Reemergence of Splenectomy for ITP Second-line Treatment?

International audienceIntroduction: Corticosteroids are still the standard first-line treatment for immune thrombocytopenic purpura (ITP). As second-line therapy, splenectomy and Rituximab are both recommended. The aim of our study was to compare the efficacy of Rituximab to splenectomy in persistent or chronic ITP patients.Methods: Between January 1999 and March 2015, we retrospectively selected all consecutive patients who underwent an ITP second-line treatment: Rituximab or splenectomy. The distinction between open (OS) and laparoscopic splenectomy (LS) was analyzed. Primary outcome was composite: hospitalization for bleeding and/or thrombocytopenia and death from hemorrhage or infection. Secondary outcomes were based on response (R) and complete response (CR) rates as defined by the American Society of Hematology.Results: Ninety-six patients were included: 30 patients received Rituximab, 37 underwent OS, and 29 underwent LS. The follow-up was 30, 60, and 120 months in Rituximab, LS, and OS groups, respectively. At 30th month, the primary outcome-free survival rate was higher in splenectomy groups (84% for OS, 86% for LS) than Rituximab group (47%) (P = 0.0002). Similarly, at 30th month, R and CR rates were higher for OS (86.5% and 75.7%, respectively) and LS groups (93.1% and 89.7%) than Rituximab (46.7% and 30%) (P = 0.0001). Moreover, R rates remained elevated at 60th month for OS and LS groups (83.7% and 89.6% respectively) and 78.4% at 120th month for OS group.Conclusion: We observed that splenectomy for ITP second-line treatment was more effective than Rituximab regarding maintenance of R, CR, and overall response rates. OS and LS had similar efficacy

A mutation in factor I that is associated with atypical hemolytic uremic syndrome does not affect the function of factor I in complement regulation.

Factor I (FI) is the major complement inhibitor that degrades Ob and C4b in the presence of cofactors such as factor H (FH) and membrane cofactor protein (MCP). Recently, mutations and polymorphisms in complement regulator molecules FH and MCP but also in FI have been associated with atypical hemolytic uremic syndrome (aHUS). HUS is a disorder characterized by hemolytic anemia, thrombocytopenia and acute renal failure. In this study, we report three unrelated patients with an identical heterozygous mutation, G261D, in the FI heavy chain who developed severe aHUS at different time points in their lives. Two of the patients also have polymorphisms in FH previously associated with risk of developing aHUS. Testing in particular one patient and control serum samples we did not observe major differences in complement hemolytic activity, FI plasma levels or the capability to degrade C4b or Ob. A recombinant protein was produced in order to analyze the functional consequences of the mutation. Mutant FI had a slightly different migration pattern during electrophoresis under reducing conditions. An alteration due to alternative splicing or glycosylation was ruled out, thus the altered migration may be due to proximity of the mutation to a cysteine residue. The recombinant mutant FI degraded Ob and C4b in a manner comparable to wild-type protein. In conclusion, despite the association between the heterozygous mutation in FI and aHUS we did not observe any abnormalities in the function of FI regarding complement regulation

ADAMTS13 Gene Mutations Influence ADAMTS13 Conformation and Disease Age-Onset in the French Cohort of Upshaw-Schulman Syndrome

BACKGROUND:  Congenital thrombotic thrombocytopaenic purpura (TTP) or Upshaw-Schulman syndrome (USS) is a rare, life-threatening, inherited thrombotic microangiopathy (TMA). USS is mostly due to bi-allelic recessive sequence variations of the a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13 (ADAMTS13) gene inducing a severe ADAMTS13 deficiency (activity < 10 IU/dL). In healthy individuals, ADAMTS13 circulates in a folded conformation where CUB domains interact with the spacer domain. The spacer-CUB interaction is abrogated when ADAMTS13 is conformationally activated. OBJECTIVE:  This article evaluates the influence of ADAMTS13 sequence variations on both clinical/biological phenotype and ADAMTS13 conformation in USS. PATIENTS AND METHODS:  All USS patients from the French registry for TMAs (1 January 2000 to 1 June 2017) were investigated for ADAMTS13 genotype, phenotype (activity, antigen and autoantibodies) and conformation. Clinical records were analysed (inaugural acute TTP and follow-up). Child-onset USS was compared with adult-onset USS. RESULTS:  Fifty-six USS patients from 51 families (34 child-onset and 22 adult-onset cases) were enrolled. Child-onset USS was characterized by a large panel of ADAMTS13 sequence variations (n = 43), spread all over ADAMTS13 gene and not correlated with either clinical features or plasmatic ADAMTS13 parameters. In contrast, adult-onset USS, consisting exclusively in pregnancy-induced TTP, included a smaller and distinct panel of ADAMTS13 sequence variations (n = 20) because of one mutation (p.Arg1060Trp) present in 82% of patients. ADAMTS13 conformation was studied in 16 USS patients (5 child-onset and 11 adult-onset USS, encompassing 16 distinct ADAMTS13 sequence variations) whose ADAMTS13 antigen levels were detectable: 14 of 16 patients (87.5%) exhibited abnormalities of ADAMTS13 conformation. CONCLUSION:  In USS, age-onset defines two entities and ADAMTS13 sequence variations modify ADAMTS13 conformation.status: publishe