A Genetic Basis for Adult Onset TTP?.

Abstract

Thrombotic thrombocytopenic purpura (TTP) presents in childhood or adult life and is caused by a deficiency of von Willebrand factor-cleaving protease (ADAMTS13) activity. Several mutations and polymorphisms have been reported in ADAMTS13 in congenital TTP. The study aim was to elucidate whether a mutation(s) may be linked to adult onset TTP, which may be precipitated by infection, pregnancy or oestrogen-containing preparations and is associated with antibodies to ADAMTS13. We investigated 58 adult onset TTP patients (median age 39 (range 16–74) years) with ADAMTS13 activity levels <5% of pooled normal plasma when tested pre-treatment during the acute phase of their TTP episode. Initial screening using WAVE® technology detected a novel sequence change in exon 24 of ADAMTS13 in 2/14 of these patients (both heterozygous). Gene sequencing identified this nucleotide change as C3178T which results in the significant amino acid substitution arginine to tryptophan (R1060W) in the terminal thrombospondin type 1 (TSP1-8) domain of ADAMTS13. We confirmed this C3178T nucleotide change using a specific PCR and restriction enzyme digest and studied the remaining 44 cases, identifying one homozygote (T3178T) and three additional heterozygous patients, giving a total of 6/58 (10.3%). Fifty-eight healthy normal subjects (median age 33 (range 22–57) years) were also screened for this C3178T nucleotide change and all had the wild-type (C3178C) genotype. There was a significant difference in prevalence of the C3178T missense mutation between the TTP patient and normal control groups (p=0.0072, χ2 test, odds ratio (OR) = 0.00, 95% confidence intervals (CI) = 0.00–0.67). The mutation was only detected in Caucasian patients (n = 6/41). It was not found in any of the Afro-Caribbeans (n = 8), Asians (n = 5) or patients in other ethnic groups (n = 4). The difference in prevalence remained significant amongst the Caucasian contingent (p=0.0024, χ2 test, OR = 0.00, 95% CI = 0.00–0.52). IgG antibodies to ADAMTS13 (found in 37/58 (63.8%) patients) were demonstrated in three of the five heterozygous C3178T TTP patients, but not in the homozygous patient. The C3178T mutation was also detected in the mother of one of these three heterozygous patients and the daughter of the homozygous patient, neither of whom have had TTP. In conclusion, the novel C3178T missense mutation appears to be associated with adult onset TTP and in some instances, antibodies to ADAMTS13. This raises the possibility that adult onset TTP may arise as a result of an interaction between genetic and acquired factors.