The clinical characteristics of acute cerebral infarction patients with thalassemia in a tropic area in China

2.1 Participants

ACI patients with thalassemia and iron-deficiency anemia (IDA) who were admitted to the First Affiliated Hospital of Hainan Medical College, the Second Affiliated Hospital, the Affiliated Provincial People’s Hospital, and the Department of Neurology of Haikou People’s Hospital (Haikou, China) from January 2008 to December 2018 were included. ACI patients with and without anemia were allocated to thalassemia group (Tha group), IDA group, and non-anemia (NA) group.

1. Inclusion criteria

   The following were the inclusion criteria: Patients who were aged ≥18 years old; patients who met the diagnostic criteria for cerebral infarction proposed by the Fourth National Cerebrovascular Disease Conference of the Chinese Medical Association, and confirmed by computed tomography (CT) or magnetic resonance imaging (MRI) of head; acute onset (duration of disease onset would be less than 72 h); patients in the Tha group met the diagnostic criteria for thalassemia or thalassemia screening test; patients in the IDA group met the criteria for IDA.

2. Diagnostic criteria

   Patients in the NA group met the peripheral blood Hb level ≥ 120 g/L (male) and ≥ 110 g/L (female).

3. Exclusion criteria

The exclusion criteria were as follows: Patients with cerebral infarction with large artery atherosclerosis and small artery occlusion; patients with cardiogenic cerebral embolism or cerebral embolism caused by other causes; patients with other anemia-associated diseases; patients with malignant tumors and multiple-organ failure; patients who received intravenous thrombolysis or interventional therapy; patients with incomplete data.

2.2 Clinical data acquisition

Gender and age of all patients were recorded.

In addition, Hb level, platelet count, cholesterol level, and homocysteine (Hcy) level were recorded, and according to the degree of anemia, patients were assigned into mild-anemia group (male: <120 g/L, female <110 g/L), moderate-anemia group (90–60 g/L), and severe-anemia group (<60 g/L).

In the present study, paresthesia, movement disorder, speech disturbance, disturbance of consciousness, ataxia, cognitive dysfunction, mental disorder, and visual disturbance were used as observational indicators.

Eight common controllable risk factors for cerebral infarction, such as hypertension, hyperlipidemia, diabetes, high Hcy level, history of smoking, history of drinking, carotid arteriosclerosis or stenosis, intracranial arteriosclerosis and stenosis, were used.

2.3 Imaging data acquisition

To localize the infarct lesions, the following brain regions were considered: lobes, corpus callosum, basal ganglia, corona radiata and centrum semiovale, brainstem, and cerebellum; according to the size of the infarct lesions, they were divided into small infarct lesions (≤3 cm), medium infarct lesions (3 cm < lesion ≤ 5 cm), and large infarct lesions (>5 cm) [7]; lesions were divided into multiple infarct lesions and single infarction lesions according to the type of attack; the location, size, and number of lesions were recorded and analyzed. In addition, the vascular distribution of the lesions is divided into anterior circulation, posterior circulation, and anterior and posterior circulation according to imaging findings; the hardening and stenosis of large arteries were also recorded. All patients were scanned by MRI or CT, including T1-weighted imaging (T1WI), T2WI, magnetic resonance angiography (MRA), diffusion-weighted imaging (DWI), and fluid-attenuated inversion recovery (FLAIR) sequences.

2.4 Statistical analysis

Statistical analysis was performed using the SPSS 21.0 software (IBM Corp., Armonk, NY, USA). Normally distributed quantitative data were expressed as mean ± standard deviation, and abnormally distributed quantitative data were expressed as median and interquartile range. Qualitative data were presented as number and frequency. The Chi-square test was used for the analysis of categorical variables. Fisher’s exact test was utilized for the expected frequency count of <5. Student’s t-test was used to analyze statistically significant differences between the two groups. P < 0.05 was considered statistically significant.

1. Ethical approval: The research related to human use has been complied with all the relevant national regulations, institutional policies and in accordance the tenets of the Helsinki Declaration, and has been approved by the authors’ institutional review board or equivalent committee. This research was approved by the Ethics Committee of the First Affiliated Hospital of Hainan Medical university No. 2018018 (Science Research).

2. Informed consent: Informed consent has been obtained from all individuals included in this study.

3.1 Clinical and demographic data

A total of 33 cases were involved in the Tha group, including 13 males and 20 females. There were 50 cases in the IDA group, including 28 males and 22 females. A total of 100 cases were included in the NA group (male [n = 67] vs female [n = 33]).

The gender-based difference between the Tha and NA groups was statistically significant (P < 0.05); the gender-based difference between the Tha and IDA groups was not statistically significant (P > 0.05). There was no statistically significant difference in mean age among the Tha, NA, and IDA groups (P > 0.05). Table 1 compares demographic data among the three groups.

Platelet counts in the Tha, NA, and IDA groups were different and statistically significant (P < 0.05). Table 2 compares the platelet count among the three groups.

The average Hb concentration in the Tha group was 83.73 ± 18.63 g/L. The average Hb concentration in the anemia group was 92.6 g ± 16.53 g/L. Compared with the Tha group, the IDA group had a lower proportion of patients with moderate anemia and a higher proportion of patients with mild anemia (P < 0.05). Table 3 compares the anemia indices between the Tha and IDA groups.

3.2 Analysis of risk factors for cerebral infarction in the three groups

The prevalence of hypertension in the Tha group was lower than that in the other two groups, and the difference was statistically significant (P < 0.05). There were significantly fewer 0–2 risk factors of cerebral infarction in the Tha and IDA groups than those in the NA group (P < 0.05). The relationship between the risk factors of cerebral infarction and Tha and IDA in the three groups is shown in Table 4.

