Abstract
Background
Thrombotic molecular markers include the thrombin-antithrombin complex (TAT), plasmin inhibitor-plasmin complex (PIC), thrombomodulin (TM), and tissue plasminogen activator-plasminogen activator inhibitor-1 complex (t-PAIC). These molecular markers facilitate the early assessment of coagulation and fibrinolysis system functions, as well as vascular endothelial injury; however, their clinical application following intravenous thrombolysis for acute ischemic stroke (AIS) remains unclear. Therefore, our study aims to evaluate the dynamic levels of these novel thrombosis-related molecular markers within 24 h after intravenous thrombolysis in patients with AIS and analyze their relationship with patients outcome.
Methods
We conducted a retrospective cohort study based on the data of 77 patients with AIS who underwent alteplase intravenous thrombolysis between November 2022 and February 2024. Thrombotic molecular markers were evaluated at four time points: prior to thrombolysis, 1 h after thrombolysis, 6 h after thrombolysis, and 24 h after thrombolysis. Based on the modified Rankin scale (mRS) score at day 90 post-discharge, patients were categorized into the excellent outcome group (mRS ≤ 1) and the non-excellent outcome group (mRS > 1). Stepwise multivariate logistic regression was employed to analyze the association between 90-day functional outcomes and the measured variables. The area under the receiver operating characteristic curve (AUC) was utilized to assess the predictive ability of novel thrombotic markers.
Results
Our study demonstrated that, compared to the non-excellent outcome group, the excellent outcome group exhibited significant lower serum TAT levels both prior to thrombolysis and at 6 h post-thrombolysis (all p < 0.05), and serum TM and t-PAIC levels were also significantly elevated in the excellent outcome group at 1 h, 6 h, and 24 h following thrombolysis (all p < 0.05). Stepwise logistic regression analysis indicated that increased serum TM and t-PAIC levels at 24 h post-thrombolysis were protective factors for a excellent 90-day outcome. The AUC values of TM, t-PAIC, and TM combined with t-PAIC for predicting 90-day functional outcomes were 0.918 (sensitivity 80.0%; specificity 85.7%), 0.658 (sensitivity 91.4%; specificity: 45.2%), and 0.984 (sensitivity: 97.1%; specificity 97.6%), respectively.
Conclusion
Thrombotic molecular markers might serve as indicators for the early monitoring of dysfunction in the coagulation-fibrinolysis system and endothelial injury following intravenous thrombolysis for AIS. TM and t-PAIC exhibit predictive value regarding the outcome of intravenous thrombolysis in AIS, providing insights for future research on the protective role of TM in AIS.
Supplementary Information
The online version contains supplementary material available at https://doi.org/10.1186/s12883-026-05134-7.
Keywords: Acute ischemic stroke, Intravenous thrombolysis, Coagulation-fibrinolysis system, Endothelial injury, Thrombomodulin
Background
Acute ischemic stroke (AIS) is associated with high mortality and disability. Recanalization therapies, such as intravenous thrombolysis (IVT) and endovascular thrombectomy (EVT), represent effective treatments for AIS. Nevertheless, despite aggressive reperfusion therapy, some patients may experience non-excellent outcomes or deteriorate [1, 2]. Imbalance in the coagulation and fibrinolysis systems, along with endothelial injury, are pivotal factors in the occurrence and progression of ischemic stroke, exerting influence on its outcome [3–5]. Thrombotic molecular markers include Thrombin-antithrombin complex (TAT), Plasmin inhibitor-plasmin complex (PIC), Thrombomodulin (TM), and Tissue Plasminogen Activator-Plasminogen Activator Inhibitor-1 Complex (t-PAIC). These molecular markers facilitate early assessment of coagulation, fibrinolysis system function, and vascular endothelial injury in the body [6, 7]. Thrombotic molecular markers have been extensively investigated in the context of ischemic stroke. Studies have suggested that elevated serum TM levels are associated with a favorable outcome for cerebral infarction [6, 8–10], while increased TAT and PIC levels may indicate an elevated risk of post-thrombectomy bleeding [11]. However, the clinical significance of these molecular markers remains debated due to variations in stroke etiology, treatment modalities, and timing of detection among patients, leading to substantial heterogeneity across different patient cohorts [12]. Therefore, our study aims to assess the dynamic levels of thrombotic molecular markers within 24 h following intravenous thrombolysis in patients with AIS and analyze their correlation with patients outcomes.
