Thrombotic Microangiopathy in Systemic Lupus Erythematosus: Efficacy of Eculizumab

El-Husseini, Amr; Hannan, Schot; Awad, Ahmed; Jennings, Stuart; Cornea, Virgilius; Sawaya, B. Peter

doi:10.1053/j.ajkd.2014.07.031

Cited by 71 publications

(44 citation statements)

References 19 publications

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“…Eculizumab was shown to be effective in one severe pediatric case of SLE with vasculitis [ 169 ] and in an adult case of SLE complicated by thrombotic microangiopathy [ 170 ]. As animal models of necrotizing glomerulonephritis have shown that C5 is involved in the renal damage, using C5a receptor defi cient mice [ 151 ], further study of complement blockade as a treatment modality in vasculitis and SLE is warranted.…”

Section: Clinical and Therapeutic Implications Of Complement Activatimentioning

confidence: 99%

Complement Interactions with Blood Cells, Endothelial Cells and Microvesicles in Thrombotic and Inflammatory Conditions

Karpman

Ståhl

Arvidsson

et al. 2015

Advances in Experimental Medicine and Biology

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The complement system is activated in the vasculature during thrombotic and inflammatory conditions. Activation may be associated with chronic inflammation on the endothelial surface leading to complement deposition. Complement mutations allow uninhibited complement activation to occur on platelets, neutrophils, monocytes, and aggregates thereof, as well as on red blood cells and endothelial cells. Furthermore, complement activation on the cells leads to the shedding of cell derived-microvesicles that may express complement and tissue factor thus promoting inflammation and thrombosis. Complement deposition on red blood cells triggers hemolysis and the release of red blood cell-derived microvesicles that are prothrombotic. Microvesicles are small membrane vesicles ranging from 0.1 to 1 μm, shed by cells during activation, injury and/or apoptosis that express components of the parent cell. Microvesicles are released during inflammatory and vascular conditions. The repertoire of inflammatory markers on endothelial cell-derived microvesicles shed during inflammation is large and includes complement. These circulating microvesicles may reflect the ongoing inflammatory process but may also contribute to its propagation. This overview will describe complement activation on blood and endothelial cells and the release of microvesicles from these cells during hemolytic uremic syndrome, thrombotic thrombocytopenic purpura and vasculitis, clinical conditions associated with enhanced thrombosis and inflammation.

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Section: Clinical and Therapeutic Implications Of Complement Activatimentioning

confidence: 99%

Complement Interactions with Blood Cells, Endothelial Cells and Microvesicles in Thrombotic and Inflammatory Conditions

Karpman

Ståhl

Arvidsson

et al. 2015

Advances in Experimental Medicine and Biology

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“…Thus a twoprong therapeutic approach may offer a better treatment regimen. When this approach has been reported, the results have been encouraging [11][12][13][69][70][71][72] (Figure 3). As described in the next section, the utility of known biomarkers to indicate activation of proximal and terminal complement activation remains a nascent field of inquiry.…”

Section: Diagnosis and Definitionmentioning

confidence: 97%

“…lupus nephritis, GVHD complication of stem cell transplant and pregnancy) as aHUS (when the differential diagnoses have been excluded) can result in significantly improved outcomes when treating the primary disease fails to resolve the TMA [11][12][13][69][70][71][72]. This has recently been described as a phenotypic expression of aHUS without the risk of recurrence as occurs in 'classic' or 'primary' aHUS as it is presently understood (vida infra) [73].…”

Section: Diagnosis and Definitionmentioning

confidence: 99%

Atypical hemolytic uremic syndrome: a syndrome in need of clarity

Berger

2018

Clinical Kidney Journal

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Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy (TMA) originally understood to be limited to renal and hematopoietic involvement. Whereas aberrations in complement regulatory proteins (CRPs), C3 or complement factor B (CFB) are detected in 60% of patients, a complement-derived pathogenesis that reflects dysregulation of the alternative pathway (AP) of complement activation is present in 90% of patients. aHUS remains a diagnosis of exclusion. The discovery of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) and its utility in the diagnosis of thrombotic thrombocytopenic purpura (TTP) has resulted in the appreciation that cases of aHUS have been inappropriately diagnosed as TTP. Thus there has been an evolving appreciation of clinical manifestations of aHUS that renders the appellation aHUS misleading. This article will review the pathogenesis and the evolving clinical presentations of aHUS, present a hypothesis that there can be a phenotypic expression of aHUS due to a complement storm in a disorder where direct endothelial damage occurs and discuss future areas of research to more clearly define the clinical spectrum and management of aHUS.

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“…As expected, complement inhibition is effective in patients who have a mutation in complement molecules or autoantibodies against factor H. The efficacy of therapeutic complement inhibition in patients with secondary HUS has not been systematically assessed, but it has been shown to be beneficial in a number of patients who do not have a mutation in any of the studied complement proteins. 117 These include patients with autoimmunity (eg, scleroderma), 118 systemic lupus erythematosus, 119,120 or catastrophic antiphospholipid syndrome 121,122 and secondary HUS associated with postpartum period, 123 HIV infection, 124 use of cytotoxic drugs, 35 and either bone marrow or solid organ transplantation. 27,28 On the basis of these multiple single cases, it seems that complement is involved in at least some patients with secondary HUS.…”

Section: Therapeutic Complement Inhibition Provides Insight Into Pathmentioning

confidence: 99%

HUS and atypical HUS

Jokiranta

2017

Blood

232

260

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Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy characterized by intravascular hemolysis, thrombocytopenia, and acute kidney failure. HUS is usually categorized as typical, caused by Shiga toxin–producing Escherichia coli (STEC) infection, as atypical HUS (aHUS), usually caused by uncontrolled complement activation, or as secondary HUS with a coexisting disease. In recent years, a general understanding of the pathogenetic mechanisms driving HUS has increased. Typical HUS (ie, STEC-HUS) follows a gastrointestinal infection with STEC, whereas aHUS is associated primarily with mutations or autoantibodies leading to dysregulated complement activation. Among the 30% to 50% of patients with HUS who have no detectable complement defect, some have either impaired diacylglycerol kinase ε (DGKε) activity, cobalamin C deficiency, or plasminogen deficiency. Some have secondary HUS with a coexisting disease or trigger such as autoimmunity, transplantation, cancer, infection, certain cytotoxic drugs, or pregnancy. The common pathogenetic features in STEC-HUS, aHUS, and secondary HUS are simultaneous damage to endothelial cells, intravascular hemolysis, and activation of platelets leading to a procoagulative state, formation of microthrombi, and tissue damage. In this review, the differences and similarities in the pathogenesis of STEC-HUS, aHUS, and secondary HUS are discussed. Common for the pathogenesis seems to be the vicious cycle of complement activation, endothelial cell damage, platelet activation, and thrombosis. This process can be stopped by therapeutic complement inhibition in most patients with aHUS, but usually not those with a DGKε mutation, and some patients with STEC-HUS or secondary HUS. Therefore, understanding the pathogenesis of the different forms of HUS may prove helpful in clinical practice.

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Thrombotic Microangiopathy in Systemic Lupus Erythematosus: Efficacy of Eculizumab

Cited by 71 publications

References 19 publications

Complement Interactions with Blood Cells, Endothelial Cells and Microvesicles in Thrombotic and Inflammatory Conditions

Complement Interactions with Blood Cells, Endothelial Cells and Microvesicles in Thrombotic and Inflammatory Conditions

Atypical hemolytic uremic syndrome: a syndrome in need of clarity

HUS and atypical HUS

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