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Critical appraisal and concerns regarding a meta-analysis on prothrombin complex concentrate (PCC) for trauma-induced coagulopathy: unveiling methodological nuances and treatment variances

The Original Article was published on 02 November 2023

To the Editor,

We read with interest the paper “Prothrombin complex concentrate (PCC) for treatment of trauma-induced coagulopathy: systematic review and meta-analyses” [1]. We appreciate our colleagues’ efforts in advancing our understanding of PCCs in trauma patient management. However, it is crucial to highlight that the primary goal of a systematic review and meta-analysis is to precisely determine effect sizes, which requires the exclusion of studies that could induce bias in the results. This paper drew our attention due to the apparent absence of strict criteria for including studies in the meta-analysis.

The first study of concern, conducted by Khurrum et al. [2], compared patients in the intervention group treated with four-factor prothrombin complex concentrate (4F-PCC) and whole blood (WB) to those in the control group treated only with WB. While the aim of the article is to assess the impact of 4F-PCC, we note the inconsistency in comparing studies that use WB with others utilizing fresh frozen plasma (FFP) as the control treatment. Recent research suggests that WB displays an improved functional clotting profile compared to the conventional 1:1:1 transfusion ratio of packed red blood cells, fresh frozen plasma, and platelets [3].

The second concerning study was conducted by Schlimp et al. [4]. Unlike the other studies using FFP as the control treatment, this study employed fibrinogen concentrate (FC) instead. FFP has low doses of fibrinogen, posing challenges in maintaining fibrinogen blood concentration with plasma alone during resuscitation. Additionally, while the other studies in the meta-analysis excluded patients on anticoagulation, the authors explicitly state that it was not a criterion of exclusion. Moreover, examining the results, we note that the intervention group (PCC + FC) had 18 deaths out of 63 patients, while the control group (FC) had 7 deaths out of 85 patients (29% vs. 8%, respectively, p = 0.0001). However, it is noticeable that the intervention group exhibited higher injury severity score, base deficit, lactate concentration, and a lower pH than the control group, differences that influence mortality rates [4].

It is noteworthy how the articles utilize either 3F-PCC or 4F-PCC for trauma-induced coagulopathy (TIC) treatment. The primary distinction between the two forms of PCC lies in the higher concentration of coagulation factor VII and the inclusion of anticoagulant proteins in 4F-PCC [5]. Despite the similarities in composition, studies show that 4F-PCC is likely more effective than 3F-PCC in reducing the international normalized ratio and the need for blood transfusions [6, 7]. Therefore, a deeper exploration of the differences between these two formulations could help optimize TIC treatments.

Addressing these concerns, we recalculated the odds ratio (OR) for the mortality outcome without Khurrun et al. and Schlimp et al. [2, 4, 8,9,10,11,12]. Additionally, we separated 3F-PCC and 4F-PCC articles in subgroup analysis. Given the expected heterogeneity between the studies, we performed a random-effect meta-analysis using the inverse variance method (Fig. 1) [13]. In our analysis, the use of PCC is associated with reduced mortality (OR 0.68, 95% confidence interval [CI] 0.51–0.90, I2 0%), contrasting with the review’s results (OR 0.94, 95% CI 0.60–1.45, I2 64%) [1]. In addition, our corresponding heterogeneity was much lower (I2 0%) than that presented by Hannadjas and colleagues (I2 64%) [1]. The subgroup analysis showed a reduction in mortality rates with 4F-PCC (OR 0.65; 95% CI 0.47–0.89, I2 0%), while the 3F-PCC group exhibited no significant impact (OR 0.79; 95% CI 0.45–1.38, I2 0%).

Fig. 1
figure 1

Forest plot comparison of mortality in patients treated with PCC vs control treatment in subgroup analysis

To explore the heterogeneity in the review, we propose Baujat’s graphic method, which detects sources of heterogeneity and assesses their contribution to the overall result [14]. In Fig. 2, each study is represented by a dot on the graph. Notably, Schlimp et al. [4] stand out as the primary contributor to the overall heterogeneity and moderate influence on the overall result. While Khurrum et al. [2] showed some treatment variations, their contribution to overall heterogeneity was not significant.

Fig. 2
figure 2

Baujat’s graphic method

To enhance our comprehension of the impact of individual studies on the effect size and heterogeneity, we conducted a leave-one-out meta-analysis, as illustrated in Fig. 3. Upon excluding Schlimp et al. from the meta-analysis, a significant shift in effect size is observed in favoring 4F-PCC, along with a substantial reduction in heterogeneity (the I2 values decrease from 64 to 0%) [4].

Fig. 3
figure 3

Leave-one-out meta-analysis method

Finally, the inclusion of Schlimp et al. [4] appears inappropriate due to its impact on overall results, heterogeneity, and inadequate comparability with other studies. Meticulous study selection is essential for unbiased and precise inferences. Therefore, our methodological approach has led to conclusions that diverge from those presented by the original author. However, we agree with the authors that drawing a recommendation would be warranted with the publication of additional randomized trials. Moreover, a comprehensive understanding of the distinctions between 4F-PCC and 3F-PCC in TIC treatment requires further studies.

