The current study is, so far as we know, the first to clarify the predictive value of elevated baseline RDW level in patients with TIA. The most important result of our study is to show that(1) the higher RDW, the earlier the stroke onset and(2) RDW ≥ 13.95%has a 2.52-fold risk of stroke in TIA patients.
Previous studies found an association between RDW and the incident stroke in a general population, which was independent of anaemia[15]. The higher RDW values measured in stroke patients were associated with adverse functional outcomes and mortality[8].Moreover, increased RDW has proven to be a potent predictor of neuronal damage[16], hemorrhagic transformation[17], higher mortality after intravenous thrombolysis[18], and atrial fibrillation[19] in AIS patients.
The mechanism by which high RDW is associated with stroke progression and clinically poor prognosis is not fully understood. In fact, high RDW is known to reflect high oxidative stress and inflammation[10]. Oxidative stress can reduce RBC lifespan[20],and inflammation is closely related to suppressed RBC production[21], both of which may increase RDW levels. Lorente et al. found that patients with malignant middle cerebral artery infarction(MMACAI) and eventual death show higher RDW, higher blood malondialdehyde(MDA) levels, and higher tumor necrosis factor-α (TNF-α)levels than survivors, and these parameters are correlated. They suggest that the association between mortality and RDW in MMACAI patients may be due to higher oxidative status and higher inflammatory status[22].
As mentioned above, RDW is associated with the potential inflammatory state and oxidative damage, and may predict the incidence and prognosis of stroke patients. The explanation of correlation between an increased RDW level and stroke after TIA may be as follows.
First, higher oxidative stress status in stroke patients after TIA. Several studies have shown that patients with elevated RDW are more likely to suffer high oxidative stress and low antioxidant levels. Oxidative damage and antioxidant levels have been shown to be associated with neuronal damage/protection during cerebral ischemic and reperfusion, which play a role in functional outcome and mortality[23].
Ischemia and reperfusion injury can induce oxidative stress through production of reactive oxygen species(ROS)[24].The TIA animal model suggested that oxygen free radicals produced during reperfusion of ischemic brain injury might be the main cause of reperfusion injury[25]. A 24-month follow-up study of 786 women with moderate and severe disabilities found that their serum oxidant levels increased as RDW increased. Inversely, serum antioxidant concentrations decreased with RDW. An increased RDW level has been identified as a marker of greater oxidative stress status[26]. We found that the stroke patients in respect to the TIA patients had higher RDW, indicating higher oxidative stress.
The antioxidant and oxidant systems were not balanced, and oxidative stress occurred when lots of ROS were produced or the antioxidant were exhausted[27].ALB and TBIL are the main antioxidants participating in removal of ROS and reactive nitrogen species (RNS) produced by various reactions[28]. Our study found lower serum TBIL and ALB levels in stroke patients, suggesting lower antioxidant status in stroke after TIA patients. To sump up, the stroke patients experience higher levels of oxidative stress than TIA both in terms of oxidative stress and antioxidant markers. Therefore, oxidative stress may participate in the pathology of high RDW in stroke after TIA.
Second, higher inflammation status in stroke patients after TIA. The role of inflammation in the ischemic cascade after TIA is well known. Inflammatory mechanisms are central to the pathogenesis and progression of atherosclerosis, plaque rupture[29],thrombosis[30], and stroke[31]. A rich body of literature demonstrates that inflammation is associated with increased stroke risk and may be an important determinant of outcomes[32]. Inflammatory biomarkers such as P-selectin have been considered to be predictors of stroke after TIA[33].
A study of 3845 adult outpatient subjects further supported this hypothesis. the scholars demonstrated a strong, hierarchical and independent relationship between RDW and hsCRP levels[34]. In addition, some scholars have found that RDW and CRP are positively correlated, which further confirmed the hypothesis that RDW is an inflammation marker[35]. Moreover, another study revealed that older women in higher quartile of RDW were associated with higher concentration of interleukin-6, suggesting predictive values of RDW in serum antoxidants and inflammation[36]. To some extent, our results are consistent with the conclusion of their researches. In our study, both the values of RDW, N/L and the CRP were significantly higher in stroke patients. It seems that stroke patients experience higher levels of inflammation than TIA.
Third, higher RDW means microcirculation disturbance and insufficient oxygen supply. With the increase of RDW, the size of RBC is not uniform, and its deformation causes changes in peripheral blood circulation function. This may be an independent or synergistic factor for increased circulatory resistance and the result of vascular occlusion[37].Increased RBC aggregation and reduced deformability are observed in the pathophysiology of circulatory disorders, including myocardial infarction, inflammation, and stroke[38]. These hemorheological parameters interrupt microcirculation through narrow capillaries in ischemic tissue[39].Some scholars found that elevated RDW can lead to poor collateral flow and increased final infarct volume in stroke patients[40].
In addition, elevated RDW levels were negatively correlated with blood oxygen saturation[41].Lower oxygen saturation and decreased erythrocyte deformability were observed in patients with increased RDW in previous studies[37]. With the increased of RDW value, oxygen supply in the brain is lower[42], which may directly contribute to the progression of TIA.
More importantly, the comparison of different AUCs(Fig. 2, 0.731 vs 0.613) supported that the use of RDW value could improve predictive power when compared with the ABCD2 score. To further investigate the necessity of addition of RDW to a scoring system, larger-sample studies are needed.
As a conclusion, our finding confirmed the prognostic value of RDW in patients with TIA. Increased RDW likely reflects the presence of oxidative stress, inflammation, microcirculation underfilling and/or hyoxemia or a combination thereof. Based on the above evidence, we look forward to more studies confirming that RDW is a powerful predictor of subsequent stroke in TIA patients.
LIMITATIONS
One limitation of our study is that several markers of inflammation and oxidative stress, such as TNF-α, and MDA, were not adequately evaluated. Another limitation in our study was that the RDW was measured only once, which may increases the possibility of analyzing defects. Thirdly, the sample of this retrospective study is small, which may lead to biases in the results of the study. Therefore, large sample, multi-center studies are needed to verify our findings.