Safety and efficacy of thromboelastography guidance of antifibrinolytic therapy in trauma patients: An observational cohort analysis.

BACKGROUND: Tranexamic acid (TXA) is an antifibrinolytic therapy intended to decrease blood loss and improve hemostasis in traumatic hemorrhage. Viscoelastic assays, such as thromboelastography (TEG), allow for the identification of a patient's specific hemostasis. The purpose of this research study was to explore the safety and efficacy of TEG-guided antifibrinolytic therapy in trauma patients.
METHODS: This study was a retrospective review of trauma patients meeting institution-specific inclusion criteria for TXA. Patients were assigned to fibrinolytic groups per TEG LY30 data. Safety outcomes (24-h mortality, overall in-hospital mortality, and thromboembolic events) were compared between patients who did or did not receive TXA and within fibrinolytic groups. Mortality outcomes were adjusted for baseline Injury Severity Score (ISS). Secondary aims included blood product utilization, length of hospital, and intensive care unit stay.
RESULTS: Hypofibrinolysis was the most common fibrinolytic phenotype. Adjusting for ISS, there were no significant differences in mortality. A 30.7% thromboembolism incidence was identified in the TXA group compared to 16.6% not receiving TXA (P = 0.26), with 72.7% of these patients experiencing fibrinolytic shutdown.
CONCLUSIONS: There were no differences in 24-h mortality, all-cause mortality, or secondary outcomes. The difference in thromboembolic rates between patients receiving TXA and those who did not, while not statistically significant, poses clinical concern. Copyright:

INTRODUCTION

Hemorrhage management is a multifaceted, interdisciplinary process that has evolved from primary strategies, including triaging a patient's hemodynamics through utilizing blood products for resuscitation. Adjunctive therapies, such as tranexamic acid (TXA), have played an increasing role in traumatic hemorrhage resuscitation. TXA is an antifibrinolytic therapy with the intended utility of decreasing blood loss by ceasing fibrinolysis in bleeding patients. It was initially shown to be beneficial in reducing postoperative blood loss, which prompted the evaluation of TXA in trauma patients.[12] The Clinical Randomization of an Antifibrinolytic in Significant Haemorrhage-2 (CRASH-2) was a large, randomized landmark trial that analyzed the efficacy of TXA administration in trauma patients either at risk for, or with, significant hemorrhage. Results of this trial suggest a 28-day mortality benefit for patients who receive TXA within the first 3 h of injury.[3] With this, CRASH-2 made a place for antifibrinolytic therapy in traumatic hemorrhage management efforts and protocols. However, a limitation of CRASH-2 is the trial's lack of determining the degree of patient's fibrinolysis.

Viscoelastic assays, such as thromboelastography (TEG), provide insight to a patient's specific deficits in clot formation, clot integrity, and fibrinolysis.[4] This enables health-care professionals to guide blood product selection and adjunctive therapy use to manage various types of coagulopathies.[5] A full spectrum of fibrinolytic response to injury has been identified and can be stratified into three major groups: hyperfibrinolytic, physiologically fibrinolytic, and hypofibrinolytic (or fibrinolytic shutdown).[678910] The fibrinolytic shutdown phenotype is found in up to 65% of severely injured patients within 12 h of admission which provides the opportunity for the evaluation TXA's place in therapy.[689]

While the literature begins to address the relationship between fibrinolytic groups and TXA, there is still opportunity for better understanding of how TEG technology can guide and facilitate the best practice of antifibrinolytic therapy. To date, there is no study designed in a way to address how TEG-guided TXA therapy affects mortality among trauma patients. This prompted the aim to determine the effectiveness and safety of TEG-guided TXA therapy in trauma patients.

METHODS

Study design and population

This was a retrospective cohort analysis of patients who presented to a Level 1 Trauma Center, between May 1, 2017 and October 31, 2018. This manuscript is compliant with STROBE guidelines. Patients 18 years and older were included in the study if they met institutional criteria for TXA administration (arrived within 3 h of injury and receiving blood transfusion during transport or in the trauma bay) and received TEG collection both within 3 h of arrival and before TXA administration. Patients were excluded if they were therapeutically anticoagulated.

