The efficacy of coagulation factor concentrates in the management of patients with trauma- induced coagulopathy: a systematic review and meta-analysis

doi:10.21203/rs.3.rs-3808865/v1

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The efficacy of coagulation factor concentrates in the management of patients with trauma- induced coagulopathy: a systematic review and meta-analysis

https://doi.org/10.21203/rs.3.rs-3808865/v1

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Introduction: Uncontrolled bleeding during the early phase of trauma is primarily attributable to death, which is exacerbated by Trauma-induced coagulopathy (TIC). Several randomized controlled trials (RCTs) have investigated interventions of supplementation for transfusion, coagulation factors, and tranexamic acid for hemostasis of trauma. Although several systematic reviews and meta-analyses have been conducted, no systematic review and meta-analysis has focused on the TIC. Therefore, a comprehensive synthesis of the available evidence on interventions for TIC is needed.

Methods and analysis: We conducted a systematic review and meta-analysis of blood component products and tranexamic acid administrations for severe trauma patients with TIC. TIC was defined as abnormalities of coagulo-fibrinolytic laboratory markers or clinically evident bleeding tendency during the resuscitation phase. We included randomized controlled trials and non-randomized controlled trials. The study population included in this review was patients who required transfusion with any coagulopathy associated with trauma and a detailed definition in each included study. The intervention was the administration of blood component products and tranexamic acid. The control group was administered with ordinal transfusion or placebo. The primary outcome of the study is mortality due to all causes and the quantity of the transfusion. We searched electronic databases such as MEDLINE (PubMed), Web of Science, and the Cochrane Central Register of Controlled Trials. Two reviewers independently screened the title and abstract, retrieved the full text of the selected articles, and extracted the essential data. We applied uniform criteria for evaluating the risk of bias associated with individual RCTs and non-randomized trials based on the Cochrane risk of bias tool. Values of the risk ratio were expressed as a point estimate with 95% confidence intervals (CIs). Data of continuous variables were expressed as the mean difference along with their 95% CIs and P values. We assessed the strength of evidence using the Grading of Recommendations Assessment, Development, and Evaluation approach.

Results: Four RCTs and seven observational studies were included in the qualitative synthesis. Fibrinogen concentrate (FC) administrations may reduce mortality with very low certainty of evidence. Prothrombin coagulation cofactors (PCC) administrations may result in a large reduction in in-hospital mortality with low certainty of evidence. Combination administrations of FC and PCC (FC + PCC) probably result in an increase in mortality with moderate certainty of evidence. Recombinant activated factor VII (rFⅦa) administrations may have increased in-hospital mortality with very low certainty of evidence. FC administrations may reduce amounts of red blood cell (RBC) transfusion with very low certainty of evidence. PCC administrations result in a large reduction of RBC transfusion. FC + PCC administrations result in a large reduction in RBC with high certainty of evidence. FC and FC + PCC administrations tend to reduce multiple organ failure with very low to moderate certainty of this evidence.

Conclusions:

The present study indicates that FC and/or PCC administrations tend to reduce mortality and transfusion amounts in patients with coagulopathy-associated trauma. Furthermore, complications were reduced by FC and PCC administration. As our systematic review and metanalysis did not reveal high certainty of evidence, blood component products, such as FC and PCC supplementation for TIC should be investigated in more well-constructed trials.

This study protocol has been funded through a protocol registry. The registry number is UMIN000050170, Registered 29 January 2023.

trauma-induced coagulopathy

coagulation factor

transfusion

Uncontrolled bleeding exacerbated by trauma-induced coagulopathy (TIC) is the leading cause of trauma death [1-3]. TIC involves blood loss, coagulation factor consumption, dilution, and fibrinolytic activation [1-4]. The International Society on Thrombosis and Haemostasis recently proposed a conceptual definition of TIC [2]. Although some studies have defined TIC by prothrombin time, activated partial thromboplastin time, platelet count, hypofibrinogenemia, or viscoelastic devices [4-8], the clinical definition of TIC has not reached a consensus. However, early detection and effective treatment of TIC are crucial for decreasing deaths following trauma [2-4].

Blood component products, such as cryoprecipitate, fibrinogen concentrate (FC), prothrombin complex concentrate (PCC), which contains factors II, VII, IX, and X, and recombinant activated factor Ⅶ (rFⅦa) have several theoretical advantages over blood transfusion in treatments for patients with TIC. These products contained high concentrations and large amounts of coagulation factors. Although several systematic reviews and meta-analyses have been conducted on the effectiveness of transfusion and administration of blood component products for haemostasis following severe trauma [9-11], no systematic review and meta-analyses focusing on severe trauma patients with TIC have been reported. The administration of tranexamic acid for severe trauma is now used globally for early-stage trauma management, with a proven lifesaving benefit from large RCTs and meta-analysis [11-14]. We speculate that tranexamic acid, an antifibrinolytic agent, plays an important role in TIC, which is characterised by dysregulated fibrinolysis [1]. However, the efficacy of TXA in treating TIC has not yet been investigated.

