Highlights
- FARES-II, the largest randomized controlled trial to date, demonstrated superior hemostatic efficacy of 4F-PCC compared with frozen plasma (FP) in cardiac surgery-associated coagulopathic bleeding.
- 4F-PCC use reduced the need for allogeneic blood product transfusions, including red blood cells and platelets, while demonstrating a favorable safety profile, with fewer serious adverse events and lower rates of acute kidney injury.
- Mechanistic studies show 4F-PCC rapidly restores thrombin generation and coagulation factor levels, contributing to improved hemostasis in the early postoperative period.
- Meta-analyses and pilot trials reinforce the clinical benefits of PCC over FP, including improved laboratory coagulation parameters and reduced transfusion requirements, without increasing thromboembolic risks.
Background
Excessive bleeding remains a significant and prognostically important complication of cardiac surgery, with coagulopathy frequently occurring after cardiopulmonary bypass (CPB). Traditionally, fresh frozen plasma (FFP) or frozen plasma (FP) has been utilized to replace coagulation factors and arrest bleeding. However, FFP administration entails large volume transfusions that may exacerbate fluid overload and transfusion-related complications, including transfusion-related acute lung injury and right ventricular failure. Four-factor prothrombin complex concentrate (4F-PCC), containing concentrated vitamin K-dependent factors II, VII, IX, X and proteins C and S, offers advantages such as rapid bedside reconstitution, smaller infusion volumes, and potential efficacy benefits, positioning it as a promising alternative therapy for acquired coagulopathic bleeding post-cardiac surgery.
Figure 1. Enrollment, Randomization, and Treatment of Patients in the Factor Replacement in Surgery II Trial.
Key Content
Chronological Development of Evidence for PCC vs FP
Since the early 2010s, studies have explored PCC as a factor replacement in cardiac surgery patients. Initial pilot trials (e.g., PROPHESY, 2019; Karkouti et al., 2021) established feasibility and safety, showing comparable hemostatic effects with smaller volumes than FP. By 2022, several randomized controlled trials (RCTs) and observational studies suggested PCC may reduce transfusion requirements and improve laboratory coagulation profiles more efficiently than FP (Bartoszko et al., 2022).
Table 1. Characteristics of the Study Population and Dosing Details.
The FARES-II trial (Karkouti et al., 2025) represents a pivotal, multicenter randomized noninferiority trial comparing PCC with FP in adults with coagulopathic bleeding after CPB. Conducted across 12 hospitals in North America with 538 patients randomized, it demonstrated that PCC not only met noninferiority criteria but was superior to FP with 77.9% hemostatic effectiveness versus 60.4% for FP (P<.001). PCC recipients received significantly fewer transfusions (mean difference 2.7 units; P=.002) and experienced fewer serious adverse events (36.2% vs 47.3%, P=.02), including a markedly reduced rate of acute kidney injury (10.3% vs 18.8%, P=.02).
Figure 2. Difference in Hemostatic Response Failure Rates.
Evidence by Therapeutic Class
A systematic review and meta-analysis by Callum et al. (2025) incorporating four RCTs with 671 patients found that PCC significantly improved postintervention hemoglobin levels and reduced red blood cell transfusion needs within 24 hours compared with FP, without increasing adverse events. The analysis further noted improvements in international normalized ratio (INR) post-PCC.
Laboratory mechanistic data (Bartoszko et al., 2025) elucidated that PCC administration restored thrombin generation more rapidly than FP following CPB without promoting hypercoagulability, supported by higher early postoperative levels of vitamin K-dependent clotting factors and natural anticoagulants such as proteins C and S.
Additional pilot studies examined intraoperative prophylactic use of PCC in high-risk cardiac surgery patients, reporting reductions in chest tube output and transfusion rates, with low incidences of right ventricular failure and thrombotic events (Dhamoon et al., 2022).
Comparative Safety and Efficacy
While PCC demonstrates advantages, concerns of hypercoagulability and thromboembolism have been evaluated extensively with reassuring safety profiles reported in RCTs and meta-analyses. The FARES-II trial reported significantly fewer serious adverse events in the PCC group compared with FP. Similarly, a randomized trial investigating PCC versus FP for rapid vitamin K antagonist reversal in urgent procedures (Pabinger et al., 2015) found PCC to be superior in hemostatic efficacy without increased thrombotic complications.
Some earlier retrospective analyses noted a higher incidence of acute kidney injury with PCC (Hickey et al., 2019), though this finding was not consistently observed across RCTs, including in FARES-II, where PCC had lower AKI rates.
