Abstract Number: PB1890
Meeting: ISTH 2020 Congress
Background: Thrombotic thrombocytopenic purpura (TTP) is a life-threatening illness due to deficiency in ADAMTS13 activity; this can be either congenital (inherited), or acquired (autoimmune), being this last condition the 95% of cases.
Aims: To report the finding of two novel genetic variants (GV) and one known variant in five patients with diagnosis of aTTP.
Methods: ADAMTS13-activity (normal value [nv]=40-130%), IgG (nv< 15U/uL), IgM (nv< 2.5 arbitrary units/uL[au/uL]), IgA (nv< 1.5au/uL) anti ADAMTS13 and neutralizing ADAMTS13-inhibitor (nv< 30%) were evaluated by ELISA.
The 29 exons and intron-exon boundaries of ADAMTS13 were amplified (PCR) and sequenced (Sanger method).
Twelve in-silico prediction tools were used: PolyPhen-2; SIFT; Panter; Mutation-tester; I-Mutant; Meta-SNP; CADD; SNP&GO; FATHMM; PhD-SNP; Provean.
Informed consent and institutional ethical approval was obtained from the patient.
P1: Female; diagnosis at 28 years.
P2: Female; diagnosis at 29 years.
P3: Female; diagnosis at 13 years.
P4: Female; diagnosis at 25 years.
P5: Female; diagnosis at 36 years.
Results: Plasmatic parameters of ADAMTS13 during acute crisis and GV found in the patients are shown in the table 1. All GV were found in heterozygous state.
Plasmatic parameters of ADAMTS13 | ||||||
Patient | Activity (%) | IgG (U/mL) | IgM (au/uL) | IgA (au/uL) | Neutralizing inhibitor (%) | Genetic Variant |
P1 | 8 | 9 | 1.9 | 0.35 | 90 | p.Val195Ile (Novel) |
P2 | 6 | 3 | 4.1 | 0.43 | 0 | p.Pro952Ser (Novel) |
P3 | <5 | 109 | 1.54 | 0.46 | 0 | p.Arg1096His. |
P4 | <5 | 55 | 1.04 | 0.56 | 11 | p.Arg1096His. |
P5 | 12 | 12 | 0.12 | 3.66 | 24 | p.Arg1096His. |
[Table 1: Plasmatic parameters and genetic study of ADAMTS13]
Conclusions: p.Val195Ile and p.Pro952Ser were predicted as deleterious in 54.5% and 81.8% of in-silico tools, respectively; whereas p.Arg1096His was predicted as neutral by 100% of in-silico tools, but decreased stability of protein.
p.Arg1096His has been described as polymorphism (rs61751476) and as like benign GV in clinical database (ClinVar and VarSome), and also associated with a reduction in functional activity by 50%.
The finding of heterozygous GV in these patients could suggest that their presence would be associated with changes in specific epitopes in domains of ADAMTS13 to develop of neutralizing ADAMTS13-inhibitor (P1), IgM (P2), IgG (P3, P4), IgA (P5); however, further studies and patients are needed to confirm this relationship.
To cite this abstract in AMA style:
Paiva J, Woods AI, Kinen A, Casinelli MM, Sanchez-Luceros A. Genetic Variants in ADAMTS13 in Patients with Acquired TTP (aTTP) [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/genetic-variants-in-adamts13-in-patients-with-acquired-ttp-attp/. Accessed March 21, 2024.« Back to ISTH 2020 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/genetic-variants-in-adamts13-in-patients-with-acquired-ttp-attp/