Methods
Study design and participants
This prospective cohort study enrolled patients with AIS who underwent intravenous thrombolysis at the Stroke Center of our hospital between November 2022 and February 2024, with follow-up conducted up to the 90th day post-discharge. This was a pilot study evaluating the dynamic levels of TAT, PIC, TM, and t-PAIC within 24 h after intravenous thrombolysis in AIS patients and analyzing their relationship with outcomes. Accordingly, sample size calculation was not performed in this study. Definition of AIS: A sudden onset of focal neurological deficit (with or without global cerebral dysfunction), where imaging examinations (primarily computed tomography or magnetic resonance imaging) exclude intracranial hemorrhage or other non-vascular etiologies (e.g., tumors, infections, etc.) and confirm the presence of ischemic lesions consistent with clinical symptoms [1]. The inclusion criteria were: (1) age ≥ 18 years; (2) first-time AIS meeting the emergency intravenous thrombolysis criteria according to the American Heart Association/American Stroke Association guidelines and receiving alteplase intravenous thrombolysis [1]. The exclusion criteria were: (1) baseline modified Rankin Scale (mRS) ≥ 2; (2) severe heart (New York Heart Association classification system, class III-IV), hepatic (serum alanine aminotransferase or aspartate aminotransferase >2 times of the upper limit of normal), or renal (serum creatinine >1.5 times of the upper limit of normal) failure; (3) patients who underwent endovascular intervention following intravenous thrombolysis; and (4) lack of blood samples, clinical data, or follow-up information. This study was approved by the Ethics Committee of Ganzhou Hospital-Nanfang Hospital, Southern Medical University (TY-ZKY2023-053-01) and adhered to the principles outlined in the Helsinki Declaration. Written consent was obtained from the patients or their legal representatives for this study.
Clinical data collection
We collected the following clinical data: (1) age and gender; (2) medical history; (3) parameters of intravenous thrombolytic treatment, including onset to thrombolysis time (OTT), door to needle time (DNT); (4) location of the stroke lesion in the responsible vessel, divided into internal carotid artery, basilar artery and vertebral artery; (5) based on the lesion area size, cerebral infarction lesions were categorized into massive cerebral infarction (maximum lesion diameter ≥ 40 mm) and non-massive cerebral infarction (maximum lesion diameter < 40 mm); (6) the Fazekas grading scale was employed to assess the burden of white matter hyperintensities, with the burden categorized into grades 1, 2, and 3 in ascending order of severity; (7) stroke severity assessed using the National Institutes of Health Stroke Scale (NIHSS), with assessments conducted before and 24 h after thrombolysis; (8) stroke etiology defined using the Trial of Org 10,172 in Acute Stroke Treatment (TOAST) criteria, categorized as atherosclerotic large artery disease, cardiac embolism, small vessel disease, or unknown causes (definition of unknown causes of stroke is a stroke in which two or more potential etiologies are identified upon evaluation, with the patient presenting two or more pathogenic factors, and the attending clinician is unable to ascertain which specific etiology is responsible for the index stroke); and (9) 90-day functional outcome evaluated using mRS, with scores ranging from 2 to 6 indicating non-excellent outcome. All study results were validated by certified neurovascular specialists and radiologists through blinded verification of clinical data.
Blood sample collection and measurements
The blood samples were collected at four time points: 0 h (on admission, before thrombolysis), 1 h, 6 h, and 24 h after thrombolysis. Heparin-coated blood collection tubes were used for sample collection. Subsequently, the blood samples underwent centrifugation at 1500 g for 15 min followed by a second centrifugation at 13,000 g for 3 min to isolate plasma. The obtained plasma was aliquoted and stored at -80 °C until use, with thawing conducted at 37 °C prior to analysis. Levels of TAT, PIC, t-PAIC, and sTM were quantified using an automatic chemiluminescence analyzer (MI600; Yingkai Biotech, Shenzhen, China) in conjunction with specific reagent kits as per the manufacturer’s instructions. The normal reference ranges provided by the manufacturer are as follows: TAT ≤ 4 ng/mL, PIC ≤ 0.8 µg/mL, t-PAIC (male: ≤17.0ng/mL; female: ≤10.5 ng/mL), sTM (3.8–13.3 TU/mL), and D-dimer ≤ 0.5 µg/mL.
