Activation of Coagulation and Fibrinolysis in Childhood Diarrhoea-associated Haemolytic Uraemic Syndrome

Abstract

SummaryDiarrhoea-associated haemolytic uraemic syndrome (D+ HUS) is usually caused by verotoxin producing Eschericia coli. We hypothesized that verotoxin binding to glomerular endothelial cells causes localised endothelial cell activation and thus activation of coagulation and reduction of fibrinolytic potential. We also proposed that treatment with fresh frozen plasma or dialysis would not affect these changes. Markers of activation of coagulation and fibrinolysis were measured in 30 children with acute D+ HUS serially, in healthy children and in children on dialysis.In acute D+ HUS, levels of thrombin-antithrombin III complex and prothrombin fragment 1+2 were significantly increased (p <0.001). The source of thrombin generation was unclear. Factor Xlla levels were increased in patients and controls with renal failure. Factor VIIa levels were not significantly raised in children with acute D+ HUS. D-dimers were increased, but fibrinolytic potential as measured by fibrin plate was reduced. Levels of plasminogen activator inhibitor antigen and activity and tissue plasminogen activator antigen were increased.Neither peritoneal dialysis nor administration of blood products, the most common treatments, altered parameters of coagulation or fibrinolysis.

Neutral Glycosphingolipid-dependent Inactivation of Coagulation Factor Va by Activated Protein C and Protein S

“…Moreover, an Escherichia coli-derived verotoxin, verotoxin B, is known to be a Gb 3 Cer-specific-binding protein that is a pathological factor for the hemolytic uremic syndrome. In patients with hemolytic uremic syndrome, activation of the coagulation system and glomerular thrombotic microangiopathy are observed, and these effects are mediated by the binding of verotoxin B to Gb 3 Cer (43). Administration of verotoxin B causes fibrin deposition in an animal model (44).…”

Eculizumab reduces complement activation, inflammation, endothelial damage, thrombosis, and renal injury markers in aHUS

“…Increased F112 levels preceded renal injury in other TMA studies in Shiga toxinproducing Escherichia coli HUS. 71,72 Reduction of F112 and D-dimer levels with eculizumab suggests that prevention of C5a and C5b-9 formation and bioactivity, through terminal complement blockade, downregulates the coagulation cascade. This is consistent with a study of paroxysmal nocturnal hemoglobinuria, which demonstrated that eculizumab treatment results in a significant decrease in thrombosis 73 and in markers associated with thrombin generation and reactive fibrinolysis, including plasma D-dimer, thrombin-anti-thrombin complexes, interleukin 6, soluble P-selectin, and microparticles with prothrombotic activity.…”

Plasminogen Activator Inhibitor-1 in Chronic Kidney Disease

“…In children who have Escherichia coli 0157:H7 infection and later develop hemolytic uremic syndrome (11), plasma PAI-1 levels increase before the onset of renal disease. Plasma PAI-1 activity correlates with renal disease severity and long-term outcome (12)(13)(14)(15). One pediatric study found that PAI-1 activity also increases during acute renal failure of other causes (16).…”