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Clinical and molecular traits of hereditary TTP
ADAMTS13 IgG antibodies if the titer value was < 25 for the for- mer method,11 and < 15 arbitrary units/mL for the commercially available ELISA (Technoclone®) method.
DNA extraction from leukocytes, amplification of all 29 ADAMTS13 exons with flanking intron–exon boundaries and sequencing were performed using standard methods. Amino acids and nucleotides are numbered according to the recommendation of the Human Genome Variation Society.31
Overt disease onset and acute episode definitions
Definition of overt disease onset and acute episode can be found in the Online Supplementary Appendix.
Statistical analysis
The statistical analysis is described in the Online Supplementary Appendix.
Results
Demographics, clinical and biochemical characteristics
During the period from the beginning of the project in 2006 (clinicaltrials.gov identifier NCT01257269) until the end of 2017, 149 patients were assessed for enrollment in the Hereditary TTP Registry; seven patients were excluded as they did not have cTTP. Of the 142 enrolled patients, 19 patients from 19 families were categorized at the end of 2017 as suspected cTTP patients and did not undergo fur- ther analysis in this study; the remaining 123 patients from 117 families had confirmed cTTP (Table 1 and Online Supplementary Figure S1). The female to male ratio was 1:1. Fifty-five and 52 patients were enrolled from Europe and Asia, respectively, 14 from the Americas, and 2 from one site on the African continent (Online Supplementary Figure S2). Accordingly, 65 participants were Caucasian, 52 Asian, and 3 Hispanic. Median age at enrollment was 26.1 years (range: 0.1-75.0 years), median age at clinical diagno- sis was 16.7 years (range: 0-69.8 years), and median age at reported overt disease onset was 4.5 years (range: 0-69.8 years). Figure 1 shows the relationship between overt dis- ease onset, clinical diagnosis, and confirmation of the diagnosis for each patient over time.
ADAMTS13 activity values were reported for 121 of 123 patients and ≤10% in 121/121 (Table 1). Despite miss- ing ADAMTS13 activity values, two patients were diag- nosed with cTTP based on the molecular analysis of the ADAMTS13 gene showing two disease-causing muta- tions.
ADAMTS13 functional inhibitors were negative in all reported cases, but 12 of 103 patients analyzed had a pos- itive anti-ADAMTS13 antibody result by ELISA (Table 1). Consanguinity of the parents was acknowledged in 14 out of 104 cTTP patients for whom this information was pro- vided. Forty-seven patients were homozygous and 76 compound heterozygous mutation carriers. In total, 98 different ADAMTS13 mutations were identified in 123 confirmed cTTP patients.
Occurrence of diseases and disorders up until enrollment
Information on the occurrence of concomitant diseases and disorders up until enrollment was available for 120 cTTP patients (Table 2). Jaundice (due to hemolysis or liver disease, 49%) and arterial thromboembolic events
Table 1. Demographic and clinical features and ADAMTS13-related laboratory findings in congenital thrombotic thrombocytopenic purpu- ra patients at enrollment.
Characteristic
Median age at enrollment (n=118)†
Median age at overt disease onset (n=111) Median age at clinical diagnosis (n=122) Gender (F/M)
Ethnicity (self-reported)
Caucasian Hispanic Asian Other
All patients (N=123)
26.1 [0.1, 15.1, 37.2, 75.0]
4.52 [0.00, 0.01, 20.1, 69.8] 16.7 [0.00, 4.00, 28.6, 69.8] 62/61
65 (53%) 3 (2.4%) 52 (42%) 3 (2.4%) 121/121 0/114 12/103 14/104 47/123 76/123
ADAMTS13 activity (≤10%) ADAMTS13 functional inhibitor (+) Anti-ADAMTS13 antibodies (+)§ Consanguinity of parents Homozygous genotypes
Compound heterozygous genotypes
N: total number of patients; n: number of patients with available values; F: female; M: male. Continuous variables are presented as median (minimum, 25th percentile, 75th percentile,maximum).Categorical variables are presented as number and percentage of all patients, or as number of n patients. †Five patients from five families were enrolled postmortem by consent of their family members. §A patient’s sample was defined positive for Anti-ADAMTS13 IgG antibodies if the titer value was >25 for the in- house ELISA method,11 and >15 arbitrary units/mL for the commercially available ELISA (Technoclone®) method.
(28%) were frequently reported. Stroke had occurred in 21%, and transient ischemic attack in 10%. Arterial thromboembolic events had occurred in all age groups. In the groups >40-50 years and >50 years, 50% or more of the cTTP patients had suffered from at least one arterial thromboembolic event (Figure 2). Other neurological dis- orders included epileptic seizures (6 patients), headache (5 patients), and psychiatric conditions (depression, behav- ioral and mental disorders; 20 patients).
Renal insufficiency occurred in 25% of the cohort. Twelve patients needed hemodialysis and 3 underwent a kidney transplantation. Autoimmune disorders (hypothy- roidism, IgA nephritis, hyperthyroidism) were rare. Finally, transfusion-transmitted viral diseases were report- ed in 13 of 120 patients (11%).
Reported acute episodes and their context
A total of 291 distinct acute TTP episodes were record- ed in 81 patients (Online Supplementary Table S2), while there was no detailed information on acute episodes in 42 patients. Patients had experienced a median of 2 episodes (range: 1-22) prior to enrollment, corresponding to a medi- an of 0.10 (range: 0.02-8.91) acute episodes per year. Median duration of an episode was seven days (range: < 1-128 days).
For 287 of the 291 episodes, information on possible triggers of the acute episode was available; in 190 of 287 episodes one or more trigger(s) was/were presumed by the treating physicians (Figure 3). Infection was the most frequent trigger reported (41% of episodes). Alcohol excess was the trigger for 30 episodes and was observed only in male patients, while 28 episodes occurred during
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