Intracranial hemorrhage (ICH) after traumatic brain injury (TBI) commonly increases in size and coagulopathy has been implicated in such progression. Our aim is to perform a meta-analysis to assess their relationship. Cochrane library, PubMed, and EMBASE were searched for literatures. Pooled effect sizes and 95% confidential intervals (CIs) were calculated using random-effects model. We included six studies, involving 1700 participants with 540 progressive hemorrhagic injuries (PHIs). Our findings indicate that PT, D-dimer level, and INR value are positively associated with the risk of PHI. Higher level of PLT and Fg seemed to suggest a lower risk of PHI. Among these parameters, higher D-dimer level and INR value would possess more powerful strength in predicting PHI.
Traumatic brain injury (TBI) remains the leading cause of death after trauma, often leading to long term physical and neuropsychiatric deficits [
PHI is generally defined as the appearance of new hemorrhage lesion or evident expansion of previous hematoma [
However, data regarding the association between laboratory tests and PHI have been somewhat inconsistent. Stein and associates indicated that abnormal values of INR, APTT, and PLT were independently correlated with PHI [
Two investigators (Danfeng Zhang and Shun Gong) independently searched Cochrane Library, PubMed, and Embase for pertinent studies examining the association between coagulation parameters and the risk of PHI after TBI. Six main coagulation parameters at admission were investigated, respectively. The search was limited to studies published between 1970 and October 2014. The language was restricted to English. The reference lists of retrieved articles were scrutinized to identify additional relevant studies.
We defined PHI as “the appearance of new lesion(s) or a conspicuous increase in the size of hemorrhagic lesion(s), which amounted to no less than a 25% or more increase versus the first post-injury CT scan” [
Categorization, exposure, continuous data, and definition of PHI of included studies. (Units of measure: PLT,
Study, the year of publication | Study outcome | Exposure | Cutoff point of every coagulation parameter or coagulopathy | Mean ± SD of PHI group versus non-PHI group | Definition of PHI |
---|---|---|---|---|---|
Oertel et al., 2002 [ |
PHI | PLT | 143 | 226 ± 74 versus 233 ± 69 | PHI was defined as an unambiguous increase in the full film appearance of lesion size; this amounted to a 25% or more increase in at least one dimension of one or more lesions seen on the first postinjury CT scan. |
PT | 11.5 | 12 ± 1.2 versus 12.2 ± 1.5 | |||
PTT | 33.4 | 26.2 ± 5.4 versus 25.2 ± 4.2 | |||
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Sun et al., 2011 [ |
PHI | PLT | — | 166.5 ± 53.5 versus 172.4 ± 57.2 | PHI was defined as increased appearance of lesion size, which amounted to no less than a 25% increase in one dimension of one or more lesions from the first postinjury CT scan. |
PT | N/A | — | |||
PTT | — | 25.4 ± 3.5 versus 26.2 ± 5.8 | |||
D-dimer | — | 2.1 ± 2.3 versus 1.3 ± 1.1 | |||
FIB | — | 2.6 ± 1.7 versus 2.8 ± 2.8 | |||
INR | — | 1.9 ± 1.0 versus 1.1 ± 0.5 | |||
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Tian et al., 2010 [ |
PHI | PLT | 100 | — | PHI was defined as the appearance of new lesion(s) or a conspicuous increase in the size of hemorrhagic lesion(s), that is, a 25% increase or more versus the first postinjury CT scan. |
PT | 17 | — | |||
PTT | 48 | — | |||
D-dimer | 5 | — | |||
Fg | 2.0 | 2.33 ± 0.62 versus 2.60 ± 0.65 | |||
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White et al., 2009 [ |
PIH | PLT | — |
221 ± 84 versus 245 ± 65 | Contusion growth was defined as an increase of at least 33% from the initial volume as measured by image analysis on the second CT compared with the baseline CT scan. |
PTT | — |
29 ± 5 versus 28 ± 4 | |||
INR | — | 1.4 ± 0.3 versus 1.2 ± 0.2 | |||
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Tong et al., 2012 [ |
PIH | PLT | 100 | 168.57 ± 55.22 versus 175.91 ± 51.11 | PIH was diagnosed if a patient’s repeat CT scan was read as worsening because of new lesions or an increase in the original volume of abnormalities (25% increase in the lesion on the first postinjury CT scan). |
PT | 15.5 | 14.06 ± 1.54 versus 13.39 ± 1.15 | |||
PTT | 39 | 34.67 ± 6.54 versus 34.46 ± 6.39 | |||
D-dimer | 2.6 | 80.20 ± 76.75 versus 11.41 ± 14.05 | |||
Fg | 1.8 | 2.30 ± 1.10 versus 2.56 ± 0.65 | |||
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Yuan et al., 2012 [ |
PIH | PLT | 150 | PHI was defined as the appearance of new lesions or a conspicuous increase in the size of hemorrhagic lesions (i.e., a 25% increase or more compared to the first postinjury CT scan). | |
PT | 14 | ||||
PTT | 40 | ||||
D-dimer | 5 | ||||
Fg | 2.0 | ||||
INR | 1.2 |
APTT: activated partial thromboplastin time; D-D: D-dimer; DTICH: delayed traumatic intracerebral/intracranial hemorrhage; Fg/FIB: fibrinogen/fibrin; INR: international normalized ratio; N/A: not available; PHI: progressive hemorrhagic injury; PIH: progressive intracerebral/intracranial hemorrhage; PLT: platelet counts; PT: prothrombin time; SD: standard deviation.
