November 2016 Volume 14, Issue 11, Supplement 11 Authors Jeffrey Laurence, MD Professor of Medicine Division of Hematology and Medical Oncology New York Presbyterian Hospital and Weill Cornell Medical College Atypical Hemolytic Uremic New York, New York Syndrome (aHUS): Hermann Haller, MD Professor of Medicine Department of Nephrology Essential Aspects of an and Hypertension Hannover Medical School (MHH) Hannover, Germany Accurate Diagnosis Pier Mannuccio Mannucci, MD Professor of Medicine IRCCS Cà Granda Foundation Maggiore Policlinico Hospital Milan, Italy Masaomi Nangaku, MD, PhD Professor of Medicine Division of Nephrology and Endocrinology The University of Tokyo Graduate School of Medicine Tokyo, Japan Manuel Praga, MD Professor of Medicine Division of Nephrology Complutense University Madrid, Spain Santiago Rodriguez de Cordoba, PhD Professor, Department of Cellular and Molecular Medicine El Centro de Investigaciones Biológicas and El Centro de Investigación Biomédica en Red de Enfermedades Raras Madrid, Spain ON THE WEB: hematologyandoncology.net Indexed through the National Library of Medicine (PubMed/MEDLINE), PubMed Central (PMC), and EMBASE REVIEW ARTICLE Atypical Hemolytic Uremic Syndrome (aHUS): Essential Aspects of an Accurate Diagnosis Jeffrey Laurence, MD, Hermann Haller, MD, Pier Mannuccio Mannucci, MD, Masaomi Nangaku, MD, PhD, Manuel Praga, MD, and Santiago Rodriguez de Cordoba, PhD Abstract: Atypical hemolytic uremic syndrome (aHUS), a thrombotic microangiopathy (TMA), is a rare, life-threatening, systemic disease. When unrecognized or inappropriately treated, aHUS has a high degree of morbidity and mortality. aHUS results from chronic, uncontrolled activity of the alternative complement pathway, which activates platelets and damages the endothelium. Two-thirds of aHUS cases are associated with an identifiable complement-activating condition. aHUS is clinically very similar to the other major TMAs: Shiga toxin–producing Escherichia coli (STEC)-HUS, thrombotic thrombocytopenic purpura (TTP), and disseminated intravascular coagulation (DIC). The signs and symptoms of all the TMAs overlap, complicating the differential diagnosis. Clinical identification of a TMA requires documentation of micro- angiopathic hemolysis accompanied by thrombocytopenia. DIC must be recognized and treated before it is possible to discriminate among the other 3 major TMAs. STEC-HUS can be excluded through testing for Shiga toxin–producing E. coli. aHUS can be distinguished from TTP on the basis of ADAMTS13 (a disintegrin and metalloproteinase with a thrombos- pondin type 1 motif, member 13) activity, with a severe decrease characteristic of TTP. This test, as both an activity assay and an inhibitor assay, should be ordered before the initiation of plasma therapy in any patient presenting with a TMA. Finally, it is important to recognize that aHUS remains a clinical diagnosis, but in complex scenarios, tissue biopsy may be a useful adjunct in diagnosis. Introduction angiopathy (TMA) that is clinically fragmented red blood cells or schisto­ very similar to aHUS.2­5 However, a cytes on peripheral blood smear, low In October 2012, this journal pub­ major challenge per sists: how to make haptoglobin levels, elevated lactate lished a review on “Making the diag­ an efficient and accurate differential dehydrogenase (LDH) and indirect nosis” of atypical hemolytic uremic diagnosis among the TMAs. bilirubin, and a decline in baseline syn drome (aHUS).1 Recent advances Table 1 lists the 4 major TMAs: hemoglobin—accompanied by throm­ have enabled the implementation aHUS, TTP, Shiga toxin–producing bocytopenia. These laboratory changes of directed therapy, with dramatic Escherichia coli (STEC)­HUS, and must occur in concert with clinical declines in morbidity and mortality disseminated intravascular coagula­ involvement of at least 1 organ system, over the historical interventions used tion (DIC). Clinical recognition of the most common sites being the cen­ in thrombotic thrombocytopenic any TMA requires the documentation tral nervous system, the kidneys, and purpura (TTP), a thrombotic micro­ of microangiopathic hemolysis—with the gastrointestinal tract. DIC, usually Disclaimer Funding for this supplement has been provided by Alexion Pharmaceuticals, Inc. Support of this supplement does not imply the supporter’s agreement with the views expressed herein. Every effort has been made to ensure that drug usage and other information are presented accurately; however, the ultimate responsibility rests with the prescribing physician. Millennium Medical Publishing, Inc, and the participants shall not be held responsible for errors or for any consequences arising from the use of information contained herein. Readers are strongly