Molecular Mechanisms of “Antiphospholipid Antibodies” and Their Paradoxical Role in the Pathogenesis of “Seronegative APS”

Misasi, Roberta; Longo, Agostina; Recalchi, Serena; Caissutti, Daniela; Riitano, Gloria; Manganelli, Valeria; Garofalo, Tina; Sorice, Maurizio; Capozzi, Antonella

doi:10.3390/ijms21218411

Cited by 22 publications

(28 citation statements)

References 144 publications

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“…Antiphospholipid antibodies are a heterogeneous group of immunoglobulins directed against negatively charged phospholipids, cofactors or phospholipid-cofactor complexes that are usually present in monocyte, trophoblast, endothelial and platelet cell membranes [13][14][15]. The laboratory criteria for APS include the detection of lupus anticoagulant (LA), IgG/IgM anticardiolipin antibodies (aCL) with titers >40 GPL or MPL or >99th percentile or IgG/IgM anti-β2glycoprotein-1 (aβ2GPI) antibodies with titers >40 AU or >99th percentile.…”

Section: Clinical Criteriamentioning

confidence: 99%

“…There are women fulfilling only the clinical criteria but failing to reach the laboratory values defining OAPS [7,9]. There are cases with low aCL and/or aβ2GPI titers, only one positive test for LA and/or aCL and/or aβ2GPI or only showing positivity for non-criteria antiphospholipid antibodies e.g., IgG or IgM or IgA isotypes of antiphosphatidylserine/prothrombin (aPS/aPT), anti-phosphatidylethanolamine (aPE), antiannexin A5 (aAnA5) and even anti-aβ2GPI-domain 1 [8,[10][11][12][13][106][107][108]. These cases are known as seronegative or non-criteria APS [109,110].…”

Section: Nc-oapsmentioning

confidence: 99%

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Pathogenesis, Diagnosis and Management of Obstetric Antiphospholipid Syndrome: A Comprehensive Review

Alijotas‐Reig

Esteve-Valverde

Anunciación-Llunell

et al. 2022

JCM

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Antiphospholipid syndrome is an autoimmune disorder characterized by vascular thrombosis and/or pregnancy morbidity associated with persistent antiphospholipid antibody positivity. Cases fulfilling the Sydney criteria for obstetric morbidity with no previous thrombosis are known as obstetric antiphospholipid syndrome (OAPS). OAPS is the most identified cause of recurrent pregnancy loss and late-pregnancy morbidity related to placental injury. Cases with incomplete clinical or laboratory data are classified as obstetric morbidity APS (OMAPS) and non-criteria OAPS (NC-OAPS), respectively. Inflammatory and thrombotic mechanisms are involved in the pathophysiology of OAPS. Trophoblasts, endothelium, platelets and innate immune cells are key cellular players. Complement activation plays a crucial pathogenic role. Secondary placental thrombosis appears by clot formation in response to tissue factor activation. New risk assessment tools could improve the prediction of obstetric complication recurrences or thromboses. The standard-of-care treatment consists of low-dose aspirin and prophylactic low molecular weight heparin. In refractory cases, the addition of hydroxychloroquine, low-dose prednisone or IVIG improve pregnancy outcomes. Statins and eculizumab are currently being tested for treating selected OAPS women. Finally, we revisited recent insights and concerns about the pathophysiology, diagnosis and management of OAPS.

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Section: Clinical Criteriamentioning

confidence: 99%

Section: Nc-oapsmentioning

confidence: 99%

Pathogenesis, Diagnosis and Management of Obstetric Antiphospholipid Syndrome: A Comprehensive Review

Alijotas‐Reig

Esteve-Valverde

Anunciación-Llunell

et al. 2022

JCM

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“…Genetic deletion as of TLR9 well as exogenous inhibition of TLR9 leads to the impairment of thrombus resolution and enhanced leukocyte infiltration in mice [ 246 ]. Antiphospholipid syndrome, an autoimmune disease characterized by a hypercoagulable condition, is accompanied by a significant increase in peripheral mononuclear cell expression of both TLR2 and TLR4 and the activation of MyD88 and NF-kB pathways [ 87 , 247 ]. Activation of TLR8 in subjects with the antiphospholipid syndrome has been suggested to contribute to arterial and/or venous thrombosis through the enhancement of TNFα values and consequent inflammatory responses [ 112 ].…”

Section: The Role Of Toll-like Receptors In Cvdsmentioning

confidence: 99%

Toll-Like Receptor Signaling Pathways: Novel Therapeutic Targets for Cerebrovascular Disorders

