Mechanisms of Endothelial Dysfunction in Antiphospholipid Syndrome: Association With Clinical Manifestations

Abstract

The endothelium is a monolayer of cells that covers the inner surface of blood vessels and its integrity is essential for the maintenance of vascular health. Endothelial dysfunction is a key pathological component of antiphospholipid syndrome (APS). Its systemic complications include thrombotic endocarditis, valvular dysfunction, cerebrovascular occlusions, proliferative nephritis, deep vein thrombosis, and pulmonary embolism. In women, APS is also associated with pregnancy complications (obstetric APS). The conventional treatment regimens for APS are ineffective when the clinical symptoms are severe. Therefore, a better understanding of alterations in the endothelium caused by antiphospholipid antibodies (aPL) may lead to more effective therapies in patients with elevated aPL titers and severe clinical symptoms. Currently, while in vivo analyses of endothelial dysfunction in patients with APS have been reported, most research has been performed using in vitro models with endothelial cells exposed to either patient serum/plasma, monoclonal aPL, or IgGs isolated from patients with APS. These studies have described a reduction in endothelial cell nitric oxide synthesis, the induction of inflammatory and procoagulant phenotypes, an increase in endothelial proliferation, and impairments in vascular remodeling and angiogenesis. Despite these lines of evidence, further research is required to better understand the pathophysiology of endothelial dysfunction in patients with APS. In this review, we have compared the current understanding about the mechanisms of endothelial dysfunction induced by patient-derived aPL under the two main clinical manifestations of APS: thrombosis and gestational complications, either alone or in combination. We also discuss gaps in our current knowledge regarding aPL-induced endothelial dysfunction.

Change of serum B-cell activating factor level in patients with positive antiphospholipid antibodies and previous adverse pregnancy outcomes and its significance

“…Endothelial cells treated with IgG-aPL can activate cells to increase the expression of tissue factors, IL-6, IL-8, and TNF-α, leading to thrombosis and placental tissue injury. [ 19 ] Therefore, higher serum BAFF levels may be indicative of the intensive inflammatory status. Although the specific roles of BAFF in the pathogenesis of OAPS are still unclear, the above findings suggest that BAFF may be a potential marker to predict pregnancy outcomes of OAPS patients.…”

Impact of Nitric Oxide Synthesis Modulators on the Cytokines Profile in Experimental Antiphospholipid Syndrome

“…In particular, attenuation of eNOS activation by aPL was mediated by reduced phosphorylation of eNOS serine. This inhibition of eNOS phosphorylation was shown to be dependent upon protein phosphatase 2A, β2GPI, and apolipoprotein E receptor 2. aPL inhibition of eNOS activity contributes to thrombus formation, increased leukocyte adhesion, and alterations in vascular tone [4].…”

“…In CAPS a systemic inflammatory response, systemic endothelial dysfunction and DIC develop. These processes are the pathogenetic basis for development of multiple organ failure [3,4]. SNAPS is negative for lupus anticoagulant and antiphospholipid antibodies [2].…”

“…One of the links that are involved in the mechanisms of APS development is the nitric oxide (NO) system. In obstetric APS, the synthesis and bioavailability of nitric oxide (NO), which is involved in the regulation of vascular tone and blood coagulation properties, are impaired in the endothelium [4]. According to Cella M [13], a decrease in NO levels causes abortion and premature birth.…”

Tongue Stiffness as Presentation of Antiphospholipid Syndrome: A Case Report

“…The main laboratory feature of APS is the presence of antiphospholipid antibodies (APLA) such as anticardiolipin, Lupus anticoagulant, anti-beta 2 glycoprotein I, and have been shown to enhance activation of platelets, endothelial cells and monocytes, thus causing an overproduction of tissue factor and thromboxane A2, as well an excessive activation of the complement factors. Inappropriate initiation of this pro inflammatory and prothrombotic cascade can result in diffuse thrombosis of and/or well-defined obstetrical manifestations [ 1 - 3 ].…”