Mitomycin-induced hemolytic-uremic syndrome

Four patients who took the antitumor agent mitomycin manifested microangiopathic hemolytic anemia, thrombocytopenia, and renal failure. At autopsy, kidneys from all four patients had a microangiopathy typical of the hemolytic-uremic syndrome (HUS), with thromboses in glomerular capillaries and arterioles, fibrin deposition in mesangium, and prominent cellular intimal proliferation of the interlobular arteries. Development of the HUS was an important factor contributing to death in all four patients. From a review of the literature and our initial results of a randomized chemotherapy protocol for metastatic adenocarcinoma of the colorectum, it appears that mitomycin was the most likely cause for the development of the HUS in these patients. As more patients are being treated with mitomycin, particular care must be taken to monitor them for development of a drug-induced HUS.     

Prothrombotic factors in nephrotic syndrome

Nephrotic syndrome is a hypercoagulable state with variable prevalence of clinical thrombosis. The role of platelet aggregation, fibrinogen and antithrombin III and protein S levels in the pathogenesis of hypercoagulable state in these patients is controversial. Since no study on Indians is available, the clinical and laboratory profile of 22 patients of nephrotic syndrome (age 18-35 years with an MF ratio of 4:3), have been studied. The coagulation profile revealed a prolonged APTT in 12 patients (54.5%), and a prolonged TT in four (18.1%). In the rest APTT and TT were normal. PT was raised in two patients. Fibrinogen, an acute phase reactant was raised in five patients (22.7%). Antithrombin III levels were reduced in 19 patients (86.4%), normal in one and raised in two patients. Free Protein S levels were high in 12(54.5%), normal in seven and decreased in three patients. Platelet aggregation with adrenaline and adenosine diphosphate was raised in 6 patients. Ultrasonographically detected deep vein thrombosis was seen in one patient only (4.5%) who had ATIII levels of 48%. This low incidence can be explained by elevated protein S levels which was found to be raised in 12(54.5%) cases, protein S being an anticoagulant factor. This low level of clinical thrombosis in Indian patients of nephrotic syndrome may be an ethnic variable factor. It is thus concluded that although patients with nephrotic syndrome have a hypercoagulable state, clinical thrombosis is rarely seen in Indian patients with nephrotic syndrome.     

Kidney morphology in hemolytic-uremic syndrome

Morphology of the kidneys in hemolytic-uremic syndrome is considered basing on autopsy findings obtained for 3 infants with 5-17-day history of acute renal failure. A newborn infant of 17 days developed the disease after feto-fetal hemotransfusion when macerated fetus-donor hemolysis products entered the circulation of the fetus-recipient through monochorionic placenta. The second case in an infant of 6 months was due to ADTP Vaccine. The last infant aged 16 months manifested the syndrome in the presence of Proteus-induced ulcerative colitis. Varying in etiology, renal morphology exhibited similar features: fibrin deposits in the lumens of glomerular capillary loops, afferent glomerular arterioles and intrarenal arteries; fibrinoid necrosis of the wall in the arterioles. The renal affection ranged from acute thrombotic glomerulonephritis to cortical necrosis, these variations being dependent on the degree of thrombogenesis, caliber of impaired intrarenal vessels and time from the onset of acute renal failure.     

Pathogenesis of hemolytic-uremic syndrome]

Current literature on the pathogenesis of the hemolytic-uremic syndrome (HUS) is analyzed. A variety of etiologic factors and mechanisms of HUS development is considered. The emphasis is laid on the endotoxinemia, damage of the renal vessel and glomerular mesangium endothelium and other mechanisms.     

Prothrombotic changes in platelet, endothelial and coagulation function following hemodialysis

