Indications of underdiagnosis of atypical haemolytic uraemic syndrome in a cohort referred to the Coagulation Unit in Malmo, Sweden, for analysis of ADAMTS13 2007–2012

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Complement‐mediated atypical haemolytic uraemic syndrome (aHUS) is associated with an excessive activation of the alternative complement pathway. It is characterized by microangiopathic haemolytic anaemia (MAHA), thrombocytopaenia and acute renal failure.1 Histopathologic examination of a kidney biopsy typically shows thrombotic microangiopathy (TMA); a histopathological manifestation affecting the endothelial structures in the microvasculature of end‐organ arterioles and capillary beds. In complement‐mediated aHUS it partly results from excessive deposition of membrane attack complexes (MAC) on the host cells.2 There is no firmly defined appliance of terminology in the field of study why aHUS to some extent may also be referred to with other mechanisms of action in mind. Consequently, we will refer to complement‐mediated disease as complement‐mediated aHUS.
Complement‐mediated aHUS has historically been treated with plasma therapy. Although the overall response rate is approximately 70%3 the proportion of long‐term renal recovery is low.3 In 2011 an alternative treatment for complement‐mediated aHUS was approved by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) following successful single‐arm clinical trials.4 Eculizumab (Soliris; Alexion Pharmaceuticals, Cheshire, CT, USA) is a recombinant, monoclonal IgG targeting complement component C5. It is associated with a time‐dependent improvement of renal function. As the great majority of conditions acutely presenting with MAHA are life‐threatening and specific and effective treatment targeting excessive complement activation is now available, the underlying condition should be diagnosed promptly.
In several studies only 5–10% of the total HUS cases are classified as complement‐mediated.6 This may be due to the fact that verification of disease is complicated, particularly in adults where a multitude of differential diagnoses must be considered. Different genetic aberrations as well as presence of antibodies account for diverse severity of disease. It is suggested that the presence of a rare genetic mutation, a common at‐risk genetic variant (e.g. single nucleotide polymorphisms and haplotype blocks) and an extrinsic factor (e.g. infection) triggering a complement response may be necessary for manifestation of disease.8 Without proper treatment, the complement‐mediated aHUS is associated with a 50% rate of progression to end‐stage renal disease and a mortality‐rate of approximately 25% in the acute phase.7
To shorten the time to diagnosis, schemes of clinical prediction have been proposed, but these do not accurately differentiate aHUS from thrombotic thrombocytopenic purpura (TTP) in the acute phase.10 Due to the present lack of easily accessible laboratory gold standard and robust clinical definitions, no solid numbers on incidence of complement‐mediated aHUS are available in the Swedish population. In some cohorts1 the suggested incidence is 1–2/1 000 000 annually, which translated into Swedish conditions would correspond to approximately 10–20 people being afflicted yearly. Most likely however, the prevalence of complement‐mediated aHUS is underestimated.
In this study we aimed to evaluate the prevalence of suspected complement‐mediated aHUS with or without potential triggering events and known underlying causes in a retrospective Swedish cohort referred to the Coagulation Unit in Malmo (Department of Laboratory Medicine, Skane) on the clinical suspicion of TTP for analyses of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) between the years of 2007–2012. We show that a significant part of these patients may potentially have been diagnosed with complement‐mediated aHUS if accurate diagnostic work up had been available.

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