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.

Current insights into thrombotic microangiopathies: Thrombotic thrombocytopenic purpura and pregnancy

“…Of note, 2 pregnancy-onset cases had a homozygous and heterozygous ADAMTS13 p.R1060W mutation, respectively (26). Carriers of the ADAMTS13 p.R1060W mutant were shown to display small residual ADAMTS13 activity (27). Studying 29 hereditary TTP patients from 4 European centers (Milan, United Kingdom, Bergamo, France), Lotta et al found 4 unrelated USS patients with homozygous p.R1060W mutations, all displaying some residual ADAMTS13 activity (about 5-7% as compared to normal plasma) and all having a disease onset in adulthood, pregnancy being a common trigger of a first TTP attack (27).…”

“…Carriers of the ADAMTS13 p.R1060W mutant were shown to display small residual ADAMTS13 activity (27). Studying 29 hereditary TTP patients from 4 European centers (Milan, United Kingdom, Bergamo, France), Lotta et al found 4 unrelated USS patients with homozygous p.R1060W mutations, all displaying some residual ADAMTS13 activity (about 5-7% as compared to normal plasma) and all having a disease onset in adulthood, pregnancy being a common trigger of a first TTP attack (27). A cross-sectional overview of the national registry of the French Reference Center for Thrombotic Microangiopathies from 2000 -2010 including 592 adulthood-onset severely ADAMTS13 deficient TTP patients (417 of them women, 280 women aged less than 45 years) revealed 42 women with a pregnancy-onset TTP (corresponding to 15% of women of childbearing age) (28).…”

Hereditary thrombotic thrombocytopenic purpura and the hereditary TTP registry

“…The other half of patients remain asymptomatic into adulthood, when they present with a first acute episode often triggered by well recognized risk factors, such as pregnancy, alcohol binge drinking or other situations known to be associated with VWF release and high VWF levels (24)(25)(26)(27)(28).…”

“…As a considerable number of patients experience relapses only in situations of increased risk, such as pregnancy (25,26), the challenge is to identify those patients that benefit most from regular prophylactic plasma infusions. This is particularly challenging in patients with an adult onset and only occasional acute episodes.…”

“…Residual ADAMTS13 activity, as determined by new generation ADAMTS13 activity methods, employing a VWF A2 domain peptide of 73 amino acids as a substrate, is observed in the plasma of a number of USS patients, including R1060W carriers and seems to delay disease onset, to reduce the number of recurrences and the need for regular prophylactic plasma infusions (26,29).…”