Increased tendency of cancer patients to develop venous thromboembolism (VTE) is associated with high rates of mortality. Elevation of procoagulant proteins and down regulation of naturally occurring coagulation inhibitors appears to form the basis of high risk of VTE in malignancy. A reduced level of anticoagulant protein like antithrombin (AT) will influence both coagulation and angiogenesis, as its cleaved and latent conformations show potent antiangiogenic activity. We show a concentration dependent perturbation in the secondary and tertiary structures of AT conformers exposed to hypochlorous acid (HOCl). Modulated under a very narrow concentration range of HOCl, native AT undergoes oligomerization, aggregation and fragmentation based on spectroscopic, SDS and native-PAGE studies. Factor Xa inhibition assay demonstrated a progressive decrease in inhibition activity of AT on modification by HOCl. Bis-ANS result showed that hydrophobic patches were more exposed in the case of HOCl-modified AT when assessed fluorometrically. Dosage of HOCl-modified AT in experimental animals induced high titer antibodies showing more specificity towards modified forms in comparison to unmodified forms. Auto-antibodies isolated from cancer patients also showed enhanced binding with HOCl-modified AT in comparison to native counterpart. Compared to normal AT, structurally and functionally altered conformation of HOCl-modified AT showed increased immunogenic sensitivity. HOCl modified AT can contribute to prothrombotic and angiogenic environment during cancer progression/development.

中文翻译：

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次氯酸修饰的抗凝血酶的结构改变表明新表位的产生。

癌症患者发展静脉血栓栓塞症（VTE）的趋势增加与高死亡率相关。促凝蛋白的升高和天然凝结抑制剂的下调似乎形成了恶性肿瘤中VTE高风险的基础。降低水平的抗凝血蛋白（如抗凝血酶（AT））将影响凝血和血管生成，因为其裂解和潜在构象显示出强大的抗血管生成活性。我们在暴露于次氯酸（HOCl）的AT构象异构体的二级和三级结构中显示出浓度依赖性的扰动。在很窄的HOCl浓度范围内进行调节，天然AT会根据光谱，SDS和天然PAGE研究进行寡聚，聚集和断裂。Xa因子抑制试验证明AT对HOCl修饰的抑制活性逐渐降低。Bis-ANS结果表明，当用荧光法评估时，在HOCl修饰的AT情况下疏水性斑块更易暴露。实验动物中HOC1修饰的AT的剂量诱导了高滴度的抗体，与未修饰的形式相比，其对修饰的形式显示出更高的特异性。与天然对应物相比，从癌症患者中分离出的自身抗体还显示出与HOC1修饰的AT结合增强。与正常AT相比，HOC1修饰的AT的结构和功能改变的构象显示增加的免疫原性敏感性。HOCl修饰的AT在癌症进展/发展过程中可能有助于血栓形成和血管生成环境。Bis-ANS结果表明，当用荧光法评估时，在HOCl修饰的AT情况下疏水性斑块更易暴露。实验动物中HOC1修饰的AT的剂量诱导了高滴度的抗体，与未修饰的形式相比，其对修饰的形式显示出更高的特异性。与天然对应物相比，从癌症患者中分离出的自身抗体还显示出与HOC1修饰的AT结合增强。与正常AT相比，HOC1修饰的AT的结构和功能改变的构象显示增加的免疫原性敏感性。HOCl修饰的AT在癌症进展/发展过程中可能有助于血栓形成和血管生成环境。Bis-ANS结果表明，当用荧光法评估时，在HOCl修饰的AT情况下疏水性斑块更易暴露。实验动物中HOC1修饰的AT的剂量诱导了高滴度的抗体，与未修饰的形式相比，其对修饰的形式显示出更高的特异性。与天然对应物相比，从癌症患者中分离出的自身抗体还显示出与HOC1修饰的AT结合增强。与正常AT相比，HOC1修饰的AT的结构和功能改变的构象显示增加的免疫原性敏感性。HOCl修饰的AT在癌症进展/发展过程中可能有助于血栓形成和血管生成环境。实验动物中HOC1修饰的AT的剂量诱导了高滴度的抗体，与未修饰的形式相比，其对修饰的形式显示出更高的特异性。与天然对应物相比，从癌症患者中分离出的自身抗体还显示出与HOC1修饰的AT结合增强。与正常AT相比，HOC1修饰的AT的结构和功能改变的构象显示增加的免疫原性敏感性。HOCl修饰的AT在癌症进展/发展过程中可能有助于血栓形成和血管生成环境。实验动物中HOC1修饰的AT的剂量诱导了高滴度的抗体，与未修饰的形式相比，其对修饰的形式显示出更高的特异性。与天然对应物相比，从癌症患者中分离出的自身抗体还显示出与HOC1修饰的AT结合增强。与正常AT相比，HOC1修饰的AT的结构和功能改变的构象显示增加的免疫原性敏感性。HOCl修饰的AT在癌症进展/发展过程中可能有助于血栓形成和血管生成环境。HOCl修饰的AT的结构和功能改变的构象显示增加的免疫原性敏感性。HOCl修饰的AT在癌症进展/发展过程中可能有助于血栓形成和血管生成环境。HOCl修饰的AT的结构和功能改变的构象显示增加的免疫原性敏感性。HOCl修饰的AT在癌症进展/发展过程中可能有助于血栓形成和血管生成环境。