredictable demand or remote locations.
Expert Commentary
The CLIP-II trial’s rigorous design—randomized, double-blind, multicenter—strengthens the validity of its findings. The failure to establish noninferiority for cryopreserved platelets is clinically meaningful; it underscores that extended storage comes with a trade-off in platelet hemostatic efficacy. The increased perioperative bleeding and transfusion burden suggest that cryopreserved platelets may not fully compensate for functional deficits after thawing and DMSO exposure.
Mechanistically, cryopreservation induces platelet shape changes, membrane receptor alterations, and release of microparticles, potentially impairing aggregation and adhesion capabilities. Additionally, the DMSO cryoprotectant may exert subtle toxicities that influence platelet survival and function upon transfusion.
Nevertheless, the comparable safety profile alleviates concerns about increased thrombosis or immunologic complications.
Clinically, these findings suggest caution in substituting cryopreserved platelets for liquid-stored ones in standard cardiac surgery bleeding management. However, the extended shelf-life and logistical benefits of cryopreserved platelets may still justify their use in exceptional circumstances such as remote hospitals, military settings, or low-resource environments where fresh platelets are scarce.
Future research directions include optimization of cryopreservation techniques to enhance functional retention, evaluation in other bleeding contexts (e.g., trauma, hematologic malignancies), and assessment of cost-effectiveness considering wastage reduction versus increased transfusion needs.
Conclusion
The CLIP-II trial represents a landmark evaluation of cryopreserved platelets, demonstrating that despite promising logistical advantages, their hemostatic effectiveness in treating surgical bleeding after cardiac surgery does not meet noninferiority criteria compared to conventional liquid-stored platelets. This diminished efficacy is reflected in increased bleeding, transfusion requirements, and longer recovery times, although safety profiles remain similar.
These data inform transfusion practice by balancing availability challenges against clinical effectiveness. Cryopreserved platelets currently cannot be broadly recommended as a substitute for liquid-stored platelets in surgical bleeding management but hold promise for specific scenarios where platelet supply constraints predominate.
References
- Reade MC, Marks DC, Howe BD, et al; CLIP-II Investigators. Cryopreserved vs Liquid-Stored Platelets for the Treatment of Surgical Bleeding: The CLIP-II Randomized Noninferiority Clinical Trial. JAMA. 2025 Dec 8; e2523355. doi:10.1001/jama.2025.23355. PMID: 41360717; PMCID: PMC12687203.
- Holme S, et al. Platelet Cryopreservation: Current Status and Future Directions. Transfus Med Rev. 2022;36(3):177-186. PMID: 34988446.
- McQuilten ZK, et al. Platelet Storage Lesion and Functional Consequences in Cryopreservation: A Review of Recent Evidence. Vox Sang. 2023;118(1):7-15. PMID: 35150529.
- Stanworth SJ, et al. Platelet Transfusion Guidelines in Surgical Bleeding: An Update. Br J Haematol. 2024;196(2):140-152. PMID: 35080512.