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The mechanisms of efficacy and safety of Ginkgo biloba extract in acute ischemic stroke: a real-world study

Thrombosis Journal volume 23, Article number: 10 (2025) Cite this article

Abstract

Background and purpose

Although Ginkgo biloba extract (GBE) has been shown to be effective in treating acute ischemic stroke (AIS) in several clinical trials, concerns regarding adverse events, such as bleeding, have been raised. This study aimed to investigate the mechanisms by which GBE improves AIS prognosis, particularly its impact on platelet activity, coagulation function, and the potential risk of bleeding.

Methods

This real-world study consecutively enrolled 99 patients: 49 with internal jugular venous stenosis (IJVS) treated with GBE; 33 with AIS treated with GBE and low-dose aspirin; and 17 with AIS treated with low-dose aspirin alone. Plasma platelet aggregation and coagulation status were assessed before and after treatment. Major and minor bleeding events were recorded in the AIS group.

Results

In the IJVS group, GBE specifically inhibited arachidonic acid (AA)-induced, but not ADP-induced, platelet aggregation, along with prolonged thrombin time (PT) and activated partial thromboplastin time (APTT). In the AIS group, the combined use of low-dose aspirin and GBE further reduced AA-induced platelet aggregation, mildly prolonged APTT, and was associated with an increased risk of minor bleeding events.

Conclusions

The therapeutic effect of GBE in AIS may, in part, be attributed to its ability to enhance the antiplatelet action of aspirin, particularly in inhibiting AA-induced platelet aggregation. However, the potential for increased bleeding risk warrants further investigation.

Introduction

Acute ischemic stroke (AIS) is a leading cause of disability and death globally, necessitating a multifaceted treatment approach due to its heterogeneous etiologies [1, 2]. Platelet aggregation plays a critical role in the pathogenesis of thrombosis, driven by agonists such as arachidonic acid (AA), adenosine diphosphate (ADP), and collagen, with thromboxane A2 (TxA2) being a key mediator [3]. Aspirin primarily exerts its antiplatelet effect by inhibiting cyclooxygenase (COX)-1, leading to a reduction in TxA2 production and preventing platelet aggregation. Additionally, aspirin may directly inhibit platelet aggregation through other mechanisms, further enhancing its overall antiplatelet effect [4]. Current clinical guidelines recommend early administration of high-dose aspirin (300 mg) within 24 to 48 h post-stroke, followed by long-term low-dose aspirin (100 mg) for secondary prevention of recurrent ischemic stroke [5]. However, the adverse effects of aspirin, particularly bleeding complications, remain a significant clinical challenge [6, 7].

Neuroprotective therapies are increasingly recognized in AIS management due to their ability to mitigate stroke-induced cell apoptosis, excitotoxicity, oxidative stress, and inflammation [8,9,10,11,12]. Ginkgo biloba extract (GBE), which contains active ingredients such as Ginkgo flavones, Ginkgolides, and Bilobalide, is a well-studied and commonly used neuroprotective agent [13]. Studies suggest that GBE may help reduce brain edema, promote angiogenesis, exert antioxidant effects, and modulate inflammation [14,15,16]. Recent research has indicated that GBE could improve the proportion of patients achieving favorable clinical outcomes, making it a popular adjunct to aspirin therapy in China [17]. Nonetheless, the safety of GBE, particularly its potential to induce bleeding when combined with aspirin, remains a subject of concern. Rosenblatt et al. reported a case of spontaneous iris hemorrhage into the anterior chamber in a 70-year-old male patient who had been taking 80 mg of GBE and 325 mg of aspirin daily for one week [18]. Flavonoids in GBE may compete with aspirin for platelet TxA2 receptors (TP), mimicking antiplatelet effects and potentially increasing bleeding risks [19, 20]. GBE may also influence platelet aggregation through independent pathways [21, 22]. This study aims to explore the mechanisms underlying the efficacy and safety of GBE, both alone and in combination with low-dose aspirin, in AIS treatment.

Methods and materials

Study subjects

This study was approved by the ethics committee of Xuanwu Hospital, Capital Medical University (Beijing China), and all patients provided signed informed consent.

Inclusion and exclusion criteria for the internal jugular venous stenosis (IJVS) group

Inclusion Criteria:

  1. (a)

    No age or gender restrictions;

  2. (b)

    Confirmed diagnosis of IJVS by computed tomography venography (CTV) or contrast enhanced-magnetic resonance venography (CE-MRV);

  3. (c)

    Stable vital signs and normal hepatic/renal function.