Statistical analysis
In our study, a two-tailed p value of less than 0.05 was considered statistically significant. Statistical analyses were conducted using R (version 3.6.3, R Foundation for Statistical Computing, Vienna, Austria). Noncontinuous variables and continuous variables that deviated from the normal distribution were explored with non-parametric approaches (Mann–Whitney–Wilcoxon for two groups and Kruskal–Wallis for multigroups) and are presented as the median and interquartile range. Continuous variables following the normal distribution are presented as the mean and standard deviation; for these variables, the t test was adopted. Categorical variables are expressed as counts (percentages) and analyzed with the chi-square test. According to the 90-day mRS score, we divided patients into two groups: a excellent outcome group (mRS: 0–1) and a non-excellent outcome group (mRS: 2–6). Initially, we performed a univariate analysis on clinical baseline data and coagulation molecular markers to identify potential variables with a p value < 0.05. Subsequently, stepwise multivariate logistic regression was employed to examine the association between these potential variables and 90-day outcome, with adjustment for potential confounding factors. To evaluate the predictive ability of hemostatic molecular markers, we calculated the area under the receiver operating characteristic curve (AUC).
Results
Baseline characteristics
A total of 77 patients were enrolled in this study, consisting of 50 males and 27 females, with an average age of 66.30 ± 11.00 years. Table 1 presents the baseline characteristics of the selected patients stratified by their 90-day functional outcomes. No significant differences were observed between the two groups regarding gender, age, comorbidities, DNT, OTT, pre-thrombolysis NIHSS scores, stroke location, diameter of infarction lesions, Fazekas grade, prior medications, and etiology (all p > 0.05). The incidence of intracranial hemorrhage following thrombolysis was lower in the excellent outcome group, while NIHSS scores at both 24 h and one week post-thrombolysis were higher compared to those in the non-excellent outcome group.
Table 1.
Characteristics of study population
| Variables | Excellent outcome | Non-excellent outcome | P |
|---|---|---|---|
| N | 35 | 42 | |
| Male, n (%) | 23 | 27 | 0.898 |
| Age (years), mean ± SD | 64.80 ± 11.74 | 67.55 ± 10.33 | 0.278 |
| Condition at admission | |||
| Fever, n (%) | 1(2.8) | 2(4.8) | 0.467 |
| Blood glucose(mmol/L), median (IQR) | 5.7(4.8–7.9) | 5.8(4.6–8.0) | 0.567 |
| Systolic pressure(mmHg), median (IQR) | 138(125–164) | 136(123–163) | 0.712 |
| Comorbidities | |||
| TIA, n (%) | 4 (11.4) | 5 (11.9) | 0.661 |
| Coronary artery disease, n (%) | 2 (5.7) | 5 (11.9) | 0.587 |
| Hypertension, n (%) | 30 (85.7) | 33 (78.6) | 0.608 |
| Diabetes, n (%) | 8 (22.9) | 16 (38.1) | 0.234 |
| Atrial fibrillation, n (%) | 5 (14.3) | 8 (19.0) | 0.803 |
| Dyslipidemia, n (%) | 11 (31.4) | 11 (26.2) | 0.800 |
| Drinking, n (%) | 11(31.4) | 12(28.6) | 0.775 |
| Smoking, n (%) | 13(37.1) | 12(28.6) | 0.753 |
| Drug abuse, n (%) | 0 | 0 | |
| Prior medications, n (%) | |||
| Antiplatelet | 15(42.8) | 17(40.5) | 0.773 |