Study protocol

This study was approved by the Institutional Review Board at OhioHealth (#1309276-2). Demographic and clinical variables were collected retrospectively by a single reviewer from the institutional trauma database through a SAS-based query or from the electronic medical record through manual chart review using a standardized, electronic data collection tool. Potential risk or bias included loss of confidentiality. This was minimized by limiting access of data and de-identifying data during analysis. Data collected included demographics (age at the time of admission, and sex, medical history, hospital information (mechanism of injury, type of injury, initial Glasgow Coma Scale (GCS), Injury Severity Score (ISS), incidence of acute kidney injury (AKI) during admission, hospital and intensive care length of stay, 24-h mortality, and all in-hospital mortality, TEG data (time to TEG, Alpha angle, MA, LY30%), TXA data (TXA yes/no), blood product administration (massive transfusion, red blood cells in units, fresh frozen plasma in units, platelets in units, cryoprecipitate in units), and thromboembolic events (stroke/transient ischemic attack, deep vein thrombosis, pulmonary embolism, other).

Outcomes of interest

The primary outcome was 24-h in-hospital mortality for patients within different fibrinolysis phenotypes and receiving TXA or not receiving TXA. Fibrinolytic groups were defined per TEG LY30 data and stratified into the following categories: hyperfibrinolytic (LY30 >2.9%), physiologically fibrinolytic (LY30 0.8%-2.9%), and hypofibrinolytic/fibrinolytic shutdown (LY30 <0.8%).[1011] Mortality outcomes were adjusted for baseline ISS. Secondary outcomes compared were both safety and efficacy. Secondary safety outcomes included all-cause in-hospital mortality and incidence of thromboembolic events. Efficacy outcomes included blood product utilization, hospital length of stay, intensive care unit (ICU) length of stay, and incidence of AKI.

Statistical analysis

The study was initially proposed to analyze 100 patient records based on historical trauma data and TEG utilization from the study site. Demographic and clinical characteristics of patients who did and did not receive TXA were described using mean, median, standard deviation, minimum, and/or maximum for continuous variables and frequencies and percentages for binary or categorical variables. P values of less than or equal to alpha-level of 0.05 are considered statistically significant for demographic and clinical characteristics. Continuous outcome variables were compared using analysis of variance for normally distributed data or Kruskal–Wallis test for nonnormally distributed data. Categorical variables were compared using Chi-square tests or Fisher's exact tests, as appropriate. In addition, confounders were addressed with logistic regression modeling to compare groups while adjusting for covariates (age, gender, type of injury, initial GCS, and ISS). Patients with missing data were not included in statistical analyses.

Because multiple comparisons were planned, Bonferroni's adjustment on the overall alpha-level for statistical significance was calculated for outcome data. P values less than or equal to alpha-level of 0.001 are considered statistically significant, to control for multiple comparisons.

RESULTS

Patient characteristics

A total of 55 patients were included in this study. There were 33 patients (60%) in the hypofibrinolytic group, 14 patients (25.5%) in the physiologically fibrinolytic group, and 8 patients (14.5%) in the hyperfibrinolytic group [Figure 1]. Baseline characteristics of the 55 patients included in the study are presented in Table 1. There were no descriptive data missing from included patients. The majority of patients were male (70.9%) with a mean age of 36 years old. Blunt trauma was more frequent than penetrating trauma (73% vs. 17%), which is consistent with historical data at the study site. Patients that received TXA were younger than those who did not (no-TXA: 42.4 ± 16.4 years old vs. TXA: 31.5 ± 15.0 years old) and had a lower median initial GCS (no-TXA: 12.5 vs. TXA: 3.0); compared between fibrinolytic phenotype, hyperfibrinolytic patients presented with a significantly lower median initial GCS compared to physiological fibrinolytic and hypofibrinolytic patients (3.0 vs. 13.0 vs. 13.0; P ≤ 0.05) [Table 2]. There were no other significant differences in baseline characteristics.

