Stroke is a major contributor to increased morbidity and mortality in Indonesia and worldwide. In Indonesia, the prevalence of stroke in 2023 reached 8.3 per 1000 people (Ministry of Health of the Republic of Indonesia, 2024). The aetiology of stroke involves atherosclerotic plaque rupture, which exposes collagen and causes thrombus aggregation. These aggregations or clots obstruct cerebral blood arteries and cause local occlusion (Wells BG et al., 2009). To date, alteplase is one of the medications commonly used to treat acute ischaemic stroke. Alteplase is a tissue plasminogen activator (rt-PA) that lyses fibrin and fibrinogen by transforming plasminogen into the proteolytic enzyme plasmin. Common side effects of alteplase therapy include bleeding, angioedema, anaphylactic reactions, and fever (Wells BG et al., 2009). According to a study by Lin et al. (2020), intracerebral haemorrhage after intravenous alteplase delivery occurred 6% of the time. Other studies indicate that the incidence of haemorrhagic transformation in patients with acute ischaemic stroke following thrombolysis ranges from 2.4 to 4.9%, with a mortality rate of up to 90%. Bleeding related to alteplase therapy includes cerebral bleeding and peripheral bleeding. Peripheral bleeding considers bleeding from the gums, skin, gastrointestinal tract, urinary tract, and respiratory tract (Romano et al., 2015).

Ischaemic stroke patients who experienced bleeding after intravenous thrombolysis are associated with a higher mortality rate (Zhang et al., 2021). A study by Du (2020) showed that gastrointestinal bleeding occurring in patients with acute ischaemic stroke following in-hospital fibrinolysis can increase the risk of stroke recurrence. Patients with intracranial haemorrhage, major surgery, cerebrovascular disease, trauma or significant bleeding, uncontrolled hypertension, acute pericarditis, increasing age, prior stroke, and atrial fibrillation are at the highest risk of bleeding (Kerndt, Health and Trainability, 2020). The results of the literature review above highlight the dangers of bleeding in patients with acute ischaemic stroke, as it leads to increased mortality and recurrent stroke in patients. This study aims to evaluate risk factors of bleeding in patients with acute ischaemic stroke undergoing alteplase therapy. The results of this study are expected to serve as a guide for healthcare professionals to prevent bleeding in patients undergoing alteplase therapy for acute ischaemic stroke.

This is an observational study with a retrospective case-control design conducted at Gadjah Mada University Hospital in Indonesia during the period from January 2020 to October 2025. The inclusion criteria for this study were patients aged ≥18 years, diagnosed with acute ischaemic stroke, and receiving alteplase therapy. Patients with haematological problems and those with inadequate data were excluded from this investigation. The patients were divided into two groups: the bleeding group and the non-bleeding groups. The data collected in this study includes blood measurement, blood glucose levels, triglyceride levels, and information regarding the patient’s history of chronic conditions such as hypertension, diabetes mellitus, dyslipidaemia, heart failure, atrial fibrillation, prior stroke and antiplatelet use. The Gadjah Mada University Academic Hospital’s Ethics Committee gave its approval to this study under the number 089/RSA/KEP/EC/2025. The requirement for informed consent was waived by the Ethics Committee because the study was retrospective in nature. This study employed an observational design and did not involve human as research subjects. Statistical analysis was performed using SPSS version 26. The Kolmogorov-Smirnov/Shapiro-Wilk test for evaluating data normalcy was the statistical test employed, the independent t test/Mann-Whitney test for identifying risk factors for bleeding in numerical data, the chi-square test/Fisher’s exact test for categorical data, and regression analysis to assess the influence of one or more independent variables on a dependent variable.

Eighty one patients were included in this study, with a mean age of 62.38 ± 9.72 years. There were 26 (32.1%) female patients and 55 (67.9%) male patients. Based on the outcomes we classified 26 patients (32.1%) to the bleeding group and 55 patients to the non-bleeding group. In bleeding groups, the were more patients with major bleeding (22.22%) than those with minor bleeding (9.88%) ( Table 1).

Bivariate analysis was performed to determine the variations in each factor influencing the frequency of bleeding in patients. Only two variables had p-values <0.05; those were blood glucose levels (p = 0.001) and triglyceride levels (p = 0.002). There were five variables with p-value <0.25; sex (p = 0.07), diabetes mellitus (p = 0.087), level of consciousness (p = 0.176), age (0.096), and alteplase dose (p = 0.181). Hypertension, heart failure, prior stroke, atrial fibrillation, dyslipidemia, and blood pressure were having p-value >0.25. ( Table 2) ( Table 3).

