Sage Journals: Discover world-class research

Abstract

The respective weights of head and extra-head injuries to the occurrence of coagulopathy following traumatic brain injury (TBI) remain unclear. We hypothesized that the severity of extra-head injuries would be the main contributor to coagulopathy following TBI. This was a retrospective study from a multicenter, prospective trauma registry. All adult patients directly admitted following TBI (Abbreviated Injury Score [AIS]) head ≥1) from 2012 to 2021 were included. Coagulopathy was defined as a prothrombin time ratio (PTr) >1.2, platelets <100 G.L^-1, or fibrinogen level <1.5 g.L^-1 on hospital admission. TBI severity was assessed by the Glasgow Coma Scale (GCS). Severe extracranial injuries were defined by at least one of the extra-head AIS scores ≥3 (AIS_extra-head ≥3). Incidences of coagulopathy were determined and compared according to TBI severity in patients with or without severe extracranial injuries. Risk factors for coagulopathy were identified using bivariate analysis and then multivariable analysis. In 9,610 TBI patients analyzed, the overall incidence of coagulopathy was 28.5% (n = 2,738). The incidence of coagulopathy increased gradually with TBI severity, from 8% for GCS 14–15% to 42% for GCS 3 in patients without severe extracranial injuries, and from 27% for GCS 14–15% to 70% for GCS 3 in patients with severe extracranial injuries. In multivariable analysis, AIS_extra-head ≥3 (odds ratio = 2 [1.8–2.3], p < 0.001) and GCS ≤8 (odds ratio = 1.3 [1.1–1.6], p = 0.001) were independent risk factors for coagulopathy. Coagulopathy was associated with both head and extra-head injury severities, yet to a greater extent with severe extracranial injuries.

Keywords

extracranial injuries trauma-induced coagulopathy traumatic brain injury

Introduction

Traumatic brain injury (TBI) is the leading cause of mortality in young adults and a major cause of death and long-term disability across all ages worldwide.¹ The occurrence of coagulopathy following TBI has been associated with progression of hemorrhagic lesions^2,3 and increased mortality and morbidity.^4–7 Coagulopathy on hospital admission is present in about 25–35% of TBI patients, although the incidence of hemostatic disorders remains not clearly defined, with a wide range reported from 7% to 63%.^4,5,7,8 This wide range of coagulopathic patients might be related to very disparate injury types and severities across different series. Although the occurrence of coagulopathy is thought to be associated with brain injury severity, some studies only identified fatal or critical levels of head injury (assessed by Abbreviated Injury Score [AIS] = 5 or 6) as independent risk factors for coagulopathy.^7,9 More recently, Böhm et al.⁸ did not identify brain injury severity as an independent predictor of coagulopathy in a prospective cohort of 598 patients with isolated TBI, and thus, the link between coagulopathy and isolated TBI has been questioned by some authors.¹⁰ Coagulopathy following TBI is also deemed to be correlated with extracranial injuries, although most of the studies excluded TBI patients with associated extracranial lesions.^4,10,11 Thus, the respective contributions of head and extra-head injuries to the occurrence of coagulopathy following TBI remain unclear. We hypothesized that the main contributor of coagulopathy on hospital admission following TBI would be the severity of extracranial injuries, and that head injury severity would contribute to a lesser extent to the occurrence of coagulopathy.

Patients and Methods

Design and setting of the study

This retrospective, multicenter study was conducted in France on patients whose data were prospectively collected in the Traumabase® between January 2012 and December 2021. The Traumabase group (http://www.traumabase.eu) is a French severe trauma registry initiated in 2011 and includes patients suspected of severe trauma from the scene based on national triage criteria and admitted to 1 of the 22 participating trauma centers.¹² Sociodemographic, clinical, biological, therapeutic, and evolution data from the pre-hospital scene to hospital discharge are systematically collected for all consecutive trauma patients. The Traumabase integrates algorithms for data consistency and coherence, and data monitoring by a central administrator.¹³

Ethics approval

The Traumabase registry was approved by the Advisory Committee for Information Processing in Health Research (No. 11.305 bis) and the National Commission on Informatics and Liberties Data Protection Agency (911461 and 2211878). The study met the requirements of local and national ethics committees (Comité de Protection des Personnes, Paris VI) and was approved by the Ethics Committee of Paris Nord Hospitals (Approval No.: CER-2022-148).

Characteristics of participants

All consecutive trauma patients registered in the Traumabase during the aforementioned period were included. Patients without TBI, managed after secondary transfer, aged <15 years, pregnant, on anticoagulant or antiplatelet therapy prior to trauma, with transfusion of any blood product prior to hospital admission, and those with missing coagulation data on admission were excluded.

Patients’ categorization

The first pre-hospital Glasgow Coma Scale (GCS) before sedation and the AIS¹⁴ were used to define the study population and to assess trauma severity. The GCS assesses the level of consciousness in patients with brain injuries, especially TBI. Head injury severity is graded as mild (GCS 14 or 15), moderate (GCS 9–13), severe (GCS 4–8), or extremely severe (GCS 3).^15–18

The AIS is an anatomically based injury severity scoring system that classifies each injury by body region (head and neck, face, chest, abdominal, extremities, external) on a 6-point scale (from 1 = minor to 6 = fatal—AIS score of 0 corresponds to no injury in that anatomic region). AIS is the system used to determine the Injury Severity Score (ISS) for multiply injured patient.¹⁹ TBI was defined by AIS_head score ≥1. Severe extracranial injuries were defined by AIS_extra-head ≥3: any AIS_extra-head score (i.e., face, chest, abdominal, extremities, or external) ≥3.

Admission coagulopathy was defined by the presence of at least one of the following conditions at hospital admission: prothrombin time ratio (PTr) >1.2,^20,21 platelet count <100 G/L, and Clauss fibrinogen level <1.5 g/L. These laboratory tests are routinely performed on hospital admission, as recommended.²⁰ Severe hemorrhage was defined by transfusion of at least 4 red blood cell (RBC) units within the first 6 h of management and/or death from hemorrhagic causes, regardless of the level of transfusion.