Studies were considered eligible if they (1) were controlled observational studies; (2) included people suffering TBI; (3) investigated the relationship between abnormal coagulation tests and PHI.
Three authors (Danfeng Zhang, Shun Gong, and Hai Jin) extracted the data in standardized data-collection forms, and 2 authors (Wei Zou and Ping Sheng) assessed the study quality. The Newcastle-Ottawa Scale was used to evaluate the methodological quality [
We pooled continuous and dichotomous data extracted from pertinent articles, respectively, using the random-effects model. When both data were available in one paper, they were pooled into different aspects of our meta-analysis. Mean difference and odds ratio (OR) were selected as the effect sizes. Correlation coefficient
The results of study-selection process were shown in Figure
The flow diagram for identifying eligible studies.
A total of 6 studies were included for the meta-analysis, consisting of 4 case-control studies [
Characteristics of included studies of coagulation tests and risk of PHI.
Study, the year of publication | Study design | Study population | Number of participants | % men | Age (mean or range) (years) | Exposure | Endpoints (number of cases) | Time of 2nd HCT after admission (mean or range) (hours) |
---|---|---|---|---|---|---|---|---|
Oertel et al., 2002 [ |
Nested case-control | American | 142 | 81 | 34 ± 14 (>16) | PLT, PT, and PTT | PHI (60) | <24 |
Sun et al., 2011 [ |
Nested case-control | Asian (Chinese) | 352 | 68 | 18–87 | INR, PT, APTT, FIB, D-DT, and PLT | PHI (122) | 4.9 ± 2.1 |
Tong et al., 2012 [ |
Case-control | Asian (Chinese) | 498 | 73 | 44 ± 18 | PT, APTT, Fg, PLT, and D-D | PIH (139) | 4–6 |
Yuan et al., 2012 [ |
Case-control | Asian (Chinese) | 468 | 78 | 47 | PT, APTT, Fg, PLT, D-D, and INR | PHI (108) | <24 |
Tian et al., 2010 [ |
Case-control | Asian (Chinese) | 194 | 79 | 43.9 ± 15.4 | PT, APTT, Fg, PLT, D-D, and INR | PHI (81) | <24 |
White et al., 2009 [ |
Case-control | American | 46 | 82 | 38 (11–78) | PLT, PTT, and INR | PHI (30) | 12 ± 6.5 |
APTT: activated partial thromboplastin time; D-D: D-dimer; DTICH: delayed traumatic intracerebral/intracranial hemorrhage; Fg/FIB: fibrinogen/fibrin; INR: international normalized ratio; N/A: not available; PHI: progressive hemorrhagic injury; PIH: progressive intracerebral/intracranial hemorrhage; PLT: platelet counts; PT: prothrombin time; SD: standard deviation.
Quality scores of case-control studies using Newcastle-Ottawa Scale (maximum score of 9).
