Complement activation in patients with isolated antiphospholipid antibodies or primary antiphospholipid syndrome

Breen, Karen; Seed, Paul; Parmar, Kiran; Moore, Gary; Stuart‐Smith, Sara; Hunt, Beverley J.

doi:10.1160/th11-08-0554

Cited by 91 publications

(28 citation statements)

References 24 publications

(29 reference statements)

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“…The hypocomplementemia pattern that we observed affected C3 and C4, indicating that complement activation in thrombotic APS is produced mainly via the classic pathway. It was recently reported that patients with aPL had significantly increased levels of complement activation products [21]. Hypocomplementemia can be associated with increased immune complex formation.…”

Section: Discussionmentioning

confidence: 99%

CD8+DR+ T-Cells and C3 Complement Serum Concentration as Potential Biomarkers in Thrombotic Antiphospholipid Syndrome

Sarmiento

Dale

Arraya

et al. 2014

Autoimmune Diseases

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Purpose. To assess complement factors and T lymphocyte activation subset abnormalities in patients with thrombotic antiphospholipid syndrome (APS) as potential biomarkers for development of clinical complications. Methods. We assessed C3, C4, factor B concentrations (nephelometry), complement haemolytic functional activity (CH100, radial immune diffusion), and the activation status of CD4+ and CD8+ T-cells (three-colour flow cytometry) in patients with thrombotic APS. Antiphospholipid (aPL) positive patients without APS-related clinical criteria, systemic lupus erythematosus (SLE) patients, and healthy individuals were evaluated as controls. A clinical followup was performed to assess the potential relationship between the immunological parameters and development of APS-related complications. Results. Lower concentrations of C3 and higher levels of CD8+DR+ cells were risk factors for development of APS-related complications during followup, including rethrombosis and neuropsychiatric symptoms. Patients with diagnosed thrombotic APS had significantly lower levels of C3, C4, and CH100 as well as higher percentages of activated CD4+DR+ and of CD8+DR+ T-cells than healthy controls but similar to that observed in autoimmune disease controls. Conclusion. Lower C3 and C4 complement levels and higher percentages of CD8+DR+ T-cells were observed in thrombotic APS patients. The potential role of these abnormalities as biomarkers of clinical outcome warrants further evaluation in a multicenter study.

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Section: Discussionmentioning

confidence: 99%

CD8+DR+ T-Cells and C3 Complement Serum Concentration as Potential Biomarkers in Thrombotic Antiphospholipid Syndrome

Sarmiento

Dale

Arraya

et al. 2014

Autoimmune Diseases

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“…105, 106 However, while increased levels of complement activation products have been detected in patients with APS, these have not been demonstrated to correlate with thrombosis. 107 Complement factor H (CFH), a homologue of β 2 GPI, also binds to anionic phospholipids and some patients with APS have antibodies against CFH; 108 however their role in the pathogenesis of thrombosis has not been demonstrated. There is evidence supporting activation of the classical and alternative complement pathways in patients with catastrophic APS, 109 and eculizumab (humanized anti-C5a monoclonal antibody) has been successfully used in CAPS and APS complicating renal transplantation.…”

Section: Pathogenesis Of Apsmentioning

confidence: 99%

Diagnosis and management of the antiphospholipid syndrome

2017

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Antiphospholipid syndrome (APS) is characterized by thrombosis and/or pregnancy complications in the presence of persistent antiphospholipid antibodies (APLA). Laboratory diagnosis of APLA depends upon the detection of a lupus anticoagulant, which prolongs phospholipid-dependent anticoagulation tests, and/or anticardiolipin (aCL) and anti-β2-glycoprotein-1 (β2GPI) antibodies. APLA are primarily directed towards phospholipid binding proteins. Pathophysiologic mechanisms underlying thrombosis and pregnancy loss in APS include APLA induced cellular activation, inhibition of natural anticoagulant and fibrinolytic systems, and complement activation, among others. There is a high rate of recurrent thrombosis in APS, especially in triple positive patients (patients with lupus anticoagulants, aCL and anti-β2GPI antibodies), and indefinite anticoagulation with a vitamin K antagonist is the standard of care for thrombotic APS. There is currently insufficient evidence to recommend the routine use of direct oral anticoagulants (DOAC) in thrombotic APS. Aspirin with low molecular weight or unfractionated heparin may reduce the incidence of pregnancy loss in obstetric APS. Recent insights into the pathogenesis of APS have led to the identification of new potential therapeutic interventions, including anti-inflammatory and immunomodulatory therapies. Additional research is needed to better understand the effects of APLA on activation of signaling pathways in vascular cells, to identify more predictive biomarkers that define patients at greatest risk for a first or recurrent APLA-related clinical event, and to determine the safety and efficacy of DOACs and novel anti-inflammatory and immune-modulatory therapies for refractory APS.

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“…The dysregulation of complement has been implicated in a variety of adverse pregnancy outcomes including hypertensive diseases of pregnancy (Lynch et al, 2012; Lynch et al, 2008; Lynch, Wagner, Giclas, et al, 2016),antiphospholipid antibody syndrome associated fetal loss (Breen et al, 2012), recurrent fetal loss and PTB (Lynch et al, 2012; Lynch et al, 2011; Lynch, Wagner, Deterding, et al, 2016). In the hypertensive diseases of pregnancy, antiphospholipid syndrome, and PTB studies, complement dysregulation was determined by the discovery of elevated circulating plasma levels of complement activation fragments (e.g., C3a/Bb) in the presence of the select health complication.…”

Section: The Microbiome As a Mechanism For Preterm Birthmentioning

confidence: 99%

The Microbiome and Complement Activation: A Mechanistic Model for Preterm Birth

Dunn

Dunlop

Hogue

et al. 2017

Biological Research For Nursing

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Preterm Birth (PTB, < 37 completed weeks' gestation) is one of the leading obstetrical problems in the United States affecting approximately 1 of every 9 births. Even more concerning are the persistent racial disparities in PTB with particularly high rates in African Americans. There are several recognized pathophysiologic pathways to PTB, including infection and/or exaggerated systemic or local inflammation. Intrauterine infection is a causal factor linked to PTB, thought to result most commonly from inflammatory processes triggered by microbial invasion of bacteria ascending from the vaginal microbiome. Trials to treat various infections have shown limited efficacy in reducing PTB risk, suggesting that other complex mechanisms, including those associated with inflammation, may be involved in the relationship between microbes, infection, and PTB. A key mediator of the inflammatory response, and recently shown to be associated with PTB, is the complement system, an innate defense mechanism involved in both normal physiologic processes that occur during pregnancy implantation, as well as processes that promote the elimination of pathogenic microbes. The purpose of this paper is to present a mechanistic model of inflammation-associated PTB, which hypothesizes a relationship between the microbiome and dysregulation of the complement system. Exploring the relationships between the microbial environment and complement biomarkers may elucidate a potentially modifiable biological pathway to preterm birth.

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Complement activation in patients with isolated antiphospholipid antibodies or primary antiphospholipid syndrome

Cited by 91 publications

References 24 publications

CD8+DR+ T-Cells and C3 Complement Serum Concentration as Potential Biomarkers in Thrombotic Antiphospholipid Syndrome

CD8+DR+ T-Cells and C3 Complement Serum Concentration as Potential Biomarkers in Thrombotic Antiphospholipid Syndrome

Diagnosis and management of the antiphospholipid syndrome

The Microbiome and Complement Activation: A Mechanistic Model for Preterm Birth

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