Page 211 - 2019_10 resto del Mondo_web

Coagulation & its Disorders
The International Hereditary Thrombotic Thrombocytopenic Purpura Registry: key findings at enrollment until 2017
Ferrata Storti Foundation
Hendrika A. van Dorland,1,2 Magnus Mansouri Taleghani,1 Kazuya Sakai,3 Kenneth D. Friedman,4 James N. George,5 Ingrid Hrachovinova,6
Paul N. Knöbl,7 Anne Sophie von Krogh,8 Reinhard Schneppenheim,9 Isabella Aebi-Huber,1,2 Lukas Bütikofer,10 Carlo R. Largiadèr,11
Zuzana Cermakova,12 Koichi Kokame,13 Toshiyuki Miyata,13,14 Hideo Yagi,3,15 Deirdra R. Terrell,5 Sara K. Vesely,5 Masanori Matsumoto,3
Bernhard Lämmle,1,16 Yoshihiro Fujimura3,17 and Johanna A. Kremer Hovinga;1,2 Hereditary TTP Registry
1Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, Bern, Switzerland; 2Department for BioMedical Research, University of Bern, Bern, Switzerland; 3Department of Blood Transfusion Medicine, Nara Medical University, Kashihara, Japan; 4Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI, USA; 5Department of Biostatistics Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; 6NRL for Hemostasis, Institute of Hematology and Blood Transfusion, Prague, Czech Republic; 7Division of Hematology and Hemostasis, Department of Medicine 1, Medical University of Vienna, Austria; 8Department of Hematology, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway; 9Department of Paediatric Haematology and Oncology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany; 10CTU Bern, University of Bern, Bern, Switzerland; 11University Institute of Clinical Chemistry, Inselspital, Bern University Hospital, Bern, Switzerland; 12Blood Center, University Hospital Ostrava, Ostrava, Czech Republic; 13Department of Molecular Pathogenesis, National Cerebral and Cardiovascular Center, Suita, Japan; 14Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan; 15Department of Hematology, Nara Prefecture General Medical Center, Nara, Japan; 16Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany and 17Japanese Red Cross Kinki Block Blood Center, Ibaraki, Osaka, Japan
Haematologica 2019 Volume 104(10):2107-2115
ABSTRACT
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 for a study which aimed to improve 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 thrombo- cytopenic purpura was confirmed by severely deficient ADAMTS13 activ- ity (≤10% of normal) in the absence of a functional inhibitor and the pres- ence of ADAMTS13 mutations on both alleles. By the end of 2017, 123 con- firmed patients had been enrolled from Europe (n=55), Asia (n=52, 90% from Japan), the Americas (n=14), and Africa (n=2). First recognized disease manifestation occurred from 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 of 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% vs. 37%), despite the fact that ADAMTS13 activity was <1% in 18 of 20 homozygous, but in only 8 of 14 compound heterozygous carriers. An evaluation of overt disease onset in all patients with an available sensitive ADAMTS13 activity assay (n=97) shows that residual ADAMTS13 activity is not the only determinant of age at first dis- ease manifestation. Registered at clinicaltrials.gov identifier NCT01257269.
Correspondence:
JOHANNA A. KREMER HOVINGA
johanna.kremer@insel.ch
Received: January 16, 2019. Accepted: February 20, 2019. Pre-published: February 21, 2019.
doi:10.3324/haematol.2019.216796
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/10/2107
©2019 Ferrata Storti Foundation
Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or inter- nal use. Sharing published material for non-commercial pur- poses is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for com- mercial purposes is not allowed without permission in writing from the publisher.
haematologica | 2019; 104(10)
2107
ARTICLE