Decrease of thrombomodulin contributes to the procoagulant state of endothelium in hemolytic uremic syndrome

Abstract

The typical form of hemolytic uremic syndrome (D+HUS) is a thrombotic microangiopathy that causes acute renal failure in children. The etiology of this disease is a toxin called Shiga-like toxin (Stx), present in certain strains of gram-negative bacteria. Vascular endothelial cell (EC) injury appears to be central in the pathogenesis of D+HUS. Thrombomodulin (TM) is a glycoprotein present in EC with anti-thrombogenic properties. The objective of this study was to investigate the effects of Stx on the surface expression of TM in EC using an in vitro culture of human glomerular microvascular endothelial cells. We also evaluated other inflammatory mediators [tumor necrosis factor-alpha (TNF-alpha) and lipopolysaccharide], which are known to increase Stx receptor expression and are potentially involved in the pathogenesis of D+HUS. Stx2 induced a significant decrease of TM expression in this cell type after pre-incubation with TNF-alpha. This decrease could not be attributed to the inhibition of protein synthesis only, as cycloheximide, another inhibitor of protein synthesis, did not affect TM surface expression. These results suggest that the Stx2-induced decrease of TM expression in glomerular EC might contribute to the local procoagulant state present in D+HUS.

The protein C pathway in tissue inflammation and injury: pathogenic role and therapeutic implications

“…For instance, in patients with hemolytic uremic syndrome, a decrease of TM has been shown and consequently contributes to the procoagulant state of the endothelium, leading to glomerular injury. 104 Similarly, in patients with renal insufficiency and in patients on peritoneal dialysis or hemodialysis, the concentration of sTM in plasma was significantly higher. This increase was accompanied by other markers of endothelial activation, such as increased levels of vascular cell adhesion molecule-1, suggesting involvement of the PC system in glomerular damage.…”

Thrombomodulin and Endothelial Dysfunction: A Disease-Modifier Shared between Malignant Hypertension and Atypical Hemolytic Uremic Syndrome

“…The placental expression of TM was lowest in those preeclamptic women with the highest diastolic blood pressure [23]. Patients with MHT have abnormalities of microvascular function including increased circulating endothelial cells and endothelial progenitor cells [47].…”

Hemolytic uremic syndrome–associated Shiga toxins promote endothelial-cell secretion and impair ADAMTS13 cleavage of unusually large von Willebrand factor multimers

“…1,2,41 The thrombin generation (and fibrin formation) may be potentiated by Stx disruption of the interaction between thrombin and thrombomodulin and consequent interference with the protein C/S coagulation control pathway. 80,81 As the thrombotic lesions progress, Stx-stimulated ULVWF string secretion, along with ADAMTS13 inhibition, may continue to induce platelets to accumulation in the HUS lesions.…”