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Basic and Clinical Researches of Antiphospholipid Syndrome

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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Immunology and Immunotherapy".

Deadline for manuscript submissions: closed (31 December 2023) | Viewed by 26606

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Dr. Polona Žigon

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Immunology Laboratory, Department of Rheumatology, University Medical Centre, Ljubljana, Slovenia
Interests: antiphospholipid syndrome; autoantibodies; diagnostic biomarkers; extracellular vesicles
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Dear Colleagues,

We cordially invite you to contribute your research to the Special Issue, titled Basic and Clinical Researches of Antiphospholipid Syndrome.

Antiphospholipid syndrome (APS) is a systemic autoimmune disorder known as acquired thrombophilia, characterized by vascular thrombosis and/or pregnancy-related morbidity in the presence of persistently positive antiphospholipid antibodies. "Seronegative APS" represents patients who have only clinical manifestations without laboratory confirmation, i.e., those that do not meet the standard classification criteria for APS and are therefore less likely to be treated, which carries the risk of recurrent thrombosis and/or pregnancy loss.

The heterogeneity and non-specificity of potential clinical signs highlight that APS is a true systemic autoimmune disease and underscores the need for a better understanding of disease mechanisms to facilitate a personalized treatment approach. In the general population, the incidence of clinical manifestations of APS is high and could often be triggered by many other underlying factors. Therefore, the diagnosis of APS relies primarily on laboratory measurements. However, current laboratory tests are hampered by technical limitations in the preanalytical and analytical phases.

This Special Issue aims to collate research articles and reviews on the pathogenic mechanisms underlying APS in order to provide new insights at the molecular level and refine understanding on disease development and progression, with the hope of consequently improving APS diagnosis.

Dr. Polona Žigon
Guest Editor

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Keywords

antiphospholipid snydrome
antiphospholipid antibodies
thrombosis
obstetric morbidity
thrombophilia
APS novel markers
non-criteria manifestations
pathogenesis

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Related Special Issue

Basic and Clinical Researches of Antiphospholipid Syndrome: 2nd Edition in Biomedicines

Published Papers (11 papers)

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12 pages, 878 KiB

Open AccessArticle

Determining Thrombogenicity: Using a Modified Thrombin Generation Assay to Detect the Level of Thrombotic Event Risk in Lupus Anticoagulant-Positive Patients

by Pavla Bradáčová, Luděk Slavík, Jana Úlehlová, Eva Kriegová, Eliška Jará, Lenka Bultasová, David Friedecký, Jana Ullrychová, Jana Procházková, Antonín Hluší, Gayane Manukyan and Lenka Štefaničková

Biomedicines 2023, 11(12), 3329; https://doi.org/10.3390/biomedicines11123329 - 16 Dec 2023

Viewed by 1193

Abstract

The aim of this study was to determine the thrombogenicity of lupus anticoagulant (LA) antibodies using a modified thrombin generation assay (TGA) with the addition of activated protein C (APC) in a group of 85 patients with LA-positive samples. Of these, 58 patients had clinical manifestations of antiphospholipid syndrome (APS) according to the Sydney criteria classification, i.e., each patient had thrombosis or foetal loss, and 27 patients did not show any clinical manifestations of APS. A comparison of the two groups’ TGA results revealed statistically significant differences (Fisher’s test p = 0.0016). The group of patients exhibiting clinical manifestations of APS showed higher thrombogenicity in 56.9% of patients, while the group of patients not yet exhibiting clinical manifestations of APS showed higher thrombogenicity in 25.9% of patients. There were no significant differences in the specificity of the TGA test between the groups of patients exhibiting similar clinical manifestations. Receiver operating characteristic curve analysis showed a more significant relationship (p = 0.0060) for TGA than for LA titre (p = 0.3387). These data suggest that the determination of LA thrombogenicity with the TGA assay leads to an increased prediction of the manifestation of a thromboembolic event. Our findings appear to be particularly relevant for the prediction of thrombotic events in patients with laboratory-expressed APS and no clinical manifestations. Full article