Bleeding is a primary side effect in patients following alteplase therapy. The current study included 81 patients with acute ischaemic stroke who were treated with alteplase. Twenty-six patients developed a bleeding group, while the remaining patients developed a non-bleeding group. This result was higher than previous reports, which range from 2% to 13.33% (Das et al., 2020); Fekete et al., 2013; Kamal et al., 2021; Lin et al., 2020; Nassar et al., 2024; Romano et al., 2015) The difference is likely because previous studies focused solely on major bleeding, whereas this study included both major and minor bleeding events. The predominance of minor bleeding events compared to major bleeding indicates that the hospital has strictly implemented patient selection protocols for alteplase therapy.

Significant findings were obtained from a bivariate analysis of the association between blood glucose levels and the incidence of bleeding after alteplase therapy (p = 0.001). The mean blood glucose levels in the bleeding group were higher at 207.5 ± 114.58 mg/dl. This study also indicates that the association between blood glucose levels and the occurrence of bleeding was not influenced by the individual’s history of diabetes mellitus; patients with diabetes mellitus accounted for 22.22% of the total, and the number of subjects who experienced bleeding was only 9 subjects. The risk factor of diabetes mellitus in this study had an OR of 2.7 (95% CI 0.92–7.95) with statistically not significant results (p = 0.087). These findings suggest that high blood glucose levels may lead to bleeding events, regardless of whether or not the patient has diabetes mellitus. However, other studies report different results; hyperglycaemia and diabetes mellitus prior to alteplase therapy significantly influence bleeding events (OR 13.12; 95% CI 3.37–51.1; P > 0.001) (Zeinhom et al., 2024). There are three possible explanations for the correlation between blood glucose levels and extracranial haemorrhage. First, elevated levels of inflammatory markers (superoxide, plasma kallikrein, and tumour necrosis factor-alpha) are a result of elevated blood glucose levels. Elevated levels of these markers can impair endothelial function and potentially lead to bleeding. (Therapy et al., 2025). Second, hyperglycaemia can worsen hypoxia and dystrophy, increasing the risk of necrosis and degeneration of blood vessel walls. Third, cellular metabolic disturbances caused by hyperglycaemia lead to increased plasma osmolality and intracellular lactate accumulation, which ultimately trigger endothelial cell damage and acidosis (Das et al., 2020).

This study identified high triglyceride levels as a significant risk factor for bleeding events (p = 0.002). Previous research has also demonstrated that elevated triglyceride levels, in conjunction with low LDL and HDL cholesterol, are associated with an increased risk of symptomatic intracerebral haemorrhage (sICH) in patients with acute ischaemic stroke following alteplase therapy (Huang and Yi, 2023). Elevated triglyceride levels indicate the presence of broader metabolic dysfunction, thereby increasing the risk of bleeding complications following thrombolytic therapy (Uyttenboogaart et al., 2008). The present study also found that a history of heart failure was not significantly associated with bleeding events during alteplase therapy (OR: 1.76, 95% CI: 0.54–5.74, p = 0.36). Prior studies indicate that while heart failure is an independent risk factor for poor long-term functional outcomes, it does not impact the safety or efficacy of intravenous thrombolysis and mechanical recanalisation. Thus, a history of heart failure does not appear to contribute to bleeding events as a side effect of thrombolytic therapy (Breuer et al., 2019).

In this study, all patients received the same dose at 0.9 mg/kg. Therefore, the effect of variying alteplase doses on the incidence of bleeding could not be clearly determined. Statistical analysis revealed no significant correlation between the occurrence of bleeding and the alteplase dose (p = 0.181). According to earlier research, low doses of alteplase are linked to a decreased incidence of symptomatic cerebral haemorrhage (Chen et al., 2020). In this study, systolic blood pressure (p = 0.624) and diastolic blood pressure (p = 0.984) did not significantly correlate with bleeding incidence. These findings are consistent with the study by Nassar et al. (2024), who reported that systolic blood pressure (p = 0.693) and diastolic blood pressure (p = 0.791) did not influence the incidence of bleeding after patients received alteplase therapy. However, in contrast to the recent study by Morten et al. (2026), systolic blood pressure was substantially linked to the incidence of sICH after adjusting for age, sex, and NIHSS score at admission, with an OR of 1.022 (95% CI 1.003–1.042, p = 0.0022). The discrepancy between the results of this study and previous studies is likely due to differences in the parameters used to classify bleeding events. In previous studies, risk factor analysis focused on major haemorrhage, whereas this study analysed risk factors for all haemorrhages (major and minor). Excessive blood pressure rises damage brain cells in the infarct tissue, disrupting the blood-brain barrier and causing intracranial haemorrhage (Rusanen, Saarinen and Sillanpää, 2015).