Methodological Advances and Future Research Directions
The FARES-II trial featured rigorous randomized design and large sample size, advancing evidence quality over prior pilot and observational studies. However, it was unblinded, and additional blinded studies are underway to replicate findings and clarify subgroup efficacy by sex and ethnicity. The mechanistic understanding of how PCC reduces serious adverse events remains incomplete, warranting further investigation into coagulation dynamics and inflammatory pathways.
Moreover, exploration of PCC use in under-represented surgery types and long-term outcomes remains necessary. Ongoing trials aim to confirm optimal dosing strategies, timing of administration, and comparative cost-effectiveness of PCC versus FP.
Expert Commentary
Current guidelines have traditionally favored FP for coagulopathic bleeding in cardiac surgery primarily due to extensive historical use and availability. However, emerging evidence, including the landmark FARES-II trial, supports a paradigm shift favoring 4F-PCC as a frontline therapy.
The smaller volume and rapid reconstitution of PCC reduce fluid overload risk, a crucial advantage in cardiac surgical patients vulnerable to hemodynamic instability. Enhanced restoration of thrombin generation addresses a key pathophysiological mechanism of post-CPB bleeding.
Notwithstanding, the unblinded nature of FARES-II and the exclusion of some surgery subtypes limit generalizability. Additional trials, particularly with diverse patient cohorts and blinded protocols, are essential before wholesale clinical implementation. Potential cost implications and resource availability may also influence adoption.
The mechanisms underlying lower serious adverse events and acute kidney injury incidence in PCC-treated patients remain to be elucidated—hypotheses include reduced transfusion-related immunomodulation and volume overload effects.
Conclusion
The 4F-PCC presents a clinically superior and safe alternative to frozen plasma for managing coagulopathic bleeding in cardiac surgery, as demonstrated in the recent large-scale FARES-II randomized trial and supported by multiple prior studies. PCC offers hemostatic efficacy advantages, reduces blood transfusion requirements, and minimizes adverse events, including acute kidney injury.
Future research should address sex- and race-specific responses, mechanistic pathways of benefit, and evaluate PCC in a wider spectrum of cardiac surgical procedures. Integration of PCC into clinical practice guidelines should be considered carefully in light of accumulating high-quality evidence.
References
- Karkouti K, Callum JL, Bartoszko J, et al. Prothrombin Complex Concentrate vs Frozen Plasma for Coagulopathic Bleeding in Cardiac Surgery: The FARES-II Multicenter Randomized Clinical Trial. JAMA. 2025;333(20):1781-1792. doi:10.1001/jama.2025.3501 IF: 55.0 Q1 . PMID: 40156829 IF: 55.0 Q1
- Bartoszko J, Gabarin N, Tanaka K, Callum J. Will prothrombin complex concentrate replace plasma in cardiac surgical bleeding in North America? Curr Opin Anaesthesiol. 2025. doi:10.1097/ACO.0000000000001602 IF: 2.1 Q2 . PMID: 41384776 IF: 2.1 Q2
- Callum JL, Refaai MA, Estcourt L, et al. The Impact of Prothrombin Complex Concentrate Versus Fresh Frozen Plasma for Hemorrhage Management in Cardiac Surgery: A Systematic Review and Meta-analysis of Randomized Clinical Trials. J Cardiothorac Vasc Anesth. 2025;39(12):3333-3337. doi:10.1053/j.jvca.2025.09.009 IF: 2.1 Q2 . PMID: 41027796 IF: 2.1 Q2
- Bartoszko J, Callum JL, Tanaka KA, et al. Thrombin generation after prothrombin complex concentrate or plasma transfusion during cardiac surgery. J Thromb Thrombolysis. 2025;58(2):309-318. doi:10.1007/s11239-024-03061-3 IF: 2.2 Q2 . PMID: 39633218 IF: 2.2 Q2
- O’Connell K, et al. Pre-emptive intraoperative administration of PCC4 in cardiac surgery patients at high risk of bleeding: A pilot study. J Card Surg. 2022;37(12):5130-5134. doi:10.1111/jocs.17224 IF: 1.3 Q3 . PMID: 36423240 IF: 1.3 Q3
- Hickey M, et al. Prothrombin complex concentrate in cardiac surgery: a systematic review and meta-analysis. Ann Thorac Surg. 2019;107(4):1275-1283. doi:10.1016/j.athoracsur.2018.10.013 IF: 3.9 Q1 . PMID: 30458156 IF: 3.9 Q1
- Pabinger I, et al. Four-factor prothrombin complex concentrate versus plasma for rapid vitamin K antagonist reversal in patients needing urgent surgical or invasive interventions: a phase 3b, open-label, non-inferiority, randomised trial. Lancet. 2015;385(9982):2077-2087. doi:10.1016/S0140-6736(14)61685-8 IF: 88.5 Q1 . PMID: 25728933 IF: 88.5 Q1
