Hyperfibrinolysis and Fibrinolysis Shutdown in Patients with Traumatic Brain Injury

doi:10.21203/rs.3.rs-1597470/v2

Download PDF

Article

Hyperfibrinolysis and Fibrinolysis Shutdown in Patients with Traumatic Brain Injury

https://doi.org/10.21203/rs.3.rs-1597470/v2

This work is licensed under a CC BY 4.0 License

You are reading this latest preprint version

Background: Traumatic brain injury (TBI) has been associated with coagulation/fibrinolysis disorders, but the pathogenesis of hyperfibrinolysis and subsequent fibrinolysis shutdown in the acute phase of TBI is not well understood. We sought to analyze the time course of coagulation, fibrinolysis, and subsequent fibrinolysis shutdown in the acute phase, and the relationship of each to long-term outcome.

Methods: We retrospectively evaluated 61 consecutive cases of isolated TBI transported to the hospital within 1 h after injury. Plasma levels of the coagulation marker thrombin-antithrombin III complex (TAT), the fibrinolysis marker D-dimer, and the fibrinolysis inhibition marker plasminogen activator inhibitor-1 (PAI-1) were measured on arrival and 3 h, 6 h, 12 h, 1 d, 3 d and 7 d after injury. The differences in plasma TAT, D-dimer, and PAI-1 levels between the good outcome group with an extended Glasgow Outcome Scale (GOS-E) of 6–8 at 6 months post-injury and the poor outcome group with a GOS-E of 1–5 at 6 months post-injury were compared using a generalized linear mixed model. Multivariate logistic regression analysis was performed to identify prognostic factors for coagulation and fibrinolysis at each time point.

Results: Plasma TAT levels peaked at admission and decreased significantly until 1 d after injury. Plasma D-dimer levels increased significantly, peaking up to 3 h after injury, and significantly decreased up to 3 d after injury. Plasma PAI-1 levels increased significantly up to 3 h after injury, the upward trend continuing until 6 h after injury, followed by a decrease lasting until 3 d after injury. The plasma TAT, D-dimer, and PAI-1 levels were all higher in the acute phase of TBI in patients with a poor outcome than in patients with a good outcome at 6 months. On multivariate logistic regression analysis, elevated D-dimer levels from admission to 3 h after injury and elevated PAI-1 levels from 6 h to 1 d after injury were significant negative prognostic indicators.

Conclusions: After TBI, hypercoagulation, fibrinolysis, and fibrinolysis shutdown were activated consecutively. Hyperfibrinolysis immediately after injury and subsequent fibrinolysis shutdown were associated with poor long-term outcome.

Brain injuries

traumatic

Blood coagulation disorders

Fibrinolysis

Thrombin

Fibrin fibrinogen degradation products

Plasminogen activator inhibitor-1

The acute phase of traumatic brain injury (TBI) is known to be associated with disruptions of the coagulation/fibrinolysis system [1–3]. In particular, the hemorrhagic diathesis associated with hyperfibrinolysis has a significant impact on the mortality and functional outcome of TBI patients [2, 4–6]. We previously investigated the time course of D-dimer, a marker of fibrinolysis, in patients with isolated TBI and an Abbreviated Injury Scale (AIS) [7] of ≥ 3, and demonstrated that the plasma concentration of D-dimer was already abnormally high in 98.7% of patients within 1 h after injury and peaked at about 3 h after injury. Age and D-dimer levels were independent predictors of functional outcome at 3 months post-injury [8]. After hyperfibrinolysis, fibrinolysis shutdown by plasminogen activator inhibitor-1 (PAI-1), which is synthesized by vascular endothelial cells, occurs somewhat later, but its pathogenesis is not well understood, and there have been no reports on its time course or relationship to long-term outcome. A deeper understanding of the pathogenesis of fibrinolysis shutdown is critically important, as it relates to the use of anti-fibrinolysis agents and thrombus formation. We hypothesized that hyperfibrinolysis and subsequent fibrinolysis shutdown may be associated with long-term prognosis.

In this study, we evaluated the time course of coagulation abnormalities and subsequent fibrinolysis and fibrinolysis shutdown in the acute phase of TBI and their relationship to long-term outcome, focusing on blood biomarkers.

Patients

We studied the demographic, clinical, and radiological data of TBI patients admitted to Kawaguchi Municipal Medical Center from April 2018 to September 2021. Cases were included if the diagnosis was isolated TBI with intracranial AIS ≥ 3 and extracranial AIS < 3, as described previously [1, 3, 8].

The diagnosis of TBI was established from cranial computed tomography (CT) findings. Intracranial and extracranial AIS and CT scans were independently evaluated by intensivists and neurointensivists (Y.F., G.S., Y.N.) at the study institution. Exclusion criteria were lack of information about the time of injury, first blood draw > 1 h after injury, age < 16 y, presence of diseases or drugs that affect coagulation and fibrinolysis parameters such as hepatic failure, anticoagulant medication, cardiopulmonary arrest prior to admission or on arrival, and withdrawal from active treatment.

