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Abstract

Objectives:

The objectives of this study were to determine the prevalence of anti-β2glycoprotein-1 antibodies (anti-β2GPI) in Pakistani patients clinically suspected to have antiphospholipid syndrome (APS) and assess their association with clinical manifestations.

Introduction:

The antiphospholipid syndrome (APS) is a complex disorder characterized by recurrent thrombotic and obstetric complications.

Methods:

An analytical cross-sectional study was conducted at Aga Khan University Hospital from January to June 2022, after obtaining ethical approval (ERC ID: 2021-6404-19580). A total of 133 patients aged 18–60 years, clinically suspected of having APS based on the updated international consensus (Sydney) classification criteria, were recruited. Anti-β2GPI antibodies were tested using the same blood samples provided for aCL testing, with verbal consent. Demographic, clinical, and biochemical data were collected via a structured questionnaire, while information on lupus anticoagulant testing was retrospectively obtained from prior records.

Results:

The study included 120 females (90.2%) and 13 males (9.8%) with a mean age of 31.3 ± 8.8 years. Predominant clinical manifestations included unexplained miscarriages at >10 weeks of gestation (n = 77/120 female, 64.2%), while deep venous thrombosis (DVT) was a common non-obstetric clinical feature (n = 18/133, 13.5%). The median level of anti-β2GPI was 2.12 U/ml (1.34–7.04) and 7.5% (n = 10) were positive. Of the 10 positive patients, 2 displayed positive anti-β2GPI while concurrently testing negative for other aPL antibodies. A significant association was identified between the presence of anti-β2GPI and the occurrence of DVT and other venous thromboembolic events (VTE).

Conclusion:

This study highlights the prevalence and diagnostic utility of anti-β2GPI in Pakistani patients suspected of APS, identifying cases missed by other aPL tests and showing significant associations with thrombotic manifestations like DVT and VTE. However, the cross-sectional design, lack of confirmatory testing, and absence of locally derived cut-offs limit causal inferences.

Keywords

antiphospholipid syndrome anti-β2GPI antibodies vascular thrombosis obstetric complications diagnostic workup

Introduction

Antiphospholipid syndrome (APS) is a multifaceted autoimmune prothrombotic disorder characterized by various clinical manifestations, including recurrent arterial or venous thrombosis, obstetric complications such as preeclampsia, recurrent spontaneous abortions before the tenth gestational week, and fetal loss later in pregnancy.^1,2 While these clinical manifestations represent APS, no pathognomonic hallmarks can establish the diagnosis of APS on clinical grounds alone. Instead, the updated international consensus (Sydney) classification (ICS) criteria for definite antiphospholipid syndrome require the presence of a lupus anticoagulant (LA) and/or IgG or IgM anticardiolipin antibodies (aCL) present in medium or high titer (i.e. >40 GPL or MPL or >99th percentile), and/or anti-β2glycoprotein-1 (anti-β2GPI) >99th percentile.³ These aPL should be persistent, defined as being present on two or more consecutive occasions at least 12 weeks apart.

The aPL antibodies encompass a heterogeneous group of autoantibodies that target phospholipids, phospholipid-protein complexes, or phospholipid-binding proteins located on the membranes of various cells involved in secondary hemostatic pathway.⁴ These include LA, aCL of both IgG and IgM types, as well as anti-β2GPI IgG or IgM antibodies. Among these antibodies, LA exerts its mechanism of action by interfering with phospholipid-dependent coagulation pathways, leading to a prothrombotic state. The aCL can bind to phospholipids on cell surfaces, platelets, and endothelial cells, activating the coagulation cascade, inhibiting fibrinolysis, and endothelial dysfunction, and ultimately promoting thrombosis. While anti-β2GPI bind to β2GPI (a phospholipid-binding protein that circulates in the bloodstream) modifying its conformation, enhancing this protein’s signaling through transmembrane and intracellular ligands, and eventually facilitating prothrombotic actions.⁵

The association between clinical APS and the presence of a single aPL antibody is highest for LA, followed by anti-β2GPI and then aCL.⁶ Although anti-β2GPI exhibit greater specificity for APS compared to aCL, their testing is not widely available in our region. Nevertheless, cases of isolated anti-β2GPI positivity are still noteworthy. In a prospective study involving 500 healthy obstetric subjects, 4% of the cohort (n = 20/510) displayed isolated anti-β2GPI while testing negative for aCL and LA. These individuals had a significantly higher incidence of pre-eclampsia and eclampsia compared to aPL-negative women.⁷