Statistical analysis

This study follows the STrengthening the Reporting of OBservational studies in Epidemiology guidelines.²² All variables were checked for normality. Continuous data are presented as mean (±standard deviation). Categorical data are expressed as counts and percentages (%). The proportions of patients with admission coagulopathy were determined and compared according to head-injury severity (assessed by GCS) to the presence or absence of concomitant severe extracranial injuries (assessed by AIS_extra-head ≥3) using the chi-squared test. We also described the proportion as counts and percentages of patients with admission coagulopathy according to the zone (face, chest, abdominal, extremities, external) of severe extracranial injuries. Intensive care unit (ICU) mortality and transfusion requirement within 6 h after hospital admission were also determined and compared according to GCS and the presence or absence of severe extracranial injuries by using the chi-squared test. To identify risk factors independently associated with admission coagulopathy, we first performed bivariate analysis in patients with and without admission coagulopathy using the chi-squared and Student’s t tests, depending on variable type. Then, all variables having a p value <0.20 in the bivariate analysis were checked for collinearity and entered in a logistic regression model for multivariable analysis using stepwise regression. Missing data were handled using multiple imputation by chained equation (all data had <20% missing values). Coagulopathy-related variables were not imputed. Bivariate analysis was performed by using observed data, and multivariable analysis was performed by using imputed data. Statistical significance was set at p < 0.05, and statistical analysis was performed with R software (version 4.1.2; January 11, 2021) for Macintosh (R Foundation for Statistical Computing, Vienna, Austria).

Results

Among the 33,875 patients admitted to the 22 participating trauma centers from January 2012 to December 2021, 9,610 patients met the inclusion criteria and were analyzed (Fig. 1).

FIG. 1.

Flowchart of the study. RBC, red blood cell; TBI, traumatic brain injury.

Characteristics of patients

Baseline, pre-hospital, and hospital characteristics of the patients are presented in Table 1.

Table 1.

Baseline, Pre-Hospital, and Hospital Characteristics of the Study Population

	TBI patientscomplete cohortn = 9,610	TBI patients without admission coagulopathyn = 6,872	TBI patients with admission coagulopathyn = 2,738	Missing datan (%)	p Value
Age (years)	39 ± 18	40 ± 17	38 ± 19	0	<0.001
Sex (male)	7,421 (78)	5,351 (79)	2,070 (76)	36 (0.4)	0.018
SAPS 2	34 ± 22	28 ± 18	49 ± 23	70 (1)	<0.001
ISS	22 ± 15	18 ± 12	32 ± 16	0	<0.001
Pre-hospital
First pre-hospital GCS				121 (1)	<0.001
GCS 14–15	4,940 (51)	4,109 (60)	831 (30)
GCS 9–13	1,435 (15)	1,038 (15)	397 (14)
GCS 4–8	1,709 (18)	1,052 (15)	657 (24)
GCS 3	1,405 (15)	577 (8)	828 (30)
Pupillary abnormality	1,809 (19)	823 (12)	986 (37)	131 (1)	<0.001
Pre-hospital osmotherapy	1,904 (20)	895 (13)	1,009 (37)	142 (1)	<0.001
Pre-hospital Shock index > 1	2,695 (32)	1,377 (23)	1,318 (57)	1,154 (12)	<0.001
Crystalloid fluids (mL)	689 ± 598	572 ± 487	982 ± 735	1,245 (13)	<0.001
Pre-hospital cardiac arrest	528 (6)	145 (2)	383 (14)	140 (1)	<0.001
Pre-hospital orotracheal intubation	4,215 (44)	2,297 (34)	1,901 (70)	94 (1)	<0.001
Pre-hospital care time (min)	79 ± 45	77 ± 44	84 ± 53	2,218 (23)	<0.001
Injury subtypes
Penetrating trauma	604 (6)	425 (6)	179 (7)	59 (0.6)	<0.001
Gunshot	190 (2)	96 (1)	94 (3)	59 (0.6)	<0.001
AIS_extra-head ≥3	4,622 (48)	2,682 (39)	1,940 (71)	0	<0.001
Face	446 (5)	223 (3)	223 (8)	0	<0.001
Chest	3,259 (34)	1813 (26)	1,446 (53)	0	<0.001
Abdomen	941 (10)	390 (6)	553 (20)	0	<0.001
Extremities	1,865 (19)	968 (14)	897 (33)	0	<0.001
External	9 (0.01)	4 (0.01)	5 (0.2)	0	<0.001
At admission
Hemoglobin (g/dL)	12.8 ± 2.2	13.5 ± 1.7	11.3 ± 2.5	9 (0.1)	<0.001
Temperature (°C)	36.2 ± 1.2	36.4 ± 1.0	35.6 ± 1.5	752 (8)	<0.001
Base excess	−4 ± 6	−3 ± 6	−7 ± 7	1,455 (15)	<0.001
Lactate (mmol/L)	2.4 ± 2.7	1.8 ± 1.6	3.9 ± 4.1	903 (9)	<0.001
SBP (mm Hg)	124 ± 28	129 ± 24	112 ± 32	154 (2)	<0.001
Vasopressors	1,605 (17)	590 (9)	1,015 (38)	204 (2)	<0.001
Severe hemorrhage^a	961 (10)	119 (2)	842 (30)	0	<0.001
Coagulation parameters
PTr >1.2	2,504 (26)	0 (0)	2,504 (92)	0	<0.001
Platelet count <100 G/L	271 (3)	0 (0)	271 (10)	0	<0.001
Fibrinogen <1.5 g/L	1,210 (13)	0 (0)	1,210 (44)	0	<0.001
Patients requiring transfusion at H6
RBC	944 (10)	118 (2)	826 (30)	0	<0.001
FFP	843 (9)	90 (1)	753 (28)	0	<0.001
Platelet	129 (1)	3 (0.1)	126 (5)	0	<0.001
Evolution
SOFA score (Day 1)	5 ± 5	4 ± 4	8 ± 5	5,313 (55)	<0.001
Neurosurgery within 24 h	997 (11)	659 (10)	338 (13)	5,237 (54)	<0.001
Mechanical ventilation (days)	6 ± 12	5 ± 11	9 ± 15	1,314 (14)	<0.001
Hospital LOS (days)	20 ± 31	18 ± 27	25 ± 37	859 (9)	<0.001
ICU Mortality				347 (4)
All cause	1,497 (16)	491 (7)	1,006 (38)		<0.001
Due to hemorrhage	85 (0.9)	2 (0.4)	83 (8)		<0.001