| Anticoagulation | 4(11.4) | 5(11.9) | 0.802 |
| Fazekas grade, n (%) | 0.438 | ||
| Grade 1 | 12(34.3) | 12(28.5) | |
| Grade 2 | 15(42.8) | 19(45.3) | |
| Grade 3 | 8(22.9) | 11(26.2) | |
| DNT (minutes), median (IQR) | 27(20.5–36.5) | 31.5(26–44) | 0.190 |
| OTT (minutes), median (IQR) | 150(120–210) | 180(120–200) | 0.141 |
| NIHSS, median (IQR) | |||
| Pre-thrombolysis | 6(5-8.5) | 8(6–10) | 0.203 |
| Post-thrombolysis 24 h | 3(1–4) | 8(5–10) | <0.001 |
| Post-thrombolysis 1 week | 1(1-2.5) | 6(4–9) | <0.001 |
| Stroke location n (%) | 0.322 | ||
| Internal carotid artery | 24(68.6) | 34(81.0) | |
| Basilar artery | 8 (22.9) | 6 (14.3) | |
| Vertebral artery | 3 (8.5) | 2 (4.7) | |
| Diameter of infarction lesions (mm), n (%) | |||
| ≥40 | 4(11.4) | 5(11.9) | |
| <40 | 31(89.6) | 37(89.1) | |
| Etiology, n (%) | 0.164 | ||
| LAA | 14 (40.0) | 20 ( 47.6) | |
| CE | 3 ( 8.6) | 9 ( 21.4) | |
| SVD | 15 (42.9) | 9 ( 21.4) | |
| Unknown causes | 3 ( 8.6) | 4 ( 9.5) | |
| Intracranial hemorrhage after thrombolysis, n (%) | 1 (2.9) | 9 (21.4) | 0.038 |
SD Standard deviation, DNT Door-to-needle time, IQR Interquartile range, OTT Onset-to-thrombolysis time, NIHSS National Institutes of Health Stroke Scale, LAA Large artery atherosclerosis, CE Cardioembolism, SVD Small vessel disease
Levels of thrombotic molecular markers in patients with different outcomes
Our study found that compared with the non-excellent outcome group, the serum TAT level in the excellent outcome group was significantly lower before [ TAT, 2.130 (0.960–5.085) ng/ml vs. 4.800 (3.405–9.162) ng/ml; p < 0.01 ] and 6 h [ TAT, 3.300 (1.775–6.695) ng/ml vs. 4.790 (3.338–9.337) ng/ml p < 0.05 ] after thrombolysis. Moreover, the serum TM and t-PAIC levels were significantly higher at 1 h [ TM, 17.800 (12.245–21.605) TU/ml vs. 7.725 (5.995–11.673) TU/ml; p < 0.01. t-PAIC, 17.880 (11.085–23.875) ng/ml vs. 10.542 (4.028–18.412) ng/ml; p < 0.05 ], 6 h [ TM, 18.400 (14.830–20.900) TU/ml vs. 8.055 (5.998–11.885) TU/ml; p < 0.01. t-PAIC, 9.970 (7.710-14.085) ng/ml vs. 8.190 (3.458–12.242) ng/ml; p < 0.05 ], and 24 h [ TM, 15.990 (13.765–19.440) TU/ml vs. 7.560 (5.315–10.828) TU/ml; p < 0.01. t-PAIC, 9.140 (6.561–11.334) ng/ml vs. 6.297 (2.460–9.518) ng/ml; p < 0.05 ] following thrombolysis (Fig. 1).
Fig. 1.
Concentrations of thrombotic molecular markers in patients with excellent and non-excellent outcome. *p < 0.05, **p < 0.01, NS, not significant. TAT, thrombin-antithrombin complex; PIC, plasmin inhibitor-plasmin complex; TM, thrombomodulin; t-PAIC, tissue plasminogen activator-plasminogen activator inhibitor-1 complex
Associations between thrombotic molecular markers and 90-day functional outcomes
Utilizing stepwise logistic regression analysis, the elevation of serum TM and t-PAIC levels 24 h post-thrombolysis was identified as a protective factor for excellent outcome at 90 days, as illustrated in (Table 2). Receiver operating characteristic analysis showed that the AUC values of TM, t-PAIC and TM combined with t-PAIC in differentiating 90-day functional outcome were 0.918 (sensitivity 80.0%; specificity 85.7%), 0.658 (sensitivity 91.4%; specificity: 45.2%), and 0.984 (sensitivity: 97.1%; specificity 97.6%), respectively (Fig. 2; Table 3).
Table 2.