Availability of data and materials

Not applicable.



Three-factor prothrombin complex concentrate


Four-factor prothrombin complex concentrate


Confidence interval


Fibrinogen concentrate


Fresh frozen plasma


Odds ratio


Prothrombin complex concentrate


Trauma-induced coagulopathy


Whole blood


  1. Hannadjas I, James A, Davenport R, Lindsay C, Brohi K, Cole E. Prothrombin complex concentrate (PCC) for treatment of trauma-induced coagulopathy: systematic review and meta-analyses. Crit Care. 2023;27(1):422.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Khurrum M, Ditillo M, Obaid O, Anand T, Nelson A, Chehab M, et al. Four-factor prothrombin complex concentrate in adjunct to whole blood in trauma-related hemorrhage: does whole blood replace the need for factors? J Trauma Acute Care Surg. 2021;91:34–9.

    Article  CAS  PubMed  Google Scholar 

  3. Kornblith LZ, Howard BM, Cheung CK, Dayter Y, Pandey S, Busch MP, et al. The whole is greater than the sum of its parts: hemostatic profiles of whole blood variants. J Trauma Acute Care Surg. 2014;77(6):818–27.

    Article  CAS  PubMed  Google Scholar 

  4. Schlimp CJ, Voelckel W, Inaba K, Maegele M, Schöchl H. Impact of fibrinogen concentrate alone or with prothrombin complex concentrate (+/- fresh frozen plasma) on plasma fibrinogen level and fibrin-based clot strength (FIBTEM) in major trauma: a retrospective study. Scand J Trauma Resusc Emerg Med. 2013;21(1):74.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Grottke O, Levy JH. Prothrombin complex concentrates in trauma and perioperative bleeding. Anesthesiology. 2015;122(4):923–31.

    Article  PubMed  Google Scholar 

  6. Mangram A, Oguntodu OF, Dzandu JK, Hollingworth AK, Hall S, Cung C, et al. Is there a difference in efficacy, safety, and cost-effectiveness between 3-factor and 4-factor prothrombin complex concentrates among trauma patients on oral anticoagulants? J Crit Care. 2016;33:252–6.

    Article  CAS  PubMed  Google Scholar 

  7. Zeeshan M, Hamidi M, Kulvatunyou N, Jehan F, O’Keeffe T, Khan M, et al. 3-Factor versus 4-factor PCC in coagulopathy of trauma: four is better than three. Shock. 2019;52(1):23–8.

    Article  CAS  PubMed  Google Scholar 

  8. Joseph B, Aziz H, Pandit V, Hays D, Kulvatunyou N, Yousuf Z, et al. Prothrombin complex concentrate versus fresh-frozen plasma for reversal of coagulopathy of trauma: is there a difference? World J Surg. 2014;38(8):1875–81.

    Article  PubMed  Google Scholar 

  9. Joseph B, Khalil M, Harrison C, Swartz T, Kulvatunyou N, Haider AA, et al. Assessing the efficacy of prothrombin complex concentrate in multiply injured patients with high-energy pelvic and extremity fractures. J Orthop Trauma. 2016;30(12):653–8.

    Article  PubMed  Google Scholar 

  10. Jehan F, Aziz H, O’Keeffe T, Khan M, Zakaria ER, Hamidi M, et al. The role of four-factor prothrombin complex concentrate in coagulopathy of trauma: a propensity matched analysis. J Trauma Acute Care Surg. 2018;85(1):18–24.

    Article  CAS  PubMed  Google Scholar 

  11. Zeeshan M, Hamidi M, Feinstein AJ, Gries L, Jehan F, Sakran J, et al. Four-factor prothrombin complex concentrate is associated with improved survival in trauma-related hemorrhage: a nationwide propensity-matched analysis. J Trauma Acute Care Surg. 2019;87(2):274–81.

    Article  CAS  PubMed  Google Scholar 

  12. Bouzat P, Charbit J, Abback PS, Huet-Garrigue D, Delhaye N, Leone M, et al. Efficacy and safety of early administration of 4-factor prothrombin complex concentrate in patients with trauma at risk of massive transfusion: the PROCOAG randomized clinical trial. JAMA. 2023;329(16):1367–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Reeves BC, Deeks JJ, Higgins JPT, et al. Chapter 24: including non-randomized studies on intervention effects. In: Higgins JPT, Thomas J, Chandler J, et al., editors. Cochrane handbook for systematic reviews of interventions. Version 6.2. Cochrane; 2021.

  14. Baujat B, Mahé C, Pignon JP, Hill C. A graphical method for exploring heterogeneity in meta-analyses: application to a meta-analysis of 65 trials. Stat Med. 2002;21(18):2641–52.

    Article  PubMed  Google Scholar 

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BA raised the question. BA, MD, and EP were responsible for analysis and writing. All authors reviewed the manuscript.

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Correspondence to Bruno Caldeira Antônio.

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Antônio, B.C., Denardin, M.S., Neves, H.A.F. et al. Critical appraisal and concerns regarding a meta-analysis on prothrombin complex concentrate (PCC) for trauma-induced coagulopathy: unveiling methodological nuances and treatment variances. Crit Care 27, 454 (2023).

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