p Values refer to bivariate analysis on the observed data in patients with and without admission coagulopathy. Results are expressed as mean (± standard deviation) or as n (%).

Severe hemorrhage: transfusion of at least 4 RBC within the first 6 h of management and/or death from hemorrhagic causes without having reached the 4 transfused RBC.

AIS, Abbreviated Injury Score; FFP, fresh frozen plasma; GCS, Glasgow Coma Scale; HR, heart rate; ICU, intensive care unit; ISS, Injury Severity Score; LOS, length of stay; RBC, red blood cell; SAPS 2, Simplified Acute Physiology Score 2; SBP, systolic blood pressure; Shock index = maximum HR/minimal SBP; SOFA, Sequential Organ Failure Assessment; TBI, traumatic brain injury.

In bivariate analysis, TBI patients with admission coagulopathy were significantly younger, more frequently female, more severely injured (higher ISS, AIS_extra-head, blood lactate, base excess, and proportions of patients requiring mechanical ventilation and vasopressors at admission), and especially more severely head-injured (lower pre-hospital GCS, higher proportion of patients with AIS_head ≥3, pupillary abnormalities, or requiring pre-hospital osmotherapy), when compared to patients without coagulopathy. TBI patients with coagulopathy were more likely to be transfused, to have neurosurgical or hemostatic procedures, and less likely to survive in ICU.

Admission coagulopathy was observed in 2,738 (28.5%) patients of the cohort. The most frequent criterion for coagulopathy was PTr >1.2, followed by fibrinogen <1.5 g.L^-1 and platelet count <100 G.L^-1 (respectively, present in 92%, 44%, and 10% of the patients with admission coagulopathy; Table 1); 1,621 patients (59%) had one criterion, 987 (36%) had two criteria, and 130 (5%) had all three criteria for admission coagulopathy (Supplementary Table S1 and Fig. S1).

Contribution of head and extra-head injuries to admission coagulopathy in TBI patients

Figure 2 shows the proportion of patients with admission coagulopathy according to TBI severity assessed by GCS (and assessed by AIS_head in Supplementary Figs. S2 and S3), with or without severe concomitant extracranial injuries. Overall, the lower the GCS, the higher the proportion of patients exhibiting coagulopathy (p < 0.001), regardless of the presence of extracranial injuries. Without concomitant severe extracranial injuries, the incidence of coagulopathy was 8% in GCS 14–15 patients and gradually increased with decreasing GCS reaching a maximum of 42% in GCS 3 patients. With concomitant severe extracranial injuries, the incidence of coagulopathy was 27% in GCS 14–15 patients and gradually increased with decreasing GCS reaching a maximum of 70% in GCS 3 patients. For each grade of TBI severity, the proportion of patients with coagulopathy was significantly higher in patients with concomitant severe extracranial injuries (p < 0.001). No difference was observed regarding the distribution of the criteria for coagulopathy between the different groups of head and extra-head injury severity (Supplementary Fig. S1).

FIG. 2.

Proportion of patients with admission coagulopathy according to head and extra-head injury severity. ***p < 0.001. p Value refers to bivariate analysis on the proportion of patients with admission coagulopathy in patients with and without severe extracranial lesions (AIS_extra-head ≥ ou < 3, respectively), according to head injury severity (assessed by GCS). AIS, Abbreviated Injury Score; CI, confidence interval; GCS, Glasgow Coma Scale.

The proportion of patients with coagulopathy according to TBI severity and the zone of severe extracranial injuries is described in Supplementary Table S2.

Mortality and transfusion according to head and extra-head injuries

ICU mortality, RBC transfusion, and FFP transfusion or administration of fibrinogen concentrate (FC) within 6 h after admission are presented in Table 2. Patients with lower GCS values and severe extracranial lesions were more likely to be coagulopathic, transfused with RBC and FFP or given FC in bivariate analysis. Mortality was significantly higher in the presence of severe extracranial lesions (compared to the absence) in patients with GCS 14–15 and GCS 3.

Table 2.

Coagulopathy, Mortality, and Transfusion According to Head and Extra-Head Injury Severities

Head injury severity	GCS 3n = 1,405		p Value	GCS 4–8n = 1,709		p Value	GCS 9–13n = 1,435		p Value	GCS 14–15n = 4,940		p Value
Severe extracranial lesions	Presentn = 853	Absentn = 552	p Value	Presentn = 835	Absentn = 874	p Value	Presentn = 641	Absentn = 794	p Value	Presentn = 2,247	Absentn = 2,693	p Value
Coagulopathy, n (%)	598 (70)	230 (42)	<0.001	438 (52)	219 (25)	<0.001	277 (43)	120 (15)	<0.001	609 (27)	222 (8)	<0.001
ICU mortality, n (%)	545 (64)	290 (42)	<0.001	199 (24)	200 (23)	0.58	58 (9)	56 (7)	0.18	85 (4)	53 (2)	<0.001
RBC transfusion at H6, n (%)	271 (32)	35 (6)	<0.001	184 (22)	26 (3)	<0.001	122 (19)	10 (1)	<0.001	261 (12)	26 (1)	<0.001
FFP or FC administration at H6, n (%)	314 (37)	58 (11)	<0.001	221 (27)	47 (5)	<0.001	138 (22)	17 (2)	<0.001	273 (12)	32 (1)	<0.001

p Values refer to bivariate analysis on the observed data in patients with and without severe extracranial lesions (defined by any extracranial AIS score [face, chest, abdominal, extremities, or external] ≥ 3) for each grade of TBI (assessed by GCS). Results are expressed as n (%).