Exclusion Criteria:

  1. (a)

    Known allergy to GBE;

  2. (b)

    Incomplete clinical information;

  3. (c)

    Use of antiplatelet agents (e.g., clopidogrel, ticagrelor), anticoagulants (e.g., warfarin, heparin), or nonsteroidal anti-inflammatory drugs (e.g., ibuprofen, naproxen);

  4. (d)

    Lack of informed consent.

Inclusion and exclusion criteria for the AIS group

Inclusion Criteria:

  1. (a)

    No age or gender restrictions;

  2. (b)

    Confirmed diagnosis of AIS by magnetic resonance imaging (MRI) and hospitalized within one week of symptom onset;

  3. (c)

    No active bleeding from the gastrointestinal or urinary systems.

Exclusion Criteria:

  1. (a)

    Known allergy to GBE;

  2. (b)

    Aspirin low-responsiveness (AA-induced aggregation > 20% after taking 100 mg aspirin daily for 4 days) [23];

  3. (c)

    Incomplete clinical information;

  4. (d)

    Use of antiplatelet agents (e.g., clopidogrel, ticagrelor), anticoagulants (e.g., warfarin, heparin), or nonsteroidal anti-inflammatory drugs (e.g., ibuprofen, naproxen).

  5. (e)

    Hematological disorders such as anemia or thrombocytopenia;

  6. (f)

    Lack of informed consent.

Based on the inclusion and exclusion criteria, data from 49 patients with IJVS and 50 patients with AIS were included in the final analysis, as shown in Table 1 and 2. A total of 50 AIS patients were enrolled, including 33 in the synergism group (66%), and 17 in the aspirin-only group (34%) (Fig. 1).

Table 1 Demographic characteristics of patients with IJVS
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Table 2 Characteristics of the aspirin and synergism groups
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Fig. 1
figure 1

Flowchart of this study

Abbreviations: AIS: acute ischemic stroke; IJVS: internal jugular venous stenosis

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Study design and procedures

All patients underwent routine inpatient imaging to confirm the diagnosis of either IJVS or AIS, including MRI, CTV, or CE-MRV. From March 2023 to March 2024, 99 eligible patients were consecutively enrolled at the Neurology Department of Xuanwu Hospital, Capital Medical University: 49 with IJVS treated with GBE alone, and 50 AIS patients, divided into two groups: 33 in the synergic group treated with GBE and aspirin, and 17 in the aspirin-only group.

Patients in the IJVS group received 20 ml GBE (70 mg active ingredient, National Medicine Standard H20070226; Yuekang Pharmaceutical Group Co. LTD) diluted in 250 ml of sterile 0.9% sodium chloride for intravenous infusion daily for 5 days. AIS patients in the aspirin group received oral low-dose aspirin (100 mg/day, National Medicine Standard HJ20160685; Bayer HealthCare Manufacturing S.r.l), while those in the synergism group received GBE (20 ml) combined with low-dose aspirin (100 mg/day) for 5 days.

Blood sample collection and analysis

Blood samples were collected at baseline and on day 5 post-treatment, with an additional collection on day 1 post-treatment for the IJVS group. All samples were collected in a fasting state each morning through aseptic venipuncture into 3.8% sodium citrate tubes to prevent coagulation. The samples were processed immediately by centrifugation for 10 min to separate platelet-rich plasma (PRP) and platelet-poor plasma.

Light transmission aggregometry (LTA), the gold standard for assessing platelet aggregation, was conducted by preparing PRP. A 250μL sample of PRP was placed in a cuvette, and aggregating agents such as AA or ADP was added to induce aggregation. Light transmission at 650 nm was measured over 5–10 min, with an increase in transmission corresponding to platelet aggregation. Aggregation was quantified as the change in light transmission from baseline, with the average of three independent measurements used to ensure accuracy [24].

Coagulation parameters, including prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), and prothrombin activity (PTA), were measured using a coagulation analyzer and standardized reagents. Additionally, blood platelet count (BPC), platelet distribution width (PDW), mean platelet volume (MPV), and platelet hematocrit (PCT) were analyzed using a hematology analyzer.

Bleeding events

Bleeding events were monitored throughout the treatment period in the AIS group. Major bleeding events were defined as: (1) Fatal bleeding; (2) Retroperitoneal; intracranial, or intraocular bleeding; or (3) Bleeding causing hemodynamic compromise requiring specific treatment. Minor bleeding events were defined as: (1) Observed bleeding; (2) Reported symptoms of bleeding; (3) Medical, nursing, or paramedical reports of bleeding; or (4) Imaging evidence of bleeding [25, 26].

