Haemolytic-uraemic syndrome and thrombotic thrombocytopenic purpura--new insights into underlying biochemical mechanisms.

Abstract

Haemolytic-uraemic syndrome (HUS) and thrombotic cancer, and have been variously referred to as TTP, thrombocytopenic purpura ( TTP) are two clinically HUS, TTP/HUS, TTP-like disease or secondary TTP. similar disorders characterized by severe microangi- It appears that endothelial cell injury is primarily opathic haemolytic anaemia and thrombocytopenia. involved in the sequence of events leading to acute HUS is characterized by thrombocytopenia, anaemia episodes of HUS and TTP. and renal insufficiency, whereas the pentad of signs and symptoms including thrombocytopenia, anaemia, neurologic deficit, renal dysfunction and fever is Endothelial cell activation in HUS observed in TTP. However, about 60% of patients diagnosed with acute TTP lack one or more of these The majority of cases with HUS occur in the childhood criteria, while about 30% of those receiving a diagnosis and are preceded by bloody diarrhoea, usually caused of HUS exhibit neurologic symptoms and fever. Thus, by some strains of enterohaemorrhagic Escherichia coli the two disorders are often difficult to distinguish. or Shigella dysenteriae. It is generally held that in Given the lack of consistent clinical findings, the same diarrhoea-associated HUS (D+HUS ), activation of disorder might be diagnosed as HUS by a nephrologist endothelial cells with subsequent release of von while a haematologist might call it TTP. Since both Willebrand factor (vWF ) and increased endothelial HUS and TTP have been reported to occur in siblings secretion of plasminogen activator inhibitor I (PAI-1), and on different occasions even in the same patient, it is central to clumping of platelets in the renal microcirsometimes appears that the two disorders are different culation. Shiga-toxin receptors are most abundant in manifestations of the same pathophysiologic process. the proximal tubular cells. Shiga-toxin appears to The terms TTP/HUS, microangiopathic haemolytic produce tubular epithelial cell damage and to induce anaemia and thrombotic microangiopathy are some- tumour necrosis factor ( TNFa) in kidneys but not in times used to avoid an uncertain differential diagnosis. other organs [1]. HUS and TTP are characterized by disseminated mic- Atypical HUS, also denoted as sporadic HUS, is rothrombi composed of agglutinated platelets, that characterized by the absence of antecedent diarrhoea occlude arterioles and capillaries in the microcircul- (D−HUS), the tendency to relapse, a generally poor ation. In HUS the platelet microthrombi are primarily outcome, and often by a positive family history. confined to the kidneys, and thus renal failure is the Hypocomplementaemia and low complement C3 levels dominant feature. In TTP the microvascular occlusions have been observed in atypical HUS. Several cases of may occur in any tissue and lead to fluctuating familial HUS have been reported [2–5] with deficiency ischaemic dysfunction of the respective organs, most of complement factor H, also denoted as b 1 H globulin. frequently of the brain, producing intermittent neuro- Factor H is a cofactor for the factor I-mediated logical symptoms. Markers of activated coagulation cleavage of the active form C3b of the complement are only mildly increased in contrast to disseminated factor C3. Factor H accelerates the decay of the C3 intravascular coagulation. No significant amounts of convertase and inhibits its formation. Low levels or fibrin are formed and rather low amounts of fibrin absence of factor H result in increased activation of degradation products are present. Blood clotting times the alternative complement pathway. In addition to (prothrombin time, activated partial thromboplastin abnormal factor H, abnormalities of other regulators time) are usually normal. The hypotheses concerning of the alternative pathway may also be implicated in the aetiology of HUS and TTP are controversial and the development of HUS. suggest that different pathogenetic mechanisms may trigger the disease. Acute episodes of thrombotic microangiopathies have been observed in association Proteolytic cleavage of von Willebrand factor