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 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 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 disease manifestation. Registered at clinicaltrials.gov identifier NCT01257269.

Blood Center University Hospital Ostrava Ostrava Czech Republic

CTU Bern University of Bern Bern Switzerland

Department of Biostatistics Epidemiology University of Oklahoma Health Sciences Center Oklahoma City OK USA

Department of Blood Transfusion Medicine Nara Medical University Kashihara Japan

Department of Blood Transfusion Medicine Nara Medical University Kashihara Japan Department of Hematology Nara Prefecture General Medical Center Nara Japan

Department of Blood Transfusion Medicine Nara Medical University Kashihara Japan Japanese Red Cross Kinki Block Blood Center Ibaraki Osaka Japan

Department of Hematology and Central Hematology Laboratory Inselspital Bern University Hospital Bern Switzerland

Department of Hematology and Central Hematology Laboratory Inselspital Bern University Hospital Bern Switzerland Center for Thrombosis and Hemostasis University Medical Center Mainz Mainz Germany

Department of Hematology and Central Hematology Laboratory Inselspital Bern University Hospital Bern Switzerland Department for BioMedical Research University of Bern Bern Switzerland

Department of Hematology St Olavs Hospital Trondheim University Hospital Trondheim Norway

Department of Molecular Pathogenesis National Cerebral and Cardiovascular Center Suita Japan

Department of Molecular Pathogenesis National Cerebral and Cardiovascular Center Suita Japan Department of Cerebrovascular Medicine National Cerebral and Cardiovascular Center Suita Japan

Department of Paediatric Haematology and Oncology University Medical Centre Hamburg Eppendorf Hamburg Germany

Division of Hematology and Hemostasis Department of Medicine 1 Medical University of Vienna Austria

Division of Hematology and Oncology Medical College of Wisconsin Milwaukee WI USA

NRL for Hemostasis Institute of Hematology and Blood Transfusion Prague Czech Republic

University Institute of Clinical Chemistry Inselspital Bern University Hospital Bern Switzerland

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