(This article belongs to the Special Issue Basic and Clinical Researches of Antiphospholipid Syndrome)

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13 pages, 976 KiB

Open AccessArticle

Antiphospholipid Antibodies and Vascular Thrombosis in Patients with Severe Forms of COVID-19

by Mirjana Zlatković-Švenda, Milica Ovuka, Manca Ogrič, Saša Čučnik, Polona Žigon, Aleksandar Radivčev, Marija Zdravković and Goran Radunović

Biomedicines 2023, 11(12), 3117; https://doi.org/10.3390/biomedicines11123117 - 22 Nov 2023

Cited by 2 | Viewed by 1366

Abstract

Antiphospholipid antibodies (aPLA) are a laboratory criterion for the classification of antiphospholipid syndrome (APS) and are known to cause clinical symptoms such as vascular thrombosis or obstetric complications. It is suggested that aPLA may be associated with thromboembolism in severe COVID-19 cases. Therefore, we aimed to combine clinical data with laboratory findings of aPLA at four time points (admission, worsening, discharge, and 3-month follow-up) in patients hospitalized with COVID-19 pneumonia. In 111 patients with COVID-19 pneumonia, current and past history of thrombosis and pregnancy complications were recorded. Nine types of aPLA were determined at four time points: anticardiolipin (aCL), anti-β2-glycoprotein I (anti- β2GPI), and antiphosphatidylserine/prothrombin (aPS/PT) of the IgM, IgG, or IgA isotypes. During hospitalization, seven patients died, three of them due to pulmonary artery thromboembolism (none were aPLA positive). Only one of the five who developed pulmonary artery thrombosis was aPLA positive. Out of 9/101 patients with a history of thrombosis, five had arterial thrombosis and none were aPLA positive at admission and follow-up; four had venous thrombosis, and one was aPLA positive at all time points (newly diagnosed APS). Of these 9/101 patients, 55.6% were transiently aPLA positive at discharge only, compared to 26.1% without a history of thrombosis (p = 0.041). Patients with severe forms of COVID-19 and positive aPLA should receive the same dose and anticoagulant medication regimen as those with negative aPLA because those antibodies are mostly transiently positive and not linked to thrombosis and fatal outcomes. Full article

(This article belongs to the Special Issue Basic and Clinical Researches of Antiphospholipid Syndrome)

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16 pages, 2525 KiB

Open AccessArticle

Thrombosis and Hyperinflammation in COVID-19 Acute Phase Are Related to Anti-Phosphatidylserine and Anti-Phosphatidylinositol Antibody Positivity

by Jaume Alijotas-Reig, Ariadna Anunciación-Llunell, Stephanie Morales-Pérez, Jaume Trapé, Enrique Esteve-Valverde and Francesc Miro-Mur

Biomedicines 2023, 11(8), 2301; https://doi.org/10.3390/biomedicines11082301 - 18 Aug 2023

