Zwaginga J J, IJsseldijk M J, de Groot P G, Vos J, de Bos Kuil R L, Sixma J J
Department of Hematology, University Hospital, Utrecht, The Netherlands.
Arterioscler Thromb. 1991 May-Jun;11(3):733-44. doi: 10.1161/01.atv.11.3.733.
Uremia is associated with bleeding diathesis. Platelet adhesion to the subendothelium is inhibited by a factor in uremic plasma that may play a role in the disturbed hemostasis of uremic patients. In the formation of the hemostatic plug, platelet adherence is followed by stimulus-induced platelet aggregation and reinforcement by thrombin-generated fibrin. To study these processes in uremic blood, a newly developed thrombosis model was used. Perfusates anticoagulated with low-molecular-weight heparin were circulated over a matrix of stimulated cultured endothelial cells. By stimulation of the endothelial cells, tissue factor was synthesized and deposited in the matrix. When this tissue factor rich-matrix was exposed to flowing blood, local thrombin was formed via activation of the extrinsic coagulation pathway. With this system, platelet adhesion, thrombin-dependent platelet activation, and fibrin formation can all be studied at the same surface. In addition to an adhesion defect, decreased aggregate formation was also found in uremic perfusates. Normal platelets in uremic plasma showed similar results, which indicates that a factor in uremic plasma caused this adhesion and aggregation defect. Platelet aggregation in the system was dependent on endogenously formed thrombin. Fibrinopeptide A generation, however, was normal in uremic perfusates; therefore, uremic plasma has a normal capacity to form thrombin. Resuspension of washed uremic platelets in control plasma did not reverse the aggregation defect in perfusions. In contrast, aggregometer studies with isolated uremic platelets could not detect an abnormal response to threshold concentrations of exogenous thrombin. Thus, uremic toxin(s) cause defective aggregate formation in flow, but not necessarily in the aggregometer. This apparent discrepancy may be due to the higher shear forces in the flow system, which may prevent aggregate formation that is allowed in the aggregometer. Another explanation, that uremic platelets are less responsive to locally formed thrombin than they are to exogenously added thrombin, seems less likely.
尿毒症与出血倾向有关。尿毒症血浆中的一种因子可抑制血小板黏附于内皮下，该因子可能在尿毒症患者止血功能紊乱中起作用。在止血栓形成过程中，血小板黏附后会发生刺激诱导的血小板聚集，并由凝血酶生成的纤维蛋白进行强化。为研究尿毒症血液中的这些过程，采用了一种新开发的血栓形成模型。用低分子量肝素抗凝的灌注液在刺激的培养内皮细胞基质上循环。通过刺激内皮细胞，组织因子被合成并沉积在基质中。当富含组织因子的基质暴露于流动血液时，通过外源性凝血途径的激活形成局部凝血酶。利用该系统，可在同一表面研究血小板黏附、凝血酶依赖性血小板活化和纤维蛋白形成。除了黏附缺陷外，在尿毒症灌注液中还发现聚集物形成减少。尿毒症血浆中的正常血小板也表现出类似结果，这表明尿毒症血浆中的一种因子导致了这种黏附和聚集缺陷。该系统中的血小板聚集依赖于内源性生成的凝血酶。然而，尿毒症灌注液中纤维蛋白肽A的生成正常；因此，尿毒症血浆具有正常的凝血酶生成能力。将洗涤后的尿毒症血小板重悬于对照血浆中并不能逆转灌注中的聚集缺陷。相比之下，对分离的尿毒症血小板进行的凝集仪研究未检测到对外源性凝血酶阈值浓度的异常反应。因此，尿毒症毒素会导致流动状态下聚集物形成缺陷，但在凝集仪中不一定如此。这种明显的差异可能是由于流动系统中较高的剪切力，这可能会阻止凝集仪中允许的聚集物形成。另一种解释是，尿毒症血小板对局部形成的凝血酶的反应性低于对外源性添加的凝血酶的反应性，这种解释似乎不太可能。
