Background: There is increasing evidence on the prognostic significance of D-dimer and fibrinolysis in stroke. However, the systematic analysis of their relationship with adverse outcomes after stroke is lacking. Herein, we comprehensively assessed the correlation of D-dimer and fibrinolysis with stroke outcomes through meta-analysis. Methods: Studies for systematic literature review were retrieved from PubMed, EMBASE, and Cochrane Library databases. The association of D-dimer and fibrinolysis with outcomes of stroke patients was expressed as an odds ratio (OR) with 95% confidence intervals (95% CI). Results: Totally, 52 studies comprising 21,473 stroke patients were included. The results showed that the high D-dimer level was significantly associated with peripheral venous thrombosis after stroke (OR 1.03, 95% CI 1.01–1.05), poor outcome (MRS >2) after stroke (OR 1.731, 95% CI 1.464–2.048), death after stroke (OR 2.367, 95% CI 1.737–3.224), stroke recurrence (OR 1.229, 95% CI 1.113–1.358), and early neurologic deterioration (NIHSS >4) (OR 1.791, 95% CI 1.117–2.870). Moreover, high fibrinogen level was significantly associated with poor outcome (MRS >2) after stroke (OR 1.650, 95% CI 1.314–2.071), death after stroke (OR 1.310, 95% CI 1.128–1.520), stroke recurrence (OR 1.228, 95% CI 1.166–1.422), early neurologic deterioration (NIHSS >4) (OR 2.381, 95% CI 1.156–4.904), and coronary events after stroke (OR 1.427, 95% CI 1.232–1.653). Conclusion: Fibrinogen and D-dimer may be associated with adverse outcomes in patients with stroke, suggesting that they may serve as possible biomarkers for post-stroke adverse outcomes.

Epidemiological statistics have shown that stroke represents a devastating disease with high mortality, adult disability, socioeconomic burdens, and poor outcomes worldwide [1, 2]. Stroke is an acute cerebrovascular disease characterized by blood flow obstruction and brain damage [3]. Studies have shown that restoration of blood flow is the primary method to reduce nerve injury [4, 5], but this method does not completely eliminate the adverse outcomes [6, 7]. Many factors are associated with stroke outcomes (such as age, sex, stroke severity, atrial fibrillation, congestive heart failure, diabetes, etc.). Predicting stroke outcomes is difficult, even for experienced neurologists [8]. Therefore, developing new predictors can help to manage the outcomes of patients with stroke [9]. Current studies have shown [10‒16] that the combination of many molecular biomarkers could greatly improve the accuracy of stroke outcome prediction.

Plasminogen-plasmin and the coagulation system are importantly involved in stroke [17]. As a fibrin degradation product, D-dimer is the most frequently used indicator to reflect the activation of the coagulation system. Fibrinogen is a key factor involved in the coagulation cascade. Fibrinogen is the first clotting factor to reach severely low levels of less than 2–4 g/L in major bleeding, which is associated with increased bleeding, clotting disorders, and worsening clinical outcomes [18‒21]. Fibrinogen and D-dimer of the plasminogen-plasmin and coagulation systems are reported to be associated with stroke prognosis. For example, it has been recently reported that D-dimer was associated with death and poor outcome after stroke [22]. However, the predictive relationship for poor prognosis was incomplete (such as venous thromboembolism, death, poor outcome).

We, therefore, in this systematic review and meta-analysis, provided a comprehensive overview of fibrinogen and D-dimer in stroke outcomes. Our finding may help to improve risk assessment of stroke.

We conducted and reported this systematic review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement [23] (see online suppl. materials at www.karger.com/doi/10.1159/000526476). The review protocol was registered in the International Platform of Registered Systematic Review and Meta-analysis Protocols (INPLASY, https://inplasy.com/) with the registration number of INPLASY202210025.

Literature Search

Two independent researchers systematically retrieved three databases (PubMed, EMBASE, and Cochrane). Studies on fibrinogen and D-dimer in stroke and published prior to November 2021 were screened. The search terms were “D-dimer fibrin,” “D-dimer,” or “fibrin fragment DD” or “fibrin fragment D-dimer” or “D-dimer fragments” or “Fibrinogen” or “Coagulation Factor I” or “Factor I” or “gamma Fibrinogen” and “Stroke” or “Cerebrovascular*” and “Humans.” The specific details of the search strategies are provided in Table 1. The reference lists of all included studies and relevant review articles were manually searched to avoid missing any eligible studies. When relevant information was unavailable, efforts were made to contact corresponding authors.