Case data, including age, sex, GCS score at admission, AIS [7], administration of tranexamic acid (TXA), and amount of fresh frozen plasma (FFP) transfused within 7 d of injury were collected. CT scans at admission and afterwards were independently evaluated and the type of head injury based on radiological findings was classified as acute subdural hematoma (ASDH), acute epidural hematoma (AEDH), intracerebral hematoma and contusion (ICH), and traumatic subarachnoid hemorrhage (TSAH). The coagulation marker thrombin-antithrombin III complex (TAT), the fibrinolysis marker D-dimer, and the fibrinolysis inhibition marker PAI-1 were assessed over time. Blood samples were analyzed upon arrival at the emergency department to determine the initial (within 1 h after injury) TAT, D-dimer, and PAI-1 levels. The tests were repeated at 3 h, 6 h, 12 h, 1 d, 3 d, and 7 d after injury for a total of seven time points.

Management of TBI

Immediately upon arrival at the emergency room, the patients were treated according to the Guidelines for the Management of Head Injury, 4th edition, of the Japan Society of Neurotraumatology [9]. All patients underwent brain CT after detailed neurological evaluation and initial stabilization. A second CT scan was performed within 3 h of admission and whenever there were signs of worsening clinical symptoms or increased intracranial pressure.

Assessment of coagulation/fibrinolysis parameters

Blood samples were drawn into ethylenediaminetetraacetic acid [EDTA] plasma and citrate. D-dimer was measured by a latex immunoassay method (LIAS Auto D-dimer Neo®, Sysmex Corp., Kobe, Japan). TAT was measured by a chemiluminescent enzyme immunoassay method (STACIA CLEIA TAT®, LSI Medience Corp., Tokyo, Japan). PAI-1 was measured by a latex immunoassay method (LPIA-tPAI test®, LSI Medience Corp., Tokyo, Japan).

Statistical Analysis

Data are presented as number (%) or median (interquartile range [IQR]). The multiple imputation method was used for missing data [10, 11]. Patients were divided into two groups according to the extended Glasgow Outcome Scale (GOS-E) [12, 13] at 6 months post-injury. The GOS-E is divided into the following eight categories: (1) dead, (2) vegetative state, (3) lower body severe disability, (4) upper body severe disability, (5) lower body moderate disability, (6) upper body moderate disability, (7) lower body good recovery, and (8) upper body good recovery. The good outcome group consisted of cases with a GOS-E of 6–8, and the poor outcome group consisted of patients with a GOS-E of 1–5. The GOS-E was assessed by neurointensivists (Y.F. and T.K.) at the study institution, who contacted patients, patient families, and hospitals to which patients were transferred from our hospital after discharge, by telephone and mail. Demographic, clinical, and radiological parameters for both groups were analyzed using Student’s t-test, the Mann-Whitney U-test, or the χ² test for continuous normal, continuous non-normal, and dichotomous data, respectively. A paired t-test was used to determine whether there were a statistically significant differences in plasma TAT, D-dimer, and PAI-1 levels at each time point. A generalized linear mixed model (GLMM) was used to compare the distributions of plasma TAT, D-dimer, and PAI-1 levels between the good outcome and the poor outcome groups at the seven measurement time points. Spearman’s rank correlation coefficient was used to investigate the correlation of plasma D-dimer and PAI-1 levels. Multivariate logistic regression analysis by the forced entry method was conducted to identify prognostic coagulation and fibrinolysis parameters at each time point [14]. A value of p < 0.05 was considered statistically significant. All statistical analyses were performed using commercial software (SPSS Version 25.0®; IBM Corp., Armonk NY, USA).

A total of 61 consecutive TBI cases were included in the study. There were 122 missing values (5.3%) in this study’s dataset, which were complemented by the multiple imputation method. Demographic, clinical, and radiological characteristics are summarized in Table 1. ASDH was found in 49 patients (80.3%), AEDH in 10 patients (16.4%), ICH in 52 patients (85.2%), and TSAH in 58 patients (95.1%) (some patients had more than one diagnosis). The good outcome group consisted of 30 cases (49.2%) and the poor outcome group consisted of 31 cases (50.8%). Seven patients died between 1 and 3 d after injury and five patients died between 3 and 7 d after injury due to TBI. Age was significantly lower in the good outcome group than in the poor outcome group (median 48 y [IQR 32–66 y] vs. 78 y [IQR 59–82 y], p < 0.001). There was no difference in gender between the two groups. The good outcome group had higher GCS scores at admission (median 13 [IQR 11–15] vs. 6 [IQR 4–13], p < 0.001), lower AIS-head (median 4 [IQR 3–5] vs. 5 [IQR 5–5], p < 0.001), lower incidence of ASDH (63.3% vs. 96.8%, p = 0.009), and lower volume of FFP transfusion (median 0 mL [IQR 0–0 mL] vs. 0 mL [IQR 0–1200 mL], p = 0.008) than the poor outcome group. There was no difference in the rate of TXA use between the two groups.

