Key-words:
Coagulopathy - GOS - isolated head injury
Introduction
Traumatic brain injury (TBI) is the major cause of mortality and permanent disability
in India and abroad. The primary and secondary injury affects its outcome. Primary
insult of a brain cannot be altered, but secondary insults are preventable. Thus,
the management of TBI should target measures that minimize the secondary injury.[[1]],[[2]],[[3]],[[4]]
Coagulopathy is one of the causes of secondary insult.[[5]],[[6]] Acute intrinsic coagulopathy arising in severely injured trauma patients is termed
as trauma-induced coagulopathy (TIC).[[7]] TIC may result from dilution, dysfunction, or loss of the coagulation proteases.
Its early identification through a set of coagulation tests along with its prompt
intervention is the need of the hour.
There is a lack of Indian data on TIC in moderate-to-severe isolated TBI (iTBI) patients.
Therefore, a study was planned to find out the incidence of TIC and its outcome in
patients with moderate-to-severe iTBI.
Materials and Methods
After getting clearance from the Institutional Ethics Committee, the study was registered
in Clinical Trial Registry-India (CTRI/2017/12/010836). A prospective observational
study was carried out on patients admitted to intensive care units (ICUs) of a Level
I Trauma Center in India. Patients of age group of 18–65 years with moderate-to-severe
iTBI admitted to hospital within 24 h of injury were included in this study after
taking informed consent from the nearest kin of the patient. Pregnant patients, pediatric
patients, patients having the previous history of coagulation disorder, patients on
anticoagulant therapy were excluded from the study. Patients with a history of liver
or kidney disease or patients unwilling to participate in the study were not included
in this study. Patients who were included in the study but have undergone an operation
during the study were also excluded from the final analysis. All patients underwent
detailed clinical evaluation followed by categorization into moderate and severe head
injury group by GCS. Non-contrast CT scan of head (NCCT) head to diagnose the type
of injury and Marshall scoring system to grade the severity of the injury were included
in the assessment of the patients.
Samples for coagulation tests which included prothrombin time (PT), PT index (PTI),
international normalization ratio (INR), activated partial thromboplastin time (aPTT),
and platelet count were collected at 5 points of time namely at the time of admission
and were repeated at the time of ICU/high dependency unit (HDU) admission, 24, 48,
and 72 h of injury. If any patient had deranged coagulation in any 3 of the total
readings during the 72 h period, was considered to have TIC. Our laboratory values
which were considered normal for the above-mentioned test were as follows: PT – 12–14
s, PTI – 100%, INR <1.4, aPTT – 25–32 s, and platelet count – 1.5–4 lac/ml.
Cutoff limits for the abnormal coagulation parameters were PT >16 s, PTI <80%, aPTT
>32 s, INR >1.4, and platelets <100 × 103/mm 3.
The patients who have deranged values at admission were assessed for D-dimer and fibrinogen
levels with cutoff values for abnormal coagulation parameters being D dimer >260 ng/ml
and fibrinogen level >4 g/L.
All patients recruited in the study were followed up till death in hospital or discharge
from the hospital. During the hospital stay, they were assessed for the number of
ventilator days, ICU days, and hospital days. All patients discharged from the hospital
were followed up telephonically at 1 and 3 months interval to assess neurological
outcome using the Glasgow Outcome Scale (GOS). GOS score ≤3 was taken as poor GOS
and GOS ≥4 was taken as good GOS.
The data were analyzed using Statistical Package for the Social Sciences software
version 21 for Microsoft Windows (SPSS Inc., Chicago, IL, USA). Continuous variables
are presented as the mean ± standard deviation or frequency (n) and percentage (%).
Discrete variables were analyzed and presented as proportions. Categorical data were
analyzed using the Chi-square test and Fisher's exact test. Parametric test such as
t-test and Student's t-test was used to see the significance of different variables
to the development of coagulopathy and to find their significance in the difference
in the outcome. Logistic regression analysis was applied to determine the independent
predictors of mortality among PT, PTI, INR, aPTT, and platelets count. The P < 0.05
was considered statistically significant.
Results
A total of 100 patients admitted to the hospital within 24 h of injury were included
in the study. Road traffic accident (RTA) was the most common mode of trauma (n =
90), followed by fall from height (n = 6), and assault (n = 4). As per the definition
of TIC, of 100, 62 patients were found to have deranged coagulation parameters in
at least 3 readings in 72 h after admission while 38 patients did not have coagulopathy
in the posttraumatic period. Patients were divided into two groups, those with coagulopathy
and the others without coagulopathy. Demographic parameters of the two groups were
comparable. Contusion was the most common computed tomography finding (n = 63), followed
by Sub-dural haemorrhage; SDH (n = 26), Sub-arachnoid haemorrhage; SAH (n = 10), Diffuse
axonal injury; DAI (n = 18). Based on the admission GCS score, patients were divided
into moderate and severe head injury groups. The incidence of coagulopathy in severe
head injury was more when compared to a moderate head injury (63.75% vs. 55%). [[Table 1]] shows demographic parameters and the incidence of coagulopathy.