To address this knowledge gap, we conducted a systematic review and meta-analysis to evaluate the effectiveness and safety of TIC interventions by administering blood component products and tranexamic acid.

Protocol registration

The study protocol was registered in the University Hospital Medical Information Network (UMIN registration number: UMIN000057146, Registered 29 January 2023. URL: https://center6.umin.ac.jp/cgi-bin/ctr_e/ctr_view.cgi?recptno=R000057146) and published [15]. This systematic review and meta-analysis was conducted according to The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Protocols guidelines [16].

Study population

We included patients with severe trauma and TICs upon hospital admission. The features of TIC were defined as abnormalities in coagulofibrinolytic laboratory markers or clinically evident bleeding tendencies during the resuscitation phase [3]. Therefore, we included patients who required transfusion for any coagulopathy associated with trauma and collected a detailed definition for each included study. Furthermore, we evaluated the definition of trauma-associated coagulopathy used in previous studies. Our review was not restricted by country. Patients and the general public were not involved in the design of the protocol.

Types of studies

We included controlled trials (RCTs and other controlled trials) published until 3 November 2023. Studies that did not report the population, treatment, or outcomes of interest were excluded. Animal studies were excluded from analyses. Two or more studies were published using the same or overlapping cohorts, and the most recent or larger cohort was included. We have restricted the language to English.

Intervention and control

Intervention types of interest were the supplementation of blood component products such as cryoprecipitate, PCC, FC, rFⅦa, platelet, and tranexamic acid in the treatment for haemostasis. The control group received an ordinal transfusion treatment (FFP) or placebo. We also collected data on the time phase of administration of coagulation factors. We did not restrict our review to the product type, amount, or timing of coagulation factor administration.

Outcomes

The primary outcome was all-cause mortality due to all causes and transfusion quantities. Secondary outcomes included thrombotic events (deep venous thromboses, pulmonary embolisation, myocardial infarctions, strokes, etc.), multiple organ failure, length of ICU stay, and hospital stay.

Database search

To retrieve relevant articles, we performed a literature search of the following major electronic bibliographic databases: MEDLINE (PubMed), Web of Science, and the Cochrane Central Register of Controlled Trials. We examined the references cited in the relevant articles to determine whether additional studies could be found. Details of the search strategy and the protocol of this systematic review and meta-analysis　are available in the appendix [15].

Data extraction

Using a standardised pre-pilot form, data from the included studies were extracted to assess the quality of the studies and methods of data synthesis. The extracted information included data on the following variables: study setting, study population, baseline characteristics of the participants, details of the interventions and control conditions, study methodologies, outcomes, and risk of bias assessments. Two reviewers (YI and YT) independently extracted the data, and discrepancies were resolved through discussion with a third author (MH). Missing data were not obtained at the authors’ request.

Selection of studies

Citations were stored using the EndNote Software (Thomson Reuters, Toronto, Ontario, Canada). Systematic review processes, such as removing duplicates, were performed using Rayyan software [17]. The titles and abstracts of the studies retrieved using the search strategy were independently screened by two reviewers (YI and YT) to identify studies that met the inclusion criteria. The full texts of potentially eligible studies were retrieved and assessed independently by two reviewers (YI and YT). Any disagreement regarding the eligibility of the studies was resolved through consultation with a third reviewer (MH) if needed.

Assessment of risk of bias in individual studies

Two independent reviewers (YI and YT) assessed the risk of bias in individual studies and the methodological quality of the articles; disagreements were resolved by discussion with a third reviewer (MH). We applied uniform criteria to evaluate the risk of bias associated with individual RCTs based on the Revised Cochrane risk of bias tool for randomised trials (RoB2.0) [18]. Each study was assessed for (1) random sequence generation, (2) allocation concealment, (3) blinding of participants and personnel, (4) blinding of related outcome assessment, (5) incomplete outcome data, (6) selective reporting, and (7) other bias. We also used the Risk of Bias in Nonrandomised Studies of Interventions (ROBINS-I) with individual Non-randomised studies [19].

