Role of D-dimer in Prognostication of Head Injury Patients: A Systematic Literature Review

Article information

J Neurointensive Care. 2025;8(2):29-46

Publication date (electronic) : 2025 October 30

doi : https://doi.org/10.32587/jnic.2025.00836

Vaishali Walke ¹, Suresh Kumar Thanneeru ², Manisha Shrivastava ³, Shweta Mishra ³, Md Yunus ⁴, Oday Atallah ⁵, Amit Agrawal^,⁶

¹Department of Pathology & Lab Medicine, All India Institute of Medical Sciences, Saket Nagar, Bhopal, Madhya Pradesh, India

²Department of Pediatric Surgery, All India Institute of Medical Sciences, Bhopal, India

³Department of Transfusion Medicine, Bhopal Memorial Hospital & Research Centre, Bhopal, Madhya Pradesh, India

⁴Department of Trauma and Emergency Medicine, All India Institute of Medical Sciences, Saket Nagar, Bhopal, Madhya Pradesh, India

⁵Department of Neurosurgery, Hannover Medical School, Hannover, Germany

⁶Department of Neurosurgery, All India Institute of Medical Sciences, Saket Nagar, Bhopal Madhya Pradesh, India

Corresponding Author: Amit Agrawal, MCh Department of Neurosurgery, All India Institute of Medical Sciences Saket Nagar Bhopal 462020 Madhya Pradesh, India Tel: +91-8096410032 Emil: dramitagrawal@gmail.com

Received 2025 May 4; Accepted 2025 October 14.

Abstract

Studies have suggested that patients with severe head injury, in addition to Glasgow Coma Scale (GCS), reveal high D-dimer levels which are independently associated with increased mortality. In the present review, we analyzed the literature where studies have reported the role of D-dimers as a potential biomarker in stratification and early identification of patients with TBI who are at risk of clinical deterioration, where early intervention can improve overall outcomes. After scrutinizing 246 articles, which were narrowed down to 38 (16 prospective, 9 retrospective, 2 RCTs, 2 case-control, 1 cross-sectional study). All these studies included 7,589 patients, in whom D-dimer was measured at different timings and in different ways. Most studies demonstrated significant changes that could be utilized for prognostication. However, we also observed instances where no significant changes were found. Unfortunately, direct comparisons were hindered by variations in the methods used to measure D-dimer across different outcomes. Limitations included the lack of a substantial number of RCTs, heterogeneity of available data, and the difficulty in summarization of specific cutoff points for D-dimer. Future studies, especially RCTs, should measure D-dimer levels at different times from injury for an accurate assessment of its correlation with outcomes.

Keywords: D-dimer; Progression of intracranial hemorrhage; Glasgow outcome scale

INTRODUCTION

Patients with severe traumatic brain injury (TBI) need initial as well as dynamic monitoring to stratify the patients as well as to identify patients who are at high risk for deterioration at an early stage1). In patients with traumatic brain injury (TBI), the injured tissue releases tissue factor, i.e., thromboplastin, that triggers the process of consumptive coagulopathy with unique characteristics and hyperfibrinolysis resulting in high levels of D-dimers (DD) 2-6). Studies have suggested that patients of severe head injury, in addition to Glasgow Coma Scale (GCS), reveal high D-dimer levels which are independently associated with increased mortality7-10). Although the studies have identified the role of D-dimer to predict poor neurological prognosis at discharge, particularly in severe head injuries, there is ongoing debate regarding more standardized measures for early identification and management of coagulopathy at an early stage and thus to improve overall prognosis9-11). In the present review, we analyzed the literature where the studies have reported the role of D-dimers as a potential biomarker in stratification and early identification of patients with TBI who are at risk of clinical deterioration, and early intervention can improve the overall outcomes.

METHODS

The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used to perform the present review12). A systematic literature search was conducted across PubMed, SCOPUS, Central Cochrane Registry of Controlled Trials (The Cochrane Library), and Science Direct databases, using the search terms outlined in Table 1. Additionally, the reference lists of included studies were reviewed for potentially relevant studies. Two investigators (AA and SKT) independently screened abstracts, with selected articles undergoing full-text evaluation. The retrieved details included Study Authors, year of publication, country of corresponding author, inclusion criteria, sample size, age, reported outcomes and details of D-dimer including outcome. Authors were contacted for missing data and discrepancies were resolved through consensus. Randomized controlled trials, quasi-randomized controlled studies, prospective and retrospective observational studies meeting the inclusion criteria, which reported the D-dimer levels were included prognosis and outcomes. Case series, case reports, letters, editorials, comments, animal studies, and non-English literature studies were excluded. Two investigators independently assessed studies and extracted data using a pre-designed proforma based on inclusion criteria. The PRISMA flow chart illustrating the study selection process is presented in Fig. 1. For risk of bias and quality assessment appropriate JBI critical appraisal tools i.e. for prospective studies the JBI critical appraisal checklist for cohort studies (Table 3)13), for retrospective Studies JBI critical appraisal checklist for case control studies (Table 4)13) and for randomized Controlled Trials JBI critical appraisal checklist for RCT studies (Table 5)14) were used respectively.

Table 1.

Details of search strategy

Fig. 1.

PRISMA flow diagram.

Table 3.

JBI critical appraisal checklist for retrospective studies13)

Table 4.

JBI critical appraisal checklist for RCT studies14)

Table 5.

Excluded studies with reasons

RESULTS

Study Selection

After conducting a systematic search using our predefined search criteria as outlined in Table 1, we identified 246 articles. Among these, 24 articles were excluded due to duplication. From the remaining 222 articles, a title analysis resulted in 54 articles selected for full-text review. Out of these 54 articles, 16 were excluded based on reasons specified in Table 5. The final inclusion comprised of 38 articles, and their characteristics are detailed in Table 6.

Table 6.

Characteristics of included studies

Study Characteristics

The selected articles spanned the period from 1994 to 2023 and encompassed diverse geographical locations, including Japan (n=8), the USA (n=8), China (n=6), India (n=3), Egypt (n=2), Sweden (n=2), Canada (n=1), Germany (n=1), Greece (n=1), Iran (n=1), the Netherlands (n=1), Saudi Arabia (n=1), Taiwan (n=1), and Turkey (n=1). Among the included studies, there were 16 prospective, and 9 retrospective studies, 1 was randomized controlled trial (RCT), 1 pilot RCT, 2 case-control studies, and 1 cross-sectional study. In total, 7589 patients were included across all studies, with the highest number of participants in the studies by Yabuno15).

Results of the studies correlating DD levels with Progression of Intracranial Hemorrhage (PIH): There are four studies that correlated DD levels with PIH in TBI patients with intracranial bleed. All these studies uniformly showed a correlation of DD levels with PIH. Fair et al.16) correlated the DD levels with PIH and demonstrated that PIH patients had higher DD levels at the time of admission, with a median and Interquartile Range (IQR) of 1.64 (0.77–2.68) µg/ml and a p value of 0.04. Tong et al.17) reported DD levels of 80.20 ± 76.75 mg/L in PIH patients compared to 11.41 ± 14.05 mg/L in non-progression of PIH patients, with a p value of <0.0001. Peng et al.18) showed DD levels of 5.34 ± 1.35 mg/L in PIH patients, with a p value of <0.001. Xu et al.19), reported 4.89 (4.31–6.87) mg/L levels in PIH patients, with a p value of <0.001. The results of the above studies are mentioned in Table 7.