Multivariate logistics regression analyses of thrombotic molecular markers associated with 90-day functional outcome
| Time points | Outcome | PIC,µg/ml median (IQR) |
TAT, ng/ml median (IQR) |
TM, TU/ml median (IQR) |
t-PAIC, ng/ml median (IQR) |
|---|---|---|---|---|---|
| 0 h | Excellent |
0.580 (0.415–0.910) |
2.130 (0.960–5.085) |
9.760 (6.965–12.395) |
7.033 (2.397–12.350) |
| Non-excellent |
0.845 (0.455–1.653) |
4.800 (3.405–9.162) |
7.700 (5.488–10.218) |
4.920 (1.040–9.656) |
|
| OR (95% CI) | 1.16(1.11–1.21) | 1.06 (0.95–1.12) | 1.18(1.03–1.32) | 0.83(0.73–1.12) | |
| p value | 0.861 | 0.253 | 0.121 | 0.454 | |
| 1 h | Excellent |
18.400 (7.970–28.370) |
6.850 (3.995–19.330) |
17.800 (12.245–21.605) |
17.880 (11.085–23.875) |
| Non-excellent |
21.650 (7.428–29.803) |
5.065 (3.535–8.085) |
7.725 (5.995–11.673) |
10.542 (4.028–18.412) |
|
| OR (95% CI) | 1.21(1.16–1.28) | 0.97 (0.92–1.06) | 0.73(0.70–0.81) | 0.82(0.68–1.05) | |
| p value | 0.151 | 0.080 | 0.064 | 0.246 | |
| 6 h | Excellent |
8.920 (3.195–14.785) |
3.300 (1.775–6.695) |
18.400 (14.830–20.900) |
9.970 (7.710−14.085) |
| Non-excellent |
4.545 (1.650–8.713) |
4.790 (3.338–9.337) |
8.055 (5.998–11.885) |
8.190 (3.458–12.242) |
|
| OR (95% CI) | 0.82 (0.77–0.89) | 1.14 (1.06–1.18) | 0.74(0.69–0.82) | 0.87(0.77–0.98) | |
| p value | 0.077 | 0.121 | 0.087 | 0.167 | |
| 24 h | Excellent |
0.900 (0.480–1.990) |
2.32 (1.250–6.785) |
15.990 (13.765–19.440) |
9.140 (6.561–11.334) |
| Non-excellent |
0.750 (0.470–5.900) |
3.500 (1.958–5.985) |
7.560 (5.315–10.828) |
6.297 (2.460–9.518) |
|
| OR (95% CI) | 0.96 (0.89–1.02) | 1.12 (1.04–1.17) | 0.78(0.72–0.84) | 0.88(0.83–0.94) | |
| p value | 0.179 | 0.312 | 0.002 | 0.029 |
TAT Thrombin-antithrombin complex, PIC Plasmin inhibitor-plasmin complex, TM Thrombomodulin, t-PAIC Tissue plasminogen activator-plasminogen activator inhibitor-1 complex, IQR Interquartile range, OR Odds ratio, CI Confidence interval
Fig. 2.
Receiver operator characteristic curve analyses for thrombotic molecular markers to predict 90-day functional outcome. AUC, area under the receiver operating characteristic curve; TM, thrombomodulin; t-PAIC, tissue plasminogen activator-plasminogen activator inhibitor-1 complex
Table 3.
Multivariate logistic regression analysis and receiver operating characteristic curve analysis of thrombotic molecular markers associated with 90-day functional outcome
| Variable | OR (95% CI) | p value | AUC (95% CI) | Sensitivity | Specificity | Cut-off value |
|---|---|---|---|---|---|---|
| TM | 0.78(0.72–0.84) | 0.002 | 0.918 (0.890–0.947) | 0.800 | 0.857 | 12.57 TU/ml |
| t-PAIC | 0.88(0.83–0.94) | 0.029 |
0.658 (0.552–0.706) |
0.914 | 0.452 | 8.76 ng/ml |
OR Odds ratio, CI Confidence interval, AUC Area under the receiver operating characteristic curve, TM Thrombomodulin, t-PAIC Tissue plasminogen activator-plasminogen activator inhibitor-1 complex
Discussion
Our study observed the dynamic changes of novel thrombotic markers in serum within 24 h after intravenous thrombolysis in AIS patients for the first time. We found that the levels of TM and t-PAIC after thrombolytic therapy were significantly higher in patients with a excellent outcome than in those with a non-excellent outcome. After conducting multivariate logistic regression analysis, we discovered that the elevation of TM and t-PAIC levels at 24 h after thrombolysis is a related factor for a excellent outcome. Therefore, TM and t-PAIC serve as biomarkers for predicting the outcome of AIS patients treated with intravenous thrombolysis.