Data summary and synthesis

We performed a meta-analysis when data were available from one or more trials according to the “Cochrane Handbook for Systematic Reviews of Interventions”. For　binary variables, the risk ratio or odds ratio values were expressed as point estimates with 95% confidence intervals (CI). Continuous variables, such as the length of ICU stay, were expressed as their mean difference with a 95% confidence interval (CI) and p-value. If the data were composed of minimum, median, and maximum values, the sample mean values and standard deviations were estimated [20, 21] and summarised for application in the meta-analysis.

We estimated the findings of the included studies using a random-effects model. A random-effects model incorporates statistical heterogeneity and provides a more conservative pooled effect size estimate than a fixed-effects model. All statistical analyses, including the risk of bias within and/or across studies, were performed using Review Manager, Version 5.4. (RevMan; The Cochrane Collaboration 2019, The Nordic Cochrane Centre, Copenhagen, Denmark) [22]. The level of statistical significance was set at p < 0.05.

Assessment of heterogeneity and publication bias

Statistical heterogeneity was assessed using the Mantel-Haenszel χ²test and the I²(the value of I² > 50% = significant heterogeneity) [23]. Clinical heterogeneity was considered when deciding to conduct a quantitative synthesis of the data or perform sensitivity analyses.

To assess publication bias, we checked funnel plots with the Review Manager.

Rating the strength of evidence using the GRADE approach

Two authors (YI and YT) independently assessed the strength of the evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach [24]. The quality of evidence was assessed for each outcome and categorised as high, moderate, low, or very low (critical for observational studies) according to the GRADE approach. The results were obtained according to the GRADE guidelines 26 [24].

Search results and characteristics of included trials

After removing duplicates, 3,015 records were identified in a November 3, 2023 search. Nineteen full-text articles were identified and assessed for eligibility, and four RCTs and seven observational studies were included in the qualitative synthesis (Figure 1). For the PRISMA flow chart) [4-8, 25-30]. Table 1 summarises the studies included in this synthesis. RCTs and observational studies were analysed separately for each outcome.

The definition of TIC in each study

The definitions of trauma-associated coagulopathy in the included studies are summarised in Table 1. PT-INR > 1.2, 1.3, 1.4 or 1.5 were the thresholds used in these studies. Other studies set APTT > 36 s, platelet count less than 100 x10⁹/L or hypofibrinogenemia < 200 mg/d, and viscoelastic devices. Regarding the various definitions that were generally unified in each intervention, we did not perform subgroup analysis for each definition.

Mortality

RCTs

According to data from three trials, FC administration may reduce mortality compared to FFP administration (Figure 2a). However, owing to the moderate weight of the high risk of bias, high heterogeneity, and very low number of events for optimal information size, the certainty of this evidence was very low (Table 2a). The combined administration of FC and PCC (FC + PCC administration) probably increased mortality compared to FFP administration, according to data from one trial (Figure 2b). However, due to the high heterogeneity and low number of events, the certainty of this evidence was moderate (Table 2b).

Observational studies

According to data from three trials, PCC administration may significantly reduce in-hospital mortality compared to FFP administration. However, owing to the bias of confounding and confidence intervals straddling thresholds, the certainty of this evidence was low (Table 2c). rFⅦa administrations may increase in-hospital mortality compared to FFP administrations, according to data from three trials (Figure 2d). However, owing to the critical risk of bias and a very low number of events for optimal information size in all studies, the certainty of this evidence was very low (Table 2d).

RBC transfusion amounts after admission

RCTs

FC administration reduced RBC transfusion amounts during the first 24h compared to FFP administration, according to data from one trial (Figure 3a). However, owing to the moderate weight of the high risk of bias and the very low number of events, the certainty of this evidence was very low (Table 2a). FC+PCC administration resulted in a large reduction in RBC transfusion amounts compared to FFP administration, according to data from one trial (Figure 3b), and the certainty of this evidence is high (Table 2b).

Observational studies

According to the data from three trials, PCC administration significantly reduced RBC transfusion amounts during hospital admission compared to FFP administration (Figure 3c). However, owing to the bias of confounding factors, the certainty of this evidence was very low (Table 2c). rFⅦa administrations did not have this outcome.

FFP transfusion amounts after admission

RCTs

FC and FC + PCC did not have this outcome.

Observational studies

According to the data from three trials, PCC administration reduced FFP transfusion amounts during hospital admission compared to FFP administration (Figure 4b). However, owing to confounding biases and very high heterogeneity, the certainty of this evidence is very low (Table 2c). rFⅦa administrations did not have this outcome.

PC transfusion amounts after admission.

RCTs

According to data from one trial, FC+PCC administration may have little to no effect on PC transfusion amounts compared to FFP administration (Figure 5a). However, owing to the moderate weight of the high risk of bias and the very low number of events, the certainty of this evidence was low (Table 2b). However, the FC administration did not have this outcome.