Cited by 4 | Viewed by 1642

Abstract

Antiphospholipid antibodies (APLA) are strongly associated with thrombosis seen in patients with antiphospholipid syndrome. In COVID-19, thrombosis has been observed as one of the main comorbidities. In patients hospitalised for COVID-19, we want to check whether APLA positivity is associated with COVID-19-related thrombosis, inflammation, severity of disease, or long COVID-19. We enrolled 92 hospitalised patients with COVID-19 between March and April 2020 who were tested for 18 different APLAs (IgG and IgM) with a single line-immunoassay test. A total of 30 healthy blood donors were used to set the cut-off for each APLA positivity. Of the 92 COVID-19 inpatients, 30 (32.61%; 95% CI [23.41–43.29]) tested positive for APLA, of whom 10 (33.3%; 95% CI [17.94–52.86]) had more than one APLA positivity. Anti-phosphatidylserine IgM positivity was described in 5.4% of inpatients (n = 5) and was associated with the occurrence of COVID-19-related thrombosis (p = 0.046). Anti-cardiolipin IgM positivity was the most prevalent among the inpatients (n = 12, 13.0%) and was associated with a recorded thrombosis in their clinical history (p = 0.044); however, its positivity was not associated with the occurrence of thrombosis during their hospitalisation for COVID-19. Anti-phosphatidylinositol IgM positivity, with a prevalence of 5.4% (n = 5), was associated with higher levels of interleukin (IL)-6 (p = 0.007) and ferritin (p = 0.034). Neither of these APLA positivities was a risk factor for COVID-19 severity or a predictive marker for long COVID-19. In conclusion, almost a third of COVID-19 inpatients tested positive for at least one APLA. Anti-phosphatidylserine positivity in IgM class was associated with thrombosis, and anti-phosphatidylinositol positivity in IgM class was associated with inflammation, as noticed by elevated levels of IL-6. Thus, testing for non-criteria APLA to assess the risk of clinical complications in hospitalised COVID-19 patients might be beneficial. However, they were not related to disease severity or long COVID-19. Full article

(This article belongs to the Special Issue Basic and Clinical Researches of Antiphospholipid Syndrome)

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12 pages, 288 KiB

Open AccessArticle

Criteria and Non-Criteria Antiphospholipid Antibodies in Antiphospholipid Syndrome: How Strong Are They Correlated?

by Simona Caraiola, Laura Voicu, Ciprian Jurcut, Alina Dima, Cristian Baicus, Anda Baicus, Claudia Oana Cobilinschi and Razvan Adrian Ionescu

Biomedicines 2023, 11(8), 2192; https://doi.org/10.3390/biomedicines11082192 - 3 Aug 2023

Cited by 4 | Viewed by 2004

Abstract

The place of non-criteria antiphospholipid antibodies (aPLs) in the diagnosis of antiphospholipid syndrome (APS) is still debatable. The aim of this research was to evaluate the correlations between the titres of non-criteria aPLs (anti-phosphatidylethanolamine (aPE), anti-phosphatidylserine (aPS), and anti-prothrombin (aPT) antibodies), and the ones of the already studied criteria aPLs (anti-cardiolipin (aCL) and anti-β2 glycoprotein I-aβ2GPI antibodies). Altogether, 72 APS (30 primary and 42 secondary) patients were included in our study. High correlation coefficients (rs) were found between aPS IgM and aCL IgM, overall (0.77, p < 0.01), as well as in the primary (0.81, p < 0.01), and secondary (0.75, p < 0.01) APS subgroups. Low or statistically insignificant correlations were observed between IgG/IgM isotypes of aPT and aCL, or aβ2GPI, in the entire study population, and when evaluating the subgroups. Therefore, moderate correlations were mainly identified between the tested non-criteria antibodies and the criteria ones, suggesting little added value for the use of the tested non-criteria aPLs, with the exception of aPT, which seems to have different kinetics and might be a promising APS diagnostic tool. Full article

(This article belongs to the Special Issue Basic and Clinical Researches of Antiphospholipid Syndrome)

10 pages, 560 KiB

Open AccessArticle

Methylenetetrahydrofolate Reductase 677T Allele Is a Risk Factor for Arterial Thrombosis in Chinese Han Patients with Antiphospholipid Syndrome

by Zihan Tang, Hui Shi, Honglei Liu, Xiaobing Cheng, Yutong Su, Junna Ye, Yue Sun, Qiongyi Hu, Huihui Chi, Zhuochao Zhou, Jinchao Jia, Jianfen Meng, Mengyan Wang, Fan Wang, Jialin Teng, Chengde Yang and Tingting Liu

Biomedicines 2023, 11(1), 55; https://doi.org/10.3390/biomedicines11010055 - 26 Dec 2022

