ABSTRACT
BACKGROUND: ADAMTS13 mutations play a role in thrombotic thrombocytopenic purpura (TTP) pathogenesis. OBJECTIVES: To establish a phenotype-genotype correlation in a cohort of congenital TTP patients. PATIENTS/METHODS: Clinical history and ADAMTS13 activity, antigen and anti-ADAMTS13 antibody assays were used to diagnose congenital TTP, and DNA sequencing and in vitro expression were performed to identify the functional effects of the ADAMTS13 mutations responsible. RESULTS: Seventeen (11 novel) ADAMTS13 mutations were identified in 17 congenital TTP patients. All had severely reduced ADAMTS13 activity and antigen levels at presentation. Six patients with pregnancy-associated TTP and six patients with childhood TTP were homozygous or compound heterozygous for ADAMTS13 mutations located in the metalloprotease (MP), cysteine-rich, spacer and/or distal thrombospondin type 1 domains. The adults had TTP precipitated by pregnancy, and had overall higher antigen levels (median, 30 ng mL(-1) ; range, < 10-57 ng mL(-1) ) than the children (median, 14 ng mL(-1) ; range, < 10-40 ng mL(-1)). Presentation in the neonatal period was associated with more intensive treatment requirements. The two neonates with the most severe phenotype had mutations in the first thrombospondin type 1 motif of ADAMTS13 (p.R398C, p.R409W, and p.Q436H). Using transfected HEK293T cells, we have shown that p.R398C and p.R409W block ADAMTS13 secretion, whereas p.Q436H allows secretion at reduced levels. CONCLUSIONS: This study confirms the heterogeneity of ADAMTS13 defects and an association between ADAMTS13 genotypes and TTP phenotype.
Subject(s)
ADAM Proteins/genetics , Mutation , Purpura, Thrombotic Thrombocytopenic/genetics , ADAMTS13 Protein , Adult , Blotting, Western , Case-Control Studies , Child , Child, Preschool , Female , Genotype , Humans , Infant , Infant, Newborn , Male , Phenotype , Pregnancy , United KingdomABSTRACT
BACKGROUND: Increasingly, patients with acute, idiopathic, antibody mediated thrombotic thrombocytopenic purpura (TTP) are being treated with rituximab to achieve a durable remission, however, there is the potential that it is removed by plasma exchange (PEX). OBJECTIVES: To look at the pharmacokinetics and pharmacodynamics of rituximab in patients with acute idiopathic TTP undergoing PEX. PATIENTS AND METHODS: Patients who received rituximab for acute idiopathic TTP (group 1, n = 30) and a control group (group 2, n = 3) of TTP patients in remission receiving rituximab electively as maintenance were included. Rituximab levels were measured before/after each infusion, before/after PEX and in follow-up. ADAMTS-13 activity, anti-ADAMTS-13 IgG and CD19% were measured to assess response. RESULTS: The median number of PEX to remission after rituximab was 10 (range 4-25). In group 1 there was no significant incremental rise in the peak serum rituximab level until dose 4. Trough levels were lower in patients who had had PEX since their last rituximab infusion. In the control group, there was an incremental rise in the peak serum rituximab level and all patients had detectable trough levels. The median fall in rituximab per PEX was 65%. All patients achieved CD19 < 1%. In group 1, the median time to undetectable rituximab was 5 months (range 0-12 months) and to B cell return was 7 months (range 3-24 months). ADAMTS-13 increased and anti-ADAMTS-13 fell after therapy. There were three deaths and two relapses in group 1. Relapse was not temporally related to B cell return.
Subject(s)
Antibodies, Monoclonal, Murine-Derived/pharmacokinetics , Purpura, Thrombotic Thrombocytopenic/therapy , Acute Disease , Adolescent , Adult , Aged , Antibodies, Monoclonal, Murine-Derived/therapeutic use , Female , Humans , Male , Middle Aged , Rituximab , Young AdultABSTRACT
Besides other mediators like prostaglandins, kinins and histamine, oxygen radicals potentiate inflammations. Vitamin E as natural antioxidant could scavenge radicals produced during an inflammation and therefore reduce the inflammatory response. In experiments with male Wistar rats maintained on a diet deficient in or supplemented with vitamin E for 6 weeks the influence of the administration of DL-alpha-tocopherol on the inflammation of the right hind paw was tested. The irritation produced by injection of Freund's complete adjuvants was observed for 21 days. Measuring the thickness of the paw and the activity of acid phosphatase in the paw tissue there was no difference in the intensity of inflammation among the control and the vitamin-E-deficient diet groups. The supplementation with a pharmacological dose of tocopherol (324 mg DL-alpha-tocopherol/100 g food) had no effect on the inflammation of animals with different vitamin E supplements. Differences in the antioxidant status (contents of tocopherol and malondialdehyde in several organs, activity of creatine kinase in plasma) among the groups were mainly linked to the various tocopherol supplies. The irritation increased the lipid peroxidation in liver mitochondria and the activity of creatine kinase in the plasma. The data show no influence of vitamin E on this kind of inflammation.
