Hemolytic-uremic Syndrome - Pathogenesis

Pathogenesis

HUS is one of the thrombotic microangiopathies, a category of disorders that includes thrombotic thrombocytopenic purpura (TTP).

In the classical form (90% of cases), the STEC (Shigatoxigenic group of E. coli) toxin enters the bloodstream and causes damage to the body's vascular endothelium. This is especially damaging to the kidney, where the toxin attaches to the glomerular endothelium and initiates a noninflammatory reaction leading to acute renal failure. Moreover, the generalized endothelial damage leads to platelet activation that causes thrombocytopenia (low platelet count). The renal glomerular endothelial cells express a receptor for the toxin.

The typical pathophysiology involves the shiga-toxin binding to proteins on the surface of glomerular endothelium and inactivating a metalloproteinase called ADAMTS13, which is also involved in the closely related thrombotic thrombocytopenic purpura (TTP). Once the ADAMTS13 is disabled, multimers of von Willebrand Factor (vWF) form and initiate platelet activation and cause microthrombi formation. Inhibition of ADAMTS13 causes activated platelets because the large multimers of uncleaved vWF are hyperactive. Other papers have challenged the involvement of ADAMTS13. The arterioles and capillaries of the body become obstructed by the resulting complexes of activated platelets which have adhered to endothelium via large multimeric vWF. The growing thrombi lodged in smaller vessels destroy red blood cells (RBCs) as they squeeze through the narrowed blood vessels, forming schistocytes, or fragments of sheared RBCs. This mechanism, known as microangiopathic hemolysis, has been likened to the effect of a cheesewire or garotte across the vessel lumen. The presence of schistocytes is a key finding that helps to diagnose HUS. Typically, this haemolysis results in a haemoglobin level of less than 80 g/L.

The consumption of platelets as they adhere to the thrombi lodged in the small vessels typically leads to mild or moderate thrombocytopaenia with a platelet count of less than 60,000 per μL.

As in the related condition TTP, reduced blood flow through the narrowed blood vessels of the microvasculature leads to reduced blood flow to vital organs, and ischemia may develop. The kidneys and the central nervous system (brain and spinal cord) are the parts of the body most critically dependent on high blood flow, thus they are the most likely organs to be affected. However, in comparison to TTP, the kidneys tend to be more severely affected in HUS, and the central nervous system is less commonly affected.

In contrast with typical disseminated intravascular coagulation seen with other causes of septicemia and occasionally with advanced cancer, coagulation factors are not consumed in HUS (or TTP) and the coagulation screen, fibrinogen level, and assays for fibrin degradation products (such as "D-Dimers") are generally normal despite the low platelet count (thrombocytopenia).

HUS occurs after 2-7% of all E. coli O157:H7 infections. Children and adolescents are commonly affected. Grossly, the kidneys may show patchy or diffuse renal cortical necrosis. Histologically, the glomeruli show thickened and sometimes split capillary walls due largely to endothelial swelling. Large deposits of fibrin-related materials in the capillary lumens, subendothelially, and in the mesangium are also found along with mesangiolysis. Interlobular and afferent arterioles show fibrinoid necrosis and intimal hyperplasia and are often occluded by thrombi.

A somewhat less common form of HUS (~10% of cases) does not follow STEC infection and is thought to result from factor H deficiency (a complement regulatory protein) that results in uncontrolled complement activation after minor endothelial injury resulting in thrombosis.