Cited by 1 | Viewed by 1811

Abstract

Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by the persistent presence of antiphospholipid antibodies (aPL) and thrombotic or obstetric events. Given the heterogeneity of the clinical manifestations, it is likely that genetic and acquired factors are involved in the pathogenesis of APS. The inherited polymorphisms of the thrombophilic gene, including methylenetetrahydrofolate reductase (MTHFR) C677T, type 1 plasminogen activator inhibitor (PAI-1) 4G/5G, factor V Leiden (FVL) G1691A, prothrombin (PT) G20210A, antithrombin (AT), and fibrinogen (Fg) polymorphisms, were analyzed in 67 aPL(+) patients from the Chinese Han population, including 41 APS patients and 26 persistent aPL carriers. The MTHFR C677T genotypes of 105 healthy controls, and the PAI-1 4G/5G polymorphism of 120 healthy controls, from the Chinese Han population were acquired for this study. Both the MTHFR C677T genotype (χ² = 10.67, p = 0.004) and C/T allele distribution (χ² = 5.92, p = 0.019) between the aPL(+) patients and healthy controls were found to be significantly different. Furthermore, we observed that the patients with at least one T allele had a higher risk of arterial thrombosis (CT vs. CC, OR 11.00, p= 0.025; CT + TT vs. CC, OR 10.27, p = 0.018). The C677T mutation of MTHFR is a risk factor for arterial thrombosis in Chinese Han patients with APS. Full article

(This article belongs to the Special Issue Basic and Clinical Researches of Antiphospholipid Syndrome)

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15 pages, 967 KiB

Open AccessArticle

Non-Criteria Obstetric Antiphospholipid Syndrome: How Different Is from Sidney Criteria? A Single-Center Study

by Víctor M. Martínez-Taboada, Pedro Blanco-Olavarri, Sara Del Barrio-Longarela, Leyre Riancho-Zarrabeitia, Ana Merino, Alejandra Comins-Boo, Marcos López-Hoyos and José L. Hernández

Biomedicines 2022, 10(11), 2938; https://doi.org/10.3390/biomedicines10112938 - 15 Nov 2022

Cited by 4 | Viewed by 2191

Abstract

This study aims to compare the demographic characteristics, clinical features, serology, and fetal–maternal outcomes between women with obstetric antiphospholipid syndrome (APS) and those with non-criteria (NC)-APS and seronegative (SN)-APS. Two-hundred and sixty-three women with APS obstetric morbidity ever pregnant were included. Of those, 66 met the APS classification criteria, 140 were NC-APS, and 57 were SN-APS. Patients with other autoimmune diseases were excluded. Adverse pregnancy outcomes (APO) included early pregnancy loss, fetal death, preeclampsia, abruptio placentae, and preterm birth. The mean age of the study group was 33.6 ± 5.3 years, and patients were followed up for 129.5 ± 81.9 months. In the NC-APS group, 31 (22.1%) did not fulfill clinical and serological criteria (Subgroup A), 49 (35%) did meet clinical but not serologic criteria (Subgroup B), and 60 (42.9%) fulfilled the serologic criteria but not the clinical ones (Subgroup C). The cardiovascular risk burden was higher in the APS group, due to a higher proportion of smoking. Patients with criteria APS received more intensive treatment than patients in the other study groups. The addition of standard of care (SoC) treatment significantly improved live birth and decreased APO in all groups. Significant clinical differences were observed between the study groups. However, when treated with SoC, fetal–maternal outcomes were similar, with a significant improvement in live births and a decrease in APO. Risk stratification in patients with obstetric morbidity associated with APS can help individualize their treatment. Full article

(This article belongs to the Special Issue Basic and Clinical Researches of Antiphospholipid Syndrome)

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13 pages, 1926 KiB

Open AccessArticle

Antiphospholipid Antibody Syndrome-Associated Increased Surface Expression of VLA4 Integrin on Human Monocytes

by Ula Štok, Neža Štucin, Elizabeta Blokar, Aleš Ambrožič, Snežna Sodin-Šemrl, Saša Čučnik and Polona Žigon

