Effect of plasma thrombin-antithrombin complex on ischemic stroke: a systematic review and meta-analysis

Characteristics of included studies

After retrieving relevant search terms in PubMed, EMBASE, Web of Science, and Cochrane Library databases, a total of 2965 publications were researched, and 4 articles were retrieved from Google Scholar. The PRISMA flow diagram for study inclusion in our meta-analysis was depicted in Fig. 1. 1824 articles remaining after deduplication, and then the letters, reviews, cases reported, animal studies, and literature not related to the topic totaling 1242 publications were excluded by browsing the titles and abstracts. A full text of 582 potentially eligible articles was retrieved, studies were excluded again for no relation with TAT (389), study topic is not a stroke (165), and without full text (16). Finally, 12 studies were included in our meta-analysis.

Fig. 1figure 1

PRISMA flow diagram for the detailed procedures of study screening of systematic review and meta-analysis

A total of ten case-control studies and two cohort studies were incorporated into the systematic review and meta-analysis, including 1431 stroke cases and 532 healthy controls. Six studies were from Japan [17,18,19,20,21,22], two studies were from China [8, 23], and the remaining four were from Canada [24], the USA [25], Spain [26], and Finland [27]. The average ranges from 64.7 to 72.4 years old in the case group and 61 to 72.4 in the control. Computed tomography (CT) and/or magnetic resonance imaging (MRI) are the methods used in all studies to confirm the diagnosis. Serum TAT levels were measured by enzyme-linked immunosorbent assay kits (ELISA) in nine studies, two studies used enzyme immunoassays to determine the biomarker, and only one study was detected by chemiluminescence. Six of the studies conducted follow-up records (1 month to 3 years) and reported the cut-off of TAT, three of which explained the OR between TAT and adverse outcome. Table 1 summarizes the characteristics of included studies, and the follow-up results are shown in Table 2.

Table 1 Characteristics of included studies in the systematic review meta-analysisTable 2 The relationship between TAT and the outcome of ischemic stroke patients after a follow-upQuality of included studies

All studies were assessed for methodological quality by the Newcastle-Ottawa Scale (NOS). The range of quality scores is 7 to 8 for case-control, with a median of 7.5 (7.5 ± 0.53) (Supplementary Table 2). All studies reported the case and control definition, comparability, ascertainment of exposure, and the same method of ascertainment for cases. But five of them do not report the source of the control group [17,18,19, 21, 22]. All the research included a certain hospital or institution for a continuous-time, which we believe to be representativeness of the cases. However, no study describes the non-response rate. The quality scores of the two cohort studies were 6 [26] and 7 [25] respectively, both neither described comparability and non-exposed cohort, and one of which has no statement about adequacy of follow-up of the cohort [26].

Meta-analysis

Ten studies investigated the association between plasma TAT levels and ischemic stroke. The result revealed that plasma TAT level was significantly higher in ischemic patients than those in healthy controls (MD 5.31, 95% CI = 4.12–6.51, P < 0.0001, I2 = 97.8 %, Pheterogeneity < 0.00001, Fig. 2).

Fig. 2figure 2

Plasma TAT levels in ischemic stroke and healthy control

We conducted a subgroup analysis to explore the distinction in the same period among cardioembolic, lacunar, and atherothrombotic strokes and the results are shown in Figs. 3, 4, 5. The plasma TAT level in the three subgroups of ischemic stroke was significantly higher than control in the acute phase (MD 5.45, 95CI%, 3.97–6.93, P < 0.001, Fig. 3). Similarly, the ischemic stroke subgroup with a higher level of TAT than the control in subacute phases (MD 4.40, 95CI%, 3.01–5.78, P < 0.001, Fig. 4), and chronic phase (MD 2.21, 95CI%, 1.50–2.93, P < 0.001, Fig. 5). During the same period, the plasma TAT level of cardioembolic stroke is the highest, followed by atherosclerosis and lacunar stroke.

Fig. 3figure 3

Plasma TAT levels in the acute phase of cardioembolic, lacunar, and atherothrombotic strokes

Fig. 4figure 4

Plasma TAT levels in the subacute phase of cardioembolic, lacunar, and atherothrombotic strokes

Fig. 5figure 5

Plasma TAT levels in the chronic phase of cardioembolic, lacunar, and atherothrombotic stroke

Meanwhile, we analyzed the differences among different periods in each subtype of ischemic stroke. The cardioembolic stroke was shown in Supplementary Figure 1, it is significant in the acute, subacute, and chronic phases (MD 7.75, 95CI%, 6.07–9.43, P < 0.001). Although there is no difference in atherothrombotic stroke in the result of Supplementary Figure S2 (MD 3.26, 95CI%, 2.02–4.50, P = 0.13), and the plasma TAT level was markedly elevated in the acute than that in the subacute and chronic phases. Besides, no significant difference was found in the lacunar stroke which was shown in Supplementary Figure S3 (MD 1.22, 95CI%, 0.79–1.65, P = 0.34, I2 = 97.86%), and the highest plasma TAT level is the subacute phase.

We further searched for sources of heterogeneity by meta-regression, and these results are showed in the Supplementary Table 3. The moderators included year, country, cases, average age, and test method, unfortunately, none of them were sources of heterogeneity.

Systematic review

A total of six studies have reported the relationship between plasma TAT levels and the prognosis of ischemic stroke prognosis (Table 2). We conducted the systematic review because the available data did not further perform synthesis. Three studies recorded recurrence of stroke, the incidence of short-term recurrence was 33%, which was associated with a mean TAT concentration of 9.6 ng/mL [17, 24, 27]. David Tanne et al. [25] found that the baseline TAT level is related to three-month mortality when it is more than 11.2 ng/mL (OR = 1.72, 95% CI 1.26–2.34). Similarly, the study of Israel Fernandez et al. [23] indicates that there was a significant correlation between higher TAT levels and unfavorable function outcomes (poor outcome modified Rankin scale > 2) (OR = 1.283, 95% CI 1.105–1.489). On the contrary, lower plasma TAT levels in patients with ischemic stroke could be associated with a high success rate of revascularization (OR = 2.7, 95% CI 1.2–6.1) [26].

Sensitivity analysis and publication bias

Sensitivity analysis was performed through the elimination method in which one study is removed at a time and the others analyzed to estimate whether the results could have been affected markedly by a single study. However, the results showed that excluding any one study will not affect the results, this analysis confirmed the stability of the results. Another subgroup analysis was performed to explore the source of heterogeneity based on the TAT detection method. There was no significant difference between the groups (P = 0.11, Supplementary Figure S4). There is no publication bias which was estimated by Egger’s (P = 0.7787) regression test.

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