FC, fibrinogen concentrate; FFP, fresh frozen plasma; GCS, Glasgow Coma Scale; H6, within 6 h after admission; ICU, intensive care unit; RBC, red blood cell.

Risk factors for admission coagulopathy in TBI patients

Independent risk factors for admission coagulopathy are presented in Table 3. Unstable pelvic trauma and severe extracranial injuries assessed by AIS_extra-head ≥3 were independently and strongly associated with an increased risk for admission coagulopathy (odds ratio [OR] = 2.1 [1.6–2.8], p < 0.001 and OR = 2.0 [1.8–2.3], p < 0.001, respectively). A binary approach was used to assess head injury severity as an independent risk factor of admission coagulopathy. Severe head injury, defined by GCS ≤8, was also identified as an independent risk factor for coagulopathy (OR = 1.3 [1.1–1.6], p = 0.001 for GCS ≤8 patients). Pre-hospital osmotherapy was also independently associated with an increased risk for admission coagulopathy (OR = 1.7 [1.5–2.1], p < 0.001). Other independent risk factors for coagulopathy were mainly related to hypoperfusion and hemorrhagic shock: pre-hospital shock index ≥1 and fluids >1,000 mL, and vasopressors, low hemoglobin, and high blood lactate at admission (Table 3).

Table 3.

Risk Factors Independently Associated with Admission Coagulopathy in Traumatic Brain Injury Patients

Variable	OR (CI 0.95)	p
Unstable pelvic trauma	2.1 (1.6–2.8)	<0.001
AIS_extra-head ≥3	2.0 (1.8–2.3)	<0.001
Male	2.0 (1.7–2.3)	<0.001
Gunshot	1.9 (1.2–2.8)	<0.001
Pre-hospital osmotherapy	1.7 (1.5–2.1)	<0.001
Pre-hospital fluids >1,000 mL	1.5 (1.3–1.8)	<0.001
GCS ≤8^a	1.3 (1.1–1.6)	0.001
Open extremities trauma	1.3 (1.1–1.5)	<0.005
Pupillary abnormality	1.3 (1.0–1.5)	0.010
Pre-hospital shock index ≥1	1.3 (1.2–1.5)	<0.001
Vasopressors at admission	1.2 (1.0–1.5)	0.020
Blood lactate at admission	1.2 (1.1–1.2)	<0.001
Age	1.0 (1.0-1.0)	<0.001
Temperature at admission	0.9 (0.9–1.0)	0.010
Hemoglobin at admission	0.6 (0.6–0.7)	<0.001
Pre-hospital intubation	1.2 (1.0–1.4)	0.050
Pre-hospital care time	1.0 (1.0-1.0)	0.120
Amputation	1.4 (0.7–2.6)	0.330
Pre-hospital cardiac arrest	1.0 (0.7–1.5)	0.880

A binary approach was used to assess head injury severity as an independent risk factor of admission coagulopathy (severe head injury is here defined by GCS ≤8).

AIS, Abbreviated Injury Score; CI, confidence interval; GCS, Glasgow Coma Scale; OR, odds ratio.

Discussion

Main findings

In 9,610 TBI patients, the present study showed the main following findings: (1) coagulopathy was present at hospital admission in overall 28.5% of the patients; (2) without concomitant severe extracranial injuries, the incidence of coagulopathy was low in the less severely head-injured patients (8% in GCS 14–15 patients), and increased gradually with TBI severity, reaching a maximum of 42% in GCS 3 patients; (3) with concomitant severe extracranial injuries, the incidence of coagulopathy was high even in the less severely head-injured patients (27% in GCS 14–15 patients), and increased gradually and markedly with TBI severity, reaching 70% in the most severely head-injured (GCS 3) patients; (4) for each grade of TBI severity, the proportion of patients with coagulopathy was significantly higher in patients with concomitant severe extracranial injuries (p < 0.001); (5) unstable pelvic trauma and severe extracranial injuries (assessed by AIS_extra-head ≥3) were the strongest risk factors for coagulopathy following TBI (OR = 2.1 [1.6–2.8], p < 0.001 and OR 2.0 [1.8–2.3], p < 0.001, respectively).

As far as we know, this study is the largest cohort to date to examine the respective roles of head and extra-head injuries in the development of trauma-related coagulopathy. All degrees of TBI severity, from mild (GCS 14–15) to extremely severe (GCS 3), and of extracranial injuries, from none to extreme ones, were included in the present study. Previous studies often restricted their analysis to patients with moderate-to-severe TBI and without concomitant extracranial injuries.^8,11,21,23

First, the overall incidence of coagulopathy at admission was 28.5% in the present study, which is in line with the overall incidences of 32.7% and 35.2% reported in two meta-analyses including 5,357 and 7,037 patients, respectively.^5,24 These pooled proportions of patients developing coagulopathy after TBI obviously do not reflect the wide disparities related to several factors highlighted in the present study, in particular head and extra-head injury severities.