Thrombotic molecular markers, including TAT, PIC, TM, and t-PAIC, can be employed for the early assessment of the functions of the coagulation and fibrinolysis systems as well as vascular endothelial injury within the body. In the early stage of coagulation system activation, prothrombin is activated into thrombin. Under normal physiological conditions, once a tiny amount of thrombin is present in the blood, it is promptly inactivated through covalent binding with its specific inhibitor, antithrombin, to form TAT [13, 14]. An elevated TAT level can precisely reflect the generation of thrombin and the enhancement of thrombin activity, accurately indicating early coagulation dysfunction. All thrombotic diseases involve a series of pathological processes related to thrombosis formation. Excessive activation of the coagulation system and the abundant production of thrombin are the key factors for thrombosis formation [15, 16]. The generation of plasmin lies at the core of the fibrinolysis system, and its plasma level can reflect the activation degree of the fibrinolysis system. Immediately after its generation, plasmin combines with its specific inhibitor (α2 - plasmin inhibitor complex) to form PIC and becomes inactive. The half-life of plasmin in the body is only about 10 min, making it difficult to directly detect the plasma concentration of plasmin. An elevated PIC level can sensitively reflect the generation of plasmin and indicate the actual state of fibrin degradation within the body [17–19]. TM is a transmembrane glycoprotein mainly expressed on the surface of vascular endothelial cells. The soluble form of TM in the blood is produced by the hydrolysis of membrane-bound TM on endothelial cells. Under physiological conditions, the content of TM in the blood is extremely low. When vascular endothelial cells are damaged, TM production increases and is released into the blood, resulting in an abnormally elevated TM level in the blood, which is usually secondary to vascular endothelial injury. Hence, its plasma level can reflect the degree of endothelial cell injury [20, 21]. When blood vessels are damaged, tPA (tissue-type plasminogen activator) is released into the blood, specifically converting plasminogen into plasmin to dissolve fibrin [22]. There are four subtypes of its inhibitor PAI, among which the PAI-1 subtype plays an crucial role in the body’s fibrinolysis system [23, 24]. t-PAIC is the product of the combination of tPA and its specific inhibitor PAI-1 and serves as a marker reflecting the amount of tPA released upon endothelial damage. The detection of plasma t-PAIC levels can be utilized to determine the activation of the body’s fibrinolysis system and the repair degree of the endothelium.
Thrombotic molecular markers have been extensively studied in the context of ischemic stroke; however, the conclusions remain controversial [3]. Previous research has indicated that increased serum levels of TM are positively correlated with the severity of atherosclerosis, suggesting a relationship with vascular injury severity as well [25, 26]. Olivot et al. proposed that elevated serum TM serves as a protective factor for patients without prior vascular disease against developing cerebral infarction; however, once cerebral infarction occurs, higher serum TM levels are associated with increased mortality [27]. A study involving 3,532 patients with ischemic stroke reported that elevated serum TM was positively associated with favorable outcome at three months post-event [9]. Subsequent investigations suggested that TM may serve as a marker for early identification and progression of cerebral infarction [10]. In animal models of ischemic stroke, neuroprotective effects attributed to TM have been confirmed. While most studies currently suggest a protective role for TM regarding outcomes in ischemic stroke, there are also reports indicating that elevated serum levels of TM in patients undergoing intravenous thrombolysis correlate with higher mortality compared to those not receiving thrombolysis [3]. The changes in serum TM following intravenous thrombolysis and their association with outcome remain unclear. Therefore, our study revealed that among patients exhibiting favorable outcomes after AIS treated via intravenous thrombolysis, the levels of both serum TM and t-PAIC at 1 h, 6 h, and 24 h were significantly elevated compared to those observed in patients experiencing unfavorable outcomes. This further elucidates the dynamic alterations in thrombotic molecular markers during intravenous thrombolysis for AIS. Following multivariate logistic regression analysis, we found that elevated serum levels of both TM and t-PAIC at 24 h post-thrombolysis were associated with excellent outcomes. We hypothesize that these dynamic fluctuations in serum