Figure 1

Flow chart of the study population. We included a total of 55 patients in this study. We divided the patients into six groups determined by fibrinolytic phenotype per TEG LY30% data and TXA administration. There were 33 patients (60%) in the hypofibrinolytic group, 6 received TXA. There were 14 patients (25.5%) in the physiologically fibrinolytic group, 2 received TXA. There were 8 patients (14.5%) in the hyperfibrinolytic group, 5 received TXA. TXA: Tranexamic acid, TEG: Thromboelastography

Table 1

Baseline characteristics

Baseline characteristic	No TXA (n=42), n (%)	TXA (n=13), n (%)	P
Age, mean±SD	42.4±16.4	31.5±15.0	0.037
Male	29 (69.0)	10 (76.9)	0.73
Initial GCS, median (IQR)	12.5 (11.25)	3.0 (12.0)	<0.05
ISS, mean±SD	27.4±15.5	28.6±11.5	0.79
Type of injury
Blunt	31 (73.8)	9 (69.2)	0.73
Penetrating	11 (26.2)	4 (30.8)
Mechanism of injury
Fall	7 (16.7)	0 (0)	0.10
GSW	9 (21.4)	4 (30.8)
MCC	3 (7.1)	3 (23.1)
MVC	12 (28.6)	6 (46.2)
Assault	3 (7.1)	0 (0)
Other	8 (19.0)	0 (0)

TXA: Tranexamic acid, SD: Standard deviation, IQR: Interquartile range. GCS: Glasgow Coma Scale, GSW: Gunshot wound, MCC: Motorcycle crash, MVC: Motor vehicle crash

Table 2

Initial Glasgow Coma Scale per fibrinolytic phenotype

Baseline characteristic	LY30 <0.8% (n=33)	LY30 0.8%-2.9% (n=14)	LY30 >2.9% (n=8)	P
Initial GCS, median (IQR)	13 (3-14)	13 (3-14)	3 (303)	<0.05

IQR: Interquartile range. GCS: Glasgow coma scale

Outcomes

The primary safety outcome of 24-h mortality was assessed within and between fibrinolytic phenotypes, with consideration to TXA administration. Between the fibrinolytic phenotypes of hypofibrinolysis/fibrinolytic shutdown, physiological fibrinolysis, and hyperfibrinolysis, there was an overall 24-h mortality of 21.2%, 0%, and 25.0%, respectively; P value adjusted for ISS = 0.91 [Figure 2]. There was no significant difference in 24-h mortality in patients who did not receive TXA compared to those who did among hypofibrinolytic patients (no-TXA 22.2%, TXA: 16.7%) or hyperfibrinolytic patients (no-TXA 33.3%, TXA: 20%). After adjustment for baseline ISS between groups, there was no significant difference of 24-h mortality within phenotypes [Figure 2]. After adjusting for additional covariates (age, gender, type of injury, and initial GCS) in order to reduce confounders, there remained no significant differences among groups.

Figure 2

Twenty-four-hour mortality among fibrinolytic phenotypes was not significantly different. Incidence of 24-h mortality was numerically higher among patient groups not receiving TXA. TXA: Tranexamic acid

There was no difference in 24-h mortality between patients who did not and did receive TXA (16.7% vs. 15.4%, respectively; P = 1.000). After adjusting for baseline ISS, there was no significant difference, regardless of fibrinolytic phenotype [Figure 3]. There were also no significant differences in all in-hospital mortality between any of the groups after adjusting for baseline ISS.

Figure 3

Twenty-four-hour mortality was not significantly different between fibrinolytic phenotypes regardless of TXA administration. TXA: Tranexamic acid

Of the 55 patients included in the study, 11 (20%) experienced a thromboembolic event. Among the 13 total patients receiving TXA, 4 (30.7%) experienced thromboembolism versus 7 (16.6%) of the 42 patients who did not receive TXA (P = 0.26) [Figure 4]. In addition, 72.7% (8/11 patients) of the patients with thromboembolic events fell into the hypofibrinolytic phenotype.

Figure 4

Incidence of thromboembolism was not significantly different between two groups (P= 0.26). Thromboembolism was clinically more prevalent in patients receiving TXA. Fibrinolytic shutdown was the most common phenotype among patients who experienced thromboembolism. TXA: Tranexamic acid

The efficacy outcomes of the study are listed in Table 3. There was no difference in hospital length of stay (no-TXA: 14.7 ± 18.1 vs. TXA: 16.6 ± 12.0; P = 0.32) or intensive care length of stay (no-TXA: 5.8 ± 6.4 vs. TXA: 7.6 ± 7.6; P = 0.29). Patients who received TXA did not have a significantly different number of blood product transfusions compared to those not receiving TXA. There was also no difference in the incidence of AKI between the groups.