Time course of TAT, D-dimer, and PAI-1

Figure 1 shows the time course of plasma TAT, D-dimer, and PAI-1 levels of all patients on admission and 3 h, 6 h, 12 h, 1 d, 3 d, and 7 d after TBI. Plasma TAT levels (normal range: 0.0–3.0 ng/mL) at admission were abnormally high in all patients. The median plasma level of TAT decreased rapidly and significantly from admission to 1 d after injury (1–3 h: t [60] = 4.531, p < 0.001; 3–6 h: t [60] = 7.753, p < 0.001; 6–12 h: t [60] = 4.907, p < 0.001; 12 h–1 d: t [60] = 5.665, p < 0.001), subsequently decreased insignificantly from 1 to 3 d after injury (t [53] = 1.374, p = 0.17), and decreased significantly from 3 to 7 d after injury (t [48] = 2.657, p = 0.008).

The median plasma D-dimer level (normal range: 0.0–1.0 μg/mL) at admission was abnormally high in 60 (98.4%) of the 61 patients. It increased significantly from admission to 3 h after injury (t [60] = −3.198, p = 0.01) Three hours after injury, it decreased significantly up to 3 d after injury (3–6 h: t [60] = 4.709, p < 0.001; 6–12 h: t [60] = 3.629, p < 0.001; 12 h–1 d: t [60] = 4.880, p < 0.001; 1–3 d: t [53] = 4.798, p < 0.001), and subsequently increased significantly again from 3 to 7 d after injury (t [48] = −6.444, p < 0.001).

The median plasma PAI-1 level (normal range: 0.0–50.0 ng/mL) at admission was within the normal range in 53 (86.9%) of the 61 patients. It increased significantly from admission to 3 h after injury (t [60] = −5.302, p < 0.001). The upward trend continued up to 6 h after injury (3–6 h: t [60] = −1.550, p = 0.12; 1–6 h: t [60] = −4.560, p < 0.001). After 6 h post-injury, it decreased up to 3 d (6–12 h: t [60] = 0.640, p = 0.52; 12 h–1 d: t [60] = 2.309, p = 0.02; 6 h–1 d: t [60] = 3.193, p = 0.001; 1–3 d: t [53] = 3.868, p < 0.001), subsequently increasing insignificantly again from 3 to 7 d after injury (t [48] = −0.400, p = 0.69).

TAT, D-dimer, PAI-1 and long-term outcome

The plasma levels of TAT, D-dimer, and PAI-1 were higher in the poor outcome group than in the good outcome group from the time of admission to 7 d after injury as analyzed by GLMM (all p < 0.001) (Fig. 2).

Correlation between plasma D-dimer levels 3 h after injury and plasma PAI-1 levels 6 h after injury

Figure 1 shows that plasma D-dimer level as a biomarker of hyperfibrinolysis peaked 3 h after injury and plasma PAI-1 level as a biomarker of fibrinolysis shutdown peaked 6 h after injury. To investigate the correlation between hyperfibrinolysis and subsequent fibrinolysis shutdown, Spearman’s rank correlation coefficient between plasma D-dimer levels 3 h after injury and plasma PAI-1 levels 6 h after injury were calculated. Positive correlations were found between plasma D-dimer levels 3 h after injury and plasma PAI-1 levels 6 h after injury (p < 0.001, r = 0.68) (Fig. 3).

Coagulation and fibrinolysis parameters as independent risk factors for poor prognosis

To evaluate independent risk factors at admission related to poor prognosis, multivariate logistic regression analysis was performed (Table 2). The explanatory variables were age [3, 4, 15-17], GCS score [3, 16, 18-20], AIS-head [3, 4, 18], presence of ASDH [3, 16, 18, 20] and ICH [3, 16, 20, 21], and plasma levels of TAT, D-dimer, and PAI-1. The response variable was a good outcome with GOS-E of 6–8 or poor outcome with GOS-E of 1–5 at 6 months after injury. The results showed that independent risk factors at admission for poor prognosis were older age, presence of ASDH, and elevated D-dimer.

Multivariate logistic regression analysis was also performed using plasma levels of TAT, D-dimer, and PAI-1 from admission to 7 d after injury to identify reliable prognostic coagulation and fibrinolysis parameters at each time point after TBI (Table 3). Elevated D-dimer levels from admission to 3 h after injury and elevated PAI-1 levels from 6 h to 1 d after injury were significant negative prognostic indicators.