Bivariate analysis showed that males had an OR of 0.378 (95% CI 0.14–1.0, p = 0.07), indicating no significant association between the use of alteplase and the incidence of bleeding in patients with acute ischaemic stroke. The results of this study showed that the percentage of bleeding events in men (17.28%) was slightly higher than in women (14.81%), but the difference was not statistically significant. According to a study by Wiszniewska et al. (2020), there were differences in clinical outcomes among patients with acute ischaemic stroke receiving alteplase therapy based on gender. This study noted that female patients did not have a clearly higher risk of intracerebral haemorrhage; however, female patients more frequently experienced poor long-term clinical outcomes and high mortality rates. In contrast to the study conducted by Khedr and Nasreldein. (2024), the primary predictor of increased mortality was the occurrence of haemorrhage in men.

The results of the bivariate analysis showed no significant association between age and the incidence of bleeding (p = 0.096). Age is a major nonmodifiable risk factor or predictor associated with the incidence of bleeding. Previous studies on the influence of patient age as an independent risk factor for bleeding have yielded mixed results. Several studies report that advanced age is a relative contraindication for thrombolysis in patients with acute ischaemic stroke within 3–4.5 hours. One such study, conducted by Sun et al. (2020), showed that patients aged >68 years were a risk factor for haemorrhagic transformation in acute ischaemic stroke patients, with an OR of 1.835 (95% CI 1.36–2.82, p = 0.024). However, other studies report that the incidence of bleeding does not differ significantly between younger and older patients and that older patients still benefit from thrombolytic therapy (Zhang et al., 2024).

Atrial fibrillation was another variable examined in this study, although the results were not statistically significant (p = 0.38). This is due to the fact that the participants’ bleeding was primarily minor. In individuals with intracerebral haemorrhage, prior research has demonstrated a correlation between atrial fibrillation and bleeding events (Zeinhom et al., 2024; Lei et al., 2022; Nassar et al., 2024). The mechanism by which atrial fibrillation acts as a risk factor for intracerebral haemorrhage involves the extensive area of perfusion and low recanalisation rates, leading to increased infarct volume and the severity of intracerebral haemorrhage (ICH) (Saposnik et al., 2012). In this study, a history of prior stroke in patients did not significantly influence the incidence of bleeding (p = 0.509). In line with atrial fibrillation, prior stroke is a risk factor for intracerebral hemorrhage following alteplase administration (Lin et al., 2020; Chen et al., 2022). Patients with a history of stroke who received alteplase therapy had a higher likelihood of experiencing ICH and adverse clinical outcomes. A prior stroke causes a disruption of the blood-brain barrier (BBB), which typically occurs an average of 13 hours after stroke onset. An elevated rate of haemorrhagic transformation is directly linked to this disruption (Breuer et al., 2019).

The results of the multivariate analysis showed that there was only one independent factor associated with the incidence of bleeding in patients with acute ischaemic stroke receiving alteplase therapy, namely the patient’s random blood glucose level (OR 1.01, 95% CI 1.00–1.022, p = 0.045) ( Table 4). These results are consistent with other studies on the incidence of haemorrhagic transformation following reperfusion therapy in patients with acute ischaemic stroke; the multivariate analysis from that study showed that the patient’s blood glucose level had an OR of 1.207 (95% CI 1.100–1.915, p = 0.042 (Iancu et al., 2023). Another study also showed similar findings; the effect of random blood glucose on the incidence of haemorrhagic transformation following alteplase therapy in patients with acute ischaemic stroke had an OR of 1.22 (95% CI 1.12–1.34, p = 0.001) (Chen et al., 2024).

The multivariate analysis’s findings indicate that, among patients with acute ischaemic stroke undergoing alteplase therapy, only blood glucose levels were significantly correlated with the incidence of bleeding patients with acute ischaemic stroke with alteplase therapy, whereas systolic blood pressure, diastolic blood pressure, triglyceride levels, history of heart failure, and alteplase dose did not show significant results.

This study obtained formal ethical approval from the Academic Hospital of Universitas Gadjah Mada under number 089/RSA/KEP/EC/2025, confirming that the study was conducted in compliance with applicable ethical standards and institutional policies.