Second, we hypothesized that the main driver of coagulopathy on hospital admission following TBI would be the severity of extracranial injuries, and that head injury severity would contribute to a lesser extent to the occurrence of coagulopathy. On the one hand, an overall gradual increase of the risk of coagulopathy with increased severity of head injury has been shown: the lower the GCS, the higher the proportion of coagulopathic patients. Although this might appear self-evident, Wafaisade et al.⁷ and Lustenberger et al.⁹ found AIS_head, another surrogate for TBI severity, as one of the independent risk factors for coagulopathy after TBI but only for AIS_head ≥5. More recently, Böhm et al.⁸ failed to identify AIS_brain (AIS_head specifically considering brain lesions) as an independent predictor of coagulopathy in a prospective cohort of 598 patients with isolated TBI (AIS_brain ≥1 and extra-head AIS = 0). De Oliveira et al. classified 345 patients in isolated severe TBI (AIS_head ≥3 and AIS_extra-head <3) and multisystem trauma with or without severe TBI (defined by AIS_extra-head ≥3 with or without AIS_head ≥3, respectively)²⁵ and found that isolated severe TBI was not an independent risk factor for the development of coagulopathy. In the present study, inclusion of a large cohort of patients presenting a complete range of TBI severity allowed showing an increased risk of coagulopathy with increasing head injury severity in the absence of severe extracranial injuries. Of note, we used GCS to assess TBI severity because it is used worldwide as a routine tool for triage in pre-hospital and hospital settings,^1,26,27 whereas AIS_head is determined only occasionally after hospital admission. Moreover, we chose to use a commonly described categorical approach to GCS to characterize the severity of TBI, using the cutoffs classically described in the literature.¹⁷ As previously reported by other authors,^18,28 we also chose to analyze patients with GCS 3 separately from other patients with severe TBI (GCS 4–5), given their particularly high level of severity. On the other hand, the incidence of coagulopathy was higher at each grade of TBI severity when concomitant severe extracranial injuries were present, reaching 70% in the most severely head- and extrahead-injured patients. Previous studies investigating coagulopathy following TBI either excluded patients with extracranial injuries or assessed whether TBI induces coagulopathy different than non-TBI does. In 795 consecutive major trauma patients with AIS_head ≥3 or other body areas with AIS score of ≥3, the dominant region of injury did not influence coagulation changes, and coagulopathy resulted from a combination of tissue injury and shock rather than a particular injury pattern.²⁹ Samuels et al. compared 479 patients with isolated extracranial injuries, 48 patients with isolated severe TBI, and 45 patients with severe TBI and extracranial injuries by using conventional coagulation tests and viscoelastic hemostatic assays.³⁰ When compared to isolated severe extracranial injuries, isolated severe TBI seemed to be independently associated with a specific coagulopathy phenotype (mainly abnormalities in the rapidity of clot initiation, fibrin cross-linking, and low fibrinogen level), conversely to the aforementioned series.^8,24 Of note, proportions of patients with international normalized ratio >1.3 were similar between the groups, and fibrinogen concentrations were not provided.³⁰ In the present large cohort, the contribution of severe extracranial injuries following TBI could be specified: coagulopathy occurred more frequently with severe extracranial injuries across all grades of TBI severity, and severe extracranial injuries such as unstable pelvic trauma and AIS_extra-head ≥3 were the strongest independent risk factors for admission coagulopathy. Beyond head and extra-head injury severities, we identified several additional risk factors for coagulopathy upon hospital admission following TBI. Since acute traumatic coagulopathy develops in response to the combination of tissue damage and systemic hypoperfusion,^31,32 it was consistent to identify variables previously described as predictors of hemorrhage or massive transfusion: unstable pelvic trauma, pre-hospital fluids >1,000 mL, shock index ≥1, vasopressors, high blood lactate, low temperature, and hemoglobin at admission.^19,25,31 We also identified gunshot as an independent risk factor for coagulopathy, and indeed, hemostatic disorders have previously been reported more frequently in penetrating than in blunt head injuries.^7,32 Pupillary abnormalities, similar to GCS, are markers of TBI severity and were associated with coagulopathy in our cohort. Pre-hospital osmotherapy may also reflect TBI severity. However, as osmotic therapy was administered before coagulation testing at admission, its potential impact on coagulation results might be considered. Experimental studies suggest that osmotic therapy with mannitol or hypertonic saline may induce mild hypocoagulable changes, mainly demonstrated by thromboelastography or thromboelastometry, including delayed clot initiation, prolonged clot formation time, and reduced clot firmness.^33–36 These effects appear dose-dependent and are typically observed with in vitro hemodilution ≥10–20%, which corresponds to osmotherapy doses exceeding those used in clinical practice.^34,35 In addition, several experimental models combined hyperosmolar agents with colloids such as hydroxyethyl starch or gelatin, both known to impair hemostasis, which may confound the interpretation of these findings.^34,37 In contrast, clinical studies in neurosurgical patients and in moderate TBI have not demonstrated significant alterations in coagulation parameters following administration of recommended doses of mannitol or hypertonic saline, suggesting that the coagulation abnormalities reported in vitro may have limited clinical relevance.^38,39 Coagulopathy after TBI results from several mechanisms, including disruption of the cerebral microvasculature, endothelial injury, platelet dysfunction, tissue factor release, and hyperfibrinolysis, processes often amplified by sympathetic activation and neuroinflammation.^40,41 When TBI occurs with extracranial injuries, systemic factors may further exacerbate trauma-induced coagulopathy. Hemorrhage and hypoperfusion can trigger systemic shock, endothelial activation, and inflammatory responses that disrupt coagulation pathways, whereas fluid resuscitation may contribute through dilutional effects. Trauma-associated endotheliopathy, acidosis, and hypothermia may also impair coagulation and platelet function.^42,43 Although these mechanisms were not directly assessed in our study, they may partly explain the association observed between extracranial injuries and coagulopathy in our cohort.

Regarding patient outcome, the more coagulopathic the patients were, the more likely they were to be transfused within the first 6 h after admission or die in the ICU.

