The International Hereditary Thrombotic Thrombocytopenic Purpura Registry: Key findings at enrolment until 2017.

van Dorland, Hendrika Anette; Mansouri Taleghani, Magnus; Sakai, Kazuya; Friedman, Kenneth D; George, James N; Hrachovinova, Ingrid; Knöbl, Paul N; von Krogh, Anne Sophie; Schneppenheim, Reinhard; Aebi-Huber, Isabella; Bütikofer, Lukas; Largiadèr, Carlo R.; Cermakova, Zuzana; Kokame, Koichi; Miyata, Toshiyuki; Yagi, Hideo; Terrell, Deirdra R; Vesely, Sara K; Matsumoto, Masanori; Lämmle, Bernhard; ... (2019). The International Hereditary Thrombotic Thrombocytopenic Purpura Registry: Key findings at enrolment until 2017. Haematologica - the hematology journal, 104(10), pp. 2107-2115. Ferrata-Storti Foundation 10.3324/haematol.2019.216796

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Congenital thrombotic thrombocytopenic purpura is an autosomal recessive inherited disease with a clinically heterogeneous course and an incompletely understood genotype-phenotype correlation. In 2006, the Hereditary TTP Registry started recruitment with the purpose of improving the understanding of this ultra-rare disease. The objective of this study is to present characteristics of the cohort until the end of 2017 and to explore the relationship between overt disease onset and ADAMTS13 activity with emphasis on the recurring ADAMTS13 c.4143_4144dupA mutation. Diagnosis of congenital thrombotic thrombocytopenic purpura was confirmed by severely deficient ADAMTS13 activity (<10% of normal) in the absence of a functional inhibitor and the presence of ADAMTS13 mutations on both alleles. By the end of 2017, 123 confirmed patients were enrolled from Europe (55), Asia (52, 90% from Japan), the Americas (14), and Africa (2). First recognized disease manifestation occurred around birth up to the age of 70 years. Of the 98 different ADAMTS13 mutations detected, c.4143_4144dupA (exon 29; p.Glu1382Argfs*6) was the most frequent mutation, present on 60/246 alleles. We found a larger proportion of compound heterozygous than homozygous carriers of ADAMTS13 c.4143_4144dupA with overt disease onset at <3 months of age (50% versus 37%), despite the fact that ADAMTS13 activity was <1% in 18/20 homozygous, but in only 8/14 compound heterozygous carriers. Evaluating overt disease onset in all patients with a sensitive ADAMTS13 activity determination available (n=97), it becomes evident that residual ADAMTS13 activity is not the only determinant of the age at first disease manifestation. clinicaltrials.gov identifier NCT01257269.

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