3.3 Statistical analysis of clinical symptoms and signs in the three groups

There was no significant difference in clinical symptoms or signs among the three groups (P > 0.05). Table 5 compares the neurological symptoms or signs among the three groups.

5.1 Current status of research on ACI patients with thalassemia

With the improvement of medical services, the average life expectancy of thalassemia patients has been prolonged, while relevant complications have also emerged. The incidence of asymptomatic cerebral infarction has been reported to be higher in children with thalassemia [10] compared with that in adults [11], especially in patients with splenectomy; thalassemia patients with splenectomy are prone to stenosis or occlusion of large intracranial arteries [12]. ACI occurred in 0.25% of patients with β-thalassemia [13], and some scholars demonstrated that ACI occurred in two patients with TI and five patients with TM through case reports. All patients had splenectomy, and the average Hb level was 7.5 g/L. Among them, there were five cases of regular blood transfusion and one case of left internal carotid artery stenosis [14]. Another study reported a 25-year-old female case of TM with infarction in the left corona radiata and centrum semiovale, in which the average Hb level was 7 g/L, and the left internal carotid artery was occluded [15].

In the present study, the clinical characteristics of ACI patients with thalassemia were analyzed. As the most common type of cerebrovascular disease, the number of patients with ACI continues to increase every year, with an average rate of 8.7% per year [6]. A previous epidemiological survey showed that the incidence rates of α-thalassemia, β-thalassemia, and α + β-thalassemia in the reproductive age population in Hainan province were 10.39, 1.38, and 1.18%, respectively [16]. Another study demonstrated that the hypercoagulable state of patients with β-thalassemia might lead to thromboembolic events in multiple organs, including brain involvement [17], while the relevant clinical characteristics of ACI patients with thalassemia have been scarcely reported.

Thalassemia, as an autosomal single-gene hereditary disease, has no significant difference in the incidence rate between men and women, while there are more female patients than male patients in some epidemiological surveys [4]. The present study also reached the same conclusion, which may be related to the promotion of prenatal diagnosis of thalassemia, as well as the significant regional differences in thalassemia and other factors. It is noteworthy that Wang et al.’s results showed that men who aged >40 years old had a higher incidence of ACI than women [18], which was different from other findings reported previously. Therefore, whether the occurrence of ACI with thalassemia is correlated with gender needs to be further studied by expanding the sample size.

Thalassemia results from inherited abnormalities of the synthesis of the globin chains of Hb. Eldor et al. [19] studied thalassemia patients and found that platelet aggregation in peripheral blood of thalassemia patients significantly increased, platelet destruction was elevated, and average lifespan was shortened. Some studies have shown that there are higher concentrations of thromboxane A2 metabolites, thromboxane B26, and 6‐keto‐prostaglandin Flα in the urinary samples of patients with thalassemia, and they are mainly the strongest vasoconstrictors and platelet aggregation agents. It was found that the expression levels of platelet activation markers (CD62P and CD63) were significantly upregulated in patients with thalassemia [20,21]. The results of the present study suggested that both the Tha group and the IDA group were in a hypercoagulable state with secondary thrombocytosis compared with the NA group during the same period, which was consistent with Karimi et al.’s results [14].

A prospective survey showed that 90% of 478 ACI patients had more than 2 risk factors for cerebrovascular disease [22], while in the present study, 19 (57.6%) patients in the Tha group had 0–2 risk factors for cerebral infarction, and there were 14 (42.4%) cases with more than 2 risk factors; in the NA group, 42 (42.0%) cases had 0–2 risk factors for cerebral infarction and 58 (58.0%) cases had more than 2 risk factors; in the IDA group, 36 (72.0%) cases had 0–2 risk factors for cerebral infarction and 14 (28.0%) cases had more than 2 risk factors. This study also indicated that there was no significant difference in clinical neurological symptoms or signs between the Tha group and the other two groups (P > 0.05). There were 3 (9.1%) patients with disturbance of consciousness in the Tha group.

5.2 Shortcomings

When anemia occurs in ACI patients, the demand for oxygen in the brain increases, and at this time, the oxygen-carrying capacity of the blood decreases, resulting in insufficient energy of neurons, causing local or comprehensive neurological dysfunction. The blood vessels in the anterior circulation occupy two-thirds of the blood supply of the brain and naturally require more oxygen; the anterior circulation is at a higher position in the brain, and the areas supplied by the anterior circulation are relatively tolerant to ischemia and hypoxia. Therefore, it is more susceptible to anemia, and the blood supply and oxygen supply are insufficient, resulting in the occurrence of infarct lesions; the watershed area, corona radiata, and centrum semiovale are generally dominated by terminal cerebral vessels, and collateral vessels are not abundant. Therefore, when anemia occurs, these areas have a high probability of hypoperfusion. If anemia is not timely treated, it may eventually develop into an infarction [23,24]. The results of the present study indicated that lesions in the Tha and IDA groups were mainly located in the region from the corona radiata and the centrum semiovale, in which multiple small infarcts were dominant, and there was no significant difference between the two groups (P > 0.05). In the NA group, patients’ lesions were mainly found in the basal ganglia area, and single small infarcts were dominant, which were significantly different from those observed in the Tha and IDA groups (P < 0.05). However, there are some differences between our findings and previously reported results. Comparing the brain MRI examination of thalassemia patients with early clinical manifestations of a series of neurological complications, it was found that thalassemia patients had infarction in the putamen, caudate nucleus, and cortex, and an abnormal iron deposition was identified in these areas. Thus, it can be speculated that infarction in patients with thalassemia is more likely to occur in the putamen, caudate nucleus, and cortex [25]. Therefore, the intracranial infarct lesions in patients with thalassemia are worthy of further investigation, and additional large-scale studies should be conducted to confirm the findings of the present study.