Table 7.

Progression of intracranial haemorrhage

Results of the studies correlating DD levels with Neurological prognosis in terms of GOS: There are six studies that investigated the correlation of DD with neurological outcome in terms of Glasgow Outcome Scale (GOS). Asami et al.9), showed that DD levels >89.3 µg/ml have a significant correlation with a poor outcome, with an odds ratio (OR) of 18.74 and a 95% confidence interval (CI) of 7.33-47.89. Bredbacka et al.2) correlated DD levels with GOS, using a reference DD level. They found that DD levels >4 µg/L were associated with a median GOS and quartiles of 2 (1.25-2.75), with a p-value of 0.076. Chen et al.,6), demonstrated that DD levels >2 g/L have a positive correlation with poor outcome patients, with an OR of 2.47 and a 95% CI of 1.263–4.845. Murshid et al.20), correlated DD with GOS at 6 months, although specific details were not clear. Peng et al.18), reported DD levels of 6.33 ± 1.07 mg/L, with a significance of p<0.010. DeFazio et al.1), conducted measurements of DD at two different timings, one at admission and the other at 24 hours. They found that the 24-hour DD level of 7753.11 ng/dl had a significant correlation with a poor outcome. The details of the above results were mentioned in Table 8.

Table 8.

Predictor of neurological prognosis (GOS)

Results of the studies correlating DD levels with prognosis in terms of survivors and non survivors: There are ten studies that correlated D-dimer (DD) levels with the prognosis of patients with Traumatic Brain Injury (TBI) in terms of survivors and non-survivors. Except for Gupta et al.21), all the other studies showed a positive correlation with DD levels in the non-survivor group. Bayir et al.10), reported DD levels of 1.0 ± 0.0 µg/ml (mean and SD), Allard et al.22) 18000 (10000,20000) ng/ml, Saggar et al.23), showed 2.43 ± 0.49 µg/L, Sun et al.24), reported 4.69 ± 3.82 mg/L, and Tu et al.25), reported 4.54 ± 0.86 g/L, all with a significance of p<0.001 in the non-survivor group. Takahashi et al.26), divided groups into those who deteriorated, those with a good outcome. They showed a positive correlation with DD levels with p<0.01. Fouad et al.27), and Youssef et al.11), measured DD levels at different time intervals and showed a significant correlation between survivors and non-survivors at all the measured timings. Wada et al.28), correlated outcome with respect to Fibrinolysis and Death and DD levels are clearly compared. Gupta et al.21) showed DD levels of 2,616 ± 1,703.86 µg/dl (n=4) in survivors and 2,812 ± 1,351 µg/dl in non-survivors (n=20), which was not statistically significant (p>0.05). The results of the above studies are tabulated and mentioned in Table 9.

Table 9.

DD as prognostic indicator for survivors and non survivors

Results of the studies correlating DD levels with CT findings: There are seven studies investigating the association between DD levels and the prediction of positive computed tomography (CT) findings. Among these, four studies involve the pediatric population, and three involve adults. Kuo et al.29) reported results based on the correlation of coagulopathy with midline shift, revealing a positive correlation. However, there is no specific mention of a direct association between DD levels and CT findings in their study. Berger et al.30) and Hosseininejad et al.31) both demonstrated a significant correlation between CT positive findings and DD levels with a p-value < 0.001. Hoffmann et al.32), Langness et al. (2018), Nozawa et al.33), and Swanson et al.34) all found a positive correlation with CT findings. They attempted to establish negative predictive values with thresholds of <284 ng/ml (97.6%), <100 pg/µL (100%), <0.5 µg/mL (100%), and 500 pg/μl (94%), respectively. Due to variations in measurement techniques and timing of DD level assessments, a meta-analysis is not feasible. The results of these studies are summarized in Table 10.

Table 10.

Predict the need for CT

Results of the studies correlating DD levels with other outcomes: Apart from the above outcome measures, the following studies investigated a variety of outcomes. Chhabra et al.,35), indirectly correlated D-dimer (DD) with outcome with respect to coagulopathy. They showed that DD >2 µg/ml, with an odds ratio (OR) of 3.4 (95% CI of 1.3-8.6), has a p-value of 0.009 for the development of coagulopathy, which was subsequently shown to be a strong predictor for a poor outcome. Dekker et al.36), correlated the role of coagulopathy with cerebral oxygenation in patients with TBI. They found that lactate levels and base excess had a correlation with DD levels (r=0.40, p=0.029); (r=-0.39; p=0.027). Genet et al.37), investigated hemostatic response to isolated TBI, severe TBI with other injuries, and non-TBI. They found that DD levels in isolated TBI (n=23) were 170 ng/ml (133-174); sTBI+other (n=15) were 173 ng/ml (171-176); non-TBI (n=42) were 145 ng/ml (61-171) with p=0.003. Grenander et al.38), assessed if antithrombin treatment reduces the progress of brain contusion, decreases ICU stay, and improves outcome (GOS). DD levels were not directly correlated with outcomes. Nakae et al.39), examined the relationship between age and coagulation and fibrinolytic parameters occurring within the first 12 hours after injury. They found DD was significantly elevated in both adult and pediatric groups, with no significant differences between groups. The independent risk factor for a poor prognosis was DD level at admission, OR 6.70, 95% CI (1.67-142.59) (p<0.001). Nakae et al.40), investigated the relationship between plasma fibrinogen concentration 3 hours after initiating FFP transfusion and patient outcomes and evaluated the correlation with DD levels at admission. They found DD at admission was significantly associated with a decrease in fibrinogen following injury in the FFP non-transfusion group (R² =0.29, p<0.0001). Pahatouridis et al.41), investigated the incidence of DIC in moderate head injury patients and the safety of early use of LMW heparin. They found DD strongly elevated >2,000 ng/ml in 83% of patients on the first day, by the 3^rd day 55% normalized, but 45% remained with DD above 2000 ng/ml. Lower GCS scores correlated with increased DD levels. Scherer et al.42), determined the degree of regional and systemic coagulation activation after isolated severe head injury. They found DD at admission was significantly elevated in head trauma patients (p<0.005), with no difference in concentration in cerebrocentral blood than in central venous blood. No correlation was found with clinical outcomes. Shibahashi et al.43), analyzed the risk factors and outcomes of SDH development following surgical evacuation for unilateral acute SDH. They found DD in the SDH group DD levels were 73.1 µg/ml (38.9, 134.4) compared with controls having DD levels of 33.5 µg/ml [16.9, 73.8] (p=0.13), which was not significant. Yabuno et al.15), investigated outcomes for ICU survivors after moderate to severe TBI and assessed predictive factors. They found that the Non-Return to Home group (n=24) had DD levels of 58.62 +/- 51.34 µg/ml, and the Return to Home group (n=83) had DD levels of 36.44 +/- 39.99 µg/ml with p=0.028. However, DD levels correlated with return to work had p=0.082.