Biomedicines 2022, 10(10), 2341; https://doi.org/10.3390/biomedicines10102341 - 20 Sep 2022

Cited by 5 | Viewed by 1805

Abstract

Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by thrombosis and/or obstetric complications in the presence of antiphospholipid antibodies (aPL). Catastrophic APS (CAPS) is the most severe form of the disease, in which microvascular thromboses develop rapidly, leading to multiorgan failure. Monocytes, along with endothelial cells, are critical players in the pathogenesis of APS. Recruitment of these cells to the site of injury/inflammation involves a series of events, including capture, rolling, adhesion enhancement, and transmigration, which are controlled by surface adhesion molecules. The aim of our study was to investigate the surface adhesion profile of monocytes from APS patients and monocytes stimulated in vitro with aPL from a CAPS patient. The surface expression of the adhesion molecules LFA1, L-selectin, MAC1, PSGL1, and VLA4 was analyzed by flow cytometry. To our knowledge, this preliminary study was the first to show that VLA4 was significantly increased on the surface of monocytes from APS patients. Moreover, in vitro stimulations mimicking CAPS showed an even greater increase in VLA4. Our data suggest that the surface adhesion profile on monocytes is altered in APS and CAPS and may be involved in the thrombotic pathophysiology of the disease by enhancing monocyte adhesion. Full article

(This article belongs to the Special Issue Basic and Clinical Researches of Antiphospholipid Syndrome)

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Review

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20 pages, 1251 KiB

Open AccessReview

Trophoblast Cell Function in the Antiphospholipid Syndrome

by Svetlana Vrzić Petronijević, Aleksandra Vilotić, Žanka Bojić-Trbojević, Sanja Kostić, Miloš Petronijević, Ljiljana Vićovac and Milica Jovanović Krivokuća

Biomedicines 2023, 11(10), 2681; https://doi.org/10.3390/biomedicines11102681 - 30 Sep 2023

Cited by 2 | Viewed by 1486

Abstract

Antiphospholipid syndrome (APS) is a complex thrombo-inflammatory autoimmune disease characterized by the presence of antiphospholipid antibodies (aPL). Women with APS are at high risk of recurrent early pregnancy loss as well as late obstetrical complications—premature birth due to placental insufficiency or severe preeclampsia. Accumulating evidence implies that vascular thrombosis is not the only pathogenic mechanism in obstetric APS, and that the direct negative effect of aPL on the placental cells, trophoblast, plays a major role. In this review, we summarize the current findings regarding the potential mechanisms involved in aPL-induced trophoblast dysfunction. Introduction on the APS and aPL is followed by an overview of the effects of aPL on trophoblast—survival, cell function and aPL internalization. Finally, the implication of several non-coding RNAs in pathogenesis of obstetric APS is discussed, with special emphasis of their possible role in trophoblast dysfunction and the associated mechanisms. Full article

(This article belongs to the Special Issue Basic and Clinical Researches of Antiphospholipid Syndrome)

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18 pages, 389 KiB

Open AccessReview

Preeclampsia and the Antiphospholipid Syndrome

by Karoline Mayer-Pickel, Manurishi Nanda, Maja Gajic and Mila Cervar-Zivkovic

Biomedicines 2023, 11(8), 2298; https://doi.org/10.3390/biomedicines11082298 - 18 Aug 2023

