The International Hereditary Thrombotic Thrombocytopenic Purpura Registry: key findings at enrollment until 2017

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 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.

Copyright© 2019 Ferrata Storti Foundation.

Figures

Figure 1.

Clinical diagnosis and confirmation of diagnosis in relation to overt disease onset: information available for 111 confirmed congenital thrombotic thrombocytopenic 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 documented 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.

Figure 2.

Number of congenital thrombotic thrombocytopenic purpura (cTTP) patients with or without a history of arterial thromboembolic events by age category at enrollment. Data are available for 120 of 123 confirmed cTTP patients. For five deceased patients, age at death was used. Yrs: years.

Figure 3.

Triggers of acute thrombotic thrombocytopenic purpura (TTP) episodes until enrollment in male and female congenital thrombotic thrombocytopenic purpura patients. For 287 of 291 acute TTP episodes documented in the Hereditary TTP Registry information on triggers of the acute bout was known. Seventy-nine patients had episodes with or without presumed triggers: for 97 episodes in 46 patients no trigger was reported; for 190 episodes in 58 patients triggers were reported. Triggers do not sum up as a patient may have had more than one trigger of an acute episode, nor do patients as they may have had episodes with or without triggers.

Figure 4.

Age at disease onset in relation to ADAMTS13 activity in 97 congenital thrombotic thrombocytopenic purpura (cTTP) patients. Ninety-seven confirmed cTTP patients had information on disease onset and an ADAMTS13 activity determination performed either at the Central Hematology Laboratory, Bern University Hospital, Switzerland, or at the Department of Blood Transfusion Medicine, Nara Medical University, Japan. Patients are labeled according to their ADAMTS13 mutations: 17 homozygous carriers and 12 compound heterozygous carriers of ADAMTS13 c.4143_4144dupA are shown with white and gray circles, respectively. Black circles represent carriers of other mutations. Spearman’s rank correlation coefficient for age at overt disease onset versus ADAMTS13 activity: rs=0.25, P<0.01. yrs: years.