PO005-MON Congenital thrombotic thrombocytopenic purpura (TTP) caused by compound heterozygosity of c.1225C>T and a novel c.2321delG ADAMTS13 gene mutations

KEMPFER AC; PAIVA-PALOMINO J; WOODS AI; SÁNCHEZ LUCEROS A; LAZZARI MA

Toronto

Congreso; XXV Congress of the International Society on Thrombosis and Haemostasis and 61st Annual SSC Meeting.; 2015

International Society on Thrombosis and Haemostasis

Background: Severe deficiency of ADAMTS13 may result in von Willebrand factor ultralarge multimers (ULVWF) spontaneously interacts with platelet receptors, resulting in recurrent attacks of microvascular thrombosis.Aims: We hypothesized that a compound heterozygous for both a known mutation (c.1225C>T) and a novel mutation (c.2321delG) may confer a more severe TTP phenotype.Methods: Patient (P) presenting purpura and jaundice, with hemolytic anemia, thrombocytopenia and reticulocytosis at birth followed by several episodes during her first year of life. ADAMTS13 activity (normal value = 40?130%), antigen (0.60?1.60 ug/mL), and IgG anti-ADAMTS13 antibody (< 15 U/mL) were assayed by ELISA kits. ULVWF (≤ 15%) was evaluated by SDS-agarose gel electrophoresis and genotyping was performed by sequencing on the ABI Prism 310. Mutations were analyzed by in silico tools to predict their effect. Informed consent and ethical approval were obtained.Results: The P had undetectable activity of ADAMTS13, antigen: 0.04 ug/mL, IgG anti-ADAMTS13 antibody=5U/mL and ULVWF= 53%. The father and the mother showed no clinical manifestations and ADAMTS13 activity values of 53% and 52% respectively,IgG anti-ADAMTS13 antibody = 2 U/mL and normal ULVWF while antigen was of 0.58 and 0.65 ug/mL respectively. Two mutations were found in P c.1225C>T inherited from the father and a novel mutation c.2321delG inherited from the mother.Conclusion: The c.1225C>T (p.R409W) mutation affects the TPS1 domain, abolishing ADAMTS13 secretion. In a family with P in homozygous state to this mutation found by Camilleri 2012, the parents, in heterozygous state, showed normal activity and subnormal levels of antigen, like our P´s father. On the other hand, in silico tools predicted the novel mutation c.2321delG (p.G774AfsX3) produced the readingframeshift with formation of a premature stop codon which would result in a nonfunctional protein.We conclude that the genotype of P, due to compound heterozygosity of two mutations, would produce the TTP phenotype.