Limitations

Our study has some limitations. First, this is a retrospective study with the inherent risks of missing data and confounding factors. However, data collection was prospective, as this study used data from the Traumabase, a multicenter national registry that secures data processing, limits missing data through reactive data tracking, and incorporates control for biases inherent in retrospective data collection.¹³ There was little missing data among variables considered for the present analysis, and all proportions of missing data are provided. We used multivariable analysis to overcome the most significant confounding variables such as degree of shock, head, and extra-head injury severities, although unmeasured confounders may have accounted for differences in the incidence of coagulopathy between subgroups of patients. Only associations but no causalities can be ascribed from the present data.

Second, we defined coagulopathy by using PTr >1.2, platelet count <100 G.L^-1, and Clauss fibrinogen level <1.5 g.L^-1. Trauma-induced coagulopathy is classically defined as a PTr of 1.2 or higher.³¹ Since PT as a single parameter could not describe the complex coagulation disorders following trauma, we also used two additional laboratory tests routinely measured on hospital admission and used as targets of the initial coagulation resuscitation: fibrinogen concentration and platelet count.²⁰ These variables have already been used to define coagulopathy, especially in the TBI context.^11,44 By reporting these three criteria for coagulopathy, we aimed at assessing a broader spectrum of hemostatic disorders following trauma. Nevertheless, some contributors to the complex pathophysiology of trauma-induced coagulopathy were not captured by the present data.

Last, we used a categorial approach of GCS to assess TBI severity. The GCS ranges used in our study are consistent with commonly accepted clinical classifications of TBI severity.^15,17 In addition, the association between GCS and mortality has been shown to be nonlinear, which further limits the validity of treating it as a continuous predictor.⁴⁵ Since other factors such as sedatives, alcohol, or shock may also influence GCS, an additional analysis by using AIS_head instead of GCS to assess TBI severity was performed and yielded similar results (Supplementary Figs. S2 and S3).

Conclusion

In this cohort of 9,610 patients with TBI, coagulopathy was present in 28.5% of patients at hospital admission and was associated with both intracranial and extracranial injury severity, with a stronger association observed for severe extracranial injuries. These findings suggest that significant extracranial trauma may help identify TBI patients at increased risk of early coagulopathy. Early coagulation assessment and closer hemostatic monitoring, using conventional laboratory tests or viscoelastic assays, may facilitate earlier detection and more timely correction of coagulopathy during the initial phase of care.

Transparency, Rigor, and Reproducibility Statement

This retrospective study was not formally registered. The analysis plan was not formally pre-registered, but the team member with primary responsibility for the analysis certifies that the analysis plan was pre-specified. The key inclusion criteria and outcome evaluations are established standards. Both the original measures of statistical error rates and the corrected measures of statistical error rates have been reported in the text. For data access requests, interested researchers can contact the Traumabase scientific committee upon reasonable request. Missing data have been handled using imputation for multivariable analysis.

Authors’ Contributions

L.W., M.R., A.H., and S.F. contributed to conception of the work, data collection, data analysis and interpretation, drafting the article, critical revision of the article, and final approval of the version to be published. J.K. contributed to data analysis and interpretation, critical revision of the article, and final approval of the version to be published. J.-D.M., P.E., M.P., A.G., J.-L.H., T.G., D.G., M.L., V.L., G.A., T.C., and P.S.A. contributed to data collection, critical revision of the article, and final approval of the version to be published. All authors read and approved the final article.

Ethics Approval and Consent to Participate

The Traumabase registry was approved by the Advisory Committee for Information Processing in Health Research (No. 11.305 bis) and the National Commission on Informatics and Liberties Data Protection Agency (911461 and 2211878). It meets the requirements of the local and national ethics committee (Comité de Protection des Personnes, Paris VI). The present study was approved by the Ethics Committee of Paris Nord Hospitals (Approval No.: CER-2022-148).

Availability of Data and Materials

Data are from the Traumabase, a collaborative project that consists of trauma practitioners from different centers all over the country, sharing the registry for research and public health issues. Even though datasets are de-identified, the National Commission for Data Protection has imposed restrictions on data sharing since they contain sensitive information on trauma. Conventions are signed for the researcher before any access to the data. For data access requests, interested researchers can contact the Traumabase scientific committee upon reasonable request with the following email address: contact@traumabase.eu (secretary of the scientific committee—Dr. Arthur James).

Footnotes

Acknowledgments

Contributors from the Traumabase are listed as investigators. Mathieu Boutonnet, Hôpital d’Instruction des Armées—Percy, Clamart, France; Benjamin Cohen, Département d’Anesthésie-Réanimation, Hôpital de Tours, Tours, France; Fabrice Cook, Centre Hospitalier de Cayenne Andrée Rosemon, Cayenne, France; Thierry Floch, Réanimation Chirurgicale et Traumatologique, CHU de Reims, Reims, France; Elisabeth Gaertner, Département d’Anesthésie-Réanimation, Hôpitaux Civils de Colmar, Colmar, France; Pierre Gosset, Département d’Anesthésie-Réanimation, CHU d’Amiens, Amiens, France; Alexia Hardy, Département d’Anesthésie-Réanimation, Centre Hospitalier de Valenciennes, Valenciennes, France; Olivier Langeron, Département d’Anesthésie-Réanimation, Hôpitaux Universitaires Henri Mondor, Créteil, France; Eric Meaudre, Fédération Anesthésie-Réanimation-Brûlés, Hôpital d’Instruction des Armées Sainte-Anne, Toulon, France; Julien Pottecher, Département d’Anesthésie-Réanimation, CHU de Strasbourg Hautepierre, Strasbourg, France; Mathieu Raux, Département d’Anesthésie-Réanimation, Hôpital Pitié-Salpêtrière, Paris, France; and Marion Scotto, Département d’Anesthésie-Réanimation, CHU de Bordeaux, Bordeaux, France.

Author Disclosure Statement

The authors declare that they have no competing interests.

Funding Information

The French Regional Health Agencies of Ile-de-France, Hauts-de-France, and Grand Est have funded a part of the trauma registry. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the article.

