Plasma from patients with thrombotic thrombocytopenic purpura induces activation of human monocytes and polymorphonuclear neutrophils

Alvarez‐Larrán, Alberto; Pétriz, Jordi; Martı́nez, Antonio; Sanz, Cristina; Pereira, Arturo

doi:10.1046/j.1365-2141.2003.04030.x

Cited by 6 publications

(5 citation statements)

References 26 publications

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“…Plasma from patients with acuteT TP or HUS induceda poptosisi nh uman microvascularendothelial cells of renal, cerebraland dermal origin, butn ot of pulmonaryo rh epatic lineage (12),w hich reflected the distribution of lesionsi nb oth disorders. In other studies, plasma from patients with TTP caused monocyte and PMNactivation, as measured by ROSproduction and CD11bexpression (13) and inducedt he formation of platelet-leukocyte aggregates ( 14), suggesting that humorals ubstances, not yet identified, are present in TTPc irculation triggering PMN activation. ADAMTS-13 activity wasn ot evaluatedi na ny of the above studies, thus whether the same pathogenetic mechanisms could also apply to TMA associatedwith ADAMTS-13 deficiency is still not understood.…”

Section: Introductionmentioning

confidence: 84%

Complement activation: the missing link between ADAMTS-13 deficiency and microvascular thrombosis of thrombotic microangiopathies

Ruiz-Torres¹,

Casiraghi²,

Galbusera³

et al. 2005

Thromb Haemost

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Endothelial injury is the central factor in the events leading to thrombotic microangiopathy (TMA); however, the mechanisms involved are not fully understood. Here we investigate the role of neutrophils (PMNs) and of complement activation in inducing microvascular damage and loss of thromboresistance in TMA associated with ADAMTS-13 deficiency. PMNs isolated during the acute phase of the disease released excessive amounts of reactive-oxygen species (ROS), N-derived oxidants and proteinases and induced damage and thromboresistance loss in human microvascular endothelial cell line (HMEC-1) ex vivo. Endothelial cytotoxicity and thromboresistance loss was also induced by TMA serum. Complement-derived products were responsible for the above effects: in fact, TMA serum caused C3 and Membrane Attack Complex (MAC) deposition on HMEC-1 and its cytotoxic effect was abolished by complement inhibition. TMA serum caused surface expression of P-selectin on HMEC-1 which may promote PMN adhesion and resulted in increased PMN cytotoxicity, indicating that complement may have a role in PMN activation. In addition, TMA serum stimulated control PMNs to release ROS and proteinases, and to cause endothelial cell cytotoxicity. All of the above effects were abrogated by complement inactivation. These data document for the first time that complement-initiated PMN activation and endothelial injury may have a crucial role in microvascular thrombosis of TMA associated with ADAMTS-13 deficiency.

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Section: Introductionmentioning

confidence: 84%

Complement activation: the missing link between ADAMTS-13 deficiency and microvascular thrombosis of thrombotic microangiopathies

Ruiz-Torres¹,

Casiraghi²,

Galbusera³

et al. 2005

Thromb Haemost

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“…In addition to being a mediator of cytotoxicity, Granzyme A has also been shown to stimulate pro-inflammatory IL-1, TNF and IL-6, secretion from macropahges [ 64 ]. Elevated levels of these cytokines have been observed in acute TTP [ 65 ], and acute TTP plasma has been shown to activate macrophages [ 66 ].…”

Section: Discussionmentioning

confidence: 99%

Ribosomal and Immune Transcripts Associate with Relapse in Acquired ADAMTS13-Deficient Thrombotic Thrombocytopenic Purpura

et al. 2015

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Approximately 40% of patients who survive acute episodes of thrombotic thrombocytopenic purpura (TTP) associated with severe acquired ADAMTS13 deficiency experience one or more relapses. Risk factors for relapse other than severe ADAMTS13 deficiency and ADAMTS13 autoantibodies are unknown. ADAMTS13 autoantibodies, TTP episodes following infection or type I interferon treatment and reported ensuing systemic lupus erythematosus in some patients suggest immune dysregulation. This cross-sectional study asked whether autoantibodies against RNA-binding proteins or peripheral blood gene expression profiles measured during remission are associated with history of prior relapse in acquired ADAMTS13-deficient TTP. Peripheral blood from 38 well-characterized patients with autoimmune ADAMTS13-deficient TTP in remission was examined for autoantibodies and global gene expression. A subset of TTP patients (9 patients, 24%) exhibited a peripheral blood gene signature composed of elevated ribosomal transcripts that associated with prior relapse. A non-overlapping subset of TTP patients (9 patients, 24%) displayed a peripheral blood type I interferon gene signature that associated with autoantibodies to RNA-binding proteins but not with history of relapse. Patients who had relapsed bimodally expressed higher HLA transcript levels independently of ribosomal transcripts. Presence of any one potential risk factor (ribosomal gene signature, elevated HLA-DRB1, elevated HLA-DRB5) associated with relapse (OR = 38.4; p = 0.0002) more closely than any factor alone or all factors together. Levels of immune transcripts typical of natural killer (NK) and T lymphocytes positively correlated with ribosomal gene expression and number of prior episodes but not with time since the most recent episode. Flow cytometry confirmed elevated expression of cell surface markers encoded by these transcripts on T and/or NK cell subsets of patients who had relapsed. These data associate elevated ribosomal and immune transcripts with relapse history in acquired, ADAMTS13-deficient TTP.

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“…Soluble complement activation related mediators, including anaphylatoxins and the terminal complement complex SC5b‐9, may directly activate endothelial cells [11,12], neutrophils [13,14] and platelets [15,16]. Indeed, plasma of TTP patients was shown to induce apoptosis of endothelial cells and platelets [17–20] and activation of neutrophils and monocytes [21], leading to the formation of platelet‐leukocyte complexes [22]. Zwart et al.…”

Section: Discussionmentioning

confidence: 99%

Complement activation in thrombotic thrombocytopenic purpura

Réti

Farkas

Csuka

et al. 2012

Journal of Thrombosis and Haemostasis

124

101

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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.

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Plasma from patients with thrombotic thrombocytopenic purpura induces activation of human monocytes and polymorphonuclear neutrophils

Cited by 6 publications

References 26 publications

Complement activation: the missing link between ADAMTS-13 deficiency and microvascular thrombosis of thrombotic microangiopathies

Complement activation: the missing link between ADAMTS-13 deficiency and microvascular thrombosis of thrombotic microangiopathies

Ribosomal and Immune Transcripts Associate with Relapse in Acquired ADAMTS13-Deficient Thrombotic Thrombocytopenic Purpura

Complement activation in thrombotic thrombocytopenic purpura

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