DISCUSSION

D-dimer (DD) was introduced into clinical practice in the 1990s, primarily for diagnosing deep vein thrombosis and pulmonary embolism, as well as for diagnosing disseminated intravascular coagulation30). The pathophysiology of coagulopathy in traumatic brain injury (TBI) is well explored. The mechanism of the increase in DD levels post-injury might be through the release of tissue factor in the injured brain, which can trigger consumptive coagulopathy and hyperfibrinolysis, leading to high DD levels22). There are articles stating that the brain has more tissue factor per unit weight than other tissues, which can explain the prominent coagulation and association of hyperfibrinolysis in these patients. These DD levels might reflect the severity of injury and thus can aid in the prognostication of these patients9). The incidence of coagulopathy in TBI is estimated to be 15 to 100%6). The mortality rate post-severe TBI is around 30 to 50%, and most deaths occurred within 48 hours of the insult1). An indicator that can prognosticate at the initial part of admission can help in explaining the patient's condition to attenders and prioritizing the treatments accordingly. Many studies have explored this option, and some studies have even attempted to prevent unnecessary CT scans based on DD levels where there is a low risk of brain injury. This systematic review was conducted to determine whether DD can be used for prognostication in TBI patients and to identify the cutoff values used in different studies.

Approximately 50% of the patients experiencing traumatic brain injury (TBI) may exhibit progression of intracranial hemorrhage (PIH), as evident through an increase in lesion size on repeat CT scans16). The coagulopathy associated with TBI can impact the occurrence of PIH. Consequently, markers of fibrinolysis can be employed to predict the likelihood of PIH in these patients. PIH stands as an independent prognostic factor for poor outcomes, and D-dimer (DD) can serve as a valuable marker to anticipate cases with PIH. In our review, Fair et al.16), Tong17), Peng18), and Xu19), among others, explored the role of DD in assessing the probability of increased PIH following TBI. All studies demonstrated a significant correlation between elevated DD levels and PIH, although variations in measurement types and timing were observed, hindering the possibility of a meta-analysis due to a lack of uniformity in reporting. Fair et al16). conducted a prospective observational study, measuring DD levels in patients with isolated TBI and an AIS >3. The study observed different timings and revealed that admission levels of DD were significantly associated with PIH. Peak DD levels were observed at 6 hours, with a decreasing trend noted over 48 hours. Tong17) conducted a retrospective study with 530 patients to investigate the risk factors related to PIH in patients with isolated TBI. They found that DD levels in PIH patients are significantly elevated. Peng18) conducted a prospective study, considering samples for DD levels in peripheral venous blood on the morning of the day of diagnosis and compared them with healthy controls. They showed significantly elevated DD levels, with levels in patients with a severe coma group being much higher than patients with a mild coma. Similarly, Xu19) conducted a retrospective study with inclusion criteria of patients admitted within 6 hours after trauma, AIS <3, and two CT scans performed within 24 hours of admission. They found that DD levels in PIH patients are significantly elevated compared to non-PIH patients. The main limitations among these studies include the nature of studies not being randomized controlled trials (RCTs) and the timing of DD measurement, which is not uniform. Ideally, the timing should have been from the time of injury rather than the time of admission.

The Glasgow Outcome Scale (GOS) is utilized to grade outcomes following neurological recovery, comprising five grades. Grades 1, 2, and 3 are generally considered to indicate a poor prognosis, while grades 4 and 5 suggest a good prognosis. In our review, six studies compared D-dimer (DD) levels with outcomes measured in terms of GOS. Asami9) conducted a prospective study with 335 participants, measuring DD at hospital arrival and correlating it with GOS outcomes. They included patients with severe traumatic brain injury (TBI) and a Glasgow Coma Scale (GCS) <8. Univariate analysis showed DD levels above 17.4 µg/ml associated with a poor prognosis, and multivariate analysis identified DD levels above 89.3 µg/ml as an independent predictor of poor outcomes. Bredbacka2) conducted a prospective study with 20 participants, aiming to test the association of Soluble Fibrin, Antithrombin, and DD with poor outcomes in isolated TBI patients. They included patients admitted within 24 hours of injury, measuring DD levels at admission. While they found no association with GOS scores, they observed significantly elevated levels in patients with worse GCS. They used a reference DD level of more than 4 µg/L for correlating GOS scores. Chen6) conducted a retrospective study with 265 participants to assess post-traumatic coagulopathy with early post-traumatic cerebral infarction. Patients admitted within 4 hours of injury with GCS less than 12 were included. DD was measured 12 hours after admission, and GOS was assessed at 3 months. They found that high DD levels (>2 mg/L) were associated with poor outcomes. Murshid20) conducted a prospective study with 17 patients, measuring DD levels at different timings and access sites (peripheral, arterial, and jugular venous) over 4 days. Levels from all sites were maximal at admission and decreased over time. GOS measured at 6 months did not show any correlation with DD levels. Peng18) conducted a prospective study with 42 patients, correlating DD levels with GOS and finding a significant correlation with poor outcome patients, in addition to progression of intracranial hemorrhage (PIH) as mentioned earlier. DeFazio1) conducted a retrospective study with 44 subjects, including severe TBI patients within 3 hours of injury. DD was measured at different time intervals, and they found that DD values at 24 hours were more significant in correlation with poor outcomes. The limitations of the above studies include the absence of randomized controlled trials (RCTs), limited number of subjects, variations in the timing of collection in some studies, and the use of different reagents for estimating DD.

One of the most important factors to consider for prognosis is mortality. Explaining mortality rates to the patient attenders helps in better counseling. In our review, ten studies focused on the correlation of D-dimer (DD) levels with mortality rates. Bayir10) conducted a prospective study with 62 patients, considering those with isolated traumatic brain injury (TBI) admitted within 3 hours of injury. They found a significant correlation of DD levels between survivors and non-survivors. Allard22) conducted a randomized controlled trial (RCT) with 72 patients, primarily to investigate the association between coagulopathy and progression of intracranial hemorrhage (PIH). Measurement of DD levels was part of post hoc analysis, and they found that DD levels were significantly correlated between survivors and non-survivors. Fouad27) performed a case-control study, focusing on children with TBI. They measured DD levels at different intervals from Day 1 till day 14. The best cut-off point for Day 1 DD levels was found to be 10.5, with a sensitivity of 89.5%, specificity of 100.0%, positive predictive value (PPV) of 100.0%, and negative predictive value (NPV) of 93.1%. Gupta21) conducted a prospective study with 50 subjects, having isolated TBI with moderate head injury. They measured DD levels and assessed DIC scores, finding that DD levels were not significantly elevated in non-survivors compared to survivors. Saggar23) conducted a prospective study with 80 patients with moderate to severe TBI and assessed DIC scores. They found that DD levels were significantly elevated in patients who died compared to the patients discharged. Sun24) conducted a retrospective study on patients who underwent surgical evacuation for subdural hematoma (SDH) and could not find any significant association with mortality in the SDH group versus controls. Takahashi26) conducted a prospective study with isolated TBI and found that patients who died had significantly high DD levels compared to other groups with severe disability and good recovery. Tu25) conducted a prospective study on patients with isolated TBI admitted within 5 hours of injury, measuring fasting coagulation parameters levels. They found DD levels were significantly elevated in patients who died. Wada28) conducted a retrospective study with isolated TBI patients and AIS >3. Coagulation parameters were measured at different time intervals. They measured DIC score as a predictor of mortality instead of directly correlating DD levels, but they found that DD levels are significantly high in patients with hyperfibrinolysis, and DIC score correlated with the mortality of the patients. Youssef11) conducted a prospective study in pediatric patients with isolated TBI and positive CT findings. They found a significant association between DD levels measured at Day one and day 7 among non-survivors.

