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H.A. van Dorland et al.
Introduction
Hereditary or congenital thrombotic thrombocytopenic purpura (cTTP; also known as Upshaw-Schulman syn- drome; OMIM: 274150) is an autosomal recessive inherit- ed thrombotic microangiopathy (TMA), which can mani- fest with acute life-threatening disease episodes and fre- quent relapses.1-5 The underlying pathophysiology is an absent or severely reduced activity of ADAMTS13 (a dis- integrin and metalloproteinase with thrombospondin type 1 repeats, member 13) caused by bi-allelic mutations in the ADAMTS13 gene.6-9 In the absence of functional ADAMTS13, large von Willebrand factor multimeric strings are not cleaved into normal-sized ones. As a result, platelets adhere to these unusually large, extremely adhe- sive multimers leading to occlusive microvascular throm- bosis. The clinical manifestations of acute TTP include the concomitant occurrence of often severe thrombocytope- nia, microangiopathic hemolytic anemia, and a variable degree of ischemic organ damage, particularly affecting the brain, heart and kidneys. If left untreated, mortality exceeds 90%.10
Congenital TTP (cTTP) is an ultra-rare disease, affecting about one per 1,000,000 persons.5,11 Its rarity makes it dif- ficult to unravel what contributes to its complex and var- ied clinical presentation and course of disease. Adding to this challenge is the large variety of ADAMTS13 gene mutations (> 200)11-14 that have been identified (missense, nonsense, splice site mutations, and frameshift mutations caused by small deletions and insertions), and new muta- tions are being continuously revealed. ADAMTS13 gene variants may abolish or impair ADAMTS13 synthesis, secretion or activity.12,14,15 Some data suggest that the sever- ity of disease in cTTP is related to residual ADAMTS13 activity.13,16 In a cohort of 29 cTTP patients, Lotta et al.17 found residual ADAMTS13 activity of < 3% to be associ- ated with an early disease onset (< 18 years of age), an annual event rate of >1, and a need for prophylactic plas- ma therapy. Age at overt onset and diagnosis of cTTP shows, in general, a seemingly dichotomous distribution, with approximately half of patients presenting within their first five years of life, and the other half experiencing disease onset in early adulthood, often during a first preg- nancy.11,18-21 Childhood-onset cTTP often starts in the neonatal period with hematologic features and severe jaundice.11,22 Moreover, Schneppenheim et al.23 and von Krogh et al.24 reported on variable disease courses in cTTP patients homozygous for the ADAMTS13 c.4143_4144dupA mutation, typically having an ADAMTS13 activity <1% of normal. Consequently, the question was asked as to whether residual ADAMTS13 activity is really the major determinant of clinical hetero- geneity in cTTP.25
The Hereditary TTP Registry (clinicaltrials.gov identifier: NCT01257269) started in 2006 as an international open and ambidirectional cohort study for patients with con- firmed and suspected cTTP and their family members.26 The Registry’s overall aim is to document individual clini- cal courses, treatment requirements, and to identify possi- ble triggers of acute TTP episodes and disease modifiers in relation to the disease-causing ADAMTS13 mutations. The primary aim of this report is to provide the demo- graphic and clinical characterization of the cTTP cohort at enrollment from when the study started until the end of 2017. A second objective was to evaluate residual
ADAMTS13 activity and its relation to apparent disease onset in the whole cohort, with emphasis on carriers of ADAMTS13 c.4143_4144dupA (p.Glu1382Argfs*6) muta- tion.
Methods
Eligibility
The Hereditary TTP Registry enrolls patients from all over the globe. Those eligible for participation are patients with confirmed or suspected cTTP and their family members (for diagnostic crite- ria see the Online Supplementary Appendix). In the current study, enrollment data from patients with confirmed cTTP were used for evaluation.
Patient recruitment
Initially, eligible patients were identified through the Bern TTP Registry and the Nara Medical University Registry on thrombotic microangiopathies (TMA), and enrolled through their treating physicians. Later, patients or their physicians approached the Registry directly through the website (www.ttpregistry.net), based on its related publications24,26 and contributions at national and international congresses. The Hereditary TTP Registry includes patients from published reports, and patients who have been newly identified. By the end of 2017, around two-thirds of the 123 confirmed cTTP patients had been reported in case reports and case series between 1981 and 2018 (Online Supplementary Appendix B), prior to their enrollment in the Registry.
The Hereditary TTP Registry was approved by the Lead Cantonal Ethics Committee (CEC) in Bern in 2006 (CEC n. 031/06). The protocol was approved by the Institutional Review Boards or Ethics Committees and Institutional Boards responsible, as applicable, at each site. All Registry participants or their legal representatives provided written informed consent before enroll- ment.
Data collection at enrollment
Data collection at enrollment is described in the Online Supplementary Appendix.
ADAMTS13 parameters
In the majority of patients (n=96), ADAMTS13 activity assays, functional inhibitors, anti-ADAMTS13 antibodies, as well as molecular analysis of the ADAMTS13 gene, were performed in the Central Hematology Laboratory, Bern University Hospital, University of Bern, Switzerland (50 patients), and in the Department of Blood Transfusion Medicine, Nara Medical University, Japan (46 patients). In the remaining 27 confirmed patients, analyses were performed in other laboratories employing various assays. For two patients, ADAMTS13 activity values were not reported.
ADAMTS13 activity was determined in Bern by the modified FRETS-VWF73 assay [lower limit of quantification (LLQ) 1%]27,28 and in Nara by the chromogenic ADAMTS13-act-ELISA (LLQ 0.5%).29
Before combining ADAMTS13 activity data for descriptive analysis, we carried out an assay comparison on 41 plasma sam- ples of cTTP patients (Online Supplementary Table S1).
Functional ADAMTS13 inhibitors were assessed by a Bethesda- like assay and reported in Bethesda units (BU)/mL, a value ≤0.4 BU/mL is considered negative.27,30 Anti-ADAMTS13 IgG antibod- ies were assessed by an in-house ELISA,11 or a commercially avail- able ELISA (Technoclone®) according to the manufacturer’s instructions. A patient’s sample was defined negative for anti-
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haematologica | 2019; 104(10)