Residual plasmatic activity of ADAMTS13 correlates 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 correlations. In this study, the residual plasmatic activity of ADAMTS13 was centrally measured by SELDI-TOF mass spectrometry (limit-of-detection=0.5%) in 29 congenital TTP patients. The results were used to study correlations between 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. At receiver operating characteristic curve analysis, 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 more severe phenotype in an allelic-dose dependent manner. Our results show that residual ADAMTS13 activity correlates with the severity of clinical phenotype in congenital TTP and provide insights into genotype-phenotype correlations.