ADAMTS13 Secretion and Residual Activity among Patients with Congenital Thrombotic Thrombocytopenic Purpura with and without Renal Impairment

Abstract

Background and objectives Acute renal impairment is observed in 11%-23% of patients with congenital thrombotic thrombocytopenic purpura (TTP) and deficiency of a disintegrin and metalloprotease with thrombospondin motifs 13 (ADAMTS13, a metalloprotease that cleaves von Willebrand factor [VWF] multimers), a substantial percentage of whom develop CKD during follow-up.Design, setting, participants, & measurements Here we investigated whether, in 18 patients with congenital recruited from 1996 to 2013 who fulfilled inclusion criteria, acute renal involvement occurred during bouts segregated with lower secretion and activity levels of ADAMTS13 mutants. We performed expression studies and a sensitive recombinant VWF (rVWF) A1-A2-A3 cleavage test (detection limit, 0.78% of normal ADAMTS13 activity).Results A higher risk of acute renal impairment during bouts was observed in patients with childhood (,18 years) onset (odds ratio [OR], 24.6 [95% confidence interval (CI), 1.11 to 542.44]) or a relapsing ($1 episode per year) disease (OR, 54.6 [95% CI, 2.25 to 1326.28]) than in patients with adulthood onset or long-lasting remission, respectively. Whatever the age at onset, patients with acute renal impairment had mutations different from those in patients without renal involvement. Moreover, mutations in patients with acute renal impairment compared with those in patients without renal involvement caused lower in vitro rADAMTS13 secretion (1.33% versus 12.5%; P,0.001) and residual activity (0.11% versus 3.47%; P=0.003). rADAMTS13 secretion #3.75% and residual activity #0.4% best discriminated patients with renal impairment (receiveroperating characteristic curve sensitivity, 100% and 100%; specificity, 100% and 83.3%, respectively; logistic regression OR, 325 [95% CI, 6 to 18339] and 91.7 [95% CI, 3.2 to 2623.5], respectively). All mutations found in patients with childhood onset or relapsing disease were associated with acute renal impairment during bouts, confirming the link between acute renal impairment and early onset or a relapsing course. ADAMTS13 activity levels in vivo, measured in patients' serum by rVWF A1-A2-A3 cleavage test, correlated with in vitro rADAMTS13 mutant activity (r=0.95; P,0.001).Conclusions In congenital TTP, renal impairment and relapsing disease might be predicted by measurements of in vitro rADAMTS13 secretion and activity levels and in vivo serum ADAMTS13 activity.

Risk of diagnostic delay in congenital thrombotic thrombocytopenic purpura

“…hemorrhagic unexplained diathesis in childhood). Similar to our case, another cTTP patient carrying a homozygous missense mutation at the same exon (p.Ile143Thr, c.428T>C) leading to low residual ADAMTS13 activity showed an early onset (at 7 years) but a detailed medical history revealed easy bruising and anemia since birth .…”

“…The homozygous missense mutation (p.Ile143Phe) identified in our patient causes a severe secretion defect with very low residual ADAMTS13 levels, which well correlates with the early TTP onset in this patient and her relapsing course. The same homozygous mutation has been recently reported in two cTTP siblings from a consanguineous family , showing similar in vitro expression levels (i.e. severe deficiency in both antigen and activity levels).…”

“…severe deficiency in both antigen and activity levels). Similar to our patient, they experienced many relapses (four events in an 8‐year follow‐up and six events in a 15‐year follow‐up, respectively) triggered by infections and/or pregnancy; unlike our patient, they had a later disease onset (at 18 and 21 years, respectively) . We speculate this discrepancy may be due to different exposures to triggers or even to different estimation of previous events (i.e.…”

Thirty five novel nsSNPs may effect onADAMTS13protein leading to Thrombotic thrombocytopenic purpura (TTP) using bioinformatics approach

“…H234Q mutation in the ADAMTS13 gene found to be damaging through insilico methods in this study was also found to the cause of repeated renal failure in an adult patient [39]. D235Y mutation has also been studied in patients with congenital TTP [40]. Similarly, C311Y and P353L mutations in the ADAMTS13 gene have been found in patients with congenital TTP in more than one study [14,37].…”

“…Sequencing of the ADAMTS gene in patients with deep vein thrombosis identified R421C mutation [41]. G761S mutation was identified in patients with impaired renal function [40], while C908S mutation was one of 10 ADAMTS13 gene mutations in six families with congenital TTP [38].…”