Observational studies

According to the data from three trials, PCC administration may reduce PC transfusion amounts during hospital admission compared to FFP administration (Figure 5b). Owing to confounding bias and confidence interval straddling thresholds, the certainty of this evidence was very low (Table 2c). rFⅦa administrations did not have this outcome.

Thrombotic events

RCTs

FC+PCC administration may reduce thrombotic events compared to FFP administration (Supplementary Figure 1a). However, due to the moderate weight of the high risk of bias and the low number of events for the optimal information size, the certainty of this evidence is moderate (Table 2b). However, the FC administration did not have this outcome.

Observational studies

According to data from one trial, PCC administration may increase thrombotic events during hospital admission compared with FFP administration (Supplementary Figure 1b). However, due to the moderate weight of the high risk of bias, the certainty of this evidence was low (Table 2c). rFⅦa administrations may have little to no effect on thrombotic events compared to FFP administrations, according to data from three trials (Supplementary Figure 1c). However, owing to the critical risk of bias and a very low number of events for optimal information size in all studies, the certainty of this evidence was very low (Table 2d).

Multiple organ failure

RCTs

According to data from one trial, FC administration may reduce multiple organ failure compared to FFP administration (Supplementary Figure 2a). However, due to the moderate weight of the high risk of bias and the very low number of events for the optimal information size, the certainty of this evidence is very low (Table 2a). FC+PCC administration likely reduced multiple organ failure compared to FFP administration (Supplementary Figure 2b). However, due to the low number of events for the optimal information size, the certainty of this evidence is moderate (Table 2b).

Observational studies

PCC and rFⅦa administrations did not have this outcome.

Length of ICU stay

RCTs

According to data from the two trials, FC administration may have little to no effect on reducing the length of ICU stay compared to FFP administration (Supplementary Figure 3a). However, owing to the moderate weight of the high risk of bias, high heterogeneity, and very low number of events for optimal information size, the certainty of this evidence was very low (Table 2a). FC+PCC administration may have little to no effect on the length of ICU stay compared to FFP administration (Supplementary Figure 3b). However, owing to the moderate weight of the high risk of bias, high heterogeneity, and very low number of events for optimal information size, the certainty of this evidence was very low (Table 2b).

Observational studies

According to data from three trials, PCC administration did not reduce the ICU length of stay compared with FFP administration (Supplementary Figure 3c). Due to the bias of confounding factors, the certainty of this evidence was low (Table 2c). 　rFⅦa administrations may increase the length of ICU stay compared to FFP administrations according to data from one trial (Supplementary Figure 3d). However, owing to the critical risk of bias and a very low number of events for optimal information size in all studies, the certainty of this evidence was very low (Table 2d).

Length of hospital stay

RCTs

FC administration may have little to no effect on the length of hospital stay compared with FFP administration, but the evidence is very uncertain according to data from three trials (Supplementary Figure 4a). However, due to the moderate weight of the high risk of bias and the very low number of events for the optimal information size, the certainty of this evidence is very low (Table 2a). FC+PCC administration may increase the length of hospital stay compared to FFP administration (Supplementary Figure 4b). However, owing to the moderate weight of the high risk of bias, moderate heterogeneity, and very low number of events for optimal information size, the certainty of this evidence was very low (Table 2b).

Observational studies

According to the data from three trials, PCC administration may have little to no effect on reducing the length of hospital stay compared to FFP administration (Supplementary Figure 4c). Due to confounding bias, the certainty of this evidence was moderate (Table 2c). rFⅦa administrations did not have this outcome.

In the present study, no study assessed platelet transfusions, cryoprecipitate transfusions, and tranexamic acid administrations for patients with TIC was found in the systematic search. We did not conduct a sensitivity analysis due to the shortage of studies with a low risk of bias. Owing to the limited variety of injury mechanisms of trauma and the categorised comparators above, we did not conduct a subgroup or sensitivity analysis. The risk of bias assessment is summarised in Supplementary Figure 5. A summary of these findings is provided in Table 2.

In this systematic review and meta-analysis, FC and PCC administration tended to reduce mortality rates. Administration of FC, PCC, and FC + PCC significantly reduced the number of RBC transfusions after admission. PCC administration reduced the number of FFP transfusions during hospital admission. The incidence of thrombotic events was lower in the FC + PCC group. The MOF was lower in the FC and FC + PCC groups. These results revealed the effectiveness of FC, PCC, and FC + PCC administration in patients with severe trauma and TIC. However, rFⅦa administrations did not reveal any positive results.

