Armand Trousseau first reported the relation between thrombosis and malignant tumors in 1865 (1). Subsequent studies have confirmed that thrombosis is a common complication of malignant tumors, which is the second leading cause of death in patients with cancer (2). Thrombotic complications of cancer include arterial or venous thromboembolism and disseminated intravascular coagulation (DIC) (3, 4). Up to 15% of patients with malignant tumors have a history of acute ischemic stroke (AIS) (5), and about 20% of patients with AIS due to an unknown cause (cryptogenic stroke) may have latent malignant tumors (6). Previous studies on gastrointestinal malignant tumor-related thromboembolism mainly focused on venous thromboembolism (7), and clinical studies on the associated AIS focused on a single type of gastrointestinal tumor (8), leading to a paucity of systematic analysis of different gastrointestinal tumor types. The present work retrospectively analyzes the 5-year clinical data of consecutive patients with gastrointestinal malignant tumor-related AIS in a single center. Prognostic factors are analyzed to improve clinical understanding of the gastrointestinal malignant tumor-related AIS.

Abnormal coagulation function is the main cause of AIS in patients with malignant tumor. Abnormal cerebrovascular coagulation is seen in patients with malignant tumors including breast cancer, leukemia, and lymphoma, after performing autopsy, which indicated the association between malignant tumors and coagulation and thrombosis (9). Kim et al. (10) conducted a prospective study and found that D-dimer levels in tumor-related cerebral infarction patients were significantly higher with increased incidence of multifocal cerebral infarction compared with conventional stroke risk factors. Tumor onset and progression are often accompanied by hypercoagulability, resulting in systemic and cerebral–arterial or venous thrombosis (11).

Adenocarcinomas, especially those of the pancreas, colon, breast, lung, prostate, and ovary induce thrombosis by producing and releasing mucin (a high-molecular weight molecule that is glycosylated and secreted by the endothelial cells) directly into the blood, which promotes a hypercoagulation state. Mucin can also interact with certain cellular adhesion molecules on endothelial cells, platelets, and lymphocytes, triggering the formation of microthrombi, which is rich in platelets (12). Meanwhile, tumor cells can produce cancer coagulants (cysteine protease that can independently activate coagulation X factor), tissue factors (binding with coagulation factor VII), and release inflammatory and vascular endothelial growth factors that can mediate coagulation and thrombosis (13–15). For example, tumor necrosis factor-α (TNF-α) affects the anticoagulant properties of the vascular endothelial cells through tissue factors, which promotes thrombin production, fibrin clot formation, and fibrin deposition in blood vessels, and can reduce fibrinolysis by inhibiting tPA activity (16). Tumors may also be associated with acute or chronic DIC. Due to excessive activation of the coagulation process, the imbalance between coagulation and fibrinolysis will eventually lead to thrombosis and arterial occlusion, resulting in AIS (17). The binding of malignant tumor cells with certain nonspecific immune signaling molecules, such as selectin, chemokines, and the corresponding receptors, is conducive to tumor invasion, migration, and adhesion. This will damage cellular connection and cause endothelial injury (18). The activation of the host immune system and the release of inflammatory factors will damage vascular endothelium and thus promote thrombosis (19). Figure 1 shows the formation mechanism of hypercoagulable state in malignant tumors.

Nonbacterial thrombotic endocarditis (NBTE) caused by platelet thrombotic inflammatory complex is another important cause of malignant tumor-related AIS. In a work which consisted of 2,627 cases of postmortem examination, found that in 16 patients with malignant tumor complicated with NBTE, seven were complicated with cerebral infarction (20). This indicated that detaching of cardiac embolus in patients with malignant tumor complicated with NBTE can directly lead to AIS. In addition, infection (21, 22), tumor-related chemotherapy (23), endocrine therapy (24, 25) and, radiotherapy (26) can also lead to AIS in patients with a malignant tumor.

A total of 68 patients with gastrointestinal cancer complicated with AIS were enrolled in this study, including 49 (72.09%) men and 19 (27.91%) women, with a mean age of 61.78 ± 6.65 years. Cases of complications included hypertension, diabetes, hyperlipidemia, and coronary heart disease, and were 45 (66.18%), 38 (55.88%), 43 (63.24%), and 45 (66.18%), respectively. Patients with a history of drinking and smoking accounted for 50.00 and 35.29%, respectively. Fifteen (22.06%) cases and 14 (20.59%) cases had a history of atrial fibrillation and stroke, respectively. The types of gastrointestinal malignant tumors included gastric cancer (42/68, 61.76%), colorectal cancer (17/68, 25.00%), gallbladder cancer (4/68, 5.88%), pancreatic cancer (2.68, 2.94%), liver cancer (2/68, 2.94%), and esophageal cancer (1/68, 1.47%). Adenocarcinoma was the main pathological tumor type, accounting for 63/68 cases (92.65%). Fifty-two (76.47%) cases had a history of malignant tumor, 16 (23.53%) cases without a previous history of tumor. Malignant tumors were diagnosed during hospitalization or follow-up due to AIS. MRI showed multiple scattered lesions. Patients with two and three territory signs accounted for 25 (36.76%) and 30 (44.12%) cases, respectively; one territory sign was only observed in seven (10.29%) cases. Figure 2 shows the characteristics of gastrointestinal malignant tumor-related AIS in MRI.

