Factor VIII expression in liver disease
Factor VIII expression in liver disease
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DOI：
10.1160/th03-05-0310
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发表时间：
2004-02-01
影响因子：
6.7
通讯作者：
van Mourik, JA
中科院分区：
文献类型：
--
作者：
Hollestellel, MJ;Geertzen, HGM;van Mourik, JA
肝脏疾病与血浆因子vll （FVIII）水平显著升高相关，而许多其他凝血因子和蛋白的合成则减少。为了明确FVIII升高的机制，我们测定了肝脏部分切除患者中FVIII mRNA和蛋白水平的表达水平。此外，还检测了血管性血友病因子（VWF）和低密度脂蛋白受体相关蛋白（LRP）的表达，这两种蛋白以调节FVIII血浆水平而闻名。选取4例肝硬化患者、9例无肝硬化肝功能衰竭患者和6例结肠癌或直肠癌肝转移患者（对照组）的组织样本进行RNA提取。肝硬化患者肝FVIII和LRP mRNA水平显著低于对照组（p <等于0.010），而VWF mRNA水平显著高于对照组（p <等于0.050）。免疫组织化学分析显示，与非肝硬化肝病患者的肝组织相比，肝硬化患者的细胞VWF蛋白分布也有所增加。在肝硬化组织中，增大的门静脉出现过度生长的FVIII，产生窦状内皮细胞。同样，肝硬化组织中产生lrp的细胞数量似乎低于对照组。肝硬化患者血浆FVIII和VWF浓度均显著高于对照组（p分别为0.038和0.010）。这些结果表明，肝硬化患者血浆FVIII水平升高与肝脏VWF生物合成增加和LRP表达降低有关，而不是与FVIII合成增加有关。
Liver disease is associated with markedly elevated plasma factorVlll (FVIII) levels,whereas the synthesis of many other coagulation factors and proteins is reduced. In order to define the mechanism of FVIII increase, we have determined the expression levels of FVIII, both at mRNA and protein level, in patients with liver disease who underwent partial liver resection. In addition, the expression of von Willebrand factor (VWF) and low density lipoprotein receptor-related protein (LRP), proteins known for their ability to modulate FVIII plasma levels, were examined. Tissue samples for RNA extraction were obtained from 4 patients with cirrhosis, 9 patients with liver failure without cirrhosis and 6 patients with liver metastasis of a colon or rectum carcinoma (control group). In patients with liver cirrhosis hepatic FVIII and LRP mRNA levels were significantly lower than controls (p less than or equal to 0.010), while VWF mRNA was significantly higher (p less than or equal to 0.050). Immunohistochemical analysis revealed that cellular VWF protein distribution was also increased in cirrhotic livers compared to liver tissue from patients with non-cirrhotic liver disease. In cirrhotic tissue enlarged portal veins appeared to overgrow FVIII producing sinusoidal endothelial cells. Similarly, the number of LRP-producing cells appeared to be lower in cirrhotic tissue than in controls. The plasma concentration of both FVIII and VWF was significantly higher in patients with cirrhosis than control subjects (p = 0.038 and 0.010 respectively). These results demonstrate that elevated plasma FVIII levels in liver cirrhosis are associated with increased hepatic biosynthesis of VWF and decreased expression of LRP, rather than increased FVIII synthesis.