Complement activation in thrombotic thrombocytopenic purpura

Abstract

To cite this article: Ré ti M, Farkas P, Csuka D, Rá zsó K, Schlammadinger Á , Udvardy ML, Madá ch K, Domjá n G, Bereczki C, Reusz GS, Szabó AJ, Prohá szka Z. Complement activation in thrombotic thrombocytopenic purpura. J Thromb Haemost 2012; 10: 791-8.Summary. Background: Ultra-large von Willebrand factor and deficiency of its cleaving protease are important factors in the events leading to thrombotic microangiopathy; however, the mechanisms involved are only partly understood. Whereas pathological activation of the alternative complement pathway is linked to atypical hemolytic uremic syndrome, the role of complement activation in thrombotic thrombocytopenic purpura (TTP) is unknown. The aim of this study was to investigate whether signs of complement activation are characteristic of TTP. Patients and methods: Twenty-three patients with TTP (18 women, median age 38 years) and 17 healthy controls (13 women, median age 38 years) were included. Complement parameters (C3, Factors H, I, B and total alternative pathway activity) together with complement activation fragments (C3a) or complexes (C1rs-INH, C3bBbP, sC5b9) were measured by ELISA or RID. ADAMTS13 activity and anti-ADAMTS13 inhibitory antibodies were measured by the VWF-FRET73 assay. Results: Increased levels of C3a, and SC5b9 were observed in TTP during acute episodes, as compared with healthy controls. Decreased complement C3 levels indicative of complement consumption occurred in 15% of acute TTP patients. Significant decrease of complement activation products C3a and SC5b9 was observed during plasma exchange (PEX). The sustained presence of anti-ADAMTS13 inhibitory antibodies in complete remission was associated with increased complement activation. Conclusion: These data document in an observational study the presence of complement activation in TTP. Further investigation is needed to determine its potential pathogenetic significance.

Elevated plasma neutrophil elastase concentration is associated with disease activity in patients with thrombotic thrombocytopenic purpura

“…Previously our group reported on the presence of complement activation in patients with acute TTP [10] an observation recently confirmed in an independent cohort [11]. Our data indicated that activation of the classical/lectin and alternative pathways that lead to the activation of the terminal pathway was present in TTP.…”

“…Previously we [10] and others [11] documented the activation of the classical/lectin, the alternative and the terminal pathways of complement in TTP. Our current results indicate the association between PMNE and C3 activation (C3a), and the presence of NETs may be a potential link between these factors.…”

“…The patient enrolment for this study was closed in January, 2011. The criteria used to guide patient stratification, diagnosis and sample selection have been described in details [10]. Briefly, diagnosis of TTP was based on one or more episodes of Coombs-negative microangiopathic hemolytic anemia with thrombocytopenia defined as serum lactate dehydrogenase (LDH) N 450 U/L; fragmented erythrocytes in the peripheral blood smear and platelet count b150 G/L; only patients with severely decreased ADAMTS13 activity levels (b5%), or history of it, were included in this study.…”

“…Increased levels of C3a and terminal pathway complex (TCC) were observed in acute TTP [10]. Therefore, we analyzed if any of the complement factors or activation products show association with activity markers of neutrophils.…”

Human neutrophil peptides and complement factor Bb in pathogenesis of acquired thrombotic thrombocytopenic purpura

“…While our results did not find a statistically significant increase in iC3b and sC5b-9 complexes in TTP patients when compared with healthy controls, other studies have demonstrated the increased levels of C3a and sC5b-9 during acute TTP. 45 Moreover, the increased levels of Bb, C3a, and C5a, and sC5b-9 appear to correlate with a worse outcome in TTP. 46 We did not find an association between any of these markers we measured and the relapse and mortality rate in our cohort of patients.…”