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Molecular Mechanism and Pathogenesis of Antiphospholipid Syndrome

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 January 2021) | Viewed by 25483

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Prof. Dr. Daniele Pastori

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Department of Clinical Internal, Anesthesiological, and Cardiovascular Sciences, Sapienza University of Rome, 00185 Rome, Italy
Interests: atherosclerosis; atrial fibrillation; oxidative stress; NAFLD; liver cirrhosis; antiphospholipid syndrome

Special Issue Information

Dear Colleagues,

Antiphospholipid antibody syndrome (APS) is a complex, systemic, and multifactorial autoimmune disease which is characterized by multiorgan involvement and an increased risk of arterial and venous thrombosis.

However, the pathogenesis of APS has only been partially described, and several other factors beyond auto-antibodies may be involved, including inflammation, oxidative stress, and platelet and clotting activation. Moreover, the relative contribution of each auto-antibody to organ-specific manifestations, such as cardiac and vascular disease, kidney impairment, and hematological abnormalities, and to the risk of different types of thrombosis is still matter of debate.

Finally, controversial evidence is actually available on the efficacy and safety of vitamin K and non-vitamin K antagonist oral anticoagulants in patients with thrombotic APS.

In this Special Issue, we will include original research articles and review/metanalysis reporting on innovative aspects related to the pathogenesis and clinical manifestations of patients with APS.

Prof. Daniele Pastori
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Keywords

antiphospholipid antibody syndrome
autoimmune disease
pathogenesis
auto-antibodies

Published Papers (7 papers)

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Review

23 pages, 1136 KiB

Open AccessReview

Extracellular Vesicles and Antiphospholipid Syndrome: State-of-the-Art and Future Challenges

by Ula Štok, Saša Čučnik, Snežna Sodin-Šemrl and Polona Žigon

Int. J. Mol. Sci. 2021, 22(9), 4689; https://doi.org/10.3390/ijms22094689 - 28 Apr 2021

Cited by 11 | Viewed by 2747

Abstract

Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by thromboembolism, obstetric complications, and the presence of antiphospholipid antibodies (aPL). Extracellular vesicles (EVs) play a key role in intercellular communication and connectivity and are known to be involved in endothelial and vascular pathologies. Despite well-characterized in vitro and in vivo models of APS pathology, the field of EVs remains largely unexplored. This review recapitulates recent findings on the role of EVs in APS, focusing on their contribution to endothelial dysfunction. Several studies have found that APS patients with a history of thrombotic events have increased levels of EVs, particularly of endothelial origin. In obstetric APS, research on plasma levels of EVs is limited, but it appears that levels of EVs are increased. In general, there is evidence that EVs activate endothelial cells, exhibit proinflammatory and procoagulant effects, interact directly with cell receptors, and transfer biological material. Future studies on EVs in APS may provide new insights into APS pathology and reveal their potential as biomarkers to identify patients at increased risk. Full article

(This article belongs to the Special Issue Molecular Mechanism and Pathogenesis of Antiphospholipid Syndrome)

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14 pages, 1125 KiB

Open AccessReview

VWF, Platelets and the Antiphospholipid Syndrome

by Shengshi Huang, Marisa Ninivaggi, Walid Chayoua and Bas de Laat

Int. J. Mol. Sci. 2021, 22(8), 4200; https://doi.org/10.3390/ijms22084200 - 18 Apr 2021

Cited by 17 | Viewed by 3369

Abstract

The antiphospholipid syndrome (APS) is characterized by thrombosis and/or pregnancy morbidity with the persistent presence of antiphospholipid antibodies (aPLs). Laboratory criteria for the classification of APS include the detection of lupus anticoagulant (LAC), anti-cardiolipin (aCL) antibodies and anti-β2glycoprotein I (aβ2GPI) antibodies. Clinical criteria for the classification of thrombotic APS include venous and arterial thrombosis, along with microvascular thrombosis. Several aPLs, including LAC, aβ2GPI and anti-phosphatidylserine/prothrombin antibodies (aPS/PT) have been associated with arterial thrombosis. The Von Willebrand Factor (VWF) plays an important role in arterial thrombosis by mediating platelet adhesion and aggregation. Studies have shown that aPLs antibodies present in APS patients are able to increase the risk of arterial thrombosis by upregulating the plasma levels of active VWF and by promoting platelet activation. Inflammatory reactions induced by APS may also provide a suitable condition for arterial thrombosis, mostly ischemic stroke and myocardial infarction. The presence of other cardiovascular risk factors can enhance the effect of aPLs and increase the risk for thrombosis even more. These factors should therefore be taken into account when investigating APS-related arterial thrombosis. Nevertheless, the exact mechanism by which aPLs can cause thrombosis remains to be elucidated. Full article