Table 3

Efficacy outcomes

Efficacy outcome	No TXA (n=42)	TXA (n=13)	P
Massive transfusion protocol, n (%)	27 (64.3)	11 (84.6)	0.95
Blood products, mean units±SD
Red blood cells	11.1±11.6	11.1±12.6	0.95
Fresh frozen plasma	8.2±9.2	9.5±10.9	0.53
Platelets	2.0±2.1	2.4±2.7	0.57
Cryoprecipitate	0.5±1.1	0.5±0.8	0.86
Hospital LOS, mean±SD	14.7±18.1	16.6±12.0	0.32
ICU LOS, mean±SD	5.8±6.4	7.6±7.6	0.29
AKI, n (%)	21 (50.0)	8 (61.5)	0.47

SD: Standard deviation, TXA: Tranexamic acid, ICU: Intensive care unit, LOS: Length of stay, AKI: Acute kidney injury

DISCUSSION

The understanding of TEG's place in TXA therapy for traumatic hemorrhage is still developing. Literature explaining the relationship between TEG and TXA is sparse, and therefore, guidance is also limited. In this study, the safety and efficacy of TEG-guided TXA therapy was evaluated in traumatic hemorrhage patients meeting inclusion criteria for TXA administration.

Meizoso et al. addressed the effects of fibrinolysis groups in trauma patients. Their prospective observational study of 181 ICU patients aimed to identify distribution and mortality among fibrinolytic groups in critically ill trauma patients. They found that fibrinolytic shutdown was the most common phenotype, accounting for 58% of patients, and that fibrinolytic shutdown was associated with an increased mortality.[10] While their study failed to incorporate the use of TXA, it was integral in the developing understanding of fibrinolysis shutdown, its incidence, and possible implications in the severely injured. Meizoso et al. proposed a follow-up study similarly evaluating fibrinolytic groups, but with the added assessment of TXA. This prospective observational study of 218 patients determined that patients receiving TXA were more likely to experience fibrinolytic shutdown.[11] In the study, 35 (16%) of patients received TXA, with 32 of them demonstrating fibrinolytic shutdown on TEG assay. A major limitation of this study was that patients underwent TEG testing after TXA administration, and therefore did not determine the state of fibrinolysis before TXA administration. While this does support the effects of TXA on fibrinolysis, it does not provide guidance for the appropriate use of TXA when the fibrinolytic status is known before the decision to administer TXA.

Moore et al. designed a study with the aim of determining mortality among fibrinolytic states, but was initially designed without consideration to TXA. A total of 232 patients were analyzed with an overall mortality of 20%. The authors later addressed TXA but were only able to include the 11% of the study population receiving the antifibrinolytic for subgroup analysis.[12] They noted an increased mortality in patients receiving TXA with physiological fibrinolysis, but the design of the study limited its ability to provide guidance on TXA administration for fibrinolysis shutdown.[12]

The incidence of hypofibrinolysis in this study was 60%. This is consistent with previous literature that demonstrates the hypofibrinolytic phenotype in up to 65% of traumatic hemorrhage patients.[689] Physiological fibrinolysis was the second most common phenotype in this study at 25% incidence.

The all in-hospital mortality rate in this study was 38%, with 16% experiencing 24-h mortality. After controlling for baseline ISS, there was no significant difference in all in-hospital or 24-h mortality regardless of fibrinolytic phenotype. However, this study did demonstrate a noteworthy clinical difference in 24-h mortality with a higher incidence exhibited in fibrinolytic shutdown. The administration of TXA did not significantly affect 24-h or all in-hospital mortality, regardless of fibrinolytic phenotype. A recently published subgroup of hyperfibrinolytic patients from a randomized controlled trial also demonstrated TXA did not affect long-term mortality at 24 h or 30 days. However, this study did not address patients presenting with other fibrinolytic phenotypes.[13] The finding from our study was contrary to our prediction that hypofibrinolytic patients would experience higher rates of mortality considering the added effects of intrinsic delayed clot lysis and TXA mechanistically further delaying clot lysis.

