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H.A. van Dorland et al.
symptoms like headache or mental disorders. Even though ADAMTS13 half-life in plasma is about 2-4 days46,47 almost all patients will have unmeasurable ADAMTS13 levels within 7-10 days after infusion of 2-4 units of fresh frozen plasma. Evidently, a prospective fol- low up of cTTP patients will be needed to optimize replacement therapy. In the near future, the availability of rhADAMTS13, successfully tested in a pharmacokinetics and safety study in 15 cTTP patients,48 will greatly facili- tate regular prophylactic treatment, and will probably allow treatment to be carried forward at home. In addi- tion, given the high risk of acute episodes, ischemic strokes and other sequelae, a general prophylactic ADAMTS13 replacement in cTTP may be indicated.
ADAMTS13 mutations were found in all except one cTTP Bi-allelic patient (Online Supplementary Table S3 and Online Supplementary Figure S4); a total of 98 different mutations spread throughout the ADAMTS13 gene were identified, including several mutations that have not so far been described. Eighty-one mutations occurred only once (58 alleles) or twice, 14 different mutations were identified on 3-6 alleles, whereas three variants were present on 11 (c.577C>T), 13 (c.3178C>T), and 60 (c.4143_4144dupA) alleles, respectively. The latter three recurring mutations have been repeatedly found in Japanese (c.577C>T)11,37 and Caucasian (c.3178C>T and c.4143_4144dupA) patients.15,20,23,24,45,49 It has been postulated that mutations leading to a completely absent ADAMTS13 activity show a more severe phenotype than those associated with some residual ADAMTS13 activity.13,16,17,49 We compared disease characteristics of 22 homozygous and 16 compound het- erozygous carriers of the c.4143_4144dupA mutation (Table 4 and Online Supplementary Figure S3A-C). Median age at diagnosis tended to be higher in homozygous carri- ers, even though there was a wide range of age at diagno- sis from 0.2-51.5 years in both groups. There was no dif- ference in any other of the disease characteristics. Despite a severely deficient ADAMTS13 activity (< 0.5-1% of nor- mal) in homozygous c.4143_4144dupA carriers, almost half of affected patients had an overt disease onset at an age of > 6 years that seemed to be higher than in com- pound heterozygotes with equally severe ADAMTS13 deficiency (Online Supplementary Figure S3C). Shang et al.50 suggested that the c.4143_4144dupA mutation might be associated with defective apical, but preserved basolateral, secretion by endothelial cells. Whether some ADAMTS13 activity at the endothelial cell layer in the absence of plas- matic ADAMTS13 activity is present that may explain a delayed TTP onset in a proportion of homozygous carriers needs further study.
We then tested whether overt disease onset was related
with residual plasma ADAMTS13 activity in all patients whose ADAMTS13 activity was measured in Nara or Bern after a comparative evaluation had shown a good agreement of activity levels in the very low range below 5-10% (Online Supplementary Table S1). For 97 patients with available information, it was evident that overt dis- ease onset was not strictly related to residual ADAMTS13 activity. Whereas about 40% of cTTP patients with an ADAMTS13 activity <1% had a neonatal disease onset, 20% seemed to have a first TTP manifestation at age >20 years. On the other hand, most cTTP patients with an ADAMTS13 activity >1-2% had a delayed apparent dis- ease manifestation (Figure 4). Thus, residual ADAMTS13 activity is clearly not the only determinant of disease severity, as reflected by age at overt onset.
In conclusion, the Hereditary TTP Registry has provided substantial information, but it will be of utmost impor- tance for the development of an optimized management strategy to enlarge the cohort by directly enrolling more patients from around the globe, and through embarking on collaborations with other established registries on cTTP. It would be highly desirable to prospectively follow all cTTP patients at regular intervals and evaluate the best prophylactic strategy to avoid unnecessary deaths and late sequelae in this treatable condition.
A complete list of the collaborators of the Hereditary TTP Registry appears in the Online Supplementary Appendix A.
Acknowledgments
Acknowledgments to the late professor Miha Furlan for his pioneering work on discovery of von Willebrand factor-cleaving protease ADAMTS13 and its deficiency in TTP more than 20 years ago. The authors thank the teams of the laboratories in Bern, Switzerland and Nara, Japan for work on ADAMTS13- related assays and molecular analyses of the ADAMTS13 gene. Corinne Eschler is thanked for her assistance in data collection and entry.
Funding
The hereditary TTP registry has received support through grants from the Swiss National Science Foundation (Grant 32003B-124892), the Mach-Gaensslen Foundation Switzerland, the ISTH 2007 Presidential Fund, the NFG Foundation, as well as research grants from Baxalta US Inc., member of the Takeda group of companies, Bannockburn, IL, USA (IIR Grant no H10-000600 and H16-36165). Furthermore, this work was supported in part by grants-in-aid from the Ministry of Health, Labor, and Welfare of Japan, and Takeda Science Foundation (to YF and MM), and National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Number 1K01HL135466 (to DRT).
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