Ahmadabad

Mirzaasgari

Gorji

et al. 2021

IJMS

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Toll-like receptors (TLRs), a class of pattern recognition proteins, play an integral role in the modulation of systemic inflammatory responses. Cerebrovascular diseases (CVDs) are a group of pathological conditions that temporarily or permanently affect the brain tissue mostly via the decrease of oxygen and glucose supply. TLRs have a critical role in the activation of inflammatory cascades following hypoxic-ischemic events and subsequently contribute to neuroprotective or detrimental effects of CVD-induced neuroinflammation. The TLR signaling pathway and downstream cascades trigger immune responses via the production and release of various inflammatory mediators. The present review describes the modulatory role of the TLR signaling pathway in the inflammatory responses developed following various CVDs and discusses the potential benefits of the modulation of different TLRs in the improvement of functional outcomes after brain ischemia.

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“…New aPL associated with APS clinical manifestations but not included in the current classification criteria have been described and are called extra-criteria aPL (31). Among them, aB2GPI of IgA isotype, IgG and IgM antiphosphatidylserine/prothrombin (aPS/PT) antibodies, and IgG anti-domain I of B2GPI antibodies stand out for their strong association with APS clinical characteristics and for the existence of well-standardized diagnostic tests (32)(33)(34). Although IgA aB2GPI were not included in the APS classification criteria, their clinical importance has increased over the last 16 years (35)(36)(37)(38)(39).…”

Section: Introductionmentioning

confidence: 99%

Presence of Extra-Criteria Antiphospholipid Antibodies Is an Independent Risk Factor for Ischemic Stroke

Naranjo

Ostos

Gil‐Etayo

et al. 2021

Front. Cardiovasc. Med.

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Background: Ischemic stroke is the most common and severe arterial thrombotic event in Antiphospholipid syndrome (APS). APS is an autoimmune disease characterized by the presence of thrombosis and antiphospholipid antibodies (aPL), which provide a pro-coagulant state. The aPL included in the classification criteria are lupus anticoagulant, anti-cardiolipin (aCL) and anti-β2-glycoprotein-I antibodies (aB2GPI) of IgG and IgM isotypes. Extra-criteria aPL, especially IgA aB2GPI and IgG/IgM anti-phosphatidylserine/prothrombin antibodies (aPS/PT), have been strongly associated with thrombosis. However, their role in the general population suffering from stroke is unknown. We aim (1) to evaluate the aPL prevalence in ischemic stroke patients, (2) to determine the role of aPL as a risk factor for stroke, and (3) to create an easy-to-use tool to stratify the risk of ischemic stroke occurrence considering the presence of aPL and other risk factors.Materials and Methods: A cohort of 245 consecutive ischemic stroke patients was evaluated in the first 24 h after the acute event for the presence of classic aPL, extra-criteria aPL (IgA aB2GPI, IgG, and IgM aPS/PT) and conventional cardiovascular risk factors. These patients were followed-up for 2-years. A group of 121 healthy volunteers of the same age range and representative of the general population was used as reference population. The study was approved by the Ethics Committee for Clinical Research (Reference numbers CEIC-14/354 and CEIC-18/182).Results: The overall aPL prevalence in stroke patients was 28% and IgA aB2GPI were the most prevalent (20%). In the multivariant analysis, the presence of IgA aB2GPI (OR 2.40, 95% CI: 1.03–5.53), dyslipidemia (OR 1.70, 95% CI: 1.01–2.84), arterial hypertension (OR 1.82, 95% CI: 1.03–3.22), atrial fibrillation (OR 4.31, 95% CI: 1.90–9.78), and active smoking (OR 3.47, 95% CI: 1.72–6.99) were identified as independent risk factors for ischemic stroke. A risk stratification tool for stroke was created based on these factors (AUC: 0.75).Conclusions: IgA aB2GPI are an important independent risk factor for ischemic stroke. Evaluation of aPL (including extra-criteria) in cardiovascular risk factor assessment for stroke can potentially increase the identification of patients at risk of thrombotic event, facilitating a decision on preventive treatments.

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Molecular Mechanisms of “Antiphospholipid Antibodies” and Their Paradoxical Role in the Pathogenesis of “Seronegative APS”

Cited by 22 publications

References 144 publications

Pathogenesis, Diagnosis and Management of Obstetric Antiphospholipid Syndrome: A Comprehensive Review

Pathogenesis, Diagnosis and Management of Obstetric Antiphospholipid Syndrome: A Comprehensive Review

Toll-Like Receptor Signaling Pathways: Novel Therapeutic Targets for Cerebrovascular Disorders

Presence of Extra-Criteria Antiphospholipid Antibodies Is an Independent Risk Factor for Ischemic Stroke

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