Concentrated Clotting Factors May Outperform Plasma in Cardiac Surgery Bleeding

Every year, hundreds of thousands of patients undergo open-heart procedures on cardiopulmonary bypass, the machine that takes over the work of the heart and lungs while surgeons operate on a still organ. That life-support technology comes with a hidden cost: it strips the blood of its ability to clot. Bypass circuits dilute plasma, deplete clotting factors by 40 to 50 percent, and cut the blood’s thrombin-generating capacity by more than half, leaving patients vulnerable to coagulopathic bleeding that prolongs hospital stays, drives up costs, and can prove fatal. For decades, the standard remedy has been fresh frozen plasma, a thawed blood product infused to replace what the bypass machine washed away. Now a new systematic review and meta-analysis of randomized controlled trials, published in Frontiers in Anesthesiology, suggests that a concentrated alternative may stop bleeding more effectively — with a safety record that is more reassuring than many clinicians feared, though far from settled.

The analysis, led by Samuel G. J. Fodop of the Winners Foundation in Yaounde, Cameroon, and colleagues across Cameroon, Kenya, and the United States, pooled five randomized controlled trials encompassing 711 adult cardiac surgery patients. Of these, 363 patients — just over half — received prothrombin complex concentrate, or PCC, a sterile powder reconstituted into a small-volume infusion containing the four vitamin K-dependent clotting factors II, VII, IX, and X, along with regulatory proteins such as protein C and protein S in some formulations. The remaining 348 patients received fresh frozen plasma, the traditional mainstay used in more than 15 percent of cardiac surgeries in the United States. The researchers searched PubMed, Embase, and the Cochrane Central Register from inception to May 2025, registered their protocol prospectively on PROSPERO, and applied the Cochrane Risk of Bias 2 tool to every included trial.

The headline finding concerns reoperation for bleeding, one of the most dreaded complications after cardiac surgery. When operative techniques or transfusions fail to stop ongoing blood loss, surgeons must reopen the chest — a rescue maneuver that is not innocuous and adversely affects outcomes. In the pooled trials, 5.83 percent of PCC patients required reoperation compared with 8.53 percent of plasma patients, a 31 percent relative reduction with a risk ratio of 0.69 and a 95 percent confidence interval of 0.48 to 0.98. The p-value of 0.04 barely clears the conventional threshold for statistical significance, and the confidence interval narrowly excludes the null, but the estimate carries moderate certainty under the GRADE framework — the strongest rating any outcome received in the analysis. Notably, heterogeneity was zero, meaning the five trials told a consistent story on this endpoint.

Chest tube drainage, the volume of blood collected through tubes placed in the chest after surgery, also favored the concentrated clotting factors. Patients receiving PCC drained an average of 143.59 milliliters less over 24 hours than those receiving plasma, with a confidence interval ranging from 278.76 to 8.41 milliliters lower. That p-value of 0.04 again sits at the edge of significance, but the certainty rating is only low, downgraded for substantial heterogeneity — an I-squared of 69 percent — reflecting genuine differences between trials. The largest and most precise study, the FARES-II trial with 420 patients, used weight-based dosing of 15 to 25 international units per kilogram, while a smaller trial used a fixed low dose of 1,000 international units. When the researchers omitted the fixed-dose trial in a leave-one-out sensitivity analysis, the pooled estimate deepened to roughly 189 milliliters and heterogeneity fell, suggesting that insufficient dosing in larger patients may explain why that trial’s results diverged.

Red blood cell transfusion requirements, a proxy for how much blood patients actually lose, shifted by nearly one full unit in favor of PCC. The mean difference was 0.93 units lower, with a confidence interval of 1.83 to 0.02 units lower and moderate certainty. At the individual level, sparing a patient a single transfused unit may sound modest, but the researchers emphasize that cumulative savings across an institution or health system could be substantial — particularly in low- and middle-income countries where blood product availability is constrained. Every avoided transfusion also sidesteps the risks inherent to donated blood, including transfusion-related acute lung injury and transfusion-associated circulatory overload, the two adverse reactions most closely tied to plasma infusion.