Supplemental Material

Abbreviations Used

References

1. Maas

AIR

, Menon

, Manley

, et al.; InTBIR Participants and Investigators. Traumatic brain injury: Progress and challenges in prevention, clinical care, and research. Lancet Neurol 2022;21(11):1004–1060; doi: 10.1016/S1474-4422(22)00309-X

2. Allard

, Scarpelini

, Rhind

, et al. Abnormal coagulation tests are associated with progression of traumatic intracranial hemorrhage. J Trauma 2009;67(5):959–967; doi: 10.1097/TA.0b013e3181ad5d37

3. Oertel

, Kelly

, McArthur

, et al. Progressive hemorrhage after head trauma: Predictors and consequences of the evolving injury. J Neurosurg 2002;96(1):109–116; doi: 10.3171/jns.2002.96.1.0109

4. Epstein

, Mitra

, Cameron

, et al. Acute traumatic coagulopathy in the setting of isolated traumatic brain injury: Definition, incidence and outcomes. Br J Neurosurg 2015;29(1):118–122; doi: 10.3109/02688697.2014.950632

5. Harhangi

, Kompanje

EJO

, Leebeek

FWG

, et al. Coagulation disorders after traumatic brain injury. Acta Neurochir (Wien) 2008;150(2):165–175; discussion 175; doi: 10.1007/s00701-007-1475-8

6. Talving

, Benfield

, Hadjizacharia

, et al. Coagulopathy in severe traumatic brain injury: A prospective study. J Trauma 2009;66(1):55–61; discussion 61–62; doi: 10.1097/TA.0b013e318190c3c0

7. Wafaisade

, Lefering

, Tjardes

, et al.; Trauma Registry of DGU. Acute coagulopathy in isolated blunt traumatic brain injury. Neurocrit Care 2010;12(2):211–219; doi: 10.1007/s12028-009-9281-1

8. Böhm

, Schaeben

, Schäfer

, et al.; CENTER-TBI Participants and Investigators. Extended coagulation profiling in isolated traumatic brain injury: A CENTER-TBI analysis. Neurocrit Care 2022;36(3):927–941; doi: 10.1007/s12028-021-01400-3

9. Lustenberger

, Talving

, Kobayashi

, et al. Time course of coagulopathy in isolated severe traumatic brain injury. Injury 2010;41(9):924–928; doi: 10.1016/j.injury.2010.04.019

10.

10. Mathur

, Suarez

. Coagulopathy in isolated traumatic brain injury: Myth or reality. Neurocrit Care 2023;38(2):429–438; doi: 10.1007/s12028-022-01647-4

11.

11. Maegele

, Schöchl

, Menovsky

, et al. Coagulopathy and haemorrhagic progression in traumatic brain injury: Advances in mechanisms, diagnosis, and management. Lancet Neurol 2017;16(8):630–647; doi: 10.1016/S1474-4422(17)30197-7

12.

12. Hamada

, Gauss

, Duchateau

F-X

, et al. Evaluation of the performance of French physician-staffed emergency medical service in the triage of major trauma patients. J Trauma Acute Care Surg 2014;76(6):1476–1483; doi: 10.1097/TA.0000000000000239

13.

13. Moyer

J-D

, Hamada

, Josse

, et al.; Traumabase Group. Trauma reloaded: Trauma registry in the era of data science. Anaesth Crit Care Pain Med 2021;40(2):100827; doi: 10.1016/j.accpm.2021.100827

14.

14.Anonymous. Rating the severity of tissue damage. I. The abbreviated scale. JAMA 1971;215(2):277–280; doi: 10.1001/jama.1971.03180150059012

15.

15. Mena

, Sanchez

, Rubiano

, et al. Effect of the modified glasgow coma scale score criteria for mild traumatic brain injury on mortality prediction: Comparing classic and modified glasgow coma scale score model scores of 13. J Trauma 2011;71(5):1185–1192; discussion 1193; doi: 10.1097/TA.0b013e31823321f8

16.

16. Teasdale

, Jennett

. Assessment of coma and impaired consciousness. A practical scale. Lancet 1974;2(7872):81–84.

17.

17. Maas

AIR

, Stocchetti

, Bullock

. Moderate and severe traumatic brain injury in adults. Lancet Neurol 2008;7(8):728–741; doi: 10.1016/S1474-4422(08)70164-9

18.

18. Chamoun

, Robertson

, Gopinath

. Outcome in patients with blunt head trauma and a Glasgow Coma Scale score of 3 at presentation: Clinical article. J Neurosurg 2009;111(4):683–687; doi: 10.3171/2009.2.JNS08817

19.

19. Baker

, O’Neill

, Haddon

, et al. The injury severity score: A method for describing patients with multiple injuries and evaluating emergency care. J Trauma 1974;14(3):187–196.

20.

20. Rossaint

, Afshari

, Bouillon

, et al. The European guideline on management of major bleeding and coagulopathy following trauma: Sixth edition. Crit Care 2023;27(1):80; doi: 10.1186/s13054-023-04327-7

21.

21. Roquet

, Godier

, Garrigue-Huet

, et al.; Traumabase^® group. Comprehensive analysis of coagulation factor delivery strategies in a cohort of trauma patients. Anaesth Crit Care Pain Med 2023;42(2):101180; doi: 10.1016/j.accpm.2022.101180

22.

22. Vandenbroucke

, von Elm

, Altman

, et al.; STROBE Initiative. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE): Explanation and elaboration. PLoS Med 2007;4(10):e297; doi: 10.1371/journal.pmed.0040297

23.

23. Cucher

, Harmon

, Myer

, et al. Critical traumatic brain injury is associated with worse coagulopathy. J Trauma Acute Care Surg 2021;91(2):331–335; doi: 10.1097/TA.0000000000003253

24.

24. Epstein

, Mitra

, O’Reilly

, et al. Acute traumatic coagulopathy in the setting of isolated traumatic brain injury: A systematic review and meta-analysis. Injury 2014;45(5):819–824; doi: 10.1016/j.injury.2014.01.011

25.