Table 1.

The systematic review and meta-analysis retrieval strategy

 The systematic review and meta-analysis retrieval strategy
 The systematic review and meta-analysis retrieval strategy

Study Eligibility

All screened studies were personally reviewed by two researchers (B.Q.J and W.X.T) after reviewing titles and abstracts. Study inclusion criteria were as follows: (1) studies reporting the relationship of fibrinogen and D-dimer with stroke outcome; (2) studies reporting patients who had suffered stroke (ischemic stroke, hemorrhagic stroke, subarachnoid hemorrhage, cryptogenic ischemic stroke, transient ischemic attack, etc.); (3) studies assessing post stroke outcome and levels of biomarkers (e.g., D-dimer and fibrinogen levels in blood); (4) studies focusing on human data; and (5) studies published in English. Study exclusion criteria were as follows: (1) studies that only reported mean levels and standard deviations of biomarkers in cases and non-cases; (2) studies without quantitative data on biomarker levels; (3) studies without original data; (4) study type of review; (5) study type of case report; and (6) study type of comment.

Data Extraction and Quality Assessment

Two independent researchers conducted the literature search, the selection of studies, data extraction, and the assessment of quality. Disagreements were resolved with a third reviewer. The study data were abstracted independently and were classified by biomarkers. Categorized data included author name, publication year, location of investigation, study design, sample size, study period, fibrinogen, D-dimer levels, pooled OR (95% CI), outcomes, follow-up duration, and adjusted variables (such as age, sex, current smoking, etc.).

The Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) was used to evaluate risk of bias of included studies [24]. All studies were scored on the following items: confounding bias, selection bias, deviation from intended intervention, missing data, measurement in outcome, selection of reported result, and classification of intervention. In addition, the Oxford Center for Evidence-Based Medicine tool was used to assess the overall level of evidence presented in the literature [25].

Statistical Analysis

We performed the analysis with Comprehensive Meta-Analysis (CMA) version 2.0. The study was a meta-analysis based on a random-effects model. We extracted cohort-specific odds ratios (ORs), hazard ratios (HRs), and relative risks (RRs) from Cox hazard models. Then, RRs or HRs were transformed into ORs for analysis. To enable consistent meta-analysis and interpretation of findings in this review, the OR estimates for the association of two markers and post-stroke outcomes were transformed to consistently correspond to the comparison of the high versus normal levels of the distribution in each study, using methods previously described [26]. To avoid possible confusion during the acute treatment of patients with acute ischemic stroke, we carefully reviewed the full text and included only studies that collected blood samples within 24 h or less of admission. Peripheral venous thrombosis, poor outcome (MRS >2 and MRS 3–6), death, stroke recurrence (ischemic stroke, recurrent vascular events, stroke, cerebrovascular recurrent events, and all ischemic vascular events), early neurologic deterioration (NIHSS >4) and coronary events (a myocardial infarction, an acute or elective percutaneous intervention, or a coronary bypass grafting) after stroke were calculated in the fibrinogen analysis. Peripheral venous thrombosis, poor outcomes (MRS >2 and MRS 3–6), death, stroke recurrence (ischemic stroke, delayed cerebral infarction, delayed cerebral ischemia, early recurrent ischemic lesions, and cerebrovascular reoccurrence events), and early neurologic deterioration (NIHSS >4) after stroke were calculated in the D-dimer analysis. When there were two or more studies, subgroup analyses of fibrinogen and D-dimer were performed based on follow-up time and stroke type.

Publication bias was assessed by funnel plot in Comprehensive Meta-Analysis (CMA version 2.0). We used the “metainf” and “forest” functions in the “meta” package to search for potential outliers in R and conducted sensitivity analysis by omitting each study or specific study. Heterogeneity between studies was determined by Cochran’s Q test and Higgins I squared. p < 0.1 or I2 > 50% was considered as heterogeneity. All p values (two-sided) less than 0.05 were considered statistically significant.

Literature Characteristics

As shown in Figure 1, 8,726 records were identified in the initial literature search. After screening titles or abstracts, 129 records were included for eligibility assessment. Then, 77 publications were excluded due to duplicate publications, case reports, systematic reviews or insufficient data. Ultimately, 52 studies were included in this meta-analysis [27‒78]. The ROBINS-I tool was used to assess the risk of methodological bias for the included non-randomized controlled trials. The specific details are provided in Table 2. Although the overall risk of bias was low in this study, serious concerns arose for inconsistent follow-up time. The overall level of evidence, based on data from the Oxford Center for Evidence-Based Medicine, was 1b.