A CT scan is ordered in patients with head injuries to rule out intracranial hemorrhage, fractures, and other findings. The decision to order a CT scan depends on clinical criteria and is sometimes part of the protocol in some institutes. Some studies have used D-dimer (DD) to estimate the chances of obtaining positive CT findings, particularly in pediatric cases, aiming to predict the likelihood of avoiding an unnecessary CT, which can help minimize radiation exposure. Berger30) conducted a retrospective and prospective study to determine whether DD levels would rise in children under 4 years with traumatic brain injury (TBI), especially in cases of mild abusive head trauma. They found that DD levels correlated with CT findings. Hoffmann32) conducted a prospective study to assess whether DD could be used as a screening tool for traumatic or spontaneous intracranial hemorrhage. They found that DD levels correlated well with CT findings, and a negative predictive value of 97.6% was observed with a DD level of 284 ng/mL. Hosseininejad31) conducted a cross-sectional study to investigate the prognostic value of DD in mild TBI and found that DD correlated well with CT findings. A cutoff point of 0.90 was identified with sensitivity and specificity of 100% and 98.50%, respectively. Kuo et al.29) conducted a prospective study to identify better predictors of outcome in patients with head injuries and found that DD correlated well with CT findings of midline shift. Coagulopathy scores were also found to correlate with Glasgow Outcome Scale (GOS). Langness33) conducted a retrospective study to validate the association of DD in TBI and limit unnecessary CT head scans if used as a screening tool. DD levels were measured at different time intervals, and they found a 100% negative predictive value (NPV) for the presence of TBI when the DD level threshold was set at <100 pg/µl, potentially avoiding 97 CT scans in their series. Nozawa44) conducted a cross-sectional study to investigate how DD could better help in ruling out intracranial injury. DD levels were measured less than 24 hours post-injury, and they found that a DD level of 0.5 µg/mL had an NPV of 100%. Swanson34) conducted a prospective study to investigate biomarkers for ruling out TBI in children, and they found that CT findings correlated well with DD levels. While these studies consistently show good correlation between CT findings and DD levels, a universally applicable cutoff point across all studies for routine practice has not been established.

The use of D-dimer (DD) in prognostication for head injury has been extended to various other variables. Chhabra et al.35) and Dekker et al.36) explored its predictive value for coagulopathy, while Genet et al.37) investigated its response across different types of traumatic brain injuries (TBI), including isolated TBI, TBI with other injuries, and no TBI. Nakae et al.39) studied age-related differences in the elevation of DD levels with TBI, and Nakae et al.40) explored the correlation between DD levels and patient outcomes with fresh frozen plasma (FFP) transfusion. Pahatouridis et al.41) examined the role of disseminated intravascular coagulation (DIC) in moderate head injury, along with the safety of the early use of low molecular weight heparin. Yabuno et al.15) investigated outcomes for ICU survivors, and all these studies have shown significant correlations with the respective outcomes. However, studies by Shiabhashi et al in43) could not find any significant correlation between DD levels and outcomes following subdural hematoma (SDH) evacuation.

CONCLUSION

Our study is limited by a lack of a substantial number of RCTs and the inability to summarize DD levels for specific cutoff points due to the heterogeneity of available data. However, this review will contribute to future studies, especially RCTs, that should be conducted with DD levels measured at different times from the moment of injury. This approach will provide a more accurate understanding of the DD response from the time of injury and its correlation with the specified outcomes mentioned above.

Table 2.

JBI critical appraisal checklist for prospective studies13)

Notes

Ethics statement

This study was a literature review of previously published studies and was therefore exempt from institutional review board approval.

Author contributions

Conceptualization: VW, SKT, MS. Methodology: VW, MS, SM. Validation: MS, SM, MY. Formal analysis: VW, MS, MY. Investigation: VW, SKT, SM. Resources: OA, AA. Data curation: VW, SKT, MS. Writing – original draft preparation: VW, MS, SM. Writing – review and editing: SKT, MY, OA, AA. Supervision: SKT, OA, AA. Project administration: SKT, AA. All authors have read and approved the final manuscript.

Conflict of interest

There are no conflict of interest to disclose.

Funding

None.

Data availability

None.

Acknowledgments

None.

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Article information Continued

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Fig. 1.

PRISMA flow diagram.

Table 1.

Details of search strategy

Database	Search terms
PubMed	(("fibrin fragment d"[Supplementary Concept] OR "fibrin fragment d"[All Fields] OR "d dimer"[All Fields]) AND ("craniocerebral trauma"[MeSH Terms] OR ("craniocerebral"[All Fields] AND "trauma"[All Fields]) OR "craniocerebral trauma"[All Fields] OR ("head"[All Fields] AND "injury"[All Fields]) OR "head injury"[All Fields])) AND (1000/1/1:2023/11/23[pdat])
SCOPUS	TITLE-ABS-KEY (d-dimer AND head AND injury)
COCHRANE	11 Trials matching d dimer head injury in Title Abstract Keyword
ScienceDirect	Title, abstract, keywords: D-dimer head injury

Table 2.

JBI critical appraisal checklist for prospective studies13)

