In the field of critical care medicine, transfusion therapy is frequently employed as a supportive treatment to address anemia, replenish blood volume, and correct coagulopathy [1]. The use of frozen plasma (FP) in intensive care units (ICUs) remains prevalent. Epidemiologic data from a recent large international multicenter study indicate that roughly 10% of critically ill patients receive plasma transfusions during their hospital stay, of which up to 37% are given for non-hemorrhagic indications [2]. This aligns with earlier observations from studies conducted in the UK, Australia, and other countries [3–5].

Several international guidelines [6–10] outline limited indications for FP use, such as active bleeding with coagulation factor deficiencies, plasma exchange, specific coagulopathies requiring replacement therapy, and massive transfusion protocols. However, the evidence supporting prophylactic FP use in critically ill patients remains limited and controversial [11]. Studies have shown that early high-ratio plasma transfusion (plasma-to-red-cell ratio ≥1:2) in patients undergoing massive transfusion can reduce mortality rates [12–14]. Conversely, research conducted in Hiroshima indicated that the lack of improvement in coagulation following FFP transfusion was independently and significantly associated with death within 28 days [15]. Additionally, Qin et al. found that early FFP transfusion in sepsis patients was significantly correlated with an increased risk of mortality [16].

Despite this, plasma transfusion remains prevalent in current clinical practice, with its potential risks often underestimated. A retrospective audit at a tertiary hospital revealed that up to 51.8% of plasma transfusions were administered outside of guideline recommendations, including unnecessary prophylactic use [17]. Such inappropriate transfusions waste limited blood resources and expose patients to a range of transfusion-related adverse effects [18,19].

Employing a retrospective cohort analysis, this study investigates the relationship between plasma transfusion dosage and mortality risk among critically ill patients. It aims to evaluate clinical outcomes to establish evidence-based risk thresholds and provide decision support for optimizing transfusion practices.

This retrospective study of 282 critically ill ICU patients aimed to investigate the impact of plasma transfusion and its dosage on mortality, clarifying the risks and benefits associated with plasma use in critical care. After adjusting for baseline confounders employing PSM, the mortality risk in the plasma transfusion group remained significantly elevated, with a hazard ratio of 3.271 (95% CI: 1.30–8.21; p-value = 0.012). Moreover, a dose-dependent relationship was evident, as the risk increased to 4.09-fold (95% CI: 1.19–14.04; p-value = 0.025) when the transfusion volume exceeded 800 mL.

Patients receiving plasma transfusions presented with poorer baseline clinical characteristics, including more severe coagulopathies, a higher incidence of sepsis, and worse liver function. This suggests that transfusion decisions largely followed clinical indications, targeting sicker patients. However, after balancing 19 baseline variables using PSM (Table 1), plasma transfusion remained independently associated with increased mortality. This indicates that, beyond reflecting illness severity, plasma transfusion itself may confer additional risk.

The increased mortality risk associated with plasma transfusion may be linked to several factors. First, immune-inflammatory storms [20,21], where plasma contains various bioactive substances (complement, cytokines) that can activate systemic inflammatory responses, leading to febrile non-hemolytic transfusion reactions, allergic reactions, transfusion-related acute lung injury (TRALI) [22], and even hemolysis [23], potentially causing direct patient mortality or complicating their condition. TRALI and transfusion-associated circulatory overload (TACO) are leading causes of transfusion-related deaths, identified as independent risk factors for ICU mortality [24,25]. For instance, the UK SHOT report attributed 52.54% of transfusion-related deaths to TACO among a total of 59 cases [26]. Second, although volume overload is effective for volume replacement and coagulation correction [27], critically ill patients often have impaired physiological functions and limited compensatory capacities, making them less tolerant to large-volume plasma transfusions, thus increasing the risk of acute left heart failure, pulmonary edema [28], citrate toxicity-induced hypocalcemia and myocardial depression. Third, plasma administration can exacerbate coagulation imbalance [29]. Because plasma is rich in procoagulant factors such as thrombin and fibrinogen, it may alter blood flow dynamics and disrupt the homeostatic balance, thereby increasing the risk of thrombosis. This can trigger secondary inflammation, tissue edema, or necrosis, ultimately worsening clinical outcomes [30]. A study on FFP transfusion efficacy in ICU patients with decompensated cirrhosis and coagulopathy found no benefit in terms of mortality but increased hospital stays and multi-organ failure risk [31].