(This article belongs to the Special Issue Molecular Mechanism and Pathogenesis of Antiphospholipid Syndrome)

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14 pages, 1888 KiB

Open AccessReview

Understanding the Pathophysiology of Thrombotic APS through Animal Models

by Alex A. Gandhi, Shanea K. Estes, Christine E. Rysenga and Jason S. Knight

Int. J. Mol. Sci. 2021, 22(5), 2588; https://doi.org/10.3390/ijms22052588 - 04 Mar 2021

Cited by 9 | Viewed by 4141

Abstract

Antiphospholipid syndrome (APS) is a leading acquired cause of thrombotic events, with a notable tendency to promote thrombosis in vascular beds of all sizes, including both arterial and venous circuits. While pathogenic antiphospholipid antibodies circulate at relatively stable levels in blood, thrombosis tends to manifest as discrete and acute events, suggesting the requirement for a “second hit.” While this two-hit model is generally accepted, much remains to be learned about exactly how antiphospholipid antibodies predispose to thrombosis in vivo and exactly how this predisposition interacts with the second hit. To this end, investigators have turned to animal models. Numerous approaches for modeling APS in animals have been described to date, each with potential advantages and disadvantages. This review will attempt to describe the most common APS models employed so far while discussing some pros and cons of each. Mechanisms of thrombotic APS that have thus far been explored in animal models will also be briefly addressed. Full article

(This article belongs to the Special Issue Molecular Mechanism and Pathogenesis of Antiphospholipid Syndrome)

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17 pages, 738 KiB

Open AccessReview

Genetic Factors in Antiphospholipid Syndrome: Preliminary Experience with Whole Exome Sequencing

by Alice Barinotti, Massimo Radin, Irene Cecchi, Silvia Grazietta Foddai, Elena Rubini, Dario Roccatello, Savino Sciascia and Elisa Menegatti

Int. J. Mol. Sci. 2020, 21(24), 9551; https://doi.org/10.3390/ijms21249551 - 15 Dec 2020

Cited by 10 | Viewed by 2929

Abstract

As in many autoimmune diseases, the pathogenesis of the antiphospholipid syndrome (APS) is the result of a complex interplay between predisposing genes and triggering environmental factors, leading to a loss of self-tolerance and immune-mediated tissue damage. While the first genetic studies in APS focused primarily on the human leukocytes antigen system (HLA) region, more recent data highlighted the role of other genes in APS susceptibility, including those involved in the immune response and in the hemostatic process. In order to join this intriguing debate, we analyzed the single-nucleotide polymorphisms (SNPs) derived from the whole exome sequencing (WES) of two siblings affected by APS and compared our findings with the available literature. We identified genes encoding proteins involved in the hemostatic process, the immune response, and the phospholipid metabolism (PLA2G6, HSPG2, BCL3, ZFAT, ATP2B2, CRTC3, and ADCY3) of potential interest when debating the pathogenesis of the syndrome. The study of the selected SNPs in a larger cohort of APS patients and the integration of WES results with the network-based approaches will help decipher the genetic risk factors involved in the diverse clinical features of APS. Full article

(This article belongs to the Special Issue Molecular Mechanism and Pathogenesis of Antiphospholipid Syndrome)

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23 pages, 865 KiB

Open AccessReview

The Weight of IgA Anti-β2glycoprotein I in the Antiphospholipid Syndrome Pathogenesis: Closing the Gap of Seronegative Antiphospholipid Syndrome

by Oscar Cabrera-Marante, Edgard Rodríguez de Frías, Manuel Serrano, Fernando Lozano Morillo, Laura Naranjo, Francisco J. Gil-Etayo, Estela Paz-Artal, Daniel E. Pleguezuelo and Antonio Serrano

Int. J. Mol. Sci. 2020, 21(23), 8972; https://doi.org/10.3390/ijms21238972 - 26 Nov 2020

Cited by 24 | Viewed by 2643

Abstract

The specific value of IgA Anti-β2glycoprotein I antibodies (aB2GP1) in the diagnosis and management of antiphospholipid syndrome (APS) is still controversial and a matter of active debate. The relevance of the IgA aB2GP1 isotype in the pathophysiology of APS has been increasingly studied in the last years. There is well know that subjects with multiple positive APS tests are at increased risk of thrombosis and/or miscarriage. However, these antibodies are not included in the 2006 APS classification criteria. Since 2010 the task force of the Galveston International Congress on APS recommends testing IgA aB2GP1 isotype in patients with APS clinical criteria in the absence of criteria antibodies. In this review, we summarize the molecular and clinical “state of the art” of the IgA aB2GP in the context of APS. We also discuss some of the characteristics that may help to evaluate the real value of the IgA aB2GP1 determination in basic research and clinical practice. The scientific community should be aware of the importance of clarifying the role of IgA aB2GP1 in the APS diagnosis. Full article

