Maggiolata, op24, nro 4

Sovitus Giovanni Giacomo Gastoldin sävelmästä.Soitinnus: lauluääni, piano.Äänitetty: [lokakuu - joulukuu 1907, Berliini].1 teos

ADAMTS13 secretion and residual activity among patients with congenital thrombotic thrombocytopenic purpura with and without renal impairment

Background and objectives Acute renal impairment is observed in 11%-23% of patients with congenital thrombotic thrombocytopenic purpura (TTP) and deficiency of a disintegrin and metalloprotease with thrombospondin motifs 13 (ADAMTS13, a metalloprotease that cleaves von Willebrand factor [VWF] multimers), a substantial percentage of whom develop CKD during follow-up. Design, setting, participants, & measurements Here we investigated whether, in 18 patients with congenital recruited from 1996 to 2013 who fulfilled inclusion criteria, acute renal involvement occurred during bouts segregated with lower secretion and activity levels of ADAMTS13 mutants. We performed expression studies and a sensitive recombinantVWF (rVWF) A1-A2-A3 cleavage test (detection limit, 0.78% of normal ADAMTS13 activity). Results A higher risk of acute renal impairment during bouts was observed in patients with childhood (,18 years) onset (odds ratio [OR], 24.6 [95% confidence interval (CI), 1.11 to 542.44]) or a relapsing ($1 episode per year) disease (OR, 54.6 [95% CI, 2.25 to 1326.28]) than in patients with adulthood onset or long-lasting remission, respectively. Whatever the age at onset, patients with acute renal impairment had mutations different from those in patients without renal involvement. Moreover, mutations in patients with acute renal impairment compared with those in patients without renal involvement caused lower in vitro rADAMTS13 secretion (1.33% versus 12.5%; P,0.001) and residual activity (0.11% versus 3.47%; P=0.003). rADAMTS13 secretion #3.75% and residual activity #0.4% best discriminated patients with renal impairment (receiveroperating characteristic curve sensitivity, 100% and 100%; specificity, 100% and 83.3%, respectively; logistic regression OR, 325 [95% CI, 6 to 18339] and 91.7 [95% CI, 3.2 to 2623.5], respectively). All mutations found in patients with childhood onset or relapsing disease were associated with acute renal impairment during bouts, confirming the link between acute renal impairment and early onset or a relapsing course. ADAMTS13 activity levels in vivo, measured in patients\u2019 serum by rVWF A1-A2-A3 cleavage test, correlated with in vitro rADAMTS13 mutant activity (r=0.95; P,0.001). Conclusions In congenital TTP, renal impairment and relapsing disease might be predicted by measurements of in vitro rADAMTS13 secretion and activity levels and in vivo serum ADAMTS13 activity

A novel atypical hemolytic uremic syndrome-associated hybrid CFHR1/CFH gene encoding a fusion protein that antagonizes factor H-dependent complement regulation

Genomic aberrations affecting the genes encoding factor H (FH) and the five FH-related proteins (FHRs) have been described in patients with atypical hemolytic uremic syndrome (aHUS), a rare condition characterized by microangiopathic hemolytic anemia, thrombocytopenia, and ARF. These genomic rearrangements occur through nonallelic homologous recombinations caused by the presence of repeated homologous sequences in CFH and CFHR1-R5 genes. In this study, we found heterozygous genomic rearrangements among CFH and CFHR genes in 4.5% of patients with aHUS. CFH/CFHR rearrangements were associated with poor clinical prognosis and high risk of post-transplant recurrence. Five patients carried known CFH/CFHR1 genes, but we found a duplication leading to a novel CFHR1/CFH hybrid gene in a family with two affected subjects. The resulting fusion protein contains the first four short consensus repeats of FHR1 and the terminal short consensus repeat 20 of FH. In an FH-dependent hemolysis assay, we showed that the hybrid protein causes sheep erythrocyte lysis. Functional analysis of the FHR1 fraction purified from serum of heterozygous carriers of the CFHR1/CFH hybrid gene indicated that the FHR1/FH hybrid protein acts as a competitive antagonist of FH. Furthermore, sera from carriers of the hybrid CFHR1/CFH gene induced more C5b-9 deposition on endothelial cells than control serum. These results suggest that this novel genomic hybrid mediates disease pathogenesis through dysregulation of complement at the endothelial cell surface. We recommend that genetic screening of aHUS includes analysis of CFH and CFHR rearrangements, particularly before a kidney transplant

Rituximab prevents recurrence of thrombotic thrombocytopenic purpura: a case report

Thrombotic thrombocytopenic purpura (TTP) is a rare disorder of small vessels that is associated with deficiency of the von Willebrand factor-cleaving protease, ADAMTS13. The presence of anti-ADAMTS13 autoantibodies is considered a factor predisposing to relapses. Despite close monitoring and intensive plasma treatment, in these patients acute episodes are still associated with substantial morbidity and mortality rates, and the optimal therapeutic option should be prevention of relapses. This study was conducted in a patient with recurrent TTP due to high titers of ADAMTS13 inhibitors, who used to have 2 relapses of TTP a year. The study compared the standard treatment plasma exchange with rituximab. Results documented that plasma exchange had only a small transient effect on ADAMTS13 activity and inhibitors; on the contrary, prophylaxis with rituximab was associated with disappearance of anti-ADAMTS13 antibodies, a progressive recovery of protease activity, and it allowed the patient to maintain a disease-free state during a more than 2-year follow-up

Alternative pathway activation of complement by shiga toxin promotes exuberant C3a formation that triggers microvascular thrombosis

Shiga toxin (Stx)-producing E.coli O157:H7 has become a global threat to public health; it is a primary cause of diarrhea-associated hemolytic uremic syndrome (HUS), a disorder of thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure with thrombi occluding renal microcirculation. In this study, we explored whether Stx triggers complement-dependent microvascular thrombosis in in vitro and in vivo experimental settings of HUS. Stx induced on human microvascular endothelial cell surface the expression of P-selectin, which bound and activated C3 via the alternative pathway, leading to thrombus formation under flow. In the search for mechanisms linking complement activation and thrombosis, we found that exuberant complement activation in response to Stx generated an increased amount of C3a that caused further endothelial P-selectin expression, thrombomodulin (TM) loss, and thrombus formation. In a murine model of HUS obtained by coinjection of Stx2 and LPS and characterized by thrombocytopenia and renal dysfunction, upregulation of glomerular endothelial P-selectin was associated with C3 and fibrin(ogen) deposits, platelet clumps, and reduced TM expression. Treatment with anti-P-selectin Ab limited glomerular C3 accumulation. Factor B-deficient mice after Stx2/LPS exhibited less thrombocytopenia and were protected against glomerular abnormalities and renal function impairment, indicating the involvement of complement activation via the alternative pathway in the glomerular thrombotic process in HUS mice. The functional role of C3a was documented by data showing that glomerular fibrin(ogen), platelet clumps, and TM loss were markedly decreased in HUS mice receiving C3aR antagonist. These results identify Stx-induced complement activation, via P-selectin, as a key mechanism of C3a-dependent microvascular thrombosis in diarrhea-associated HUS