Subgroup analysis provided further insights, revealing a statistically significant increase in mortality specifically among patients who received RBC transfusions (HR = 2.92; 95% CI: 1.22–7.00; p-value = 0.016). In contrast, this association was not significant in subgroups stratified by age, patient category, or ICU length of stay. This suggests that patients requiring concomitant RBC and plasma transfusion represent a particularly vulnerable population. In these critically ill patients that are often facing anemia, active bleeding, or hemodynamic instability, plasma may compound risks through volume overload, inflammatory activation, or coagulopathy. Thus, in multi-component transfusion settings, the risks of plasma transfusion appear amplified, necessitating cautious reassessment even when coagulation parameters seem to justify its use. Clinical practice should adhere strictly to evidence-based guidelines, prioritize treating underlying conditions, and exercise heightened vigilance when considering plasma alongside other blood products.

This study has several limitations. First, as a retrospective observational analysis, it may be subject to residual confounding despite adjustment for known factors via PSM. Second, the exact time interval between plasma transfusion and death was not consistently recorded in the medical records, limiting our ability to establish a clear temporal relationship or infer causality. To partially address this, we excluded patients with an ICU stay of <24 h, thereby reducing the likelihood of including deaths unrelated to transfusion or driven solely by the underlying disease. Nevertheless, future studies should aim to collect time-to-event data more systematically to enable time-varying exposure analyses. Third, we were unable to directly quantify specific adverse reactions such as TRALI or TACO, limiting our ability to confirm the proposed mechanisms. Fourth, the sample size was relatively modest, particularly in subgroup and dose-response analyses, which may have reduced statistical power and limited the generalizability of our findings. Therefore, these results should be considered exploratory and warrant validation in larger, multicenter prospective studies.

This study demonstrates that plasma transfusion is independently associated with significantly increased in-hospital mortality in critically ill patients, with a strong dose-dependent effect. The association remained significant after adjusting for confounding factors in PSM. Plasma use, particularly in the absence of active bleeding or clear indications, may cause more harm than benefit, likely due to complications like TRALI, TACO, and thrombosis.

Current clinical practices frequently diverge from established guidelines, potentially exposing patients to avoidable risks. Consequently, a more restrictive and evidence-based strategy for plasma transfusion is strongly warranted. Clinicians are encouraged to avoid prophylactic use, particularly in hemodynamically stable patients, and should instead focus on addressing the underlying causes of coagulopathies. These findings underscore the need for stricter adherence to transfusion guidelines and highlight the importance of future prospective studies to enhance clinical decision-making in critical care settings.

Plasma transfusion should be regarded as a high-intervention therapy that carries substantial risks and requires meticulous patient-specific evaluation before administration. Future research efforts should aim to refine existing guidelines through well-designed prospective studies and large-scale randomized controlled trials, with the goal of establishing precise, individualized dosing strategies. Ultimately, the objective is to improve patient outcomes by maximizing the therapeutic benefits of plasma transfusion while minimizing unnecessary exposure to risk.

This study was supported by the Hunan Provincial Health Commission General Project (No. 202204133544).

All listed authors have contributed to the manuscript substantially and have agreed to the final submitted version. MZ contributed to the concept of the article, wrote the draft, and modified it. CSL and FY supported in data treatment and analysis and reviewed the article. ZH, SF and FFC helped in data collection and modified the article. XSH reviewed and modified the article. HJG did the data analysis, modified thoroughly the whole article, including the tables and the figures. PL helped in funding and reviewed the article.

The data that support the findings of this study are available from the corresponding author upon reasonable request.