Molecular mechanisms involved in the resistance of fibrin to clot lysis by plasmin in subjects with type 2 diabetes mellitus
Molecular mechanisms involved in the resistance of fibrin to clot lysis by plasmin in subjects with type 2 diabetes mellitus
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DOI：
10.1007/s00125-006-0197-4
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发表时间：
2006-05-01
期刊：
影响因子：
8.2
通讯作者：
Grant, PJ
中科院分区：
文献类型：
--
作者：
Dunn, EJ;Philippou, H;Grant, PJ
目的/假设：本研究的目的是通过评估纤溶调节成分与纤维蛋白凝块之间的相互作用，确定2型糖尿病对纤溶的影响，使用从150名2型糖尿病患者和50名匹配的对照组提纯的纤维蛋白原。方法：用共聚焦显微镜测定血栓的溶解速度。纤溶酶的产生使用纤溶酶特异的显色底物来测量。用表面等离子体共振法测定纤维蛋白、组织型纤溶酶原激活物(t-PA)与谷氨酸纤溶酶原的结合作用，用微量平板法测定纤溶酶抑制物与纤维蛋白XIII因子的交联度。结果：糖尿病大鼠血栓溶解速度明显慢于对照组(1.35vs2.92umm/min，p<；0.0001)，纤溶酶生成明显减少。糖尿病组t-PA、Glu-纤溶酶原与纤维蛋白的平衡结合亲和力降低：t-PA，K-D=0.91+/-0.3Mol/L(正常对照组)，1.21+/-0.5Mol/L(糖尿病组)，P=0.001；在糖尿病患者中，凝血因子XIII增强了纤溶酶抑制物与纤维蛋白的交联性，体外交联性程度与体内血糖控制(HbA(1c))相关(r=0.59p=0.001)。结论/解释这些结果表明，糖尿病患者纤溶过程的损害是通过许多不同的机制介导的；这可能是由于他们暴露在与糖尿病相关的异常代谢环境中，对纤维蛋白原分子进行翻译后修饰的结果。
Aims/hypothesis: The aim of this study was to determine the influence of type 2 diabetes on fibrinolysis by assessing interactions between the regulatory components of fibrinolysis and the fibrin clot, using fibrinogen purified from 150 patients with type 2 diabetes and 50 matched controls. Methods: Clot lysis rates were determined by confocal microscopy. Plasmin generation was measured using a plasmin-specific chromogenic substrate. Surface plasmon resonance was used to determine the binding interactions between fibrin, tissue-type plasminogen activator (t-PA) and Glu-plasminogen; cross-linkage of plasmin inhibitor to fibrin by factor XIII was determined using a microtitre plate assay. Results: Lysis of diabetic clots was significantly slower than that of controls (1.35 vs 2.92 mu m/min, p < 0.0001) and plasmin generation was significantly reduced. The equilibrium binding affinity between both t-PA and Glu-plasminogen and fibrin was reduced in diabetic subjects: t-PA, K-D=0.91 +/- 0.3 mu mol/l (control subjects), 1.21 +/- 0.5 mu mol/l (diabetic subjects), p=0.001; Glu-plasminogen, K-D=97 +/- 19 nmol/l (control subjects), 156 +/- 66 nmol/l (diabetic subjects), p=0.001. Cross-linkage of plasmin inhibitor to fibrin by factor XIII was enhanced in diabetic subjects, with the extent of in vitro cross-linkage correlating with in vivo glycaemic control (HbA(1c)) (r=0.59, p=0.001). Conclusions/interpretations These results indicate that impairment of the fibrinolytic process in diabetic patients is mediated via a number of different mechanisms; these may be a consequence of post-translational modifications to fibrinogen molecules, resulting from their exposure to the abnormal metabolic milieu associated with diabetes.