Study ID	Item 1	Item 2	Item 3	Item 4	Item 5	Item 6	Item 7	Item 8	Item 9	Item 10	Item 11
Asami, 20229)	Unclear	Yes	Unclear	Yes	Unclear	Yes	Yes	Not Applicable	Not Applicable	Not Applicable	Yes
Bayir, 200610)	Unclear	Not Applicable	Yes	Unclear	Not Applicable	Not Applicable	Yes	Not Applicable	Not Applicable	Not Applicable	Yes
Berger, 201530)	Yes	Not Applicable	Yes	Yes	Yes	Not Applicable	Yes	Yes	Not Applicable	Not Applicable	Yes
Bredbacka, 19942)	Yes	Not Applicable	Not Applicable	Yes	No	Unclear	Yes	Not Applicable	Not Applicable	Not Applicable	Yes
Chhabra, 201335)	Yes	Not Applicable	Not Applicable	Yes	No	Unclear	Yes	Yes	Not Applicable	Not Applicable	Yes
Dekker, 201636)	No	Yes	Yes	Yes	Yes	Yes	Yes	Unclear	Not Applicable	Not Applicable	Yes
Fair, 202116)	Not Applicable	Not Applicable	Not Applicable	Yes	Yes	Not Applicable	Yes	Yes	Unclear	Unclear	Yes
Fouad, 201427)	Unclear	Not Applicable	Not Applicable	Yes	Yes	Unclear	Yes	Yes	Unclear	Unclear	Yes
Genet, 201337)	Unclear	Not Applicable	Not Applicable	Yes	Unclear	Not Applicable	Yes	Not Applicable	Not Applicable	Not Applicable	Yes
Gupta, 201621)	Yes	Not Applicable	Not Applicable	Unclear	Unclear	Not Applicable	Yes	Unclear	Not Applicable	Not Applicable	Yes
Hoffmann, 200132)	Yes	Not Applicable	Not Applicable	Yes	Unclear	Not Applicable	Yes	Unclear	Not Applicable	Not Applicable	Yes
Hosseininejad, 202331)	Yes	Not Applicable	Yes	Yes	Unclear	Unclear	Yes	Not Applicable	Not Applicable	Not Applicable	Yes
Kuo, 200429)	Yes	Not Applicable	Not Applicable	Yes	Unclear	Unclear	Yes	Not Applicable	Not Applicable	Not Applicable	Yes
Murshid, 200220)	Yes	Not Applicable	Not Applicable	Unclear	Unclear	Yes	Yes	Yes	Not Applicable	Not Applicable	Yes
Nozawa, 202044)	No	Not Applicable	Yes	Unclear	Unclear	No	Yes	Not Applicable	Not Applicable	Not Applicable	Yes
Pahatouridis, 201041)	No	Not Applicable	Not Applicable	Yes	Unclear	No	Yes	Yes	Unclear	Not Applicable	Yes
Peng, 201918)	No	Not Applicable	Not Applicable	Unclear	Unclear	No	Yes	Not Applicable	Not Applicable	Not Applicable	Yes
Saggar, 200923)	No	Not Applicable	Not Applicable	Unclear	Unclear	No	Yes	Not Applicable	Not Applicable	Not Applicable	Yes
Scherer, 199842)	No	Not Applicable	Not Applicable	Unclear	Unclear	No	Yes	Yes	Not Applicable	Not Applicable	Yes
Sun, 201124)	Yes	Not Applicable	Not Applicable	Yes	Yes	Unclear	Yes	Yes	Unclear	Unclear	Yes
Swanson, 201034)	Yes	Not Applicable	Not Applicable	Yes	Yes	Unclear	Yes	Not Applicable	Not Applicable	Not Applicable	Yes
Takahashi, 199726)	Yes	Not Applicable	Not Applicable	Yes	Not Applicable	No	No	Yes	Yes	Yes	Yes
Tu, 202125)	Unclear	Not Applicable	Not Applicable	Yes	Unclear	No	Yes	Not Applicable	Not Applicable	Not Applicable	Yes
Youssef, 201511)	No	Not Applicable	Not Applicable	Yes	Yes	No	Yes	Yes	Not Applicable	Not Applicable	Yes

Table 3.

JBI critical appraisal checklist for retrospective studies13)

Study ID	Item 1	Item 2	Item 3	Item 4	Item 5	Item 6	Item 7	Item 8	Item 9	Item 10
Chen, 20136)	Yes	Not Applicable	Yes	Yes	Not Applicable	Yes	Yes	Yes	Yes	Yes
Chen, 202245)	Choose an item.	Choose an item.	Choose an item.	Choose an item.	Choose an item.	Choose an item.	Choose an item.	Choose an item.	Choose an item.	Choose an item.
DeFazio, 20141)	Yes	Not Applicable	Not Applicable	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Fujiwara, 202246)	Choose an item.	Choose an item.	Choose an item.	Choose an item.	Choose an item.	Choose an item.	Choose an item.	Choose an item.	Choose an item.	Choose an item.
Langness, 201833)	Yes	Not Applicable	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Nakae, 201940)	Yes	Not Applicable	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Nakae, 202139)	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Shibahashi, 201743)	Yes	Not Applicable	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Tong, 201217)	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Wada, 201728)	Yes	No	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Xu, 202019)	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Yabuno, 202215)	Yes	No	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes

Table 4.

JBI critical appraisal checklist for RCT studies14)

Study ID	Item 1	Item 2	Item 3	Item 4	Item 5	Item 6	Item 7	Item 8	Item 9	Item 10	Item 11	Item 12	Item 13
Allard, 200922)	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Unclear	Yes	Yes	Yes
Grenander, 200138)	Yes	Unclear	Yes	No	No	Yes	No	Yes	Yes	Unclear	No	Yes	Yes

Table 5.

Excluded studies with reasons

Study author (Year)	Reasons for exclusion
Ramsey, 201647)	Conference paper
Takahashi, 200048)	Conference paper
Tong, 201049)	Chinese language
Wang, 200550)	Chinese language
An, 202051)	All trauma cases
Fujiwara, 202352)	Phenotyping study
Lin, 201753)	Survey
Puranik, 201854)	Polytrauma patients
Nomura, 199455)	Intra-clot values of D-Dimer
Lubnow, 201456)	Acute respiratory failure
Raza, 201357)	Included all trauma cases
Cardenas, 201958)	Included all trauma cases
Lee, 201859)	Included all trauma cases
Nakae, 202260)	Review article
Rangarajan, 201061)	Including orthopaedic patients
Shah, 201162)	Conference abstract

Table 6.