TM could exert varying impacts on patient outcomes. Prior studies have suggested that t-PAIC can indicate sustained endothelial damage alongside fibrin thrombus progression and subsequent fibrinolytic dysfunction. Elevated concentrations of t-PA and t-PAIC correlate with an increased risk for large cerebral infractions as well as heightened future stroke risk [7, 28, 29]. However, our findings demonstrated significantly higher t-PAIC levels within the excellent outcome group when compared to those within the non-excellent outcome group. We speculate that different subtypes of t-PAIC may play roles in repairing endothelial damage—a hypothesis warranting further investigation [22, 30, 31]. Previous research has shown elevations in TAT and PIC among AIS patients—suggesting their potential utility for predicting adverse outcomes along with post-endovascular thrombectomy hemorrhage events [11, 16, 32]. Our study also found that the serum TAT levels in the non-excellent outcome group before thrombolysis and 6 h after thrombolysis were higher than those in the excellent outcome group. However, after correction by multivariate logistic regression analysis, no statistical significance was observed. We analyzed the reasons for this result, which may be as follows: On the one hand, serum TAT levels in the body are in a dynamic change process and are affected by various factors; on the other hand, the sample size is small.
Our study has several limitations. Firstly, it is a prospective, single-center cohort study with a limited sample size and lacks external validation. Secondly, although we employed adjusted multivariate logistic regression analysis to account for multiple potential confounding factors, residual confounding may still influence the results. Lastly, while we observed a correlation between the levels of hemostatic molecular markers and patient outcomes, this does not necessarily imply causality; further research is required to establish such relationships.
Conclusion
The interaction mechanism between the coagulation-fibrinolysis system and vascular endothelial injury during the acute phase of ischemic stroke is extremely intricate. Thrombotic biomarkers facilitate early assessment of both coagulation-fibrinolysis system function and endothelial injury status. Our study represents the first investigation into the dynamic changes in serum levels of these novel thrombotic markers within 24 h following intravenous thrombolysis in patients with AIS. We found that patients with excellent outcomes exhibited significantly higher levels of TM and t-PAIC at 24 h post-thrombolysis compared to those with non-excellent outcomes. These findings suggest that elevated TM and t-PAIC levels might serve as pertinent prognostic indicators for positive outcomes in this patient population, providing valuable insights for future research on the potential protective role of TM in AIS.
Supplementary Information
Acknowledgements
Not applicable.
Abbreviations
- AIS
Acute ischemic stroke
- TAT
Thrombin-antithrombin complex
- PIC
Plasmin inhibitor-plasmin complex
- TM
Thrombomodulin
- t-PAIC
Tissue plasminogen activator-plasminogen activator inhibitor-1 complex
- mRS
Modified Rankin scale
- NIHSS
National Institutes of Health Stroke Scale
Authors' contributions
XL and JZ conceptualized the study and revised the manuscript. SX, FL, YX, YZ, and PW acquired the data. WS and SX analyzed and interpreted the data, drafted and revised the manuscript, and prepared the figures. All authors contributed to the writing and revisions of the paper. All authors read and approved the final manuscript.
Funding
This work was supported by the Bureau of Science and Technology of Ganzhou Municipality (2022-ZD1360) and the Joint Funds of the Jiangxi Provincial Natural Science Foundation of China (20244BAB28021).
Data availability
The original contributions made for this study are included in the article, and further inquiries can be addressed to the corresponding author.
Declarations
Ethics approval and consent to participate
This study was approved by the Ethics Committee of Ganzhou Hospital-Nanfang Hospital, Southern Medical University (TY-ZKY2023-053-01) and adhered to the principles outlined in the Helsinki Declaration. Written consent was obtained from the patients or their legal representatives for this study.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Fugan Liu, Wei Sun and Shuhua Xie contributed equally to this work and share first authorship.
Contributor Information
Jiajia Zhu, Email: 32102002@qq.com.
Xianghong Liu, Email: ganzhou_neurology@163.com.
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Data Availability Statement
The original contributions made for this study are included in the article, and further inquiries can be addressed to the corresponding author.