This study found that hypercoagulability, fibrinolysis, and fibrinolysis shutdown were activated one after another following TBI, with hypercoagulability peaking immediately after injury, fibrinolysis peaking 3 h after injury, and fibrinolysis shutdown peaking 6 h after injury. All of these coagulation and fibrinolytic changes were demonstrated to be activated at the time of TBI in patients with poor long-term outcomes, with plasma D-dimer level from admission to 3 h after injury and plasma PAI-1 level from 6 h to 1 d after injury being independent biomarkers of long-term outcome.

The cerebral arteries and astrocytes contain high concentrations of tissue factor (TF) [22, 23]. After TBI, TF from injured brain tissue enters the systemic circulation, forms a complex with factor VIIa (FVIIa), activates the extrinsic pathway of blood coagulation, and causes excessive production of thrombin [24, 25]. Thrombin converts fibrinogen to fibrin and forms thrombus, but some thrombin is inactivated on endothelial cells by forming a one-to-one complex with antithrombin III, a physiological inhibitor of thrombin. This complex is called TAT, and it is used as a marker of thrombin production in vivo to diagnose hypercoagulation. In this study, plasma TAT levels were abnormally high, peaking at admission in all TBI patients and decreasing over time, indicating that hypercoagulation after TBI is highest immediately after injury. In vivo studies have also reported the formation of microthrombi around brain contusions as early as 1 h after injury [26, 27]. In addition, plasma TAT levels were higher in the poor outcome group than in the good outcome group, indicating that hypercoagulation is related to pathological progression in the acute phase of TBI [28].

Hypercoagulation is followed by activation of fibrinolysis as a biological response. The fibrin clots formed by thrombin involvement are degraded by plasmin produced after plasminogen activation by tissue-type plasminogen activator (t-PA) or urokinase-type plasminogen activator (u-PA) to produce the fibrin degradation product, D-dimer [29, 30]. In addition, tissue hypoperfusion associated with trauma results in the release of large amounts of t-PA from injured brain tissue, further activating fibrinolysis [31]. Thus, hyperfibrinolysis secondary to hypercoagulation and hyperfibrinolysis associated with direct t-PA release from the injured brain are the hallmarks of TBI and contribute to the bleeding diathesis. In the present study, plasma D-dimer levels were abnormally high in 98.4% of TBI patients at admission and peaked 3 h after injury. This suggests that hypercoagulation is followed by hyperfibrinolysis immediately after injury, and reaches a peak 3 h after injury. In addition, plasma D-dimer levels were higher in the poor outcome group than in the good outcome group and plasma D-dimer level from admission to 3 h after injury was an independent biomarker for long-term outcome. It has been reported that hyperfibrinolysis in the acute phase of TBI contributes to poor outcome through hematoma expansion [4, 8, 32, 33], which is consistent with the results of this study.

PAI-1 is a major endogenous inhibitor of fibrinolysis. It is produced and secreted by vascular endothelial cells in response to hyperfibrinolysis, direct endothelial cell damage and inflammation associated with trauma, or tissue hypoxia due to thrombin production [34, 35]. It inhibits fibrin clot lysis by inhibiting t-PA, u-PA, thrombomodulin, and activated protein C. The timing of fibrinolysis shutdown after TBI has not been well understood, but in the present study, PAI-1 reached its peak 6 h after injury and correlated with the plasma D-dimer level 3 h after injury, suggesting that the coagulation-fibrinolysis kinetics shifted to fibrinolysis shutdown after 3 h post-injury. Figure 2 shows that the plasma PAI-1 levels of most of the cases in the good outcome group remained within the normal range, while many of those in the poor outcome group had high levels from 3 h to 1 d after the injury. In addition, plasma PAI-1 levels from 6 h to 1 d after injury were an independent biomarker for long-term outcome. The explanation may be that, besides PAI-1 being affected by hyperfibrinolysis, PAI-1 itself also exerts neurotoxic, oxidative, and inflammatory effects. In a mouse model of TBI, it has been reported that administration of a PAI-1 antagonist reduced thrombus formation in the microvasculature around the cerebral cortex after trauma, inhibited neuronal apoptosis, and improved neurological function [36]. In a rat model of TBI, administration of a PAI-1 antagonist has been shown to have antioxidant and anti-inflammatory effects and to improve behavioral test outcomes [37].

