title: The role of ADAMTS-13 activity and complement mutational analysis in differentiating acute thrombotic microangiopathies.
abstract: ESSENTIALS: Molecular diagnostics has improved the differentiation of acute thrombotic microangiopathys (TMAs). Atypical hemolytic uremic syndrome may have features mimicking thrombotic thrombocytopenic purpura. We identified novel complement mutations and a high incidence of CD46, with favorable long term outcomes. Complement mutation analysis in TMA where the diagnosis is unclear and ADAMTS-13 activity is >10%.
  
  
  BACKGROUND
  Differentiation of acute thrombotic microangiopathy (TMA) at presentation has historically been dependent on clinical parameters. Confirmation of thrombotic thrombocytopenic purpura (TTP) is increasingly reliant on demonstrating deficient ADAMTS-13 activity. The identification of alternative complement pathway abnormalities in atypical hemolytic uremic syndrome (aHUS), along with the proven efficacy of terminal complement inhibitors in treatment, has increased the need for rapid differentiation of TTP from aHUS.
  
  
  OBJECTIVE
  We describe the clinical phenotype and nature of complement mutations in a cohort of aHUS patients referred as acute TMAs.
  
  
  METHODS
  Fourteen consecutive aHUS patients were screened for mutations in C3, CD46, CFH, CFI, and CFB, as well as factor H (FH) antibodies. All aHUS patients had ADAMTS-13 activity > 10%.
  
  
  RESULTS
  Of 14 aHUS patients, 11 (79%) had platelet counts < 30 × 10(9) /L during the acute phase. Median presenting creatinine level was 295 μmol L(-1) , while five (36%) of 14 presented with a serum creatinine level < 200 μmol L(-1) . Alternative complement pathway mutations were detected in 9 (64%) of 14 patients, including CD46 mutations in five (36%) of 14 patients. Patients were identified with novel mutations in CFB and C3 that have not been previously reported.
  
  
  CONCLUSIONS
  We demonstrate that diagnostic differentiation based on platelet count and renal function is insufficient to predict an underlying complement mutation in some aHUS cases. Specifically, we demonstrate a high frequency of functionally significant CD46 mutations which may mimic TTP. ADAMTS-13 activity > 10% in a patient with a TMA should necessitate genetic screening for complement abnormalities.
authors.affiliation: Department of Haematology, University College London, London, UK.
authors.forename: E H
authors.initials: EH
authors.lastname: Phillips
authors.affiliation: Department of Haematology, University College London, London, UK.
authors.forename: J P
authors.initials: JP
authors.lastname: Westwood
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: V
authors.initials: V
authors.lastname: Brocklebank
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: E K S
authors.initials: EK
authors.lastname: Wong
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: J O
authors.initials: JO
authors.lastname: Tellez
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: K J
authors.initials: KJ
authors.lastname: Marchbank
authors.affiliation: Department of Haematology, University College London, London, UK.
authors.forename: S
authors.initials: S
authors.lastname: McGuckin
authors.affiliation: Centre for Nephrology, University College London, London, UK.
authors.forename: D P
authors.initials: DP
authors.lastname: Gale
authors.affiliation: Department of Nephrology, Royal Free Hospital, London, UK.
authors.forename: J
authors.initials: J
authors.lastname: Connolly
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: T H J
authors.initials: TH
authors.lastname: Goodship
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: D
authors.initials: D
authors.lastname: Kavanagh
authors.affiliation: Cardiometabolic Programme, NIHR/University College London Hospitals Biomedical Research Centre, London, UK.
authors.forename: M A
authors.initials: MA
authors.lastname: Scully
mesh_terms: D000071120:ADAMTS13 Protein / Q000235:genetics* / Q000378:metabolism*; D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D065766:Atypical Hemolytic Uremic Syndrome / Q000235:genetics; D002675:Child, Preschool; D003176:Complement C3 / Q000235:genetics*; D011415:Complement Factor B / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D015994:Incidence; D007223:Infant; D007677:Kidney Function Tests; D008297:Male; D051916:Membrane Cofactor Protein / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D010976:Platelet Count; D011697:Purpura, Thrombotic Thrombocytopenic / Q000175:diagnosis / Q000235:genetics; D012189:Retrospective Studies; D057049:Thrombotic Microangiopathies / Q000175:diagnosis* / Q000235:genetics*; D055815:Young Adult
chemical_list: C497857:CD46 protein, human; D003176:Complement C3; D051916:Membrane Cofactor Protein; D011415:Complement Factor B; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human
keywords: CD46; atypical hemolytic uremic syndrome; complement; diagnosis; thrombotic thrombocytopenic purpura