Table 1: Demographic parameters and incidence of coagulopathy
We found that deranged PT was present in 79% patients, PTI in 68%, INR in 33% of patients,
aPTT in 41% of patients and deranged platelet count was found in 38% patients. Deranged
coagulation parameters at five different points of time are mentioned in [[Table 2]].
Table 2: Deranged coagulation parameters at different points of time
The pattern for the development of coagulopathy was also observed throughout 72 h.
[[Figure 1]] shows the time pattern for the development of deranged coagulation. The incidence
of coagulopathy was maximum at 24 h while it gradually decreases at 72 h of injury.
Figure 1: The time pattern for the development of deranged coagulation
The patients (n = 35) who had deranged coagulogram at admission, were assessed for
D-dimer and fibrinogen levels, they were found to be abnormal in all these patients
with the mean value of 2678.17 ± 1573.56 ng/ml and 5.613 ± 0.7374 g/L, respectively.
The incidence of in-hospital death in patients included in the study was 28% (n =
28), out of which 78.57% (n = 22/28) had coagulopathy. Out of all deaths in patients
with coagulopathy, 90.9% (n = 20/22) of patients had severe iTBI. [[Figure 2]] shows the flow chart of the incidence of coagulopathy, mortality, and outcome.
Figure 2: The flow chart of incidence of coagulopathy, mortality, and outcome
Increased Marshall score were also associated with increased mortality in patients
having TIC (in Grade IV 50% and Grade V 100%).
Univariate analysis of the different coagulation parameters was done to assess the
relation of coagulation tests to in-hospital mortality. Based on the analysis, abnormal
values of PT at 24 h (P = 0.002), PTI at 24 h (P = 0.001), INR at admission (P = 0.026),
INR at 24 h (P = 0.048), and INR at 48 h (P = 0.046) after injury were found to be
significantly related to in-hospital mortality. On further multivariate analysis of
these parameters, abnormal values of INR at admission (odds ratio [OR] 4.38) and PTI
at 24 h (OR 3.913) are found to be strongly associated with in-hospital mortality
[[Table 3]].
Table 3: Multivariate analysis for prediction of mortality by coagulation parameters
The outcome of the patients having coagulopathy was also analyzed based on the number
of ventilator days, ICU days, a total length of hospital stay. The parameters were
comparable between the groups. GOS at 1 and 3 months after discharge were also noted.
It was found to be comparable [[Table 4]].
Table 4: Outcome in patients with or without coagulopathy
Seventy-two out of 100 patients included in the study were discharged from the hospital,
among which 40 patients had coagulopathy while 32 patients did not have a coagulopathy.
Among patients with TIC, 64.51% of patients were discharged from the hospital. Sixty-seven
patients discharged from the hospital were analyzed for the neurological outcome at
1 and 3 months using GOS. The incidence of poor GOS in patients with TIC at 1 month
was observed in 32 (88.88%) patients. At 3 months' follow-up, the incidence of poor
GOS among patients with TIC and the noncoagulopathy group was 43.75% and 40.74%, respectively.
The incidence of total deaths during the study which includes 3 months after discharge
was 43.54% in patients who had TIC while it was 26.31% in patients who did not have
TIC with the risk ratio of 1.72 and 95% confidence interval of 0.94–3.12.
Discussion
TBI is among the common causes of mortality and morbidity in the form of permanent
disability among trauma victims. Besides the primary insult, secondary insult which
develops over time are also responsible for its eventual outcome. One of the causes
of secondary complications is TIC.
In trauma, blood loss and tissue injury leads to tissue hypoperfusion and thus hypoxemia.
During tissue hypoperfusion, endothelium releases thrombomodulin, which complex with
thrombin and they, in turn, activates protein C, inhibiting factor V and VIII. These
events inhibit the extrinsic pathway of coagulation. Tissue plasminogen activator
is also released which activates fibrinolysis. The brain is rich in tissue factor
“thromboplastin” and is released into circulation after the patient suffers from brain
injury. It activates the extrinsic pathway of coagulation, causing a state of consumptive
coagulopathy, which may cause multiple organ dysfunction and increase the risk of
mortality. There is also a qualitative and quantitative compromise in platelet number
and function, which increases patients' susceptibility for bleeding. [[Figure 3]] shows the overall mechanism and series of events that leads to coagulopathy.
Figure 3: Overall mechanism and series of events that leads to coagulopathy
A prospective observational study was conducted in patients with iTBI admitted to
a Level I Trauma center in India to find out the incidence of coagulopathy and its
outcome.
