DataSheet1_Hemorheological profiles and chronic inflammation markers in transfusion-dependent and non-transfusion- dependent thalassemia.docx

The rheological properties of blood play an important role in regulating blood flow in micro and macro circulation. In thalassemia syndromes red blood cells exhibit altered hemodynamic properties that facilitate microcirculatory diseases: increased aggregation and reduced deformability, as well as a marked increase in adherence to the vascular endothelial cells. A personalized approach to treating thalassemia patients (transfusions, iron chelation, and splenectomy), has increased patients’ life expectancy, however they generally present many complications and several studies have demonstrated the presence of high incidence of thromboembolic events. In this study the hemorheological profiles of thalassemia patients have been characterized to point out new indices of vascular impairment in thalassemia. Plasma viscosity, blood viscosities at low and high shear rates (η1 and η200, respectively), erythrocyte aggregation index (η1/η200), and the erythrocyte viscoelastic profile (elastic modulus G', and viscous modulus G") have been studied in transfusion-dependent and non-transfusion-dependent thalassemia patients. Moreover, the levels of inflammation biomarkers in thalassemia have been evaluated to investigate a relationship between the biomarkers, the disease severity and the rheological parameters. The biomarkers studied are the main components of the immune and endothelial systems or are related to vascular inflammation: cytokines (IL-2, IL-6, IL-10, IL-17A, TNF-alpha), chemokines (IL-8, MIP-1alpha), adipocytokines (leptin and adiponectin), growth factors (VEGF, angiopoietin-1), adhesion molecules (ICAM-1, VCAM-1, E-selectin, L-selectin), and a monocyte/macrophage activation marker (CD163). This study shows that transfusion-dependent thalassemia patients, both major and intermedia, have blood viscosities comparable to those of healthy subjects. Non-transfusion-dependent thalassemia intermedia patients show high blood viscosities at low shear rates (η1), corresponding to the flow conditions of the microcirculation, an increase in erythrocyte aggregation, and high values of the elastic G' and viscous G" modules that reflect a reduced erythrocyte deformability and an increase in blood viscosity. Levels of cytokines, chemokines and adhesion molecules are different in transfusion- and non-transfusion dependent patients and positive correlations between η1 or η1/η200 and the cytokines IL-6 and IL-10 have been observed. The evaluation of the hemorheological profiles in thalassemia can provide new indicators of vascular impairment and disease severity in thalassemia in order to prevent the onset of thromboembolic events.

血液流变学特性（rheological properties of blood）在调控微循环与大循环的血流过程中发挥关键作用。在地中海贫血综合征（thalassemia syndromes）患者体内，红细胞（red blood cells）的血流动力学特性发生改变，进而诱发微循环相关疾病：表现为红细胞聚集性增强、变形能力下降，且对血管内皮细胞的黏附性显著升高。针对地中海贫血患者的个体化治疗方案（输血、铁螯合治疗及脾切除术）已延长了患者的预期寿命，但此类患者仍常出现多种并发症；多项研究已证实其血栓栓塞事件的发生率居高不下。本研究对地中海贫血患者的血液流变学特征（hemorheological profiles）进行了表征，旨在明确地中海贫血患者血管损伤的新型指标。研究对象涵盖输血依赖型与非输血依赖型地中海贫血患者，检测指标包括血浆黏度（plasma viscosity）、低剪切率与高剪切率下的全血黏度（分别记为η₁与η₂₀₀）、红细胞聚集指数（erythrocyte aggregation index，η₁/η₂₀₀），以及红细胞黏弹性特征（erythrocyte viscoelastic profile）：弹性模量G'与黏性模量G''。此外，本研究还检测了地中海贫血患者的炎症生物标志物（inflammation biomarkers）水平，以探究生物标志物、疾病严重程度与流变学参数之间的关联。本次检测的生物标志物涵盖免疫与内皮系统的主要组分，或与血管炎症相关：包括细胞因子（cytokines）：IL-2、IL-6、IL-10、IL-17A、肿瘤坏死因子-α（TNF-alpha）；趋化因子（chemokines）：IL-8、巨噬细胞炎症蛋白-1α（MIP-1alpha）；脂肪细胞因子（adipocytokines）：瘦素与脂联素；生长因子（growth factors）：血管内皮生长因子（VEGF）、血管生成素-1（angiopoietin-1）；黏附分子（adhesion molecules）：细胞间黏附分子-1（ICAM-1）、血管细胞黏附分子-1（VCAM-1）、E-选择素（E-selectin）、L-选择素（L-selectin）；以及单核细胞/巨噬细胞活化标志物（monocyte/macrophage activation marker）：CD163。本研究结果显示，重型与中间型输血依赖型地中海贫血患者的全血黏度与健康受试者相当。非输血依赖型中间型地中海贫血患者则表现为低剪切率下的全血黏度（η₁）显著升高——该指标对应微循环的血流状态，同时其红细胞聚集性增强，弹性模量G'与黏性模量G''数值升高，上述指标变化反映出红细胞变形能力下降与全血黏度升高。输血依赖型与非输血依赖型患者的细胞因子、趋化因子及黏附分子水平存在显著差异；且η₁或η₁/η₂₀₀与细胞因子IL-6、IL-10呈正相关。对地中海贫血患者血液流变学特征的评估，可为其血管损伤与疾病严重程度提供新型检测指标，进而助力血栓栓塞事件的预防。