urged to consult any relevant primary literature. No claims or endorsements are made for any drug or compound at present under clinical investigation. ©2016 Millennium Medical Publishing, Inc., 611 Broadway, Suite 310, New York, NY 10012. Printed in the USA. All rights reserved, including the right of reproduction, in whole or in part, in any form. 2 Clinical Advances in Hematology & Oncology Volume 14, Issue 11, Supplement 11 November 2016 ATYPICAL HEMOLYTIC UREMIC SYNDROME (AHUS): AN ACCURATE DIAGNOSIS secondary to infection or malignancy, Table 1. Distinguishing Among the Major Thrombotic Microangiopathies stands apart from the other TMAs because it has characteristic laboratory Category Defining Characteristic abnormalities indicative of a con­ Disseminated intravascular Coagulation abnormality with elevated INR and sumptive coagulopathy, including an coagulation (DIC) aPTT elevated international normalized ratio Thrombotic thrombocytopenic ADAMTS13 <5%­10%; autoantibody inhibitor of (INR) and activated partial throm­ purpura (TTP) ADAMTS13 (unless one of the rare congenital forms, boplastin time (aPTT). However, the with no inhibitor) signs and symptoms of all the TMAs overlap extensively, complicating the Atypical hemolytic uremic ADAMTS13 >5%­10% (exact cut­off as specified syndrome (aHUS) by the laboratory and assay technique employed); differential diagnosis. associated with a recognized complement­activating condition in two­thirds of cases; congenital mutation Historical Issues in Differentiating in complement system recognized in 70% of cases Among the TMAs E. coli E. coli Since the initial descriptions of 2 Shiga toxin–producing Stool sample or rectal swab positive for – HUS (STEC­HUS) producing Shiga toxin by culture and/or PCR (both major categories of TMA—TTP by should be performed) Moschcowitz in 19246 and HUS by Gasser in 19557—there have been ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, but a handful of critical diagnostic member 13; aPTT, activated partial thromboplastin time; INR, international normalized ratio; PCR, polymerase chain reaction. and therapeutic breakthroughs. First, there was identification of the utility of plasma exchange (PE) in the treat­ undifferentiated as “TTP/HUS.” Distinguishing Among the ment of TTP. This was followed by Indeed, the definitions of TTP and TMAs: Primary Considerations isolation of Shiga toxin–producing E. HUS had been vague from the outset: coli as the etiologic agent of many cases Gasser included a case of “Mosch­ Development of TTP and aHUS of diarrhea­associated (D+) HUS, now cowitz disease” in his HUS series, appears to require 2 conditions: (1) pre­ known as STEC­HUS. The means to and HUS was originally referred to existing susceptibility factors that are distinguish TTP from aHUS, using as “TTP of children.”8 More recently, either familial (ie, genetic) or acquired, assays for activity of the enzyme von the critical role of congenital defects and are capable of promoting endothe­ Willebrand factor (vWF) cleaving in the regulation of the alternative lial cell activation, platelet aggregation, protease, also known as ADAMTS13 complement pathway in aHUS was or both; and (2) modulating factors, (a disintegrin and metalloproteinase established, solidifying the patho­ encompassing a variety of infectious, with a thrombospondin type 1 motif, physiologic distinction of aHUS from inflammatory, autoimmune, stress, or member 13), was reported 2 decades T T P. 9 The fact that TTP and aHUS drug­related conditions, that are linked ago.5 TTP is accompanied by a severe are rare—occurring in perhaps 2 to 4 epi demiologically to both TTP and (<5%­10% of normal) deficiency in per million individuals—is a further aHUS, and that can injure the endo­ plasma ADAMTS13 activity, related impediment to an accurate diagnosis. thelium and, often, activate comple­ to an acquired autoantibody against The high morbidity and mortality ment. The latter would account, at least this protease or, in rarer instances, a associated with untreated TTP and in part, for the sporadic development congenital mutation affecting both aHUS, and the different manage­ of overt clinical signs and symptoms alleles of this enzyme. In contrast, ments they require, mandate timely of disorders predicated on congenital plasma ADAMTS13 activity may be recognition of a TMA, followed by the susceptibilities. For example, the first reduced from the normal range of 67% ability to distinguish between the 2 clinical manifestation of familial TTP, to 120% in aHUS or STEC­HUS, but conditions. This review highlights the or Upshaw­Schulman syndrome, re ­ should still remain greater than 5% differences in pathophysiology and lated to loss­of­function gene muta­ to 10%, with the exact cut­off