The only evidence-based treatment for TBI with coagulation and fibrinolysis disruption is TXA, an antifibrinolytic agent, in a subset of patients with mild-to-moderate TBI [38]. The Clinical Randomisation of Antifibrinolytic in Significant Hemorrhage (CRASH-2) trial [39], a large, international, multicenter, randomized, placebo-controlled trial investigating the effect of TXA on mortality and the need for transfusion in adult trauma patients with significant bleeding, showed that all-cause mortality was significantly lower in the TXA group than in the placebo group. A systematic review of two randomized controlled trials [40], including the CRASH-2 trial, showed that TXA administration reduced mortality in TBI patients compared with placebo. However, the results appear to be highly dependent on the timing of TXA administration. It was reported that TXA administration within 3 h after injury was effective, but after 3 h, it appeared to increase mortality [41]. Based on these results, the protocol for administering TXA in the CRASH-3 trial, another large, international, multicenter, randomized, placebo-controlled trial examining the effect of TXA on head trauma-related mortality in TBI patients, was changed to within 3 h of trauma [38]. There is no consensus on the mechanism by which TXA administration after 3 h of injury adversely affects outcome. In this study, it was shown that the peak of hyperfibrinolysis after TBI was at 3 h after injury, with a subsequent shift to fibrinolysis shutdown, reaching its peak at 6 h after injury. Since PAI-1 is a major inhibitor of the fibrinolysis system, elevated PAI-1 levels may produce a hypofibrinolytic or prothrombotic state and contribute to microthrombus formation [35]. The time of the transition to a prothrombotic state has been unclear [41], but it may be occur earlier than previously thought, and TXA administration more than 3 h after injury may have a negative prognostic effect.

Several limitations of this study warrant mention. This study has several limitations. First, the sample size was relatively small, which did not allow us to obtain sufficient power for statistical analysis. Second, there were many cases in which the plasma TAT levels at admission were 120 ng/mL, the upper limit of measurement, which may have affected the statistical analysis. Third, the data were not designed to evaluate the impact of FFP administration and surgery, and which might have affected TAT, D-dimer, and PAI-1 after 3 h post-injury. Finally, in Japan, the population is aging and the mean age of TBI patients is high [42]. As a result, it may appear that there is an overrepresentation of older patients with severe TBI.

After TBI, hypercoagulation peaked immediately after injury, fibrinolysis peaked 3 h after injury, and fibrinolysis shutdown peaked 6 h after injury. All of these coagulation and fibrinolytic pathways were activated in patients with poor long-term outcomes. Plasma D-dimer levels from admission to 3 h after injury and plasma PAI-1 levels from 6 h to 1 d after injury were independent biomarkers for long-term outcome.

AEDH: acute epidural hematoma

AIS: Abbreviated Injury Scale

ASDH: acute subdural hematoma

FFP: fresh frozen plasma

GLMM: generalized linear mixed model

GOS-E: extended Glasgow outcome scale

ICH: intracerebral hematoma and contusion

IQR: interquartile range

PAI-1: plasminogen activator inhibitor-1

TAT: thrombin-antithrombin III complex

TBI: traumatic brain injury

TSAH: traumatic subarachnoid hemorrhage

TXA: tranexamic acid

Ethical approval and consent to participate

The study was approved by our institutional review boards (Nippon Medical School: #M-2021-025, 16 February, 2022; and Kawaguchi Municipal Medical Center: #2021-35, 7 March, 2022). The need for informed consent was waived due to the retrospective nature of the study.

Consent for publication

Not applicable.

Availability of data and materials

The datasets supporting the conclusions of this article will be provided based on reasonable request to the corresponding author.

Competing interests

The authors declare that they have no competing interests.

Author details

¹Department of Emergency and Critical Care Medicine, Nippon Medical School Hospital, 1-1-5, Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan

²Department of Neurological Surgery, Nippon Medical School Hospital, 1-1-5, Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan

³Division of Acute and Critical Care Medicine, Department of Anesthesiology and Critical Care Medicine, Hokkaido University Faculty of Medicine, N17W5, Kita-ku, Sapporo-shi, Hokkaido 060-8638, Japan

⁴Emergency and Critical Care Center, Kawaguchi Municipal Medical Center, 180, Nishiaraijuku, Kawaguchi-shi, Saitama 333-0833, Japan

⁵Graduate School of Medical and Health Science, Nippon Sport Science University, 1221-1 Kamoshida-cho, Aoba-ku, Yokohama-shi, Kanagawa 227-0033, Japan

Funding

This study was supported in part by JSPS KAKENHI Grant Number 19K18367. The funders had no role in the execution of this study or interpretation of the results.

Authors’ contributions

Conception and design of the study: RN. Acquisition of data: YF, TK, GS, and YN. Analysis and interpretation of data: RN, YM, and TW. Drafting the article: RN, YM, and TW. Reviewed submitted version of manuscript: all authors. Funding acquisition: RN. Study supervision: YT, HY and SY. All authors read and approved the final manuscript.

Acknowledgment

We thank Takashi Tagami, MD, MPH, PhD, from Nippon Medical School Musashi Kosugi Hospital for advice on statistical methods, and Libby Cone, MD, MA, from DMC Corp. (www.dmed.co.jp) for editing drafts of this manuscript.

