title: Thrombotic microangiopathy without renal involvement: two novel mutations in complement-regulator genes.
abstract: ESSENTIALS: The differential diagnosis among thrombotic microangiopathies (TMAs) is challenging. We studied a case of TMA with neurologic symptoms, no renal impairment and normal ADAMTS-13 levels. Two novel mutations in complement factor I and thrombomodulin genes were identified. Complement-regulator genes can be involved in TMAs with normal ADAMTS-13 regardless of renal damage.
  
  
  BACKGROUND
  Thrombotic microangiopathies (TMAs) often represent a challenge for clinicians, because clinical, laboratory, and even genetic features are not always sufficient to distinguish among different TMAs.
  
  
  OBJECTIVE
  The aim of this study was to investigate the pathogenetic mechanisms underlying an acute case of TMA with features of both thrombotic thrombocytopenic purpura (TTP) and atypical hemolytic uremic syndrome (aHUS).
  
  
  METHODS
  We report the case of a 49-year-old woman who developed an acute TMA with neurologic involvement and no renal impairment. ADAMTS-13, von Willebrand factor, and complement-system biochemical characterization was performed on acute phase samples. Exome sequencing and direct Sanger sequencing of previously aHUS-associated genes were performed. The functional consequences of the thrombomodulin (THBD) mutation were investigated by in vitro expression studies.
  
  
  RESULTS
  Despite a clinical diagnosis of TTP, the patient had normal ADAMTS-13 levels and increased VWF antigen levels with ultra-large von Willebrand factor multimers. C3, C4, and complement factors H and I (CFI) were normal. Molecular analysis confirmed two novel heterozygous mutations in CFI (c.805G>A, p.G269S) and THBD (c.1103C>T, p.P368L), and in vitro expression studies showed a reduction in the generation of activated thrombin-activatable fibrinolysis inhibitor (TAFIa) caused by mutated THBD. This proinflammatory condition, associated with the p.G269S mutation in CFI, probably leads to a complement-mediated endothelial activation, with a relevant prothrombotic potential in case of transient environmental triggers.
  
  
  CONCLUSIONS
  This study identified the first case of acute TMA without renal involvement but with neurological damage carrying two novel mutations in complement-regulator genes, highlighting the possible role of the complement system as a common pathogenetic mechanism in TMAs.
authors.affiliation: Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Centre, Milan, Italy.|Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Peyvandi
authors.affiliation: Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Centre, Milan, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Rossio
authors.affiliation: Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Centre, Milan, Italy.
authors.forename: B
authors.initials: B
authors.lastname: Ferrari
authors.affiliation: Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Centre, Milan, Italy.
authors.forename: L A
authors.initials: LA
authors.lastname: Lotta
authors.affiliation: Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Centre, Milan, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Pontiggia
authors.affiliation: Molecular Otolaryngology and Renal Research Laboratories, University of Iowa, Iowa City, IA, USA.
authors.forename: N
authors.initials: N
authors.lastname: Ghiringhelli Borsa
authors.affiliation: Unit of Hematology, San Carlo Hospital, Potenza, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Pizzuti
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Clinical Research Center for Rare Diseases "Aldo e Cele Daccò", Ranica, Bergamo, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Donadelli
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Clinical Research Center for Rare Diseases "Aldo e Cele Daccò", Ranica, Bergamo, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Piras
authors.affiliation: Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Centre, Milan, Italy.|Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Cugno
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Clinical Research Center for Rare Diseases "Aldo e Cele Daccò", Ranica, Bergamo, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Noris
mesh_terms: D000071120:ADAMTS13 Protein / Q000097:blood; D065766:Atypical Hemolytic Uremic Syndrome / Q000097:blood / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology; D015415:Biomarkers / Q000097:blood; D025901:Carboxypeptidase B2 / Q000097:blood; D017244:Complement Factor I / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006579:Heterozygote; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D011697:Purpura, Thrombotic Thrombocytopenic / Q000097:blood / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology; D018180:Thrombomodulin / Q000235:genetics*; D014162:Transfection; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D015415:Biomarkers; C546931:THBD protein, human; D018180:Thrombomodulin; D014841:von Willebrand Factor; D025901:Carboxypeptidase B2; C493611:CFI protein, human; D017244:Complement Factor I; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human
keywords: ADAMTS-13 protein human; atypical hemolytic uremic syndrome; complement factor I; thrombomodulin; thrombotic thrombocytopenic purpura