In a previous systematic review and meta-analysis, we investigated FC administration for trauma in general, independent of TIC, in the previous systematic review and meta-analysis [31]. In this review, FC administration slightly increased in-hospital mortality and transfusion amounts [31]. However, FC administration may reduce mortality in patients with severe trauma and TICs. This discrepancy in the results may indicate that the benefit of FC administration is observed in patients with severe trauma with TIC. In this meta-analysis, FC and/or PCC administration significantly reduced the number of RBC transfusions during the first 24h after admission. In the RETIC study, FC + PCC administration significantly reduced FFP levels within 24h. However, the mean difference in the amount of FFP in the group was zero because of the small transfusion amount of FFP; this result was not included in this meta-analysis for statistical analysis (Fig. 4b) [4]. The results of the PROCOAG RCT [32] and CRYOSTAT-2 RCT [33] have recently been published. The PROCOAG RCT investigated the efficacy and safety of PCC in patients with severe trauma and reported that PCC did not reduce the number of RBC transfusions [32]. The CRYOSTAT-2 RCT reported that early and empirical high-dose cryoprecipitation did not improve all-cause 28-day mortality [33]. Neither trial clearly focused on patients with severe trauma with TIC and did not report the effectiveness of coagulation factor supplementation. Thus, we speculate that the administration of coagulation factors may be effective if limited to patients with TIC.

Recently, a meta-analysis investigating PCC administration in severe trauma was reported by Hannadjas [34]. Although this meta-analysis aimed to investigate PCC administration for TIC, a clear TIC definition did not uniformly define the inclusion criteria. In the present meta-analysis, we included studies with clear inclusion criteria based on coagulation tests such as PT-INR, fibrinogen, or viscoelastic devices.

This study had several limitations. First, the overall certainty of the evidence was reduced owing to the weight of the high risk of bias, low number of events, and high levels of heterogeneity. Therefore, our study does not provide a high level of evidence. To improve the certainty of the evidence, a double-blind design is required. Second, the definition of TIC differed in each study. The definition of TIC in each study was not uniform. Third, the results regarding mortality were combined with both in-hospital and 90-day mortality, owing to the small number of included studies. Fourth, none of the studies specified the time phase of the blood component product administration. Furthermore, transfusion practices in the control group changed significantly during the last two decades. Early intervention for haemostasis, including radiological intervention or surgery in the early phase of severe trauma, is essential to prevent early death due to exsanguination [1]. However, interventions were not measured in the included studies. Thus, these factors may represent an unmeasured bias in the efficacy of the administration.

The present study indicates that FC and PCC administrations tend to reduce mortality and transfusion rates in patients with coagulopathy-associated trauma. Furthermore, complications were reduced by the administration of FC and PCC. Our study did not reveal a high certainty of evidence, so blood component products, such as FC and PCC supplementation for TIC, should be investigated in well-constructed trials.

TIC = Trauma-induced coagulopathy, RCT = randomized controlled trial, CI = confidence interval, PT-INR = prothrombin time international normalized ratio, APTT = activated partial thromboplastin time, PCC = prothrombin complex concentrate, FC = fibrinogen concentrate, FFP = fresh-frozen plasma, rFⅦa = activated recombinant factor Ⅶ, PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-Analyses, RoB2.0 = Revised Cochrane risk of bias tool for randomized trials, ROBINS-I = Risk Of Bias In Non-randomised Studies – of Interventions, GRADE = Grading of Recommendations Assessment, Development, and Evaluation.

Ethical Approval and Consent to participate

Approval from the ethics board and patient consent were not required in our study since this was a systematic review and meta-analysis of publicly available data without any direct involvement of human participants.

Consent for publication

Not applicable.

Availability of data and materials

All relevant data are presented in the published manuscript.

Competing interests

The authors of this work have nothing to disclose.

Funding

This publication is funded by a research grant program by the Japanese Society of Thrombosis and Haemostasis.

Authors' contributions

The manuscript was drafted by YI and was revised by MH, SK, YSakamoto, YSeki, and KO. The search strategy was developed by YI, YT, and MH. YI and YT independently extracted data from the included studies, assessed the risk of bias, and completed the data synthesis. MH arbitrated in cases of disagreement and ensured the absence of errors.

Acknowledgments

This publication is part of the research project of the Scientific and Standardization Committee on DIC of the Japanese Society on Thrombosis and Hemostasis.

We would like to thank Editage (www.editage.com) for English language editing.

Conflict of interest

The authors of this work have nothing to disclose.

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Tables 1-2 is available in the Supplementary Files section.

No competing interests reported.

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The efficacy of coagulation factor concentrates in the management of patients with trauma- induced coagulopathy: a systematic review and meta-analysis

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