The baseline characteristics of all study population and univariate regression analysis of prognosis are summarized in Table 1, with 18 patients in the good prognosis group and 50 patients in the poor prognosis group. Compared with the good prognosis group, patients in the poor prognosis group of three territory sign in MRI (52.00 vs. 22.22%, P = 0.029) showed higher levels of Hcy (8.84 ± 3.03 vs. 17.00 ± 3.40 μmol/L, P = 0.047) and D-dimer (2.12 ± 0.78 vs. 1.24 ± 0.70 mg/L, P < 0.001), and also higher levels of TAT (8.07 ± 3.99 vs. 3.75 ± 1.40 ng/ml, P < 0.001), all with significant differences (P < 0.05).

Table 2 shows the multivariate analysis of prognosis. The results showed higher levels of D-dimer (OR 4.497, 95% CI 1.014–19.938) and TAT (OR 4.294, 95% CI 1.654–11.149) which are independent risk factors for the prognosis in patients with gastrointestinal malignant tumor-related AIS (P < 0.05).

The baseline levels of D-dimer and thrombin–antithrombin (TAT) were 1.89 ± 0.85 and 6.93 ± 3.98 ng/ml, respectively. The levels of D-dimer at 3, 6, and 9-month follow-up were 1.65 ± 0.80, 1.52 ± 0.97, and 1.39 ± 1.02 mg/L, respectively; the levels of TAT were 8.46 ± 6.17, 9.88 ± 8.61, and 9.33 ± 8.82 ng/ml, respectively. An ROC curve analysis showed that when the AUC of D-dimer was 0.894 with a cutoff value of 1.60 mg/L FEU, the diagnostic sensitivity and specificity were 78.0 and 94.4%, respectively; when the AUC of TAT was 0.926 with a cutoff value of 5.05 ng/mL, the diagnostic sensitivity and specificity of TAT were 86.0 and 94.4%, respectively. Figure 3 show ROC curve of TAT and D-dimer levels for prognosis in patients with gastrointestinal malignant tumor-related AIS.

Acute ischemic stroke may be identified prior to malignant tumor, which may be an early evidence of potential malignant tumor. Previous studies have found that patients with malignant tumor and with AIS as an initial symptom accounted for 0.4–3.0% of hospitalized stroke patients, and about 5.3–20% of latent stroke patients were diagnosed with malignant tumor during hospitalization, commonly including lung, breast, liver, stomach, and prostate cancers (27, 28). Malignant tumor-related AIS is prone to early neurological deterioration, with high recurrence and poor prognosis, and the prognosis varies in patients with different types of such cerebral infarctions (29). Based on the 2020 data from the International Agency for Research on Cancer (IARC), colorectal, liver, and gastric cancers were the third to fifth common malignant tumors in men, and colorectal cancer is the second common cancer in women (30). Analyzing the characteristics of gastrointestinal malignant tumor-related AIS is the basis for the treatment of such kinds of disease.

Patients with AIS related to gastrointestinal malignant tumor have a relatively poor prognosis. Increased levels of TAT and D-dimer are independent risk factors for poor prognosis. TAT has a better performance than D-dimer in predicting prognosis in patients with gastrointestinal malignant tumor-related AIS.

Some limitations have to be admitted for we report a retrospective study with a relatively small number of patients. Due to the limited number of the included cases, tumor stage and treatment were not analyzed, which could limit the statistical significance of the results. Multicenter studies and larger sample are required for analysis to better summarize the clinical characteristics of malignant tumor patients complicated with AIS in future.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Lanzhou University Second Hospital Ethics Committee. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

YLiu and XL contributed to the study design and drafted the manuscript. FS and XY analyzed the data in the literature and edited the manuscript. YLi contributed to the study design, supervised writing of the manuscript, critically reviewed the paper, and supervised the research project. All authors contributed to the article and approved the submitted version.

This work was supported by grants from the Science and Technology Foundation for Young Scientist of Gansu Province, China (Grant no. 21JR1RA163), The Natural Science Foundation of Gansu Province, China (Grant no. 21JR1RA136), The Science and Technology Project of CuiYing, Lanzhou University Second Hospital, China (Grant no. CY2018-MS06), and Major Science and Technology Projects of Gansu Province, China (20ZD7FA003).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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