Purpose: Patients on hemodialysis (HD) have an increased risk of thrombotic events, including myocardial infarction and vascular access thrombosis. The study hypothesis is that a single session of dialysis leads to platelet, endothelial and coagulation activation. Our aim is to determine the effect of a single HD session on prothrombotic vascular biomarkers before and after a single session of hemodialysis. Methods: Blood samples were taken from the vascular access of 55 patients immediately before and after a hemodialysis session. Platelet function was assessed by (1) flow cytometric measurement of P-selectin expression and fibrinogen binding +/- ADP stimulation, (2) Ultegra rapid platelet function assay (RPFA) using the agonists thrombin receptor activating peptide (TRAP) and arachidonic acid (AA), (3) soluble P-selectin, and (4) soluble CD40L. Coagulation (thrombin-antithrombin III [TAT] and D-dimer), endothelial von Willebrand factor (vWF) and high sensitivity C-Reactive protein (hsCRP) were assessed by ELISA. Results: Unfractionated heparin was given to all patients during dialysis and 30 patients (55%) were on antiplatelet agents. Post-hemodialysis there were significant increases in unstimulated platelet P-selectin (p=.037), stimulated P-selectin (p<.001), soluble P-selectin (p<.001) and soluble CD40L (p=.036). Stimulated platelet fibrinogen binding was increased post-hemodialysis (p<.001) but unstimulated fibrinogen binding was unchanged. TRAP- (p<.001] and AA-(p=.009) stimulated aggregation were reduced post-hemodialysis. There were increases post-hemodialysis in TAT (p<.001), D-dimer (p<.001), vWF (p<.001) and hsCRP (p=.011). Conclusion: This study has shown that despite heparin therapy, a single session of HD induced increases in platelet, endothelial, and coagulation activation. More effective medical strategies to reduce the prothrombotic state of patients on hemodialysis should be investigated.     

Enterohemorrhagic Escherichia coli associated with hemolytic-uremic syndrome in Chilean children.

A clinicoepidemiological study was undertaken to determine if enterohemorrhagic Escherichia coli (EHEC) was associated with hemolytic-uremic syndrome (HUS) in children in Santiago, Valdivia, and Temuco, Chile. Prospective surveillance detected 20 hospitalized cases of HUS in children less than 4 years of age in these cities from March 1988 to March 1989. Each HUS patient was matched (by sex and age) with two control children (hospitalized elective-surgery patients). To detect EHEC, DNA from stool culture isolates of E. coli was detected by hybridization with biotin-labelled DNA probes specific for the EHEC virulence plasmid, Shiga-like toxin I (SLT-I) or SLT-II. Stool cultures from 6 of 20 cases (30%) and from 2 of 38 controls (5.3%) yielded EHEC (P = 0.0158). EHEC isolates from all HUS cases hybridized with the EHEC plasmid probe and with probes for SLT-I or -II (or both). The serogroups of the isolates included O157, O26, and O111. EHEC causes HUS in Chile, and the biotinylated gene probes are practical diagnostic tools for epidemiologic studies.     

Endothelial cells and coagulation abnormalities

Endothelial cells have two important anticoagulant systems, heparan sulfate-antithrombin system and thrombomodulin-protein C system. Under physiological conditions, these two systems inhibit activation of coagulation on endothelial cells. However, under inflammatory conditions, tumor necrosis factor(TNF)-alpha or other cytokines produced by monocytes reduce the anticoagulant properties of endothelial cell by downregulating expression of heparan sulfate and thrombomodulin on endothelial cells. Antithrombin stimulates prostacyclin generation from endothelial cells by interacting with heparan sulfate of endothelial cells and generated prostacyclin inhibits TNF-alpha production by monocytes. Activated protein C inhibits TNF-alpha production by monocyte dependent of its protease activity. Thus, antithrombin and activated protein C might inhibit the endothelial perturbation induced by cytokines. Antithrombin regulates TNF-alpha induced tissue factor expression on endothelial cells by an unknown mechanism. Thus, antithrombin and activated protein C might be useful agents for treating coagulation abnormalities associated with sepsis or other inflammation because these agents inhibit not only coagulation but also downregulation of anticoagulant activities of endothelial cells.     

Mesangial involvement in hemolytic-uremic syndrome. A light and electron microscopic study.

Electron microscopic analysis of the mesangial injury in the hemolytic-uremic syndrome was performed in 10 patients. Proteinaceous material similar to that found in the subendothelial region was also seen focally in the mesangium altering the matrix and imparting a reticular appearance. This degenerative process was associated with reparative changes in the glomerular tuft. Many of the mesangial cells were hypertrophied and demonstrated phagocytic activity and peripheral extension of their cytoplasmic processes. Mitotic figures in endothelial as well as mesangial cells were regarded as evidence of a reparative process. Severe mesangial insudation of material containing fibrinogen derivatives resulted in segmental tuft necrosis with almost complete replacement and destruction of the mesangial matrix. On some occasions, a break of the glomerular basement membrane was accompanied by the escape of intraluminal contents into the urinary space, leading to crescentic epithelial cell proliferation.