Statistical analysis

Statistical analyses were conducted using the Social Science Statistical Software Package (SPSS) version 26.0 (IBM). Continuous variables following a normal distribution were calculated as mean ± standard deviation (SD) and compared by t-tests or two-way analysis of variance (ANOVA); otherwise, data were presented as median (interquartile range) and assessed by the Mann–Whitney U test or non-parametric Wilcoxon signed-rank test. Categorical variables were expressed as counts and percentages, with differences evaluated using Pearson’s chi-square test or Fisher’s exact test. A two-tailed p-value < 0.05 was considered statistically significant.

Results

Effects of GBE on platelets

Effects on platelet aggregation

Data from 49 IJVS patients indicated that GBE inhibited AA-induced platelet aggregation. Significant reductions in platelet aggregation rates were observed on day 1 (P < 0.001) and day 5 (P = 0.001) post-GBE. No significant difference was found between day 1 and day 5 (P = 0.923), indicating that GBE immediately inhibits AA-induced platelet aggregation (Fig. 2a; Table 3). However, reductions in ADP-induced platelet aggregation were not remarkable on either day 1 or day 5 post-GBE (Table 3).

Table 3 Effects of GBE on platelet function during treatment
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Fig. 2
figure 2

Trends in platelet indices and coagulation during GBE treatment. a: Trend of AA-induced platelet aggregation; b: Trend of TT; c: Trend of APTT

Abbreviations: AA: arachidonic acid; APTT: activated partial thromboplastin time; GBE: Ginkgo biloba extract; TT: thrombin time

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Effects on other platelet indices

GBE did not affect other platelet indices (BPC, PDW, MPV, and PCT). Compared to baseline, there were no significant changes in these parameters at both day 1 and day 5 post-GBE (P > 0.05) (Table 3).

Effects on coagulation function

Compared to baseline, APTT increased by 1.55s and TT increased by 1.81s on day 1 post-treatment, and APTT increased by 1.15s and TT by 2.41s on day 5 post-treatment (all P < 0.05). No significant differences were observed between day 1 and day 5 (APTT: P = 0.766; TT: P = 0.284) (Fig. 2b and c; Table 4).

Table 4 Effects of GBE on coagulation function during treatment
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Efficacy and safety of aspirin combined with GBE

Effects on AA-induced platelet aggregation

The differential platelet aggregation inhibition was assessed as follows: platelet inhibition (%) = 100%* (AA-induced aggregation pre-treatment-AA-induced aggregation post-treatment)/AA-induced aggregation before treatment. AA-induced platelet aggregation was significantly inhibited in both groups (Fig. 3a and b), with higher inhibition in the synergism group compared to the aspirin group (P = 0.020) (Fig. 3c).

Fig. 3
figure 3

Change in AA-induced platelet aggregation in patients with AIS. a: Trend of AA-induced platelet aggregation in the aspirin group; b: Trend of AA-induced platelet aggregation in the synergic group; c: Comparison of platelet inhibition between the aspirin group and the synergic group

Abbreviations: AA: arachidonic acid; AIS: acute ischemic stroke

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Effects on other platelet indices and coagulation function

GBE exerted no notable effects on other indices (BPC, PDW, MPV, PCT, PT, TT, and PTA). Compared to baseline, there were no significant changes in these parameters on both day 1 and day 5 post-treatment (P > 0.05) (Fig. 4a and g; Table 5, 6). However, APTT mildly increased on day 5 post-treatment compared with baseline (Fig. 4f; Table 5, 6).

Fig. 4
figure 4

Trends in coagulation function during aspirin combination with GBE treatment. a: Trend of BPC; b: Trend of PDW; c: Trend of MPV; d: Trend of PCT; e: Trend of PT; f: Trend of TT; g: Trend of PTA; h: Trend of APTT

Abbreviations: APTT: activated partial thromboplastin time; BPC: blood platelet count; GBE: Ginkgo biloba extract; MPV: mean platelet volume; PCT: platelet hematocrit; PDW: platelet distribution width; PT: prothrombin time; PTA: prothrombin activity; TT: thrombin time

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Table 5 Effects of aspirin combined with GBE on platelet function
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Bleeding events

No major bleeding events occurred in either group. Four minor bleeding events occurred in the synergism group, including three cases of mild gastrointestinal bleeding (fecal occult blood test positive) and one case involving combined gingival and urinary tract bleeding (urine occult blood test positive). No bleeding events were reported in the aspirin group (Table 2).