25. de Oliveira Manoel

, Neto

, Veigas

, et al. Traumatic brain injury associated coagulopathy. Neurocrit Care 2015;22(1):34–44; doi: 10.1007/s12028-014-0026-4

26.

26. Marmarou

, Lu

, Butcher

, et al. Prognostic value of the glasgow coma scale and pupil reactivity in traumatic brain injury assessed pre-hospital and on enrollment: An IMPACT analysis. J Neurotrauma 2007;24(2):270–280; doi: 10.1089/neu.2006.0029

27.

27. Wilde

, Whiteneck

, Bogner

, et al. Recommendations for the use of common outcome measures in traumatic brain injury research. Arch Phys Med Rehabil 2010;91(11):1650–1660.e17; doi: 10.1016/j.apmr.2010.06.033

28.

28. Sadaka

, Jadhav

, Miller

, et al. Is it possible to recover from traumatic brain injury and a Glasgow coma scale score of 3 at emergency department presentation? Am J Emerg Med 2018;36(9):1624–1626; doi: 10.1016/j.ajem.2018.01.051

29.

29. Lee

, Hampton

, Diggs

, et al. Traumatic brain injury is not associated with coagulopathy out of proportion to injury in other body regions. J Trauma Acute Care Surg 2014;77(1):67–72; discussion 72; doi: 10.1097/TA.0000000000000255

30.

30. Samuels

, Moore

, Silliman

, et al. Severe traumatic brain injury is associated with a unique coagulopathy phenotype. J Trauma Acute Care Surg 2019;86(4):686–693; doi: 10.1097/TA.0000000000002173

31.

31. Frith

, Goslings

, Gaarder

, et al. Definition and drivers of acute traumatic coagulopathy: Clinical and experimental investigations. J Thromb Haemost 2010;8(9):1919–1925; doi: 10.1111/j.1538-7836.2010.03945.x

32.

32. Brohi

, Singh

, Heron

, et al. Acute traumatic coagulopathy. J Trauma 2003;54(6):1127–1130; doi: 10.1097/01.TA.0000069184.82147.06

33.

33. Tan

, Tan

KHS

, Ng

, et al. The effects of hypertonic saline solution (7.5%) on coagulation and fibrinolysis: An in vitro assessment using thromboelastography. Anaesthesia 2002;57(7):644–648; doi: 10.1046/j.1365-2044.2002.02603.x

34.

34. Lindroos

A-C

, Schramko

, Tanskanen

, et al. Effect of the combination of mannitol and ringer acetate or hydroxyethyl starch on whole blood coagulation in vitro. J Neurosurg Anesthesiol 2010;22(1):16–20; doi: 10.1097/ANA.0b013e3181bd4ede

35.

35. Luostarinen

, Niiya

, Schramko

, et al. Comparison of hypertonic saline and mannitol on whole blood coagulation in vitro assessed by thromboelastometry. Neurocrit Care 2011;14(2):238–243; doi: 10.1007/s12028-010-9475-6

36.

36. Adamik

K-N

, Butty

, Howard

. In vitro effects of 3% hypertonic saline and 20% mannitol on canine whole blood coagulation and platelet function. BMC Vet Res 2015;11:242; doi: 10.1186/s12917-015-0555-x

37.

37. Palmaers

, Krämer

, Hinsenkamp

, et al. Mannitol and the combination of mannitol and gelatin impair whole blood coagulation and the platelet function in vitro. Turk J Anaesthesiol Reanim 2019;47(3):199–205; doi: 10.5152/TJAR.2019.86300

38.

38. Wilder

, Reid

, Bakaltcheva

. Hypertonic resuscitation and blood coagulation: In vitro comparison of several hypertonic solutions for their action on platelets and plasma coagulation. Thromb Res 2002;107(5):255–261; doi: 10.1016/s0049-3848(02)00335-3

39.

39. Hernández-Palazón

, Fuentes-García

, Doménech-Asensi

, et al. Equiosmolar solutions of hypertonic saline and mannitol do not impair blood coagulation during elective intracranial surgery. J Neurosurg Anesthesiol 2017;29(1):8–13; doi: 10.1097/ANA.0000000000000255

40.

40. Maegele

, Schöchl

, Cohen

. An update on the coagulopathy of trauma. Shock 2014;41(Suppl 1):21–25; doi: 10.1097/SHK.0000000000000088

41.

41. Dong

, Zhang

. Detecting traumatic brain injury-induced coagulopathy: What we are testing and what we are not. J Trauma Acute Care Surg 2023;94(1S Suppl 1):S50–S55; doi: 10.1097/TA.0000000000003748

42.

42. Moore

, Moore

, Kornblith

, et al. Trauma-induced coagulopathy. Nat Rev Dis Primers 2021;7(1):30; doi: 10.1038/s41572-021-00264-3

43.

43. Zanza

, Romenskaya

, Racca

, et al. Severe trauma-induced coagulopathy: Molecular mechanisms underlying critical illness. Int J Mol Sci 2023;24(8):7118; doi: 10.3390/ijms24087118

44.

44. Böhm

, Güting

, Thorn

, et al.; CENTER-TBI Participants and Investigators. Global characterisation of coagulopathy in Isolated Traumatic Brain Injury (iTBI): A CENTER-TBI analysis. Neurocrit Care 2021;35(1):184–196; doi: 10.1007/s12028-020-01151-7

45.

45. Udekwu

, Kromhout-Schiro

, Vaslef

, et al. Glasgow Coma Scale score, mortality, and functional outcome in head-injured patients. J Trauma 2004;56(5):1084–1089; doi: 10.1097/01.ta.0000124283.02605.a5

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

2.03 MB

Respective Contributions of Head and Extra-Head Injury Severities to the Occurrence of Early Coagulopathy Following Traumatic Brain Injury