RTAs are the most common mode of injury (90%), with the young population being affected
the most. The incidence of TIC was found in 62% of patients. Of those with TIC, it
was 63.75% in severe head injury and 55% in the moderate head injury. However, the
incidence of TIC was almost 70.83% in patients who underwent a decompressive craniotomy.
The incidence of TIC reported in various studies range between 10 and 97.3% depending
on the limits and coagulation parameter chosen and also according to the variations
in the definition of coagulopathy.[[8]] Shrestha et al. found the overall incidence of TIC to be 63% almost similar to
our observation.[[9]] Greuters et al. too reported an incidence of TIC to be 54% while Epstein et al.
found the incidence to be 35.2%.[[10]],[[11]] The incidence of coagulopathy varies with the duration of the injury. Our study
observed the maximum incidence of TIC during the first 24 h (21%) of injury, and then,
it declined over 72 h to 12%. The cause of decline could be due to the intervention
is done in ICU such as the transfusion of blood products, maintenance of temperature,
and body pH within the physiological range. Greuter et al. and Lustenberger et al.
also observed an increase in the incidence of coagulopathy in first 24 h [[10]],[[12]] while Carrick et al. reported an increase in incidence by the 3rd postinjury day
which is nearly double of the initial findings.[[13]]
We tried to analyze mortality in patients with TIC in iTBI. Coagulopathy was found
in the majority (78.57%) (n = 22/28). Of the nonsurvivors during the hospital stay,
which was statistically significant when compared to noncoagulopathy group (P = 0.041).
Folkerson et al. have also reported a higher incidence of coagulopathy among nonsurvivors.[[14]] Coagulopathy has been suggested as an independent risk factor for mortality,[[11]],[[15]] but Talving et al. after performing logistic regression to adjust for confounders
have found no association.[[16]]
Among coagulation parameters, we observed that INR at admission (OR 4.38) and PTI
at 24 h (OR 3.913) was strongly associated with in-hospital mortality. Initial abnormal
PT and PTT increase the adjusted odds for death was observed by MacLeod et al.[[17]] Selladurai et al.[[18]] found that high fibrinogen degradation product (FDP) levels predict poor outcome
independently and prognosis worsens as the level of FDP increases.
We had assessed the outcome of the patients based on the duration of ventilator days,
ICU stays, and hospital stay. Talving et al. found that coagulopathy is associated
with longer ICU lengths of stay.[[16]] Harhangi et al. and Wafaisade et al. showed an increase in hospital and ICU stay
in patients with coagulopathy.[[8]],[[19]] Sun et al. also reported an increase in ICU days and hospital stay in those with
coagulopathy.[[20]] We observed longer ventilator days, ICU days, and hospital stays in patients who
developed coagulopathy, but the difference was statistically not significant.
Neurological outcome was assessed by Glasgow Outcome Scale 1 and 3 months after discharge.
The number of patients with poor GOS at 1 month were comparable between the groups
having coagulopathy and those without it (88.9% vs. 87.09%). Similarly, on measuring
GOS at 3 months after discharge, the percentage of patients having poor GOS was found
to be less in both the groups (43.75% vs. 40.74%). However, no significant difference
was found between the groups with or without coagulopathy during follow-up in 1 and
3 months after discharge. Harhangi found an overall odds ratio for the risk of a bad
outcome (GOS 1-3) of 33.2 (95% CI: 15.9–69.1) after TBI and coagulopathy.[[8]] Sun et al. in their study assessed coagulation parameters and neurological outcome
by GOS at 3 months after injury; they observed that abnormal PT, fibrinogen (FIB),
and D-dimer (D-DT) levels on admission were associated with increase patients' mortality
and poor neurological outcome.[[20]] We found that INR at admission and PTI at 24 h was strongly associated with in-hospital
mortality (OR 4.38 and 3.913, respectively.)
There are a few limitations in this study. We measured D-dimer and fibrinogen levels
only in patients who had deranged coagulation parameters at admission and found it
to be deranged in all the cases. We should have checked these parameters in all the
cases included in the study. Viscoelastic method of assessing clotting mechanism (Sonoclot)
could have given a better view of coagulopathy.
Conclusion
We have found an incidence of TIC in isolated moderate-to-severe TBI as 62%. Coagulopathy
is more prevalent in severe head injury than in moderate head injury patients. Deranged
INR at hospital admission and PTI at 24 h of hospital admission are highly predictive
of mortality during the hospital course. Patients having TIC had increased incidence
of death in 3 months compared to those who did not have coagulopathy, though the neurological
outcome at 1 and 3 months after discharge was not different in between the groups.
This study alerts us to check for TIC and plan management accordingly to improve the
outcome of the patients with TIC in isolated TBI.