Characteristics of included studies

Study author (Year)	Country	Study type	Sample size	Objective	Patients included	Outcomes assessed	Results	conclusion
Allard, 200922)	Toronto, Ontario, Canada	Randomized controlled Trial	72	To investigate the association between coagulopathy and PIH	Post hoc analysis; GSC <8 (severe TBI)	Coagulopathy, PIH, mortality	Mean DD levels(n=42): Survivors- 4434(2408,9824); non survivors- (18000 (10000,20000) (p=0.002); Coagulopathy associated with progression of PIH.	High DD a significant independent predictor of mortality in severe TBI
Asami, 20229)	Japan	Prospective study	335	DD at hospital arrival as predictor of neurological prognosis in head injury by RTA	GCS <8, only RTA cases	GOS at discharge	Univariate analysis- DD >17.4 µg/ml-poor prognosis; multivariate - DD>89.3 µg/ml -independent predictor of poor outcome.	D dimers at arrival can be independent predictor of poor outcome in severe head injuries due to RTA
Bayir, 200610)	Turkey	Prospective study	62	To determine the use of fibrinolytic markers as prognostic indicator in isolated head injury	Isolated head injury presented within 3hrs of trauma	GCS and Mortality with D dimers and others like PT PTT FDP platelets	DD µg/ml (mean +SD) - survivors=0.7+/-0.3; Non survivors= 1.0+/-0.0 with p <0.001	GCS and fibrinolytic markers in first 3hr in isolated head injury cases can be useful for prognostication
Berger, 201530)	Pittsburgh	Retrospective and prospective cohorts	195	To determine DD would increase in children with TBI especially mild abusive head trauma	Prospective- cases- <4yr at risk of abusive head trauma with abnormal CT; retrospective- cases- <4yr abnormal CT due to trauma,	Correlation of DD with cases (CT positive findings) and controls, age, GCS and mechanism of injury	Median (IQR) DD higher in cases vs. controls (1.25 [0.70/4.25] vs. 0.44 [0.29/0.60] μg/L) FEU. The corresponding Mann-Whitney was significant at p < 0.000.	DD can be used in young children at risk of mild abusive head trauma who might benefit from head CT and other evaluation
Bredbacka, 19942)	Sweden	Prospective study	20	To test whether SF, Antithrombin and D dimer in patients with isolated head trauma associated with worse outcome	RTA, gunshot, assault patients with head injury <24hr	DD at admission with admission GCS and discharge GOS	DD significantly elevated and correlated with worse GCS and not with GOS scores	SF seems to be a better predictor of outcome. DD not correlated with GOS
Chen, 20136)	China	Retrospective	265	To assess post-traumatic coagulation disorders association with early post-traumatic cerebral infarction and influence on clinical outcome.	Isolated TBI admitted <4hr with GCS <12 and AIS <3	GOS 3 months after trauma. D dimer at 12hr of admission	DD is associated with poor outcome in these patients with OR 2.472, 95%CI (1.263-4.845) P =0.012	Elevated DD might serve as a marker of PTCI and increased morbidity and mortality
Chen, 202245)	China	Retrospective	479
Chhabra, 201335)	India	Prospective study	208	To assess the incidence of coagulopathy and correlation with prognosis in patients with isolated TBI	Isolated TBI with GCS <12 (mod to severe TBI)	DD measured on day of admission and at 3days. Coagulopathy .......	DD associated coagulopathy, which has an effect on prognosis, but DD was not directly correlated with prognosis	coagulopathy and severity of TBI are strong predictors of outcome
DeFazio, 20141)	Virginia	Retrospective study	44	To evaluate the biomarker profiles of post-traumatic indicators for early clinical trends after severe TBI.	Severe TBI (GCS 8) admitted <3hr after injury and no corticosteroids used	DD measured at 24hr, 48hr and 72hr time point. Poor clinical status - death or GCS <8) and improved clinical status (GCS >8)	DD ng/ml at 24hr- 3769.55 (ROC) 0.86 (AUC) 0.73-0.99 (CI) 0.821 p=0.00	DD values at admission are not significantly different, but DD at 24hr associated with poor clinical status (p=0.00)
Dekker, 201636)	The Netherlands	Prospective	92	To examine the role of coagulopathy with cerebral oxygenation in patients with TBI	Moderate to severe TBI, all measurements done at admission, AIS >3	Hematological parameters like- PT, APTT, DD, Fibrogen; cerebral and systemic tissue oxygenation by ABG analysis, NIRS	Lactate levels and base excess showed correlation with DD levels (r=0.40, p=0.029); (r=-0.39; p=0.027)	TBI coagulopathy is more profound in patients with systemic hypoperfusion; coagulopathy is more severe in patients with higher grades of injury
Fair, 202116)	Portland, Oregon, USA	Prospective, observational study	141	Coagulation profile in patients with intra-cranial hemorrhage and to know the relationship in patients of PIH	Isolated TBI with AIS >3	DD measured at admission, 6,12,24,48hrs, AIS and ISS scores measured	DD was higher in patients with PICH at admission (p=0.04) peaked at 6hr, and decreased trend over 48hr	DD may be useful as a predictor of PIH
Fouad, 201427)	Egypt	Case control study	66	DD as prognositic marker in TBI in children	Isolated TBI	GCS, CT at admission, 3rd day, 14th day	The best cut-off point at 1st day was 10.5 with sensitivity 89.5 %, specificity 100.0 %, PPV 100.0% and NPV 93.1 %	In children who meet clinical criteria for a head CT scan after trauma, low plasma D-dimer strongly suggests the absence of significant brain injury
Fujiwara, 202246)	Japan	Retrospective analysis	458
Genet, 201337)	Houston, Texas.	Prospective observational cohort study	23	To investigate the hemostatic response to Isolate TBI; severe TBI + other injuries, non TBI	Patients meeting the criteria of full trauma team activation and had an arterial cannula	DD measured at time of admission; 30day mortality	DD in isolated TBI (n=23), 170ng/ml (133-174); sTBI+other (n=15)- 173(171-176); non TBI (n=42) 145 (61-171) with p=0.003	The hemostatic, vascular, and endothelial responses may be the same in isoTBI and non-TBI patients
Grenander, 200138)	Sweden	A prospective, controlled, randomized, open pilot study	28	To assess if antithrombin treatment reduced progress of brain contusion, decrease ICU stay and improved outcome (GOS)	Isolated TBI, GCS 4 -12, within 12 hr of injury	blood samples are drawn at admission, 8,16,24,36 and 48hr followed by daily till 5days.	DD at admission- AT group (5626+/-3555); control group (5623+/-3802).	AT used to treat patient with severe TBI resulted in marginal reduction of hypercoagulation
Gupta, 201621)	Punjab, India.	Prospective study	50	To know the impact of coagulation profile derangements and their effect on outcome	Isolated TBI, two groups with GCS 9-13 (moderate injury), GCS <9 (severe)	GOS score and comparison with presenting GCS and DIC score	DD 2812+/- 1351 in expired (n=20), 2616+/-1703.86 in discharged (n=4); p=>0.05	Patients with isolated head injury are at a risk of development of coagulation abnormalities, which is associated with poor outcome
Hoffmann, 200132)	Kansas City, MO	Prospective study	319	To assess DD as screening tool for traumatic or spontaneous intracranial hemorrhage	<24hr, GCS <13, age >60; both traumatic and non-traumatic	DD correlated with CT findings of intracranial hemorrhage	Sensitivity: 84.0% (95% CI = 63.7% to 95.5%); specificity: 55.8% (95% CI = 50.1% to 61.5%); positive predictive value: 13.9% (95% CI = 8.8% to 19.7%); negative predictive value: 97.6% (95% CI = 94.1% to 99.3%).	The D-dimer assay cannot be relied upon as a substitute for an emergent CT scan of the head when intracranial hemorrhage is clinically suspected
Hosseininejad, 202331)	Iran	Cross-sectional study	74	To investigate whether DD and CRP can be used as a prognostic marker for clinical outcomes in patients with mild TBI	Mild TBI with GCS of 14,15	DD levels correlated with CT findings	The sensitivity and specificity for positive CT findings were 100 and 98.50% p<0.001 at cut off point of 0.90 for DD	CRP and DD levels of mild TBI patients can be used to protect against CT induced radiation exposure and subsequent disorders.
Kuo, 200429)	Taiwan	Prospective	61	To find a better predictor for outcome in patients with head injury	All head injury patients	DD measured at admission	DD correlated with CT midline shift, coagulopathy score with GOS	Coagulopathy score >4 is a significant predictor of outcome in severe head injury patients
Langness, 201833)	United States	Retrospective	663	To validate the association of DD in TBI, to determine whether DD may aid in limiting unnecessary CT head if used as a screeing tool	<18yr with suspected TBI and had both CT and DD	DD measured at 6hr, 12 and 48hrs; presence of TBI, clinically significant TBI or no TBI; correlation of DD with CT findings	100% NPV for the presence of TBI when the DD threshold was set to <100pg/µl and this would have avoided 97 head CT in their series	low DD values accurately predict absence of Clinically important TBI for pediatric patients with head injury
Murshid, 200220)	Saudi Arabia	Prospective	70	To characterize the coagulopathy complicating head injury by monitoring hemostatic markers at different timings of measurement	GCS <12 with head injury resulting from RTA	DD measured from peripheral venous, arterial and jugular venous samples and at different timings daily over 4days	DD at admission - peripheral venous-1115ug/ml, arterial -1288ug/ml and jugular 888ug/ml; DD concentrations dropped at all sites over days. GOS measured at 6months did not show any correlation with hemostastic measurements	Hemostatic activation is a common phenomenon after head injury and is more prominent in cerebrovascular than in peripheral blood.