Table 2.

Risk of bias according to Cochrane’s risk of bias assessment tool for included non-randomized controlled trials

 Risk of bias according to Cochrane’s risk of bias assessment tool for included non-randomized controlled trials
 Risk of bias according to Cochrane’s risk of bias assessment tool for included non-randomized controlled trials
Fig. 1.

Flowchart of literature search and study selection.

Fig. 1.

Flowchart of literature search and study selection.

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The 52 studies used for the meta-analysis included 42,426 patients, with sample sizes ranging from 68 to 10,518 patients. Twenty (38.5%) studies evaluated fibrinogen, 25 studies (48%) examined D-dimer, and 7 (13.5%) studies reported both fibrinogen and D-dimer. The endpoints of venous thromboembolism, death, poor outcome, and other complications were assessed in 6 (11%), 22 (40%), 26 (47%) and 16 (29%) studies, respectively. In terms of assessing functional outcome types, 22 studies used the Modified Rankin Scale, 8 studies used the NIH Stroke Scale, and 4 studies did not mention the rating scale. Multivariate analyses of outcome measures were performed in 19 studies, and confounding factors (age, sex, etc.) were adjusted. The main characteristics of 52 studies are summarized in Table 3.

Table 3.

Characteristics of the studies included in the meta-analysis

 Characteristics of the studies included in the meta-analysis
 Characteristics of the studies included in the meta-analysis

Meta-Analysis Results

The prognostic effects of plasma D-dimer and fibrinogen in stroke patients were respectively evaluated.

Association of D-Dimer Level with Outcomes after Stroke

Out of the 8,726 articles screened for biomakers and stroke patients, 31 studies presented data on stroke outcomes and plasma D-dimer. The forest plot for the association between high level of D-dimer and post stroke outcome was shown in Figures 2-6. Peripheral venous thrombosis, poor outcome, death, stroke recurrence, and early neurologic deterioration were associated with high level of D-dimer in stroke patients. The ORs were 1.03 (Fig. 2, 95% CI 1.01–1.05, p = 0.002; I2: 89.566%, n = 6), 1.731 (Fig. 3a, 95% CI 1.464–2.048, p = 0.000; I2: 92.243%, N = 16), 2.367 (Fig. 4a, 95% CI 1.737–3.224, p = 0.000; I2: 76.111%, n = 11), 1.229 (Fig. 5, 95% CI 1.113–1.358, p = 0.000; I2: 70.657%, n = 5) and 1.791 (Fig. 6, 95% CI 1.117–2.870, p = 0.016; I2: 96.298%, n = 5), respectively.

Fig. 2.

Accurate relationship between D-dimer and peripheral venous thrombosis after stroke.

Fig. 2.

Accurate relationship between D-dimer and peripheral venous thrombosis after stroke.

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Fig. 3.

Forest plot of the OR of the association between D-dimer and poor outcome after stroke. Subgroup analysis was performed according to stroke type (a) and follow-up time (b).

Fig. 3.

Forest plot of the OR of the association between D-dimer and poor outcome after stroke. Subgroup analysis was performed according to stroke type (a) and follow-up time (b).

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Fig. 4.

Forest plot of the OR of the association between D-dimer and death after stroke. Subgroup analysis was performed according to stroke type (a) and follow-up time (b).

Fig. 4.

Forest plot of the OR of the association between D-dimer and death after stroke. Subgroup analysis was performed according to stroke type (a) and follow-up time (b).

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Fig. 5.

Forest plot of the OR of the association between D-dimer and stroke recurrence. Subgroup analysis was performed according to stroke type.

Fig. 5.

Forest plot of the OR of the association between D-dimer and stroke recurrence. Subgroup analysis was performed according to stroke type.

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Fig. 6.

Forest plot of the OR of the association between D-dimer and early neurologic deterioration after stroke.

Fig. 6.

Forest plot of the OR of the association between D-dimer and early neurologic deterioration after stroke.