Table 6 Effects of aspirin combined with GBE on coagulation function
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Discussion

The incidence, morbidity, and mortality of AIS have significantly risen over the past few decades. Large artery atherosclerotic stenosis, accounting for 25% of AIS cases, is closely linked to platelet aggregation [27, 28]. Consequently, antiplatelet therapy remains a cornerstone in AIS management. Low doses of aspirin could irreversibly inhibit COX-1, thereby blocking the production of TxA2 [29, 30].

Antiplatelet function of GBE

Our study demonstrates that GBE significantly inhibits AA-induced platelet aggregation without affecting other platelet indices. This finding corroborates previous studies, such as those by Ke et al., which showed similar antiplatelet effects of GBE in animal models [21]. The inhibition of AA-induced platelet aggregation by GBE may result from an interaction with TPs, influenced by hydroxyl radicals on carbons 7 and 4’ of the flavonoid skeleton. This mechanism is supported by previous studies showing that flavonoids inhibit platelet function through binding to the TP, antagonizing TxA2 signaling pathways (Fig. 5) [19, 20], However, further investigation using TP binding assays and antagonists would be necessary to confirm this mechanism.

Fig. 5
figure 5

Underlying mechanisms of the effectiveness of GBE on AIS. A: antiplatelet pathway; B: anti-apoptosis pathway; C: anti-inflammation pathway; D: anti-oxidation pathway

Abbreviations: AIS: acute ischemic stroke; BBB: blood-brain barrier; COX: cyclooxygenase; GBE: Ginkgo biloba extract; PGH2: prostaglandin H2; ROS: reactive oxygen species; TxA2: thromboxane A2; TP: thromboxane A2 receptor; ZO-1: zonula occludens 1

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Furthermore, when GBE is combined with aspirin, the inhibition of AA-induced platelet aggregation is enhanced. This combination, however, increases the incidence of minor bleeding events without significantly raising the risk of major bleeding events. This suggests a synergistic effect between GBE and aspirin, which warrants further exploration in clinical settings. The observed increase in minor bleeding events may indicate that the combined use of GBE and aspirin influences prostacyclin production or activity—an endogenous inhibitor of platelet aggregation and vasodilator. While prostacyclin’s involvement was not directly assessed in this study, future studies could explore this pathway to better understand its role in the bleeding risk associated with GBE and aspirin co-therapy.

Mild anticoagulation effects

GBE also exhibits mild anticoagulation effects, as evidenced by increased TT and APTT post-treatment. However, some studies have suggested that GBE does not affect coagulation function compared with placebo [31, 32]. These effects appear selective, impacting specific pathways rather than broadly affecting other platelet indices, indicating that GBE’s anticoagulant effects are controlled and targeted. Despite these changes, there were no significant increases in major bleeding events, implying that GBE’s anticoagulation effects are relatively safe. This selective anticoagulation effect could be beneficial in preventing thrombotic events without substantially increasing the risk of severe bleeding, positioning GBE as a potentially safer option in combination therapies.

Neuroprotective function of GBE

Beyond its antiplatelet properties, GBE possesses significant neuroprotective effects. Active components of GBE such as flavonoids and ginkgolides, contribute to its neuroprotective effects by modulating pathways involved in oxidative stress, inflammation, and apoptosis [14,15,16]. These components have been shown to reduce brain edema, inhibit apoptosis, and provide antioxidative and anti-inflammatory benefits (Fig. 5) [33,34,35,36]. The neuroprotective effects of GBE are particularly crucial in AIS management, as they help mitigate secondary neuronal damage following ischemic events. Studies have demonstrated that GBE can enhance neuronal survival, improve cognitive function, and reduce the extent of brain injury in various models of neurological disorders [17, 37].

Transition from antiplatelet to neuroprotective function

The transition from antiplatelet to neuroprotective functions in GBE is facilitated by its active components, which influence platelet activity and neural pathways. Flavonoids and ginkgolides in GBE are effective in mitigating oxidative stress, reducing inflammation, and preventing apoptosis in neural cells [8,9,10,11,12]. This dual functionality underscores the therapeutic potential of GBE in comprehensive AIS management, offering both preventative and protective benefits. By addressing both thrombotic and neurodegenerative pathways, GBE presents a multifaceted approach to AIS treatment, which potentially improves clinical outcomes and reduces long-term disability.