Reference | Selection | Comparability | Outcome | ||||||
---|---|---|---|---|---|---|---|---|---|
Adequate definition of cases | Representativeness of cases | Selection of controls | Definition of controls | Comparability on the basis of the design or analysis | Assessment of exposure | Same method of ascertainment for cases and controls | Nonresponse rate (<20%) | Overall | |
Oertel et al., 2002 [ |
1 | 1 | 0 | 1 | 1 | 1 | 1 | 1 | 7 |
Sun et al., 2011 [ |
1 | 1 | 0 | 1 | 1 | 1 | 1 | 1 | 7 |
Tong et al., 2012 [ |
1 | 1 | 0 | 1 | 2 | 1 | 1 | 1 | 8 |
Yuan et al., 2012 [ |
1 | 1 | 0 | 1 | 2 | 1 | 1 | 1 | 8 |
Tian et al., 2010 [ |
1 | 1 | 0 | 1 | 2 | 1 | 1 | 1 | 8 |
White et al., 2009 [ |
1 | 1 | 0 | 1 | 2 | 1 | 1 | 1 | 8 |
0 = “no,” “unable to determine,” or “not available.”
Effect of coagulopathy on PHI after traumatic brain injury.
Data type | Coagulation tests | Number of studies | Population size |
|
Heterogeneity ( |
MD/OR (95% CI) |
---|---|---|---|---|---|---|
Continuous | PLT | 4 | 1003 | 0.06 | 0 | −7.24 |
PT | 2 | 630 | 0.56 | 90 | 0.25 |
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PTT | 4 | 1026 | 0.92 | 33 | 0.05 |
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D-dimer | 2 | 850 | 0.31 | 99 | 34.48 |
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Fg | 3 | 1044 | <0.001 | 0 | −0.26 |
|
INR | 2 | 398 | 0.10 | 96 | 0.50 |
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Dichotomous | PLT | 4 | 1267 | <0.001 | 35 | 2.76 |
PT | 5 | 1644 | <0.001 | 70 | 2.69 |
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PTT | 4 | 1289 | 0.15 | 70 | 2.39 |
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D-dimer | 3 | 1160 | <0.001 | 63 | 16.50 |
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Fg | 3 | 1145 | <0.001 | 0 | 3.44 |
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INR | 2 | 512 | <0.001 | 0 | 3.70 |
APTT: activated partial thromboplastin time; Fg: fibrinogen/fibrin; INR: international normalized ratio; PHI: progressive hemorrhagic injury; PLT: platelet counts; PT: prothrombin time; CI: confidence interval; MD: mean difference; OR: odds ratio.
Summary of the strength of coagulation tests in predicting PHI after traumatic brain injury.
Data type | Coagulation test | Number of studies | Population size | Fisher’s |
Weighted |
Range of effect size |
---|---|---|---|---|---|---|
Continuous | PLT | 4 | 1003 | −0.07 |
−0.06 | −0.13–−0.003 |
PT | 2 | 630 | 0.10 | — | — | |
PTT | 4 | 1026 | 0 | — | — | |
D-dimer | 2 | 850 | 0.50 |
0.46 | 0.01–0.75 | |
Fg | 3 | 1044 | −0.13 |
−0.13 | −0.23–−0.04 | |
INR | 2 | 398 | 0.52 |
0.47 | 0.36–0.59 | |
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Dichotomous | PLT | 4 | 1267 | 0.28 |
0.27 | 0.10–0.43 |
PT | 5 | 1654 | 0.34 |
0.33 | 0.16–0.48 | |
PTT | 4 | 1289 | 0.29 | — | — | |
D-dimer | 3 | 1160 | 0.80 |
0.66 | 0.44–0.81 | |
Fg | 3 | 1145 | 0.31 |
0.30 | 0.22–0.38 | |
INR | 2 | 512 | 0.37 |
0.35 | 0.27–0.42 |
APTT: activated partial thromboplastin time; Fg: fibrinogen/fibrin; INR: international normalized ratio; PHI: progressive hemorrhagic injury; PLT: platelet counts; PT: prothrombin time;
In order to unravel the connection intensity for each parameter, the correlation coefficient
Meta-analysis of pertinent studies implied a strong strength for Fg reduction (
Powerful impact strength was detected for D-dimer, with summary relative risk of 0.66 (95% CI, 0.44–0.81;
To explore whether our results were influenced by a particular study, we carried out a leave-one-out sensitivity analysis, in which one study at a time was excluded and the remaining ones were analyzed. In sensitivity analysis for PLT, PTT, and Fg, no significantly altered result was shown when excluding studies one by one, whether these indicators were examined as dichotomous variables or continuous variables. As for PT, we found that the study by Oertel et al. [
High prevalence and mortality highlight the importance of timely prognosis of PHI with good sensitivity and specificity. With repeated CT scanning which is time-consuming and costly, addressing the associations between the abnormal coagulation tests and PHI would be of great avail. So whether coagulopathy correlates with PHI occurrence, which laboratory test is meaningful, and which parameter carries the most weight in predicting PHI become burning questions confronting us.
