Systematic literature review and meta-analysis on the safety of fibrinogen concentrate versus cryoprecipitate in bleeding surgical patients

Abstract Background: Fibrinogen concentrate (FC) and cryoprecipitate are plasma-derived products used to manage bleeding in patients with hypofibrinogenemia. While both effectively restore fibrinogen levels, randomized controlled trials (RCTs) have shown no difference in efficacy or safety between products. However, it is hypothesized that cryoprecipitate may be associated with a higher risk of thromboembolic events (TEE) due to the presence of coagulation factors (e.g. factor VIII, von Willebrand factor) and of platelet-derived microparticles generated in its manufacturing process (Cushing MM, et al. Transfusion. 2020 Jun;60 Suppl 3:S17-S23, Hensley NB and Mazzeffi MA. Anesth Analg. 2021;133(1):19-28). The aim of this study was to conduct a systematic literature review (SLR) and meta-analysis (MA) to assess the comparative safety of FC vs. cryoprecipitate in patients with surgical bleeding, focusing on the risk of TEEs. Methods: An SLR was conducted to identify RCTs published from 2009 to February 2025 that co mpared FC with cryoprecipitate for safety outcomes in patients experiencing bleeding during elective surgery. Outcomes assessed included the incidence of TEE, deep venous thrombosis (DVT), pulmonary embolism (PE), any adverse events (AE) and serious AEs (SAE). Identified studies were evaluated for MA feasibility. Despite substantial heterogeneity in study design and population across the studies, all eligible studies were included in the base-case MA due to the limited number of available RCTs. The base-case analysis employed a frequentist approach, with heterogeneity assessed using the I2 statistic. To explore the potential sources of heterogeneity, subgroup analyses by age (adults vs. pediatrics) and type of surgery (cardiac vs. abdominal) were conducted where data allowed. Sensitivity analyses tested the robustness of the base-case findings by excluding studies with high risk of bias, removing an outlier study with disproportionate weight, and analysis based on per-protocol population. Exploratory analyses were performed using an empirical Bayesian (EB) approach for TEE and any AEs. All analyses were conducted in R version 4.4.1 (R Studio), using the “meta” package (version 7.0-0) for frequentist analyses and “metafor” (version 4.8-0) package for EB analyses. Frequentist analyses were performed using both fixed- and random-effects (FE and RE) models. For the EB analyses, only RE model was used. Results were reported as Odds Ratio (OR) and 95% confidence intervals (CI). Results: The SLR yielded 7 unique studies for inclusion in the MA. The base-case MA (RE model) showed a favorable trend for FC over cryoprecipitate in reducing the risk of all TEEs (n=5, OR = 0.55; 95% CI: 0.29-1.07; I² = 32%). In subgroup analyses, FC was associated with a significantly lower risk of TEEs in abdominal surgery (n=2; OR = 0.19; 95% CI: 0.05-0.70; I2 = 7%), and similar, though non-significant, trends were observed in cardiac surgery, adult, and pediatric subgroups and in sensitivity analyses. Exploratory Bayesian approach showed consistent results with the base-case analysis (n=5; OR = 0.49; 95% CI: 0.19-1.28; I² = 43%). Results for specific TEEs (DVT, PE) were consistent with the overall analysis. For DVT, the OR was 0.31 (n=3; 95% CI: 0.12-0.81; I² = 0%), indicating a significantly lower risk in patients treated with FC. For PE, a non-significant trend was observed (n=3; OR = 0.43; 95% CI: 0.06-2.99; I² = 49%). Within the abdominal surgery subgroup, a statistically significant reduction in PE risk was observed in patients treated with FC (n=2; OR = 0.23; 95% CI: 0.06-0.88; I2 = 0%). For any AEs and SAEs, FC showed a safety benefit vs. cryoprecipitate. A statistically significant reduction was observed for any AEs (n=4; OR = 0.70; 95% CI: 0.52-0.94; I² = 0%), while for SAEs, the effect also favored FC but was not statistically significant (n=3; OR = 0.50; 95% CI: 0.18-1.40; I² = 73%). Subgroup and sensitivity analyses showed consistent results for both any AEs and SAEs. The exploratory Bayesian analysis for any AEs matched the results of the base-case analysis. Conclusion: This analysis suggests that FC has a favorable safety profile regarding TEEs, as well as AEs and SAEs, compared to cryoprecipitate in patients with surgical bleeding. Due to the limited number and heterogeneity of the identified RCTs, these results should be interpreted with caution, underscoring the need for additional clinical trials.

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