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Clinical and molecular traits of hereditary TTP
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.
pound heterozygotes (1.1 years; 0-35.0 years), however, the difference was not significant (P=0.6), nor were the differences of all the other clinical characteristics (Table 4). Reported onset in homozygous ADAMTS13 c.4143_4144dupA carriers has a bimodal pattern with peaks in the neonatal period and between six years and <18 years of age, whereas in compound heterozygotes the proportion of patients with later overt onset steadily declines (Online Supplementary Figure S3A).
In 34 of 38 ADAMTS13 c.4143_4144dupA carriers, ADAMTS13 activity was assessed by the modified FRETS-VWF73 assay at the Central Hematology Laboratory, Bern University Hospital, Bern, Switzerland. ADAMTS13 activity was <1% in 18 of 20 (90%) homozy- gous and in 8 of 14 (57%) compound heterozygous carri- ers (Online Supplementary Figure S3B). The second ADAMTS13 mutation in these eight patients was: c.1520G>A (p.Arg507Glu) in 5 alleles; c.1313G>T (p.Cys438Phe), c.2455delG (p.Ala819Leufs*24), and c.4091_4092insA (p.His1364Glnfs*) each in one allele. In the five compound heterozygotes with an ADAMTS13 activity of 1% to < 5%, we found the following five muta- tions: c.1313G>T (p.Cys438Phe), c.2410T>C (p.Cys804Arg), c.2836T>C (p.Cys946Arg), c.3178C>T (p.Arg1060Trp) and c.3650T>C (p.Ile1217Thr). c.3178C>T (p.Arg1060Trp) was also present in the com- pound heterozygous carrier with an ADAMTS13 activity of 6.3%. In c.4143_4144dupA carriers having an ADAMTS13 activity <1%, information on disease onset was available in 15 homozygotes and seven compound heterozygotes, with a trend for later disease onset in homozygotes (Online Supplementary Figure S3C).
Overt disease onset and ADAMTS13 activity in all congenital thrombotic thrombocytopenic purpura patients
Reported overt disease onset in 97 cTTP patients whose ADAMTS13 activity was measured either in Bern, Switzerland, or Nara, Japan, is shown in relation to the
Type of disease/disorder
Arterial thromboembolic diseases† Myocardial infarction
Transient ischemic attack
Stroke
Other
Other neurological disorders†
Epileptic seizure Headache Various other
Renal insufficiency† Hemodialysis Kidney transplant
Jaundice (hemolysis or liver disease)
†† Hyperbilirubinemia in neonatal period
Anemia
Iron deficiency Renal anemia
Other diseases
Cancer
Autoimmune disorders Transfusion-transmitted viral infection†
HBV
HCV
HIV
All patients (N=120)
33 (28%) 5 (4.2%) 12 (10%) 25 (21%) 6 (5.0%) 27 (22%) 6 (5.0%) 5 (4.2%) 20 (17%) 30 (25%) 12 (10%) 3 (2.5%) 59 (49%) 30 (25%)
8 (6.7%) 8 (6.7%)
2 (1.7%)
4 (3.3%) 13 (11%) 3 (2.5%) 10 (8.3%) 1 (0.83%)
Table 2. Reported concomitant diseases and disorders in congenital thrombotic thrombocytopenic purpura patients up to enrollment.
N: total number of patients with information available; HBV: hepatitis B viral infection; HCV: hepatitis C viral infection; HIV: human immunodeficiency virus infection. Categorical variables are presented as numbers and percentage of all patients. †For different disease categories the total number of affected patients is given (as a patient may have incurred more than one disorder per category,the sum of all conditions per category may be larger than that of the number of affected patients).††No information reported for seven patients on hyperbilirubinemia in the neonatal period.
measured ADAMTS13 activity (Figure 4). Twenty-eight of 70 patients with ADAMTS13 activity <1% had overt dis- ease onset in the neonatal period, but there were also 20 patients with overt disease onset at age >15-57 years. Most patients with measurable ADAMTS13 activity (≥ 1%) had a reported disease onset at >5 years of age. Overall, we found a weak but significant correlation between age at overt onset and ADAMTS13 activity (rs=0.25, P<0.01).
Discussion
We report the successful implementation of an International Registry for the ultra-rare disease cTTP. After many years of preparation, patient recruitment and enroll- ment, by the end of 2017, a total of 123 confirmed cTTP patients from 117 families were included in the study by centers from all over the world with the help of numerous primary care physicians (see the complete list in Online Supplementary Appendix A).
Congenital TTP is often not recognized at the first occurrence of disease manifestation, e.g. in the newborn
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