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Subgroup Analysis

Considering the obvious heterogeneity among the studies, we also conducted subgroup analyses. First, subgroup analysis based on different stroke types (ischemic stroke and hemorrhagic stroke) was performed. For patients with ischemic stroke, peripheral venous thrombosis, poor outcome, death, and stroke recurrence were found to be associated with high level of D-dimer. The ORs were 1.644 (Fig. 2, 95% CI 1.323–2.043, p = 0.000; I2: 86.168%, n = 3), 2.063 (Fig. 3a, 95% CI 1.546–2.752, p = 0.000; I2: 0%, n = 13), 2.583 (Fig. 4a, 95% CI 1.779–3.750, p = 0.000; I2: 65.446%, n = 7) and 1.510 (Fig. 5, 95% CI 1.167–1.953, p = 0.000; I2: 34.497%, N = 3), respectively. For patients with hemorrhagic stroke, similar associations were also found between high level of D-dimer and the factors of peripheral venous thrombosis (Fig. 2, OR 1.003, 95% CI 1.001–1.005, p = 0.000; I2: 85.344%, n = 3), poor outcome (Fig. 3a, OR 1.538, 95% CI 1.288–1.946, p = 0.000; I2: 0%, n = 3), death (Fig. 4a, OR 1.952, 95% CI 1.122–3.396, p = 0.018; I2: 67.222%, N = 4), and stroke recurrence (Fig. 5, OR 1.185, 95% CI 1.064–1.321, p = 0.000; I2: 86.997%, n = 2). Then, subgroup analysis was conducted according to the follow-up time. Four studies reported mortality with 3-month follow-up with moderate heterogeneity (Fig. 4b, OR: 3.193, 95% CI: 2.071–4.921, p = 0.000; I2: 50.773%), while 2 studies evaluated mortality with 1-month follow-up with negligible heterogeneity (Fig. 4b, OR: 1.727, 95% CI: 1.104–2.702, p = 0.017; I2: 21.293%). Ten studies reported poor outcome for patients with 3-month follow-up with moderate heterogeneity (Fig. 3b, OR: 2.2, 95% CI: 1.782–2.717, p = 0.000; I2: 46.275%). However, there was a lack of association betwee 1-/12-month follow-up and poor outcome, with ORs of 1.464 (95% CI 0.951–2.253; p = 0.083; I2 = 95.3%, n = 3), and 1.511 (95% CI 0.749–3.047; p = 0.249; I2 = 86.3%, n = 2), respectively. We observed significantly decreased heterogeneity outcomes by subgroup analyses based on different follow-up periods and stroke types.

Association of Fibrinogen Level with Outcomes after Stroke

We also assessed the association of fibrinogen level with the adverse outcomes after stroke, including peripheral venous thrombosis, poor outcome, death, stroke recurrence, neurologic deterioration, and coronary events. As shown in Figures 7-9, poor outcome (Fig. 7b, OR 1.650, 95% CI 1.314–2.071, p = 0.000; I2: 61.845%, n = 9), death (Fig. 8a, OR 1.310, 95% CI 1.128–1.520, p = 0.000; I2: 86.994%, n = 8), stroke recurrence (Fig. 8b, OR 1.228, 95% CI 1.166–1.422, p = 0.000; I2: 17.298%, n = 6), early neurologic deterioration (Fig. 9a, OR 2.381, 95% CI 1.156–4.904, p = 0.019; I2: 60.227%, n = 3) and coronary events (Fig. 9b, OR 1.427, 95% CI 1.232–1.663, p = 0.000; I2: 60.227%, n = 2) were associated with high level of fibrinogen in stroke patients. On the contrary, no significant association was found between fibrinogen level and peripheral venous thrombosis (Fig. 7a, N = 3, OR 1.111, 95% CI 0.444–2.781, p = 0.822; I2: 73.868%).

Fig. 7.

Forest plot of the OR of the association between fibrinogen level and peripheral venous thrombosis (a) and poor outcome (b) after stroke.

Fig. 7.

Forest plot of the OR of the association between fibrinogen level and peripheral venous thrombosis (a) and poor outcome (b) after stroke.

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Fig. 8.

Forest plot of the Odds Ratio (OR) of the association between fibrinogen level and death after stroke (a) and stroke recurrence (b).

Fig. 8.

Forest plot of the Odds Ratio (OR) of the association between fibrinogen level and death after stroke (a) and stroke recurrence (b).

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Fig. 9.

Forest plot of the OR of the association between fibrinogen level and early neurologic deterioration after stroke (a) and other complication after stroke (b).

Fig. 9.

Forest plot of the OR of the association between fibrinogen level and early neurologic deterioration after stroke (a) and other complication after stroke (b).

Close modal

Post-stroke emotional impairment, cognitive impairment, and cancer were associated with high level of fibrinogen in stroke patients. Due to the small number of studies (less than 2), there was no further analysis. But we showed the results in Figure 9b. Further researches can be carried out in this respect in the future to enrich the predictive function of markers.