(This article belongs to the Special Issue Molecular Mechanism and Pathogenesis of Antiphospholipid Syndrome)

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23 pages, 2041 KiB

Open AccessReview

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

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

Int. J. Mol. Sci. 2020, 21(21), 8411; https://doi.org/10.3390/ijms21218411 - 09 Nov 2020

Cited by 20 | Viewed by 5023

Abstract

Antiphospholipid Syndrome (APS) is an autoimmune disease characterized by arterial and/or venous thrombosis and/or pregnancy morbidity, associated with circulating antiphospholipid antibodies (aPL). In some cases, patients with a clinical profile indicative of APS (thrombosis, recurrent miscarriages or fetal loss), who are persistently negative for conventional laboratory diagnostic criteria, are classified as “seronegative” APS patients (SN-APS). Several findings suggest that aPL, which target phospholipids and/or phospholipid binding proteins, mainly β-glycoprotein I (β-GPI), may contribute to thrombotic diathesis by interfering with hemostasis. Despite the strong association between aPL and thrombosis, the exact pathogenic mechanisms underlying thrombotic events and pregnancy morbidity in APS have not yet been fully elucidated and multiple mechanisms may be involved. Furthermore, in many SN-APS patients, it is possible to demonstrate the presence of unconventional aPL (“non-criteria” aPL) or to detect aPL with alternative laboratory methods. These findings allowed the scientists to study the pathogenic mechanism of SN-APS. This review is focused on the evidence showing that these antibodies may play a functional role in the signal transduction pathway(s) leading to thrombosis and pregnancy morbidity in SN-APS. A better comprehension of the molecular mechanisms triggered by aPL may drive development of potential therapeutic strategies in APS patients. Full article

(This article belongs to the Special Issue Molecular Mechanism and Pathogenesis of Antiphospholipid Syndrome)

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21 pages, 3388 KiB

Open AccessReview

Antiphospholipid Antibodies and Autoimmune Haemolytic Anaemia: A Systematic Review and Meta-Analysis

by Paul R.J. Ames, Mira Merashli, Tommaso Bucci, Daniele Pastori, Pasquale Pignatelli, Alessia Arcaro and Fabrizio Gentile

Int. J. Mol. Sci. 2020, 21(11), 4120; https://doi.org/10.3390/ijms21114120 - 09 Jun 2020

Cited by 13 | Viewed by 3831

Abstract

The relationship between antiphospholipid antibodies (aPL) and autoimmune haemolytic anaemia (AIHA) has never been systematically addressed. The aim of this study is to assess the link between aPL and AIHA in adult systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). This study performed an EMBASE/PubMed search from inception to June 2019 and meta-analysis using Peto’s odds ratios. The pooled prevalence (PP) of IgG/IgM anticardiolipin (aCL) and lupus anticoagulant (LA) was greater in AIHA +ve than AIHA −ve patients (34.7% vs. 27.6%, p = 0.03; 33.3% vs. 21.8%, p < 0.0001; 20.9% vs. 8.3%, p = 0.01). The PP of AIHA was greater in: (1) IgG and IgM aCL +ve than −ve patients (21.8% vs. 11.1%, p = 0.001 and 18.7% vs. 6.3%, p < 0.0001), (2) in SLE related APS than in primary APS patients (22.8% vs. 3.9% p < 0.0001), (3) in APS +ve than APS −ve SLE patients (23.2% vs. 8.4%, p = 0.01), and (4) in thrombotic APS than non-thrombotic APS/SLE patients (26.8% vs. 10%, p = 0.03). The PP of IgG/IgM aCL and LA was greater in DAT +ve than DAT −ve patients (42.4% vs. 12.8%, p < 0.0001; 26.2% vs. 12.8%, p = 0.03 and 29.2% vs. 15.7%, p = 0.004 respectively). It was found that AIHA prevalence is maximal in SLE with aPL/APS, low-moderate in SLE without aPL and minimal in PAPS. Moreover, AIHA is rightly included among the classification criteria for SLE but not for APS/aPL. The significance of an isolated DAT positivity remains unclear in this setting Full article

(This article belongs to the Special Issue Molecular Mechanism and Pathogenesis of Antiphospholipid Syndrome)

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