Epstein DS, Mitra B, O'Reilly G, Rosenfeld JV, Cameron PA. Acute traumatic coagulopathy in the setting of isolated traumatic brain injury: a systematic review and meta-analysis. Injury. 2014;45:819–24.
Harhangi BS, Kompanje EJ, Leebeek FW, Maas AI. Coagulation disorders after traumatic brain injury. Acta Neurochir (Wien). 2008;150:165–75.
Wafaisade A, Lefering R, Tjardes T, Wutzler S, Simanski C, Paffrath T, et al. Acute coagulopathy in isolated blunt traumatic brain injury. Neurocrit Care. 2010;12:211–9.
Allard CB, Scarpelini S, Rhind SG, Baker AJ, Shek PN, Tien H, et al. Abnormal coagulation tests are associated with progression of traumatic intracranial hemorrhage. J Trauma. 2009;67:959–67.
Kurland D, Hong C, Aarabi B, Gerzanich V, Simard JM. Hemorrhagic progression of a contusion after traumatic brain injury: a review. J Neurotrauma. 2012;29:19–31.
Stein SC, Spettell C, Young G, Ross SE. Delayed and progressive brain injury in closed-head trauma: radiological demonstration. Neurosurgery. 1993;32:25–30.
Association for the Advancement of Automotive Medicine. The Abbreviated Injury Scale (AIS) 1998 Revision. Des Plaines, IL: Association for the Advancement of Automotive Medicine; 1998.
Nakae R, Takayama Y, Kuwamoto K, Naoe Y, Sato H, Yokota H. Time course of coagulation and fibrinolytic parameters in patients with traumatic brain injury. J Neurotrauma. 2016;33:688–95.
Guidelines Committee on the Management of Head Injury, Japan Society of Neurotraumatology ed. Guidelines for the Management of Head Injury, 4th ed. Tokyo: Igaku-Shoin Ltd.; 2019. (in Japanese).
Janssen KJ, Donders AR, Harrell FE, Jr., Vergouwe Y, Chen Q, Grobbee DE, et al. Missing covariate data in medical research: to impute is better than to ignore. J Clin Epidemiol. 2010;63:721–7.
Little RJ, D'Agostino R, Cohen ML, Dickersin K, Emerson SS, Farrar JT, et al. The prevention and treatment of missing data in clinical trials. N Engl J Med. 2012;367:1355–60.
Jennett B, Snoek J, Bond MR, Brooks N. Disability after severe head injury: observations on the use of the Glasgow Outcome Scale. J Neurol Neurosurg Psychiatry. 1981;44:285–93.
Wilson JT, Pettigrew LE, Teasdale GM. Structured interviews for the Glasgow Outcome Scale and the extended Glasgow Outcome Scale: guidelines for their use. J Neurotrauma. 1998;15:573–85.
Katz MH. Multivariable analysis: a primer for readers of medical research. Ann Intern Med. 2003;138:644–50.
Hukkelhoven CW, Steyerberg EW, Rampen AJ, Farace E, Habbema JD, Marshall LF, et al. Patient age and outcome following severe traumatic brain injury: an analysis of 5600 patients. J Neurosurg. 2003;99:666–73.
Powers AY, Pinto MB, Tang OY, Chen JS, Doberstein C, Asaad WF. Predicting mortality in traumatic intracranial hemorrhage. J Neurosurg. 2019;132:552–59.
Vollmer DG, Torner JC, Jane JA, Sadovnic B, Charlebois D, Eisenberg HM, et al. Age and outcome following traumatic coma: why do older patients fare worse? J Neurosurg. 1991;75:S37-S49.
Lustenberger T, Talving P, Kobayashi L, Inaba K, Lam L, Plurad D, et al. Time course of coagulopathy in isolated severe traumatic brain injury. Injury. 2010;41:924–8.
Olson JD, Kaufman HH, Moake J, O'Gorman TW, Hoots K, Wagner K, et al. The incidence and significance of hemostatic abnormalities in patients with head injuries. Neurosurgery. 1989;24:825–32.
Talving P, Benfield R, Hadjizacharia P, Inaba K, Chan LS, Demetriades D. Coagulopathy in severe traumatic brain injury: a prospective study. J Trauma. 2009;66:55–61.
Adatia K, Newcombe VFJ, Menon DK. Contusion progression following traumatic brain injury: a review of clinical and radiological predictors, and influence on outcome. Neurocrit Care. 2021;34:312–24.
