Partial ADAMTS13 deficiency in atypical hemolytic uremic syndrome

Abstract

• Reduction in ADAMTS13 function and complement dysregulation coexist in a significant number of patients with aHUS.• Variations in the ADAMTS13 gene (polymorphisms and rare variants) are partly responsible for the reduced ADAMTS13 function in aHUS.Complement dysregulation leads to atypical hemolytic uremic syndrome (aHUS), while ADAMTS13 deficiency causes thrombotic thrombocytopenic purpura. We investigated whether genetic variations in the ADAMTS13 gene partially explain the reduced activity known to occur in some patients with aHUS. We measured complement activity and ADAMTS13 function, and completed mutation screening of multiple complement genes and ADAMTS13 in a large cohort of aHUS patients. In over 50% of patients we identified complement gene mutations. Surprisingly, 80% of patients also carried at least 1 nonsynonymous change in ADAMTS13, and in 38% of patients, multiple ADAMTS13 variations were found. Six of the 9 amino acid substitutions in ADAMTS13 were common single nucleotide polymorphisms; however, 3 variants-A747V, V832M, and R1096H-were rare, with minor allele frequencies of 0.0094%, 0.5%, and 0.32%, respectively. Reduced complement and ADAMTS13 activity (<60% of normal activity) were found in over 60% and 50% of patients, respectively. We concluded that partial ADAMTS13 deficiency is a common finding in aHUS patients and that genetic screening and functional tests of ADAMTS13 should be considered in these patients. (Blood.

Modified Ham test for atypical hemolytic uremic syndrome

“…However, partial ADAMTS13 deficiency may also be observed in aHUS patients with a heterozygous mutation in the ADAMTS13 gene. 42 Because aHUS cannot be solely diagnosed based on ADAMTS13 activity and genetic testing, a number of recent studies have investigated diagnostic markers of aHUS. Complement components C5a and C5b-9 have been reported to be elevated in plasma of patients clinically characterized as aHUS before treatment, as compared with ADAMTS13-deficient TTP patients.…”

Complement Factor B Mutations in Atypical Hemolytic Uremic Syndrome—Disease-Relevant or Benign?

“…Gainof-function FB mutations were reported in 12 patients from five families and are associated with a severe outcome, leading to ESRD in the majority of the cases. 13,15,[17][18][19]21 Therefore, the presence of a FB mutation is considered as a bad prognosis for the disease. C3 levels are frequently below the normal range in these patients, suggesting active complement consumption in the plasma caused by C3 convertase overactivity.…”

“…[13][14][15][16] To date, 15 FB genetic changes have been published 8,13,15,[17][18][19][20][21] (Table 1), but functional data are reported for only 5 of them. 8,17,19 FB forms the alternative pathway C3 and C5 convertases interacting with two partners (C3b and Factor D) and cleaves two substrates (C3 and C5).…”

A Case Report of Atypical Hemolytic Uremic Syndrome Presenting with Massive Proteinuria

“…There is overlap between TTP and HUS in that partial ADAMTS13 deficiency may occur in patients with complement-mediated HUS [5]. In a number of cases it is not possible to distinguish between TTP and HUS because there may be normal ADAMTS13 levels in TTP, or no defects identified in the complement pathway in HUS [5].…”

“…5 different types of arteriolar stenosis are observed overall: 1) deficiency in ADAMTS13, a vWF cleaving protease, leads to the accumulation of unusually large vWF (ULVWf), platelet aggregation, and platelet thrombi; 2) platelet fibrin thrombosis like in patients with DIC, 3) tumor cell invasion of the microvasculature in patient with metastatic cancers; 4) microvascular vasculitis; 5)thrombotic angiopathy as seen in HUS [4]. There is overlap between TTP and HUS in that partial ADAMTS13 deficiency may occur in patients with complement-mediated HUS [5]. In a number of cases it is not possible to distinguish between TTP and HUS because there may be normal ADAMTS13 levels in TTP, or no defects identified in the complement pathway in HUS [5].…”