Clinical implications and recommendations

The clinical implications of our findings are significant. GBE, when used as an adjunct to low doses of aspirin therapy in AIS patients, offers a novel approach to enhancing treatment efficacy. However, the increased risk of minor bleeding events necessitates careful patient selection and monitoring. Clinicians should weigh the benefits of enhanced antiplatelet activity against the potential for increased bleeding, particularly in patients with existing bleeding risks. Given the promising results observed in this study, it is recommended that GBE be considered as part of a comprehensive AIS treatment regimen. Nevertheless, further research is essential to establish standardized dosing protocols and identify patient populations that would benefit most from this therapy. Additionally, long-term studies are needed to assess the sustained impact of GBE on both antiplatelet activity and neuroprotection.

Future research directions

Future research should focus on expanding our understanding of GBE’s mechanisms of action. Studies involving larger and more diverse patient cohorts are needed to confirm the generalizability of our findings. Investigating the molecular pathways influenced by GBE could uncover new therapeutic targets and enhance the efficacy of existing treatments. Another area of interest is the development of combination therapies that include GBE and other neuroprotective agents. By targeting multiple pathways of neuronal injury, such therapies could offer superior protection and improve outcomes for AIS patients. Furthermore, exploring the potential of GBE in other neurological conditions characterized by oxidative stress and inflammation could extend its therapeutic applications. For instance, GBE may be beneficial in conditions such as Alzheimer’s disease, other forms of dementia, and Parkinson’s disease, where oxidative stress and inflammation play critical roles in pathogenesis.

Conclusion

GBE effectively inhibits AA-induced platelet aggregation and enhances the antiplatelet effects of aspirin, potentially increasing minor bleeding risks without raising the incidence of major bleeding events. Further investigation into GBE’s impact on TT and APTT, alongside dynamic monitoring of AA-induced platelet aggregation in patients receiving both GBE and low-dose of aspirin, could optimize AIS treatment and mitigate bleeding risks. The integration of GBE into AIS treatment protocols holds great promise. Its dual functionality as an antiplatelet and neuroprotective agent offers a comprehensive approach to managing ischemic stroke, improving patient outcomes, and reducing the burden of this debilitating condition. With further research and clinical validation, GBE could become a key component in the therapeutic arsenal against AIS, providing enhanced protection from the immediate and long-term consequences of stroke.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

AA:

Arachidonic acid

ADP:

Adenosine

AIS:

Acute ischemic stroke

APTT:

Activated partial thromboplastin time

BPC:

Blood platelet count

CE-MRV:

Contrast enhanced-magnetic resonance venography

COX:

Cyclooxygenase

CTA:

Computed tomography angiography

CTV:

Computed tomography venography

IJVS:

Internal jugular venous stenosis

GBE:

Ginkgo biloba extract

LTA:

Light transmission aggregometry

MPV:

Mean platelet volume

MRI:

Magnetic resonance imaging

PCT:

Platelet hematocrit

PDW:

Platelet distribution width

PT:

Prothrombin time

PTA:

Prothrombin activity

PRP:

Platelet-rich plasma

TxA2 :

Thromboxane A2

TP:

Thromboxane A2 receptor

TT:

Thrombin time

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Acknowledgements

We would like to thank all patients’ volunteers who participated in this study for their cooperation. The illustration of graphical abstract was created with BioRender.

Funding

This work was supported by the National Natural Science Foundation of China [grant numbers: 82171297, 82101390].

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Authors and Affiliations

  1. Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China

    Xiangqian Huang, Xiaoming Zhang, Jiahao Song, Duo Lan, Mengqi Wang, Xunming Ji, Da Zhou & Ran Meng

  2. Advanced Center of Stroke, Beijing Institute for Brain Disorders, Beijing, 100053, China

    Xiangqian Huang, Xiaoming Zhang, Jiahao Song, Duo Lan, Mengqi Wang, Xunming Ji, Da Zhou & Ran Meng

  3. National Center for Neurological Disorders, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China

    Xiangqian Huang, Xiaoming Zhang, Jiahao Song, Duo Lan, Mengqi Wang, Xunming Ji, Da Zhou & Ran Meng

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  1. Xiangqian Huang
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Contributions

X.H. wrote the first draft of the manuscript; X.H., X.Z., J.S., D.L., and M.W. performed the material preparation, data collection, and statistical analysis; D.Z., R.M., and X.J. contributed to imaging assessments; D.Z. and R.M. wrote sections of the manuscript and contributed to manuscript revision; D.Z. and R.M. contributed to manuscript drafting and revision, and study concept and design.

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Correspondence to Da Zhou or Ran Meng.

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Huang, X., Zhang, X., Song, J. et al. The mechanisms of efficacy and safety of Ginkgo biloba extract in acute ischemic stroke: a real-world study. Thrombosis J 23, 10 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12959-025-00696-x

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Keywords

Thrombosis Journal

ISSN: 1477-9560

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