Our findings showed statistically significant positive associations between PT, D-dimer level, INR, and the risk of PHI after TBI. Higher level of PLT and Fg seemed to suggest a lower risk of PHI. Independent PTT seemed to be of no indicative value. As for dichotomous variables, the contributions to PHI were as follows: DD > INR > PT > Fg > PLT. But when examined as continuous variables, the sequence seemed to be INR > DD > Fg > PLT. Meta-analysis of continuous data was perceived to be more meaningful compared with that of dichotomous data because of less conversion steps to correlation coefficient (
Meanwhile, there were some discrepancies in association strength between dichotomous and continuous data. Contributions of DD and INR were similar, with INR being a little more influential in the analysis of continuous data, while, as a dichotomous variable, DD had the strongest relationship with PHI. The distinction was speculated to derive from different conversion steps, limited included articles, and subjects. As a dichotomous variate, the predicting value for PT was significant, but that was not the case when it was examined as a continuous variate, which might owe to different test methods of included studies. In analysis for PTT as a dichotomous variate, positive association was detected when ignoring Oertel et al. [
While the quantitative association between coagulative tests and the risk of PHI has been confirmed, we have to acknowledge that four of our included studies are from China and 2 from America. But this does not significantly mean the incidence of ICH in eastern population is higher than in the counterparts, because of lacking in large prospective epidemic studies in our analysis. Potential bias from population difference should be further evaluated through more large epidemic studies.
No meta-analysis about PHI was published before. There is currently 1 publication that we are aware of that has reviewed the current etiology research available to interpret the predictor and mechanism of PHI [
Our findings implied that abnormal coagulation tests might indicate occurrence of PHI, which might lead to focused monitoring among TBI patients, and thus save plenty of medical resources. Our interpretation could form the basis for further studies exploring whether correcting these values would prevent PHI and moreover make for subsequent operation. However, there is no strong evidence that correcting laboratorial tests in this situation actually improves outcome. According to Perel et al., there is no reliable evidence from randomized controlled trials to support the effectiveness of hemostatic drugs in reducing mortality or disability in patients with TBI [
As with all meta-analysis, some caveats are in order. Firstly, bias exists because of defects in study design of included studies and meta-analysis itself, such as publication bias, selection bias, confounding bias, and recall bias. Reporting bias might have also occurred, which derived from the disparities in testing method and cutoff point for each parameter in pertinent studies, which, though moderate, might serve as the confounding factors. We tried our best to minimize the bias by excluding those studies with insufficient patient characteristics [
However, our study had strengths in including relatively newer studies with reliable imaging examinations, quantitative analyses, and precise and consistent definition of PHI as we described above. Moreover, we calculated the comparable association strength in predicting PHI after TBI for each parameter for the first time, which was much more clinically meaningful than the association alone. Thus we could assess the prognostic value of these parameters, which might further guide clinical practices.
Despite the limitations, this meta-analysis has notable clinical and public health implications, which indicate significant inverse associations for PLT level, Fg level, and positive associations for PT, D-dimer level, and INR value in predicting PHI, among which abnormal D-dimer level and INR value were more meaningful. Independent PTT seemed to be meaningless. This study suggests instant test and correction of coagulation parameters at admission to predict PHI and, possibly, better outcome of TBI patients. The focus of our meta-analysis is upon the capability for individual test to predict the presence of PHI after TBI. However, to demonstrate the relationship between coagulopathy and the extent of PHI seems more meaningful, which may be the interest of future studies. Moreover, interrelationships between coagulation tests, which were not discussed here, remain to be unraveled. Eventually, large prospective studies are needed to investigate the underlying pathogenesis better and identify effective therapy to reap the maximum benefits.
No competing financial interests exist.
Danfeng Zhang, Shun Gong, and Hai Jin contributed equally to the paper.