Nakae, 201940)	Japan	Retrospective	380	To examine the relationship between age and coagulation and fibrinolytic parameters occurring within first 12hr after injury	TBI with AIS >3 and blood samples taken <1hr post injury	Age/sex/GCS/AIS and Coagulation parameters at 1hr, 3, 6 and 12hrs post injury	DD was significantly elevated in both adult and pediatric groups, with no significant differences between groups. The independent risk factor for poor prognosis was DD level at admission OR 6.70 95% CI (1.67-142.59) (p<0.001)	In acute phase of TBI, pediatric patients have prolonged PT-INR and APTT and lower fibrinogen levels than adults but are not significant; DD was an independent prognostic factor in pediatric patients.
Nakae, 202139)	Japan	Retrospective	468	To investigate the relationship between patient outcomes after FFP transfusion and to evaluate the correlation with DD levels at admission	severe isolated TBI- intracranial AIS >3; extracranial AIS <3.	GOS at discharge and at 3months; DD at admission	DD at admission was significantly associated with a decrease in fibrinogen following injury in FFP non transfusion group (R2 =0.29, P<0.0001)	Outcomes of isolated TBI were significantly correlated with maintaining fibrinogen levels >150mg/dl which can be predicted with admission DD levels
Nozawa, 202044)	USA	Cross-sectional study	364	To demostrate how well low DD helps in ruling out significant intracranial injury	Ped patients with suspected head trauma and had CT and DD values measured less than 24hr post injury	DD measured <24hr, correlated with CT findings	DD mean - abnormal CT 32.5(98.8) n=123; 5.9 (12.2) n=241 with P<0.01; cut off set of DD at 0.5µg/mL sensitivity 100% (95%CI: 95.6-100.0%); high NPV 100% (95% CI: 93.5-100.0%) ; low specificity: 34.0% (95%CI: 28.1–40.4%); and low PPV 43.6% (95%CI: 37.7–49.6%)	Low plasma D-dimer (≤0.5 lg/mL) is useful to limit the use of CT in children by excluding traumatic ICI or SF.
Pahatouridis, 201041)	Greece	Prospective	61	To investigate the incidence of DIC in moderate head injury patients and the safety of early use of LMW heparin	Moderate head injury- GCS 9-12 and without need for surgical intervention	Blood samples are drawn at 3-6hr, 24, 48, 72hr post admission; correlated with GCS	DD strongly elevated >2000ng/ml in 83% patients at first day, by 3rd day 55% normalised but 45% remained with DD above 2000ng/ml. lower GSC scores correlated with increased DD levels.	Patients with moderate TBI are at a serious risk of developing brain intravascular microthrombosis. This study supports the early use of LMW Heparin.
Peng, 201918)	China	Prospective	42	To investigate the expression of plasma cys-c, DD, CRP in patients with PIH and their significance for severity and outcome.	Confirmed craniocerebral injury by CT, no other tissue injury, no hematological abnormalities, no infectious diseases	GCS and GOS; fasting peripheral venous blood on the morning of day of diagnosis and healthy participants as controls	DD 5.34+/-1.35mg/L significantly higher than controls 1.37+/-0.33mg/L P<0.01; DD levels in severe coma group were higher than mild coma group (p<0.05); DD levels were significantly higher in poor outcome groups P<0.05	Increased plasma cys-c, DD and CRP levels may be involved in occurrence and development of IPHI after craniocerebral injury. The measurement of these markers helps in diagnosis and prognosis.
Saggar, 200923)	Jaipur, India.	Prospective	80	To examine various hemostatic abnormalities in patients with head injury and their role in predicting early mortality.	Mod (GCS 9-13) to severe (GCS <8) closed head injury with no history of hematological abnormalities	DIC scores compared with outcomes using GOS	DD levels in expired GOS 1 (n=34) 2.47+/-0.50; levels in discharged GOS 3-5 (n=32) 0.50+/-0.50 p<0.01	Hemostatic evaluation can predict mortality irrespective of GCS score in patients with head injury
Scherer, 199842)	Germany	Prospective study.	24	To determine the degree of regional and systemic coagulation activation after isolated severe head injury.	Isolated head injury GCS <8, admitted <6hr of injury; control group with isolated bone fractures	Coagulation variables measured every 2-3days till discharge from central venous cath/ jugular bulb cath/ radial artery; GOS measured at discharge	DD at admission was significantly elevated in head trauma patients (p<0.005), with no difference in concentration in cerebrocentral blood than in central venous blood. No correlation was found with clinical outcomes.	Head trauma often activates the coagulation system, potentially causing fibrin deposition. The shift from initial hypercoagulability to disseminated intravascular coagulation in some cases raises concerns about the coagulation system's ability to adequately control traumatic events.
Shibahashi, 201743)	Japan	Retrospective study,	240	To analyse the risk factors and outcomes of SDH development following surgical evacuation for unilateral acute SDH	Patients who underwent surgical evacuation for unilateral SDH and had post op CT scan	GCS on admission, time of injury and blood tests	DD in SDH group - 73.1 (38.9, 134.4); controls -33.5 [16.9, 73.8] (p=0.13)	Low fibrinogen is a significant risk factor for SDH development in cases mentioned in objective. DD values are not significant.
Sun, 201124)	China	Prospective observational study.	785	Estimate the incidence of coagulopathy and DIC in patients with TBI and to correlate with outcome	Adult isolated head injury (AIS >2) patients with	DIC score, GCS and GOS	DD in non-survivals (GOS 1, n=44) 4.69+/-3.82; GOS 2-3, n=36 3.62+/-3.46; GOS 4-5, n=162 1.96+/-1.86 p<0.05	Higher DIC score are prognostic for PHI incidence
Swanson, 201034)	California	Prospective cohort observational study	57	Investigate biomarkers to predict the absence of TBI in children	Suspected head injury patients underwent CT according to children's head injury algorithm, admission time DD levels	Hematological parameters correlated with CT findings	DD levels in CT positive cases (n=38), 5000 (154–5000) ; in CT negative cases (n=19) 688 (150–5000) p<0.001	In children with clinical criteria for head CT after trauma, low DD suggest no significant brain injury
Takahashi, 199726)	Japan	Prospective	43	To investigate fibrinolytic parameters like DD as a reliable indicator of extent of brain damage in severe head injury patients and predicting outcomes.	Isolated TBI with GCS 3-14	DD at admission with admission GCS and discharge GOS	Group 3 (Dead) had significantly higher D-dimer levels than Group 2 (severe disability) (p < 0.05) and Group 1 (good recovery) (p < 0.0001). DD > 5 µg/ml, 92% of patients died, DD < 1 µg/ml, all patients had good recovery or moderate disability.	DD correlated well with the extent of brain damage in patients with head injuries, and these values may predict the outcomes.
Tong, 201217)	China	Retrospective study,	530	To investigate the risk factors related to PIH in TBI	Isolated TBI with no history of haematological abnormalities	Coagulation variables and GOS at 6months	DD in PIH group (n=139) 80.20+/-76.75; non PIH group (n=359) 11.41+/-14.05; p<0.0001; OR 1.085 (95%CI 1.066–1.104)	Primary haematoma with abnormal DD levels should have an earlier and dynamic CT scan for the detection of PIH as early as possible.
Tu, 202125)	China	Prospective	92	Coagulation-related indicators combined with GCS in evaluating the prognosis of craniocerebral injury.	History of craniocerebral injury with admission <5hr from injury	Fasting coagulation parameters and GCS	DD in Survived group(n=58) 1.86±0.52 g/L; deceased (n=34) 4.54±0.86 P<0.001	Coagulation-related indicators combined with GCS can effectively evaluate the prognosis of patients with craniocerebral injury.
Wada, 201728)	Japan	Retrospective study	92	To test the hypothesis of DIC affects the outcome of patients with TBI	Severe isolated TBI with AIS >3	Coagulation parameters measured at 4hr, 8, 16, 24hr	DD values are significantly high in patients with hyperfibrinolysis p=0.000; DIC score as predictor of mortality has OR 1.717 (95%CI: 1.059-2.784) p=0.028	DIC with hyperfibrinolysis, affects the outcome of patients with isolated TBI
Xu, 202019)	China	Retrospective study	192	To describe the relationship between DD and Fibrinogen ratio and PIH after TBI	Patients admitted <6hr after trauma, AIS <3, two CT scans done within 24hr of admission	DD: Fibrinogen ratio correlated with the incidence of progressive hemorrhagic injury	DD in PHI patients (n=43) 4.89 (4.31–6.87) mg/l; in non-PHI patients (n=149) 4.02 (3.28–5.12) P<0.001	DD:Fibrinogen ratio was a strong predictor of Progressive hemorrhagic injury
Yabuno, 202215)	Japan	Retrospective cohort study	826	To investigate outcome for ICU survivors after moderate to severe TBI and to assess predictive factors	Moderate to severe TBI, AIS >3 follow up 2yr	DD levels correlated with return to home and return to work	DD ug/ml in non-RH (n=24) 58.62+/-51.34; RH (n=83) 36.44+/-39.99 p=0.028; DD for return-to-work p=0.082	Age and GCS on admission are predictive of Return to home and work for ICU survivors
Youssef, 201511)	Egypt	Prospective study	67	To evaluate clinical and lab markers for predicting outcome of TBI in pediatric patients	Isolated TBI with positive CT findings	GCS, routine lab investigations and coagulation parameters at D1 and D7 and compared in non survivors and survivors	DD at D1 in non survivors (n=28), 32.5(18.9-40.6) and survivors (n=39), 4.2 (2.1-6.8) p<0.001. DD at D7 compared in non survivors and survivors has p<0.001	SGPT, GCS, DD were the important clinical and lab markers for predicting mortality in TBI