Cited by 5 | Viewed by 4510

Abstract

Antiphospholipid syndrome (APS) is characterized by venous or arterial thrombosis and/or adverse pregnancy outcome in the presence of persistent laboratory evidence of antiphospholipid antibodies (aPLs). Preeclampsia complicates about 10–17% of pregnancies with APS. However, only early onset preeclampsia (<34 weeks of gestation) belongs to the clinical criteria of APS. The similarities in the pathophysiology of early onset preeclampsia and APS emphasize an association of these two syndromes. Overall, both are the result of a defective trophoblast invasion and decidual transformation at early gestation. Women with APS are at increased risk for prematurity; the reasons are mostly iatrogenic due to placental dysfunction, such as preeclampsia or FGR. Interestingly, women with APS have also an increased risk for preterm delivery, even in the absence of FGR and preeclampsia, and therefore it is not indicated but spontaneous. The basic treatment of APS in pregnancy is low-dose aspirin and low-molecular-weight heparin. Nevertheless, up to 20–30% of women develop complications at early and late gestation, despite basic treatment. Several additional treatment options have been proposed, with hydroxychloroquine (HCQ) being one of the most efficient. Additionally, nutritional interventions, such as intake of vitamin D, have shown promising beneficial effects. Curcumin, due to its antioxidant and anti-inflammatory properties, might be considered as an additional intervention as well. Full article

(This article belongs to the Special Issue Basic and Clinical Researches of Antiphospholipid Syndrome)

9 pages, 659 KiB

Open AccessReview

Laboratory Diagnosis of Antiphospholipid Syndrome in Anticoagulated Patients

by Armando Tripodi, Erica Scalambrino, Marigrazia Clerici and Flora Peyvandi

Biomedicines 2023, 11(6), 1760; https://doi.org/10.3390/biomedicines11061760 - 19 Jun 2023

Cited by 6 | Viewed by 5212

Abstract

The laboratory diagnosis of antiphospholipid syndrome (APS) requires the measurement of solid-phase antibodies to cardiolipin or β2-Glycoprotein-I and the search for lupus anticoagulant (LA). The diagnosis of patients whilst on anticoagulation is impaired by the difficult interpretation of results, at least for LA, owing to the fact that prolongations of clotting times induced by LA superimpose those induced by anticoagulants. This is a matter of concern as treating physicians very often need to know the APS status of their patients to make a decision on secondary antithrombotic prophylaxis. This article aims to review the effect brought about by anticoagulants on APS diagnosis and discuss the options that can be used to overcome such an effect. Full article

(This article belongs to the Special Issue Basic and Clinical Researches of Antiphospholipid Syndrome)

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Other

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9 pages, 1491 KiB

Open AccessCase Report

A Rare Case of Anca Positivity and Antiphospholipid Antibodies in a Patient with Takayasu Arteritis: Case Report and Review of the Literature

by Rositsa Dacheva, Ekaterina Kurteva, Vladimira Boyadzhieva, Rumen Stoilov, Dobroslav Kyurkchiev and Nikolay Stoilov

Biomedicines 2023, 11(10), 2826; https://doi.org/10.3390/biomedicines11102826 - 18 Oct 2023

Viewed by 2376

Abstract

Takayasu arteritis (TA) is a chronic large-vessel vasculitis characterized by immune-mediated panarteritis, which predominantly affects the aorta and its main branches and is most prevalent in young women. TA is unusually associated with the presence of antiphospholipid antibodies. We present a case report of a 48-year-old Caucasian woman with acute aortic dissection as an initial feature of TA, where detailed clinical, imaging and laboratory studies were performed. Computed tomography angiography (CTA) of the chest and abdomen revealed aortic dissection DeBakey I. Bentall and De Bono surgery was performed. Additional immunological tests revealed positive antineutrophil cytoplasmic antibodies (ANCAs) with the simultaneous presence of pANCA and cANCA antibodies on indirect immunofluorescence, along with anti-MPO+PR3+antibodies positivity in the absence of a clinically relevant disease. Surprisingly, antiphospholipid antibodies (aPLs) were detected. Then, we performed a thorough review of the current literature. The coexistence of aPL antibodies and dual specificity for MPO and PR3 in a patient diagnosed with Takayasu arteritis is unusual and poses a diagnostic challenge. The presented case report outlines a rare case of aortic dissection as a presenting symptom of TA, along with atypical ANCA positivity and positive APL antibodies. Full article

(This article belongs to the Special Issue Basic and Clinical Researches of Antiphospholipid Syndrome)

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