While this study was not designed to specifically evaluate patients with traumatic brain injury (TBI), a noteworthy association was found between fibrinolytic phenotype and initial GCS. Patients presenting with a lower GCS were more likely to be hyperfibrinolytic, as demonstrated in Table 2. The recently published randomized, controlled CRASH-3 trial evaluated TXA's effects on patients with TBI.[14] A total of 9202 patients were analyzed after receiving TXA or placebo within 3 h of injury. The authors performed a head injury-related mortality analysis stratified into presenting GCS of mild-moderate (GCS 9–15) and severe (GCS 3–8). They found the relative risk of TXA was 0.78 (0.64–0.95) in higher presenting GCS scores compared to 0.99 (0.91–1.07) in lower presenting GCS scores, noting TXA may have reduced head injury-related mortality in less severe patients. When baseline GCS was used in a regression analysis, evidence was found that TXA is more effective in less severely injured patients (P = 0.007).[14] The CRASH-3 study did not address fibrinolytic phenotypes, but these results suggest that TXA has greater chance of benefit in patients presenting with higher GCS. The discovery of GCS-dependent effects from CRASH-3 and the higher incidence of hyperfibrinolysis in more severe GCS from this study may suggest the need for future studies evaluating the relationships between TXA, GCS, and fibrinolysis.

The primary safety concern with TXA use is thromboembolism. In this study, 20% of patients experienced thromboembolism, which is lower compared to previous literature.[11] Deep vein thrombosis was the most frequent subtype. Patients who received TXA were more likely to have documented thromboembolism compared to those who did not (30.7% vs. 16.6%). In addition, thromboembolism was more frequent in fibrinolytic shutdown. These results demonstrate the need for a risk versus benefit assessment before the decision to administer TXA with consideration to a patient's fibrinolytic phenotype, especially for those noted to be hypofibrinolytic.

Before this study's completion, TXA administration at this institution was established through a practice guideline developed and utilized by trauma surgeons. This supported antifibrinolytic therapy for trauma patients undergoing blood product transfusion as result of hemorrhagic shock. The guideline did not provide the opportunity for evaluation of TEG data and offered decision-making by our trauma team to be accounted by other clinical factors and judgment. With added results from previous literature and this study, this TXA practice guideline has been updated to prompt urgent TEG collection in patients with suspected hemorrhage and suggest TXA be reserved for patients with demonstrated hyperfibrinolysis.

There were several limitations to the study. First, this was a retrospective study and we were unable to control for all potential sources of bias. This was evidenced by patients with lower GCS on presentation more frequently receiving TXA as it appears that physicians preferentially administered TXA to patients with a higher acuity per GCS scoring. Second, although this study was designed in a way not currently in the literature to our knowledge, the study had a relatively low sample size and uneven distribution among patient groups. A convenience sample was utilized, and Power was not calculated. There is likelihood that this study experienced Type II error. The results of this study are intended to be hypothesis generating. Third, internal validity was limited by strict inclusion and exclusion criteria. Fourth, of excluded patients, 54% were due to TXA administration before TEG collection commonly as a result of prehospital administration. This inherently limited the study's ability to evaluate these patients. Finally, we were unable to collect data on the timing of thromboembolic events or DVT prophylaxis, which may be a confounding factor to the study's variable incidence of thromboembolism.

CONCLUSION

The results of this study are hypothesis generating, but the utilization of TEG-guided TXA therapy remains unknown. Trauma surgeons tend to administer TXA in patients presenting with higher acuity per GCS, which challenges TXA decision-making to be solely based on TEG data. Mortality did not appear to be affected by TXA or fibrinolytic phenotype. The risk versus benefit of numerous factors must be weighed. Thromboembolic events are more common in patients who receive TXA and patients who are hypofibrinolytic. This study demonstrates the need for a large multicenter, prospective, randomized controlled trial.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Research quality and ethics statement

This study was approved by the Institutional Review Board (IRB)/Ethics Committee at Ohio Health (IRB #1309276-2). The authors followed the applicable EQUATOR Network guidelines, notably the STROBE Guideline, during the conduct of this research.