Goodnight SH, Kenoyer G, Rapaport SI, Patch MJ, Lee JA, Kurze T. Defibrination after brain-tissue destruction: a serious complication of head injury. N Engl J Med. 1974;290:1043–7.
Keimowitz RM, Annis BL. Disseminated intravascular coagulation associated with massive brain injury. J Neurosurg. 1973;39:178–80.
Albert V, Arulselvi S, Agrawal D, Pati HP, Pandey RM. Early posttraumatic changes in coagulation and fibrinolysis systems in isolated severe traumatic brain injury patients and its influence on immediate outcome. Hematol Oncol Stem Cell Ther. 2019;12:32–43.
Dunbar NM, Chandler WL. Thrombin generation in trauma patients. Transfusion. 2009;49:2652–60.
Dietrich WD, Alonso O, Halley M. Early microvascular and neuronal consequences of traumatic brain injury: a light and electron microscopic study in rats. J Neurotrauma. 1994;11:289–301.
Schwarzmaier SM, Kim SW, Trabold R, Plesnila N. Temporal profile of thrombogenesis in the cerebral microcirculation after traumatic brain injury in mice. J Neurotrauma. 2010;27:121–30.
Stein SC, Graham DI, Chen XH, Smith DH. Association between intravascular microthrombosis and cerebral ischemia in traumatic brain injury. Neurosurgery. 2004;54:687–91.
Chapman MP, Moore EE, Moore HB, Gonzalez E, Gamboni F, Chandler JG, et al. Overwhelming tPA release, not PAI-1 degradation, is responsible for hyperfibrinolysis in severely injured trauma patients. J Trauma Acute Care Surg. 2016;80:16–23.
Hijazi N, Abu Fanne R, Abramovitch R, Yarovoi S, Higazi M, Abdeen S, et al. Endogenous plasminogen activators mediate progressive intracerebral hemorrhage after traumatic brain injury in mice. Blood. 2015;125:2558–67.
Wada T, Shiraishi A, Gando S, Yamakawa K, Fujishima S, Saitoh D, et al. Pathophysiology of coagulopathy induced by traumatic brain injury is identical to that of disseminated intravascular coagulation with hyperfibrinolysis. Front Med (Lausanne). 2021;8:767637.
Karri J, Cardenas JC, Matijevic N, Wang YW, Choi S, Zhu L, et al. Early fibrinolysis associated with hemorrhagic progression following traumatic brain injury. Shock. 2017;48:644–50.
Tian HL, Chen H, Wu BS, Cao HL, Xu T, Hu J, et al. D-dimer as a predictor of progressive hemorrhagic injury in patients with traumatic brain injury: analysis of 194 cases. Neurosurg Rev. 2010;33:359–65.
Gando S, Sawamura A, Hayakawa M. Trauma, shock, and disseminated intravascular coagulation: lessons from the classical literature. Ann Surg. 2011;254:10–9.
Sillen M, Declerck PJ. A narrative review on plasminogen activator inhibitor-1 and its (patho)physiological role: to target or not to target? Int J Mol Sci. 2021;22:2721.
Griemert EV, Schwarzmaier SM, Hummel R, Golz C, Yang D, Neuhaus W, et al. Plasminogen activator inhibitor-1 augments damage by impairing fibrinolysis after traumatic brain injury. Ann Neurol. 2019;85:667–80.
Kuru Bektasoglu P, Koyuncuoglu T, Akbulut S, Akakin D, Eyuboglu IP, Erzik C, et al. Neuroprotective effect of plasminogen activator inhibitor-1 antagonist in the rat model of mild traumatic brain injury. Inflammation. 2021;44:2499–517.
CRASH-3 trial collaborators. Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomised, placebo-controlled trial. Lancet. 2019;394:1713–23.
CRASH-2 trial collaborators, Shakur H, Roberts I, Bautista R, Caballero J, Coats T, et al. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet. 2010;376:23–32.
Ker K, Roberts I, Shakur H, Coats TJ. Antifibrinolytic drugs for acute traumatic injury. Cochrane Database Syst Rev. 2015:CD004896.
CRASH-2 collaborators, Roberts I, Shakur H, Afolabi A, Brohi K, Coats T, et al. The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial. Lancet. 2011;377:1096–101.
Yokobori S, Saito K, Sasaki K, Kanaya T, Fujiki Y, Yamaguchi M, et al. Treatment of geriatric traumatic brain injury: a nationwide cohort study. J Nippon Med Sch. 2021;88:194–203.

