Van Geet C, Proesmans W, Arnout J, Vermylen J, Declerck P J
Department of Pediatrics, Center for Molecular and Vascular Biology, University Hospital Gasthuisberg, Leuven, Belgium.
Kidney Int. 1998 Oct;54(4):1324-30. doi: 10.1046/j.1523-1755.1998.00103.x.
Thrombotic microangiopathy is the fundamental lesion in diarrhea-associated hemolytic uremic syndrome. The extent of the lesion in the renal parenchyma determines the severity and outcome of the disorder, bilateral renal cortical necrosis being the worst end of the spectrum. In the early years, intravascular coagulation was considered the most important pathogenic mechanism. Yet, individual coagulation factors were normal in the vast majority of patients and therapy with anticoagulants did not alter the course. Recent studies indicate that impaired fibrinolysis might be of importance.
We studied seven variables of the coagulation pathway (PT, aPTT, fibrinogen, FVIII:c, von Willebrand factor, thrombin-antithrombin complexes, prothrombin fragments 1+2) and seven parameters of the fibrinolytic system (plasminogen, alpha2-antiplasmin, C1-esterase inhibitor, tissue-type plasminogen activator, urokinase-type plasminogen activator, plasminogen activator inhibitor type 1, D-dimer) in 24 pediatric patients with diarrhea-associated hemolytic uremic syndrome and in 15 children with acute renal failure not due to hemolytic uremic syndrome. Samples were collected at diagnosis and every second day thereafter for a period of ten days. Additional samples were collected from patients who underwent dialysis, that is, before and after each session from those subjected to hemodialysis and every day from those subjected to peritoneal dialysis. The obtained data were compared with data from a control group consisting of healthy children.
Our data show four important features. (1) A significant increase in both thrombin-antithrombin complexes (P < 0.005) and prothrombin fragments 1 + 2 (P < 0.001) is observed in hemolytic uremic patients as compared to patients with acute renal failure of other causes. This finding is clearly indicative for an activation of the coagulation pathway. (2) Patients with the hemolytic uremic syndrome have significantly higher D-dimer levels, a sensitive marker of fibrin-specific fibrinolysis, as compared to patients with acute renal failure of other causes (P < 0.005). (3) Levels of plasminogen activator inhibitor-1 (active antigen as well as plasminogen activator inhibitor-1 activity) are not different in both patient groups. In contrast, plasma levels of tissue-type plasminogen activator and urokinase-type plasminogen activator are significantly higher in the hemolytic uremic patients than in those with acute renal failure of other causes (P < 0.01 and P < 0.05 respectively). (4) Hemodialysis leads to an increase in tissue-type plasminogen activator antigen and a decrease of plasminogen activator inhibitor-1 activity levels.
Our data demonstrate that in children with diarrhea-associated hemolytic uremic syndrome, limited intravascular coagulation occurs, without evidence of impaired fibrinolysis.
血栓性微血管病是腹泻相关性溶血尿毒综合征的基本病变。肾实质病变的程度决定了该疾病的严重程度和预后，双侧肾皮质坏死是最严重的结局。早年，血管内凝血被认为是最重要的致病机制。然而，绝大多数患者的个体凝血因子正常，抗凝治疗并不能改变病程。最近的研究表明，纤维蛋白溶解功能受损可能起重要作用。
我们研究了24例腹泻相关性溶血尿毒综合征患儿和15例非溶血尿毒综合征所致急性肾衰竭患儿的凝血途径的7个变量（凝血酶原时间、活化部分凝血活酶时间、纤维蛋白原、因子VIII：c、血管性血友病因子、凝血酶 - 抗凝血酶复合物、凝血酶原片段1 + 2）和纤维蛋白溶解系统的7个参数（纤溶酶原、α2 - 抗纤溶酶、C1酯酶抑制剂、组织型纤溶酶原激活物、尿激酶型纤溶酶原激活物、纤溶酶原激活物抑制剂1型、D - 二聚体）。在诊断时及之后每隔一天采集样本，持续十天。还从接受透析的患者中采集额外样本，即血液透析患者每次透析前后以及腹膜透析患者每天采集样本。将获得的数据与由健康儿童组成的对照组的数据进行比较。
我们的数据显示出四个重要特征。（1）与其他原因导致的急性肾衰竭患者相比，溶血尿毒综合征患者的凝血酶 - 抗凝血酶复合物（P < 0.005）和凝血酶原片段1 + 2（P < 0.001）均显著增加。这一发现清楚地表明凝血途径被激活。（2）与其他原因导致的急性肾衰竭患者相比，溶血尿毒综合征患者的D - 二聚体水平显著更高，D - 二聚体是纤维蛋白特异性纤维蛋白溶解的敏感标志物（P < 0.005）。（3）两组患者的纤溶酶原激活物抑制剂 - 1（活性抗原以及纤溶酶原激活物抑制剂 - 1活性）水平无差异。相反，溶血尿毒综合征患者的组织型纤溶酶原激活物和尿激酶型纤溶酶原激活物的血浆水平显著高于其他原因导致的急性肾衰竭患者（分别为P < 0.01和P < 0.05）。（4）血液透析导致组织型纤溶酶原激活物抗原增加，纤溶酶原激活物抑制剂 - 1活性水平降低。
我们的数据表明，腹泻相关性溶血尿毒综合征患儿存在有限的血管内凝血，没有纤维蛋白溶解功能受损的证据。