Safety outcomes tell a more complicated story. Overall adverse events occurred in 87.53 percent of PCC patients versus 89.36 percent of plasma patients, a risk ratio of 0.99 with a confidence interval of 0.95 to 1.04 and zero heterogeneity — essentially no difference. All-cause mortality showed a slight numerical advantage for PCC at 3.20 percent versus 3.96 percent, but the confidence interval crossed the null and the certainty was low. Stroke or transient ischemic attack, acute kidney injury, length of intensive care unit stay, and length of hospital stay all showed no statistically significant differences, with certainty ratings ranging from low to very low. The one safety signal that raised eyebrows was thromboembolic events: PCC was associated with a 22 percent relative increase, at 9.32 percent versus 7.62 percent, though the confidence interval of 0.64 to 2.33 was wide enough to include both substantial harm and substantial benefit, and the finding was not statistically significant.

That thrombotic signal is precisely why the analysis matters beyond its pooled estimates. Concentrated clotting factors deliver a potent procoagulant payload in a small volume, and clinicians have long worried that this could tip patients toward strokes, heart attacks, or venous clots — especially those with mechanical prosthetic valves or recent coronary stents. The authors are careful to note that their GRADE-informed interpretation tempers the conclusions of an earlier meta-analysis by Viana and colleagues, which had suggested PCC could be used without increased thromboembolic risk. The new analysis argues that this conclusion overstated the certainty of the evidence, since the wide confidence interval does not rule out clinically important harm. The researchers also calculated that the current evidence base of 711 patients remains below the optimal information size of roughly 800 needed to reliably detect a 25 percent relative risk reduction in binary outcomes, underscoring that the field is still underpowered.

Methodologically, the analysis distinguishes itself from its predecessors in several ways. It restricted inclusion to randomized controlled trials only, eliminating the confounding that plagues observational comparisons. It incorporated the recently published FARES-II trial, expanding the pooled sample by 28 percent over the prior meta-analysis. It applied comprehensive GRADE certainty assessments to every outcome, performed leave-one-out sensitivity analyses with influence diagnostics, and used the contemporary Risk of Bias 2 tool rather than the older Cochrane instrument. Only one trial, by Smith and colleagues, raised some concerns — because randomization assignments were disclosed to study staff — while the remaining four were rated low risk across all five bias domains. Publication bias could not be formally assessed with fewer than ten studies, leaving open the possibility that unpublished negative trials exist.

The economics add a final layer of complexity. In a heart transplantation cohort, PCC cost a median of 4,949 dollars per patient compared with 3,677 dollars for those who did not receive it — a difference of roughly 1,272 dollars. In resource-limited settings where the concentrate may simply not be available, plasma remains the only viable option. Even in well-resourced centers, the authors conclude that the modest absolute benefits and uncertain safety profile do not support routine PCC use in every cardiac surgery patient. Instead, the evidence points toward selective deployment: patients with ongoing coagulopathic bleeding after bypass, those at risk of fluid overload from large plasma volumes, or those where the logistical advantages of a rapidly reconstituted, small-volume infusion outweigh the cost differential.

What emerges from this synthesis is a picture of cautious optimism rather than revolution. Prothrombin complex concentrate probably reduces the need to reopen the chest, likely drains less blood through chest tubes, and likely spares patients nearly a full unit of transfused red cells — all without a statistically detectable increase in death, stroke, kidney injury, or hospital stay. But the certainty behind most of these claims is low to moderate, the thrombotic question remains genuinely open, and the field needs adequately powered trials of several hundred additional patients before concentrated clotting factors can claim routine superiority over plasma. For now, the analysis offers clinicians a rigorous, nuanced map of what the randomized evidence actually shows — and a clear signal of where the next chapter of this debate must be written.

Subject of Research: Medicine

Article Title: Prothrombin complex concentrate versus fresh frozen plasma in patients undergoing cardiac surgery: a systematic review and meta-analysis of randomized controlled trials

Article References: Fodop, S. G. J., Bena Nnang, J. Y., Ahidjo, O. M., Nforngang, N. B. H., K. Mekontso, J. G., & Takow, S. (2026). Prothrombin complex concentrate versus fresh frozen plasma in patients undergoing cardiac surgery: a systematic review and meta-analysis of randomized controlled trials. Frontiers in Anesthesiology, 5, Article 1843947. https://doi.org/10.3389/fanes.2026.1843947

Image Credits: AI Generated

DOI: 10.3389/fanes.2026.1843947

Keywords: cardiac surgery, prothrombin complex concentrate, fresh frozen plasma, coagulopathy, meta-analysis, transfusion medicine, cardiopulmonary bypass, bleeding, Prothrombin, complex, concentrate, versus