Assessment of Publication Bias

There were no significant differences in the relative risk of post-stroke outcomes among individuals with different stroke types (ischemic or hemorrhagic stroke) or with different durations of follow-up after adjustment for possible confounders (including geographic location, baseline health status, or study size). Risk estimates were comparable between studies with no evidence of significant heterogeneity in stroke type or duration of follow-up (Fig. 10-15).

Fig. 10.

Funnel plots for relationship between D-dimer and poor prognosis after stroke. a Peripheral venous thrombosis. b Poor outcome.

Fig. 10.

Funnel plots for relationship between D-dimer and poor prognosis after stroke. a Peripheral venous thrombosis. b Poor outcome.

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Fig. 11.

Funnel plots for relationship between D-dimer and poor prognosis after stroke. a Death. b Stroke recurrence.

Fig. 11.

Funnel plots for relationship between D-dimer and poor prognosis after stroke. a Death. b Stroke recurrence.

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Fig. 12.

Funnel plots for relationship between D-dimer and poor prognosis after stroke. Early neurologic deterioration.

Fig. 12.

Funnel plots for relationship between D-dimer and poor prognosis after stroke. Early neurologic deterioration.

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Fig. 13.

Funnel plots for relationship between fibrinogen level and poor prognosis after stroke. a Peripheral venous thrombosis. b Poor outcome.

Fig. 13.

Funnel plots for relationship between fibrinogen level and poor prognosis after stroke. a Peripheral venous thrombosis. b Poor outcome.

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Fig. 14.

Funnel plots for relationship between fibrinogen level and poor prognosis after stroke. a Death. b Stroke recurrence.

Fig. 14.

Funnel plots for relationship between fibrinogen level and poor prognosis after stroke. a Death. b Stroke recurrence.

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Fig. 15.

Funnel plots for relationship between fibrinogen level and poor prognosis after stroke. a Early neurologic deterioration. b Other complication.

Fig. 15.

Funnel plots for relationship between fibrinogen level and poor prognosis after stroke. a Early neurologic deterioration. b Other complication.

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Fibrinogen, which is mainly synthesized in the liver by hepatocytes, is a key factor involved in the coagulation cascade. It consists of two sets of disulfide bridged Aa-, Bb-, and C chains. It can be degraded by plasmin to form fibrinogen degradation products, such as D-dimer [79]. D-dimer can represent total fibrin concentration and thus can serve as a biomarker for intravascular fibrinolysis and thrombosis [80]. Increased plasma fibrinogen and D-dimer level are reported to be correlated with blood-brain-barrier (BBB) damage. It also can augment neuroinflammation by facilitating cytokine secretion from microglia and recruiting leukocytes, thereby leading to exacerbated neural injury [81‒83]. However, the exact role of plasma fibrinogen and its derivatives on the functional outcome of stroke has not been fully elucidated. To our best acknowledgment, this is the first systematic study to analyze the prognostic value of both plasma fibrinogen and D-dimer in stroke.

We noticed that fibrinogen and D-dimer levels may be associated with poor outcomes and death in patients with stroke. This is noteworthy because stroke has some unique characteristics. Studies have shown that fibrinogen levels are significantly elevated in the post-cerebral hemorrhage. Delayed blocking of fibrinogen conversion to fibrin promotes recovery from cerebral hemorrhage. These findings supported the adverse role of fibrin formation in intracerebral hemorrhage [84]. Therefore, it also supported the positive correlation of high levels of fibrinogen and D-dimer with poor prognosis of stroke. Higher-than-normal levels of fibrinogen and D-dimer might contribute to the enhanced mortality and poor outcome of stroke. We cautiously deduce that evaluation of plasma fibrinogen and D-dimer after stroke may help to predict death and poor outcomes in the future.

Another important finding was that fibrinogen levels were not significantly associated with venous thrombosis in stroke patients, whereas D-dimer was the best predictor of venous thrombosis in stroke patients. Since these two biomarkers are thought to have a common mechanism, these results seemed confusing. However, the A allele of the FGB –455G/A gene single nucleotide poly-morphism (rs1800790) is reported to be associated with high plasma fibrinogen level. The FGB-455G/A and FGB-455A/A polymorphisms in the fibrinogen gene have been shown to be associated with an increased risk of ischemic stroke and coronary heart disease [85]. Other studies have shown that the fibrinogen gene does not increase thrombosis and recurrence [86]. It has been reported that positive D-dimer after anticoagulation can identify patients at high risk for recurrence of venous thrombus embolism [87]. The mechanism of the correlation of increased plasma fibrinogen and D-dimer with venous thrombosis in stroke remains elusive. D-dimer has a relatively short half-life of 8 h, while fibrinogen has a relatively longer half-life of 4 days. Their different half-lives should also be taken into consideration. Our findings of different prediction effects of fibrinogen and D-dimer in venous thrombosis should be further confirmed.

