Advances in understanding of pathogenesis of aHUS and HELLP

Summary Both atypical haemolytic uraemic syndrome (aHUS) andthe HELLP syndrome (haemolytic anaemia, elevated liverenzymes, and low platelets) are thrombotic microangiopathiescharacterized by microvascular endothelial activation, cellinjury and thrombosis. aHUS is a disease of complementdysregulation, specifically a gain of function of the alternativepathway, due to mutations in complement regulatory proteinsand activating components. Recently, the same complementmutation identified in multiple patients with aHUS was foundin a patient with the HELLP syndrome. The pathogeneses ofboth diseases are reviewed focusing on the role of thecomplement system and how its dysfunction could result ina thrombotic microangiopathy in the kidney in the case ofaHUS and in the liver in the case of the HELLP syndrome.Keywords: thrombotic microangiopathy (TMA), aHUS, pre-eclampsia, HELLP, alternative pathway of complement.The thrombotic microangiopathy (TMA) disorders representclinically diverse entities featuring a disruption of the micro-vascular endothelium. Atypical haemolytic uraemic syndrome(aHUS) and HELLP (haemolytic anaemia, elevated liverenzymes, and low platelets) syndrome belong to this group.They are characterized by microvascular endothelial injuryevents that lead to microthrombi. Fragmented red blood cellsresult from the abnormally high levels of shear stress producedas blood flows through turbulent areas of the microcirculation(e.g. kidneys and liver) that are partially occluded by plateletand fibrin thrombi. Thrombocytopenia occurs secondary toplatelet activation and accelerated consumption. Elevatedserum enzymes, e.g. alanine transaminase, are derived fromischemic or necrotic tissue and from the lysed red cells.Disorders that are listed under the umbrella of TMA shareclinical and serological characteristics. Correct diagnosis maybe difficult but desirable as distinct therapeutic strategies maybe mandated. For example, the clinical syndrome of HUScommonly comprises part of the diagnostic pentad of throm-botic thrombocytopenic purpura (TTP): thrombocytopenia,microangiopathic haemolytic anaemia (MAHA), renal dys-function, neurological symptoms and signs, and fever. Overlapoccurs as renal abnormalities are encountered in TTP patientsand extra-renal manifestations may be present in patients withHUS. However,HUSisoften considered tobeprimarily arenaldisease with limited systemic complications while TTP is asystemic disease with a relatively low frequency of renal disease.Thrombotic thrombocytopenic purpura is now understoodto result in most cases from a hereditary (including congenital)or acquired severe deficiency of the metalloprotease enzyme,ADAMTS13 (a disintegrin and metalloproteinase with athrombospondin type 1 motif, member 13) (Veyradier et al,2003; Tsai, 2006). This protease cleaves the high molecularweight von Willebrand factor (VWF) oligomers secreted byendothelial cells, resulting in unusually large multimers ofcirculating VWF. They can aggregate to form microvascularplatelet thrombi at intravascular sites with high shear stress.Plasma exchange therapy reduces the mortality from 85–100%to 10–30% (Rock et al, 1991). There are two main subtypes ofHUS: diarrhoeal-associated/epidemic (D+ HUS) or non-diarrhoeal/atypical HUS (D) or aHUS). D+ HUS accountsfor a majority of cases and is commonly caused by a precedingillness with verocytotoxin-producing bacteria, usually Escher-ichia coli O157:H7. The vero- or shiga-toxin mediates thedamage to glomerular endothelial cells of the kidney (Tarret al, 2005). aHUS is rare, may be familial, and has a poorerprognosis with death rates up to 25% in the acute phase and50% of patients require ongoing renal replacement (Richardset al, 2007a). A defect in the regulation of the complementcascade accounts for about half of cases of aHUS and will bediscussed further in this review.The HELLP syndrome is not the only TMA that complicatespregnancy. Pregnancy may also be a precipitant for aHUS(Noris & Remuzzi, 2005) and TTP (Zheng & Sadler, 2008).Temporal association may help to identify which diseaseprocess is occurring. HELLP occurs in the third trimester in70% of patients, although cases in the second trimester andpostpartum period, usually in the first 1–2 d, are wellrecognized (Mihu et al, 2007). TTP mostly presents in the