title: Residual plasmatic activity of ADAMTS13 is correlated with phenotype severity in congenital thrombotic thrombocytopenic purpura.
abstract: The quantification of residual plasmatic ADAMTS13 activity in congenital thrombotic thrombocytopenic purpura (TTP) patients is constrained by limitations in sensitivity and reproducibility of commonly used assays at low levels of ADAMTS13 activity, blunting efforts to establish genotype-phenotype correlations. In the present study, the residual plasmatic activity of ADAMTS13 was measured centrally by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (limit of detection = 0.5%) in 29 congenital TTP patients. The results were used to study correlations among ADAMTS13 genotype, residual plasmatic activity, and clinical phenotype severity. An ADAMTS13 activity above 0.5% was measured in 26 (90%) patients and lower levels of activity were associated with earlier age at first TTP episode requiring plasma infusion, more frequent recurrences, and prescription of fresh-frozen plasma prophylaxis. Receiver operating characteristic curve analysis showed that activity levels of less than 2.74% and 1.61% were discriminative of age at first TTP episode requiring plasma infusion < 18 years, annual rate of TTP episodes > 1, and use of prophylaxis. Mutations affecting the highly conserved N-terminal domains of the protein were associated with lower residual ADAMTS13 activity and a more severe phenotype in an allelic-dose dependent manner. The results of the present study show that residual ADAMTS13 activity is associated with the severity of clinical phenotype in congenital TTP and provide insights into genotype-phenotype correlations.
authors.affiliation: Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Unitá Operativa Semplice Dipartimentale per la Diagnosi e la Terapia delle Coagulopatie, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda-Ospedale Maggiore Policlinico, Università degli Studi di Milano and Luigi Villa Foundation, Via Pace 9, Milan, Italy. 5P01HL078826-06
authors.forename: Luca A
authors.initials: LA
authors.lastname: Lotta
authors.forename: Haifeng M
authors.initials: HM
authors.lastname: Wu
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Mackie
authors.forename: Marina
authors.initials: M
authors.lastname: Noris
authors.forename: Agnes
authors.initials: A
authors.lastname: Veyradier
authors.forename: Marie A
authors.initials: MA
authors.lastname: Scully
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Remuzzi
authors.forename: Paul
authors.initials: P
authors.lastname: Coppo
authors.forename: Ri
authors.initials: R
authors.lastname: Liesner
authors.forename: Roberta
authors.initials: R
authors.lastname: Donadelli
authors.forename: Chantal
authors.initials: C
authors.lastname: Loirat
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.forename: April
authors.initials: A
authors.lastname: Horne
authors.forename: Shangbin
authors.initials: S
authors.lastname: Yang
authors.forename: Isabella
authors.initials: I
authors.lastname: Garagiola
authors.forename: Khaled M
authors.initials: KM
authors.lastname: Musallam
authors.forename: Flora
authors.initials: F
authors.lastname: Peyvandi
mesh_terms: D051722:ADAM Proteins / Q000097:blood* / Q000172:deficiency* / Q000235:genetics; D000071120:ADAMTS13 Protein; D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D001774:Blood Chemical Analysis; D001803:Blood Transfusion; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010949:Plasma; D011697:Purpura, Thrombotic Thrombocytopenic / Q000097:blood* / Q000151:congenital* / Q000235:genetics / Q000628:therapy; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D055815:Young Adult
chemical_list: D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human