Highlight
– The FiiRST-2 trial evaluated fibrinogen concentrate (FC) and prothrombin complex concentrate (PCC) versus frozen plasma (FP) for initial trauma resuscitation.
– No significant reduction in total allogeneic blood product transfusion was observed with FC-PCC compared to FP.
– Similar rates of thromboembolic complications and mortality were observed between groups.
– The trial was stopped early due to low conditional power to demonstrate superiority, highlighting the challenges in trauma resuscitation research.
Study Background and Disease Burden
Severe trauma remains a leading cause of morbidity and mortality worldwide, especially in the younger population. Massive hemorrhage with trauma-induced coagulopathy is a critical determinant of survival, often necessitating large-volume transfusions of red blood cells (RBC), frozen plasma (FP), and platelets. Coagulopathy in trauma is characterized by impaired hemostasis caused by blood loss, dilution, hypothermia, and acidosis. Achieving hemostasis rapidly and effectively is vital to reducing mortality.
Traditional management includes balanced transfusion of RBC, FP, and platelets. However, FP contains variable levels of clotting factors and carries risks including transfusion-related lung injury, allergic reactions, and logistical challenges such as thawing requirements. Factor concentrates, like fibrinogen concentrate (FC) and prothrombin complex concentrate (PCC), offer targeted replacement of critical clotting factors with rapid administration and potentially fewer complications.
The precise role and comparative effectiveness of clotting factor concentrates versus FP in initial trauma resuscitation remain insufficiently defined. The FiiRST-2 trial was conducted to address this clinical gap by evaluating whether initial clotting factor replacement with FC and PCC reduces transfusion requirements and improves outcomes compared to FP in trauma patients triggering massive hemorrhage protocols.
Study Design
The FiiRST-2 trial was a multicenter, parallel-control, superiority randomized clinical trial conducted across six level I trauma centers in Canada between April 2021 and February 2023. Eligible patients were adults aged 16 years or older presenting with activation of massive hemorrhage protocols (MHP) on arrival. Exclusion criteria included prior receipt of more than two RBC units prehospital or before randomization and catastrophic head injury, to avoid confounding by non-survivable trauma.
Participants were randomized to receive either the intervention or control treatment in the initial MHP packs. The intervention group received concentrated clotting factors comprising 4 g of fibrinogen concentrate and 2000 IU of prothrombin complex concentrate incorporated into the first two MHP packs. The control group received standard care with 4 units of frozen plasma in the same MHP packs. Both groups received 4 RBC units concomitantly (2 units per pack) along with one dose of platelets incorporated in the second pack. After administration of the second MHP pack, further FP use was at the clinician’s discretion.
The primary outcome was the total number of allogeneic blood product units (RBC, FP, and platelets) transfused within 24 hours. Secondary outcomes included thromboembolic event incidence, intensive care unit (ICU) length of stay, and mortality at 24 hours and 28 days.
Key Findings
A total of 217 patients were randomized (107 FC-PCC, 110 FP) with a modified intention-to-treat primary analysis performed on 137 patients who received at least one MHP pack post-randomization (66 FC-PCC, 71 FP). Baseline characteristics were well-matched with a median age of 38 years, predominance of males (81%) and blunt trauma mechanisms (69%). Median Injury Severity Score was 29, indicating a highly injured cohort actively requiring transfusion.
The mean total allogeneic transfusion within 24 hours was 20.8 units (95% CI, 16.7–25.9) for the FC-PCC group versus 23.8 units (95% CI, 19.2–29.4) for the FP group. The mean ratio of FC-PCC to FP transfusions was 0.87 (1-sided 97.5% CI, 0.00–1.19), with a non-significant P value of 0.20, indicating no statistical superiority.
Rates of thromboembolic events, including deep vein thrombosis and pulmonary embolism, were comparable between groups, as were mortality rates at 24 hours and 28 days. The trial was prematurely terminated after interim analysis revealed a conditional power below the 25% threshold, indicating an impractically large sample would be required to demonstrate superiority of clotting factors over FP.
Expert Commentary
This rigorous randomized clinical trial provides valuable evidence that initial clotting factor concentrate administration does not significantly reduce transfusion requirements or improve survival compared with traditional frozen plasma-based resuscitation in trauma-induced massive hemorrhage. The comparable safety profiles further support the clinical equipoise between these hemostatic approaches.
Several factors may explain these findings. First, the complexity of trauma-induced coagulopathy, with dynamic changes and multifactorial contributors, may limit the benefit of isolated factor concentrate administration. Second, the trial’s inclusion criteria selected patients early in their hemorrhagic course with limited prior transfusion exposure, potentially favoring balanced resuscitation with plasma. Third, the dosing and timing of factor concentrates remain areas for further investigation.
Current trauma resuscitation guidelines emphasize balanced transfusion strategies, including RBC, FP, and platelets in fixed ratios, supplemented by hemostatic adjuncts as needed. The FiiRST-2 trial emphasizes that established plasma-based protocols remain effective and safe initial strategies, pending further research into personalized hemostatic resuscitation.
Limitations include early trial termination limiting statistical power and a study cohort predominantly with blunt trauma, which may restrict generalizability to penetrating injuries or other populations. Future research may explore targeted factor concentrate use guided by point-of-care coagulation testing or in specific subgroups at elevated bleeding risk.
Conclusion
The FiiRST-2 randomized clinical trial indicates that initial administration of fibrinogen concentrate and prothrombin complex concentrate as part of massive hemorrhage protocols does not confer superiority over frozen plasma in reducing allogeneic blood product transfusions or improving survival in severely injured trauma patients. Both strategies exhibit similar safety and efficacy profiles. These findings support the continued use of balanced plasma-containing transfusion protocols as first-line management of trauma-induced coagulopathy, while highlighting the need for further research to refine hemostatic resuscitation tailored to individual patient needs and evolving coagulation profiles.
References
- da Luz LT, Karkouti K, Carroll J, et al. Factors in the Initial Resuscitation of Patients With Severe Trauma: The FiiRST-2 Randomized Clinical Trial. JAMA Netw Open. 2025;8(9):e2532702. doi:10.1001/jamanetworkopen.2025.32702
- Kornblith LZ, Moore HB, Cohen MJ. Trauma-Induced Coagulopathy: Pathophysiology and Treatment. Anesthesiology. 2019;130(6):1066-1079. doi:10.1097/ALN.0000000000002747
- Holcomb JB, Tilley BC, Baraniuk S, et al. Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs. a 1:1:2 ratio and mortality in patients with severe trauma: the PROPPR randomized clinical trial. JAMA. 2015;313(5):471-482. doi:10.1001/jama.2015.12
- Bucklin MH, Redick BJ, Griffen MM, et al. Comparison of factor concentrates and plasma for trauma resuscitation: A systematic review. Transfusion. 2023;63(1):185-196. doi:10.1111/trf.17113