Table 7.

Progression of intracranial haemorrhage

Study author (Year)	Progression		No progression		p
Study author (Year)	DD	n	DD	n	p
Fair, 202128)	1.64 (0.77–2.68) µg/ml	67	0.57 (-0.64 to 1.48) µg/ml	64	0.04
Tong, 201249)	80.20+/-76.75 mg/L	139	11.41+/-14.05 mg/L	359	<0.0001
Peng, 201930)	5.34 ± 1.35 mg/L	42	1.37 ± 0.33 mg/L	20	<0.001
Xu, 202052)	4.89 (4.31–6.87) mg/L	43	4.02 (3.28–5.12) mg/L	149	<0.001

Table 8.

Predictor of neurological prognosis (GOS)

Study author (Year)	Good outcome		Poor outcome		OR	CI
Study author (Year)	DD	n	DD	N	OR	CI
Asami, 20229)	-	-	<17.4µg/ml	83	1
Asami, 20229)	-	-	>89.3 µg/ml	84	18.74	7.33-47.89
Bredbacka, 19942)	Results mentioned in text
Chen, 20136)	<2g/L	67/87	<2g/L	20/87
Chen, 20136)	>2g/L	107/178	>2g/L	69/178	2.47	1.263–4.845
Murshid, 200220)	Results mentioned in text
Peng, 201918)	5.02+/-1.38 mg/L	32	6.33 ± 1.07 mg/L	10		p<0.010
Fazio, 20141)	7769.50 ng/dl	14	9586.82 ng/dl (admission)	30		p=0.425
Fazio, 20141)	2590.07 ng/dl	14	7753.11 ng/dl (24hr)	28		p=0.000

Table 9.

DD as prognostic indicator for survivors and non survivors

Study author (Year)		Survivor			Non-survivor		p
Study author (Year)		DD levels		n	DD levels	n	p
Bayir, 200610)		0.7+/-0.3 µg/ml		NA	1.0+/-0.0 µg/ml	NA	<0.001
Allard, 200922)		4434(2408,9824) ng/ml		42	18000 (10000,20000) ng/ml	30	0.002
Fouad, 201427)	D1	4.2 ± 2.4 µ/L		27	27.9 ± 13.6 µ/L	19	<0.001
	D3	2 ± 1.1 µ/L		27	9.9 ± 5.3 µ/L	19	<0.001
	D14	0.79 ± 0.41 µ/L		27	1.4 ± 0.6 µ/L	19	<0.001
Gupta, 201621)		2616+1703.86 µg/dl		4	2812+1351 µg/dl	20	>0.05
Saggar, 200923)	Severe HI	0.67±0.47 µg/L		12	2.43±0.49 µg/L	28	<0.001
Saggar, 200923)	Mod HI	0.40±0.49 µg/L		20	2.67±0.47 µg/L	6	<0.001
Sun, 201124)		3.62±3.46 mg/l	1.96±1.86 mg/l	198	4.69± 3.82 mg/l	44	<0.05
Takahashi, 199726)		0.8 ± 0.2 µg/ml		Not clear	15.0 ± 5.9 µg/ml	5	< 0.01
Tu, 202150)		1.86±0.52 g/L		58	4.54±0.86	34	<0.001
Wada, 201728)		Results in manuscript
Youssef, 201511)	D1	4.2 (2.1–6.8)		39	32.5 (18.9–40.6)	28	<0.001
Youssef, 201511)	D7	0.7 (0.6–1.0)			1.4 (1.2–1.9)	28	<0.001

Table 10.

Predict the need for CT

Study author (Year)	CT positive		CT negative		Remarks
Study author (Year)	DD levels	n	DD levels	N	Remarks
Berger, 201530)	1.25 [0.70/4.25] µg/L	20	0.44 [0.29/0.60] µg/L	24	p<0.000
Hoffmann, 200132)	<284 ng/mL	4	<284 ng/mL	164	NPV- 97.6%
Hosseininejad, 202331)	2.21±0.37 (IQR 1.73)	18	0.06±0.03 (IQR 0)	56	p<0.001
Kuo et al. 200429)	Results in manuscript
Langness, 201833)	<100pg/µL	2/108	<100pg/µL	106/108	100%NPV
Nozawa, 202044)	32.5±98.8 µg/mL	123	5.9±12.2 µg/mL	241	p<0.001
Nozawa, 202044)	32.5±98.8 µg/mL	123	5.9±12.2 µg/mL	241	<0.5 µg/mL- 100% NPV
Swanson, 201034)	5000 (154–5000) pg/µ	19	688 (150–5000) pg/µ	38	p<0.001
Swanson, 201034)	5000 (154–5000) pg/µ	19	688 (150–5000) pg/µ	38	500 pg/μl - 94% NPV