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H.A. van Dorland et al.
Figure 1. Clinical diagnosis and confirmation of diagnosis in relation to overt disease onset: information available for 111 confirmed congenital thrombotic throm- bocytopenic purpura (cTTP) patients. x-axis: each patient’s individual time point of clinical diagnosis is shown. Below the x-axis, the interval (in years, yrs) between birth, (probable) disease onset, and clinical diagnosis is shown. Above the x-axis, the interval (in yrs) between clinical diagnosis and confirmation of diagnosis is shown. Disease onset varied from as early as the new-born period up to 70 years of age. The earliest clinical diagnosis of TTP in a Registry patient was put forward in January 1974. The patient highlighted by a vertical arrow was born 22 years before the clinical diagnosis of cTTP was established although disease onset was doc- umented in the neonatal period. Confirmation of the cTTP diagnosis was achieved by means of ADAMTS13 testing 21 years after the clinical diagnosis. NB: ADAMTS13 was first described in 1996, ADAMTS13 assays became more widely available around the turn of the millennium.
pregnancy. In addition, drug/medication use was assumed as trigger for 13 episodes, and 18 episodes seemed to be triggered by the patient’s birth, injury, food poisoning, and various others.
Prophylactic treatment
Seventy-one percent of the 117 cTTP patients with available information received regular treatment, predom- inantly with plasma products (99%) (Table 3). Plasma products used included fresh frozen plasma in 68 patients, two received fresh frozen plasma and cryo-poor plasma, and 12 patients received solvent/detergent plasma. One patient received a plasma-derived FVIII product (Koate®). The median interval of the regular treatments was 14.0 days (range: 2-75 days). Thirty-four patients were treated on demand. These data represent a snap-shot at the time of enrollment, whereby regular treatment was intensified or reduced depending on the patient’s individual require- ments.
ADAMTS13 mutations
In the 123 confirmed cTTP patients, 98 different
ADAMTS13 mutations were identified in 245 alleles (Online Supplementary Table S3). There were 57 missense, 12 nonsense, 21 frameshift due to deletions or insertions, and 8 splice site mutations. In one patient, only one muta- tion was detected and diagnosis of cTTP was confirmed through a plasma infusion trial. The most frequent muta- tion observed was ADAMTS13 c.4143_4144dupA (present on 60 of 246 alleles) followed by c.3178C>T (13 of 246 alleles) and c.577C>T (11 of 246 alleles) (Online Supplementary Figure S4). In addition, there were three mutations found in six of 246 alleles (2.4%), one mutation in 5 of 246 alleles (2.0%), 4 mutations in four of 246 alleles
(1.6%), six mutations in 3 of 246 alleles (1.2%), and 81 mutations were found only once (n=58) or twice (n=23). The mutation c.3650T>C was the only mutation found on three different continents: the Americas, Asia, and Europe, involving 4, 1, and 1 alleles, respectively. Mutation c.4143_4144dupA was found on one and 59 alleles, and c.3178C>T on 3 and 10 alleles in the Americas and Europe, respectively. Mutation c.3616C>T was found with one allele in Europe and two alleles in Asia, and mutation c.4006C>T was found in both Europe and Asia with two alleles each. All other mutations were restricted to one single continent each. In Asia, c.577C>T is the most frequent mutation, found exclusively in Japan (11 alleles) (Online Supplementary Table S3).
Nineteen of the 98 mutations have not been reported before. Mutations were found across the ADAMTS13 gene and in all protein domains without indication for a genetic hot-spot.
Characteristics, overt disease onset and ADAMTS13 activity in homozygous and compound heterozygous carriers of ADAMTS13 4143_4144dupA mutation
Carriers of the ADAMTS13 c.4143_4144dupA (p.Glu1382Argfs*6) mutation in exon 29 were enrolled from sites in Austria, Czech Republic, Hungary, Norway, Poland, and the USA. The number of homozygous and compound heterozygous carriers was about equal (P=0.51). Age at first diagnosis and at enrollment tended to be lower in compound heterozygous compared to homozygous carriers (P=0.06 and P=0.08, respectively) (Table 4). Information on recognized overt disease onset was available for 14 compound heterozygotes and 19 homozygotes. Homozygotes had a numerically higher age at overt onset (5.0 years; range 0-22.3 years) than com-
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haematologica | 2019; 104(10)