Table 1 Initial demographic, clinical, and radiologic characteristics of the study population

	Total (n = 61)		Good outcome group (n = 30)		Poor outcome group (n = 31)		p
Demographic data
Age, median (IQR), y	65	(41–80)	48	(32–66)	78	(59–82)	<	0.001
Male, n (%)	38	(62.3)	19	(63.3)	19	(61.3)		0.87
Clinical scores
GCS score, median (IQR)	12	(6–14)	13	(11–15)	6	(4–13)	<	0.001
AIS-head, median (IQR)	5	(4–5)	4	(3–5)	5	(5–5)	<	0.001
CT findings
ASDH, n (%)	49	(80.3)	19	(63.3)	30	(96.8)		0.009
AEDH, n (%)	10	(16.4)	7	(23.3)	3	(9.7)		0.15
ICH, n (%)	52	(85.2)	23	(76.7)	29	(93.5)		0.07
TSAH, n (%)	58	(95.1)	28	(93.3)	30	(96.8)		0.54
Treatment
TXA, n (%)	21	(34.4)	11	(36.7)	10	(32.3)		0.72
FFP, median (IQR), mL	0	(0–720)	0	(0–0)	0	(0–1200)		0.008

Good outcome group: extended Glasgow Outcome Scale (GOS-E) of 6–8; Poor outcome group: GOS-E of 1–5

IQR interquartile range, GCS Glasgow Coma Scale, AIS Abbreviated Injury Scale, ASDH acute subdural hematoma; AEDH acute epidural hematoma, ICH intracerebral hematoma and contusion, TSAH traumatic subarachnoid hemorrhage, TXA tranexamic acid, FFP fresh frozen plasma

All values are expressed as number (%) or median (first to third quartile)

Table 2 Multivariate logistic regression analysis of initial variables as independent risk factors for poor prognosis

Factor	Odds Ratio (95% CI)		p
Age (10-y increments)	1.89	(1.16–3.08)	0.01
GCS score (1-point decrements)	1.19	(0.92–1.55)	0.18
AIS-head (1-point increments)	1.05	(0.17–6.72)	0.96
ASDH	22.35	(1.43–349.77)	0.03
ICH	6.83	(0.18–260.16)	0.30
TAT (10 ng/mL increments)	0.77	(0.53–1.10)	0.15
D-dimer (10 μg/mL increments)	1.92	(1.01–3.65)	0.046
PAI-1 (10 ng/mL increments)	1.05	(0.76–1.45)	0.75

(R² = 0.74)

95% CI 95% confidence interval, GCS Glasgow Coma Scale, AIS Abbreviated Injury Scale, ASDH acute subdural hematoma, ICH intracerebral hematoma and contusion, TAT thrombin-antithrombin III complex, PAI-1 plasminogen activator inhibitor-1

Table 3 Multivariate logistic regression analysis of coagulation/fibrinolysis parameters as independent risk factors for poor prognosis

Factor	Admission		3 h after injury		6 h after injury		12 h after injury
Factor	Odds Ratio (95% CI)	p	Odds Ratio (95% CI)	p	Odds Ratio (95% CI)	p	Odds Ratio (95% CI)	p
TAT (10 ng/mL increments)	0.93 (0.74–1.17)	0.52	1.01 (0.82–1.26)	0.91	1.00 (0.77–1.31)	0.99	0.96 (0.71–1.30)	0.79
D-dimer (10 μg/mL increments)	1.65 (1.38–1.98)	0.005	1.16 (1.02–1.33)	0.03	1.13 (0.95–1.34)	0.18	1.28 (0.94–1.73)	0.12
PAI-1 (10 ng/mL increments)	1.03 (0.81–1.30)	0.82	1.17 (0.99–1.40)	0.07	1.20 (1.04–1.39)	0.01	1.31 (1.07–1.59)	0.008

Factor	1 d after injury		3 d after injury		7 d after injury
Factor	Odds Ratio (95% CI)	p	Odds Ratio (95% CI)	p	Odds Ratio (95% CI)	p
TAT (10 ng/mL increments)	1.11 (0.46–2.66)	0.82	0.81 (0.48–1.37)	0.42	1.49 (0.66–3.12)	0.36
D-dimer (10 μg/mL increments)	1.47 (0.65–3.32)	0.36	15.45 (0.98–243.12)	0.05	1.28 (0.49–3.29)	0.62
PAI-1 (10 ng/mL increments)	1.24 (1.00–1.53)	0.047	0.96 (0.75–1.23)	0.76	1.82 (0.94–3.55)	0.08

(admission: R² = 0.51; 3 h after injury: R² = 0.48; 6 h after injury: R² = 0.45; 12 h after injury: R² = 0.51; 1 d after injury: R² = 0.33; 3 d after injury: R² = 0.25; 7 d after injury: R² = 0.16)

95% CI 95% confidence interval, TAT thrombin-antithrombin III complex, PAI-1 plasminogen activator inhibitor-1

No competing interests reported.

Download PDF

Editorial decision: Major revision
30 Sep, 2022
Reviews received at journal
15 Sep, 2022
Reviewers agreed at journal
13 Sep, 2022
Reviewers invited by journal
11 Sep, 2022
Editor assigned by journal
05 Sep, 2022
Editor invited by journal
05 May, 2022
Submission checks completed at journal
05 May, 2022
First submitted to journal
30 Apr, 2022

You are reading this latest preprint version

Hyperfibrinolysis and Fibrinolysis Shutdown in Patients with Traumatic Brain Injury

Status:

Version 2

Abstract

Figures

Background

Methods

Results

Discussion

Limitations

Conclusions

Abbreviations

Declarations

References

Tables

Additional Declarations

Status:

Version 2