Residual plasmatic activity of ADAMTS13 is correlated with phenotype severity in congenital thrombotic thrombocytopenic purpura

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 co...

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Bibliographic Details
Published in:Blood 2012-07, Vol.120 (2), p.440-448
Main Authors: Lotta, Luca A., Wu, Haifeng M., Mackie, Ian J., Noris, Marina, Veyradier, Agnes, Scully, Marie A., Remuzzi, Giuseppe, Coppo, Paul, Liesner, Ri, Donadelli, Roberta, Loirat, Chantal, Gibbs, Richard A., Horne, April, Yang, Shangbin, Garagiola, Isabella, Musallam, Khaled M., Peyvandi, Flora
Format: Article
Language:English
Subjects:
ADAM Proteins - blood
ADAM Proteins - deficiency
ADAM Proteins - genetics
ADAMTS13 Protein
Adolescent
Adult
Age Factors
Aged
Blood Chemical Analysis
Blood Transfusion
Child
Child, Preschool
DNA Mutational Analysis
Female
Genetic Association Studies
Humans
Male
Middle Aged
Mutation
Plasma
Purpura, Thrombotic Thrombocytopenic - blood
Purpura, Thrombotic Thrombocytopenic - congenital
Purpura, Thrombotic Thrombocytopenic - genetics
Purpura, Thrombotic Thrombocytopenic - therapy
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Thrombosis and Hemostasis
Young Adult
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Summary: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.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2012-01-403113