Fibrinogen has also been found to be an effective marker for predicting the risk of recurrence, cardiovascular disease, and cognitive impairment in stroke patients. Several mechanisms could be used to explain this finding. One possible explanation is that high levels of fibrinogen may affect the structure of fibrin clots, resulting in more stable fibrin clots that determine the efficacy of arterial recanalization [88]. Another possible explanation is that high fibrinogen levels may lead to high blood viscosity, which affects microvascular flow in marginally perfused brain regions [89]. The explanation for cognitive impairment is as follows. The BBB plays a key role in the production and maintenance of chronic inflammation in Alzheimer’s disease. Normally, the fibrinogen in plasma cannot enter the central nervous system due to the presence of the BBB. However, when the BBB is damaged, fibrin (fibrinogen) penetrates blood vessels and deposits in the central nervous system, worsening cognitive function [90]. Thus, there seems to be a link between fibrinogen levels and cognitive impairment after stroke. However, this hypothesis needs to be verified in future studies. Hemostatic factors (tissue-type plasminogen activator and fibrinogen) have been identified as predictors of myocardial infarction and stroke events [91]. Therefore, it is reasonable to assume that the levels of these proteins could affect the risk of coronary events after ischemic stroke. In addition, the occurrence of cancer and disability after stroke were included in this study. However, due to the sample size, they were not further analyzed. Further in-depth studies should be carried out in the future.

In this study, we demonstrated the role of fibrinogen and D-dimer in poor outcomes of stroke patients. They may be suitable for initial screening of stroke outcome during follow-up or be used in combination with other biomarkers for the diagnosis or prevention of adverse outcomes after stroke. Moreover, recombinant hirudin, a thrombin inhibitor that blocks fibrinogen and D-dimer formation, has been reported to reduce neuroinflammation and the incidence of adverse outcomes after stroke [92]. Fibrinogen inhibitors may have great advantages in the treatment of stroke. However, there is still a long way to go in terms of their clinical application in stroke patients. For example, their poor specificity for adverse outcomes after stroke is a significant limitation that requires improvement.

There are some limitations in this study. First, the included studies used different fibrinogen and D-dimer detection kits or protocols, and had different cut-off values at high and low levels. Second, although we performed subgroup analysis based on specific follow-up periods and assessment methods (i.e., functional outcomes), we could only include studies at 3 and 6 months of follow-up. Third, because fibrinogen and D-dimer may be affected by a variety of factors, such as age, gender, atrial fibrillation, dyslipidemia, venous thrombosis, cardiovascular disease, etc., they may have unknown effects on our results. Further studies are warranted in the future.

Our study provides strong evidence that fibrinogen and D-dimer may be associated with adverse outcomes in patients with stroke. Fibrinogen and D-dimer may serve as potential prognostic markers in stroke. Combining these two biomarkers in clinical follow-up therapy may help customize treatment and improve the effectiveness of current stroke treatment strategies.

The authors thank the assistance of the staff in Qinghai Provincial People’s Hospital.

An ethics statement was not required for this study type, no human or animal subjects or materials were used.

The authors declare that there is no conflict of interest regarding the publication of this article.

This research was funded by Health Commission of Qinghai Province (No. 2021-wjzd-01) and MingFei Yang was 2020 Kunlun Talents of Qinghai Province. High-End Innovation and Entrepreneurship Talent Project-Cultivate leading talents.

QiangJi Bao and XinTing Wu collected and analyzed the data and wrote the paper; Jing-Ni Zhang analyzed the data; QiangJi Bao and XinTing Wu conceived and designed this study, analyzed the data, and wrote the paper; MingFei Yang study supervision, critical revision of the manuscript for important intellectual content. All the authors (QiangJi Bao, JingNi Zhang, XinTing Wu, Kai Zhao, Yu Guo, MingFei Yang, XiaoFeng Du) reviewed the paper and read and approved the final manuscript.

All data generated or analyzed during this study are included in this article and its online supplementary material files. Further inquiries can be directed to the corresponding author.

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Additional information

QiangJi Bao and XinTing Wu are co-first authors