In the study, we found, for the first time, that the levels of D-dimer and fibrinogen were significantly higher in the non-transfusion dependent β-thalassemia group than those in the control group, suggesting that AIS patients with non-transfusion dependent β-thalassemia may have a hypercoagulable state, which was consistent with previous studies showing that patients with β-thalassemia exhibited a hypercoagulable state[12-14].
Although the non-transfusion dependent β-thalassemia related hypercoagulable state has received more and more attention, the pathogenesis remains not fully elucidated as it may be associated with several factors. First, platelet activation may contribute to the hypercoagulable state in patients with β-thalassemia. Eldor A et al. found that the level of TXB2 was increased by 4-10 times in both transfusion-dependent β-thalassemia patients who underwent splenectomy and non-transfusion dependent β-thalassemia patients who did not have splenectomy compared with healthy controls[15]. After treatment with aspirin, the level of TXB2 significantly decreased, indicating that activation and aggregation of platelets are enhanced in patients with β-thalassemia. Unfortunately, no significant difference was found in platelet count between the case group and the control group. The difference in platelet-related parameters also showed no statistical significance. Second, the hypercoagulable state in patients with β-thalassemia may be associated with iron overload. Iron overload has been found to cause oxidative stress, leading to membrane damage of red blood cells and thereby inducing hypercoagulable state[16,17]. Serum ferritin is an important marker for evaluating iron overload [18]. In the present study, we also found that the level of serum ferritin was significantly higher in the non-transfusion dependent β-thalassemia group than in the control group, indicating that iron overload in non-transfusion dependent β-thalassemia patients may be associated with a hypercoagulable state and ischemic stroke. Third, inflammation may also be involved in hypercoagulable state formation in patients with non-transfusion dependent β-thalassemia. A previous study found that pro-inflammatory cytokines can stimulate the release of procoagulant molecules from endothelial cells, leading to the formation of hypercoagulable state[19]. Our findings also showed that the level of inflammatory marker, erythrocyte sedimentation rate increased significantly in the non-transfusion dependent β-thalassemia group.
Previous studies indicated that thalassemia increased the risk of diabetes[20,21]. In contrast, we found that patients in the case and control group had similar rates of diabetes, but lower levels of glycosylated haemoglobin and fasting blood glucose in the non-transfusion dependent α-thalassaemia group. The results of our study differed from those of previous studies. One possible explanation for this was that our controls were patients with ischemic stroke instead of the general population. And we found the lower levels of ESR and fibrinogen, but higher levels of mean platelet volume and prothrombin time in the non-transfusion dependent α-thalassaemia group. However, the mechanisms of those findings remain unclear and requires further elucidation.
In the present study, we also found that the primary ischemic etiological subtype of AIS patients with non-transfusion dependent β-thalassemia was SVO which was significantly higher than that in the controls (77.3% vs. 30.3%, p=0.001). The reason for the difference in the distribution of ischemic etiological subtypes remains unclear. It may be related to the mechanism of the occurrence of ischemic stroke in NTDT patients, such as hypercoagulable state, iron overload and endothelium damage. Ribeiro Júnior RF et al. found in the study of chronic iron overload in mesenteric arteries inducing vascular reactivity and regulating endothelium that the lumen and external diameters of third-order mesenteric resistance arteries were decreased, and the wall/lumen ratio was increased[22], indicating that chronic iron overload in NTDT patients may cause small-artery narrowing and occlusion, which may support our conclusion that the primary TOAST type of AIS patients with non-transfusion dependent β-thalassemia in our study was SVO. One MRI study in NTDT patients without neurologic impairment shown that the incidence of white matter lesions (WMLs) in NTDT patients reached 36.4%[23]. And WMLs have been regarded as one of the neuroimaging manifestations of cerebral small vessel diseases (CSVD) and one of the markers of load for CSVD[24]. SVO-type cerebral infarction is also considered as a subtype of CSVD. Recently, endothelium injury has been recognized as the pathogenesis of CSVD. But there are still limited clinical studies about the underlying pathogenesis of AIS in patients with NTDT. Thus, further study should be taken to clarify the underlying pathogenesis of AIS with NTDT.
There were several limitations to this study. First, our study was a single-center retrospective study and some data were lacked. Second, it was still limited by the number of subjects involved in this study, but they were accompanied by rigid exclusion criteria. Third, our study was conducted in Guangxi province, a multi-ethnic region, and therefore the results may not generalize to other settings. Despite these limitations, the present study was the first study to investigate the features of AIS patients with NTDT. And the data of the present study were opening a great opportunity for the evaluation of the clinical benefits of AIS patients with NTDT at a larger prospective study, strengthening the present valuable findings.