Anti-β2GPI have been well-established as a key component of the classification and diagnostic criteria for APS since 2006, with their clinical utility supported by extensive evidence. However, the application of these assays in diagnostic protocols has not been explored in the Pakistani population to determine their prevalence and utility to date. This presents a critical gap, as differences in ethnic, genetic, and environmental factors could influence the expression and clinical relevance of these antibodies. Addressing this gap is essential for evaluating the generalizability of findings from other populations and for determining whether incorporating anti-β2GPI testing into regional diagnostics could enhance the detection and management of APS in Pakistan. The results obtained from this study might provide valuable insights into the Pakistani population and may serve as a reference for exploring similar trends in other South Asian populations. Hence, the objectives of this study were to determine the prevalence of anti-β2GPI in Pakistani patients clinically suspected to have APS and assess their association with clinical manifestations.

Methods

An analytical cross-sectional study was conducted at the Section of Chemical Pathology in collaboration with the Section of Hematology, Department of Pathology and Laboratory Medicine, and Department of Medicine at the Aga Khan University Hospital. The study received ethical approval from the institution’s review committee and recruited patients from January 2022 to June 2022 (ERC ID: 2021-6404-19580). STROBE Guidelines were followed when preparing the manuscript.

Inclusion criteria: Patients aged 18–60 years who consented to participate and were clinically suspected of having APS by their primary physicians were included. These patients presented clinical manifestations outlined in the ICS criteria for APS, including thrombotic and/or obstetric complications, and were referred for aCL testing.

Exclusion criteria: Patients were excluded if they did not present with clinical manifestations of APS as outlined by the ICS criteria, and if they did not provide consent to participate in the study.

A total of 133 patients were included in the study.

Sample size: A total of 133 patients were included in the analysis. The sample size was determined using the OpenEpi Version 3,⁸ an open-source calculator for proportions, based on a previous study by Danowski et al., which reported a cumulative prevalence of 10.6% for anti-β2GPI in APS patients.⁹

Anti-β2GPI were tested using the same blood sample that was provided for aCL testing, following verbal informed consent from the patients. After informed consent was obtained, a structured questionnaire was filled out for all the patients, that included demographic, biochemical investigation details, and clinical manifestations. However, the questionnaire used was not a standardized, validated tool. It was developed specifically for this study based on Revised Sapporo antiphospholipid syndrome classification criteria.³ Information on LA testing was obtained retrospectively from patients’ prior laboratory records, which were conducted at the discretion of their treating physicians as part of their clinical investigations. Since these tests were not performed as a part of our study protocol, we did not have LA testing data available for all patients included in our cohort.

For biochemical analysis of anti-β2GPI, serum samples received for aCL were stored at -20°C until analysis. Both the antibodies were analyzed using an enzyme-linked immunosorbent assay (ELISA) on an ETI-MAX 3000 analyzer (DiaSorin Diagnostic, US) using the Beta 2-Glycoprotein 1 Screen ELISA (Enzyme immunoassay for the combined quantitative and qualitative detection of IgA, IgG, and IgM antibodies against β2-glycoprotein I in human serum) by IBL International (Hamburg, Germany) and Cardiolipin IgG/IgM ELISA by IBL International (Hamburg, Germany) respectively. This test identified the presence of anti-β2GPI in the patient’s serum but did not differentiate between the different isotypes (IgG, IgA, or IgM). For anti-β2GPI, a cutoff of >24 U/ml was used to classify positive cases, while levels between 16 and 24 U/ml were labeled as equivocal and <16 U/ml negative using manufacturer’s recommendations. Regarding aCL, distinct cutoff values were applied for IgG and IgM isotypes. Positive classification for IgG was assigned for levels surpassing >14.4 U/ml, while for IgM, a threshold of >7.2 U/ml was employed. Equivocal outcomes were indicated for IgG levels ranging from 10 to 14.4 U/ml and IgM levels within 5–7.2 U/ml, whereas negative classifications were attributed to IgG levels <10 U/ml and IgM levels <5 U/ml using manufacturer’s recommendations. Information on LA testing that was obtained retrospectively from patients’ prior laboratory records were subjected to LA screening using the LA 1 Screening Reagent. This was performed through a simplified dilute Russell’s viper Venom Test using sodium-citrated plasma samples, conducted on a Sysmex CS-2500 analyzer (Siemens-Healthineers, Germany). The established reference range for LA screening in healthy individuals is between 31 and 44 s. Any screening duration surpassing 44 s was considered a screen-positive result. Internal quality controls were analyzed with each batch of serum specimens for quality assurance. Patients testing positive for anti-β2GPI were referred to a consultant hematologist for further management.

The statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS) version 23. Categorical variables were presented as frequencies, while continuous variables were reported as the median and interquartile range (IQR). A chi-squared test was conducted to assess the association of clinical manifestations with aPL antibodies.

Results

A total of 133 patients were included in the analysis, comprising 120 females (90.2%) and 13 males (9.8%). The patients had a mean age of 31.3 ± 8.8 years. Among the observed clinical manifestations, the most prevalent was unexplained miscarriages at >10 weeks of gestation, which accounted for 57.9% (n = 77) of cases. Following that, >3 unexplained consecutive miscarriages at <10 weeks of gestation were reported in 18% (n = 24) of patients. Comprehensive information about the clinical features and medication details of the patients are mentioned in Table 1.

Table 1.

Clinical and immunological findings of patients with suspected APS (N = 133).

Clinical manifestations	n (%)
Obstetric
Unexplained miscarriage >10 weeks of gestation	77 (57.9)
>3 Unexplained consecutive miscarriage <10 weeks of gestation	24 (18)
Adverse pregnancy outcome (abruptio placenta, Eclampsia)	11 (8.3)
Intrauterine growth restriction (IUGR)	8 (6)
Preterm before 34 weeks	4 (3)
Thrombotic
Deep venous thrombosis (DVT)	18 (13.5)
Raynaud’s	12 (9)
Other venous thromboembolic events (VTE)*	11 (8.3)
Transient ischemic attack (TIA)	11 (8.3)
Stroke	7 (5.3)
Peripheral artery occlusion (PAO) or gangrene of limbs	5 (3.8)
Pulmonary embolism (PE)	4 (3)
Cardiac valve pathology (CVP)	4 (3)
Livedo reticularis	4 (3)
Patients with both thrombotic and obstetric manifestations	7 (5.3)
Medication used by the patients	n (%)
Aspirin	47 (35.3)
Heparin	36 (27.1)
Warfarin	14 (10.5)
Rivaroxaban	6 (4.5)
Steroids	5 (3.8)
Clopidogrel	4 (3)
Antiphospholipid antibodies	Median (Q1–Q3)
Anti-β2glycoprotein-1antibodies (U/ml)	2.12 (1.34–7.04)
Anticardiolipin IgG antibodies (U/ml)**	2.83 (1.86–14.10)
Anticardiolipin IgM antibodies (U/ml)**	2.53 (1.12–8.50)
Lupus anticoagulant screen (s)	43.6 (39.7–53.4)

These comprised of recurrent hepatic, splenic, and other visceral venous thromboembolism.

Where IgG stands for immunoglobulin G, IgM is Immunoglobulin M.

The median levels of the aPL antibodies are shown in Table 1. Positive results for anti-β2GPI, aCL IgG, and aCL IgM were observed in 7.5% (n = 10), 25.6% (n = 34), and 27.8% (n = 37) of patients, respectively. LA screening was available in a subset of 86 patients, with screen positive results observed in 43% (n = 37) of cases. Triple positivity, indicating the simultaneous detection of anti-β2GPI, aCL, and a positive dRVVT screen, was 4.5% (n = 6). The anti-β2GPI were able to identify two patients with APS, which were missed by the other aPL antibodies. Detailed information regarding the patients positive for aCL IgG, aCL IgM, and LA can be found in Table 2.

Table 2.

Cross-tabulation demonstrating positivity of anti-β2GPI, aCL IgG/IgM, and LA.

Antibodies n (%)	anti-β2GPI	aCL IgG (n = 133)			aCL IgM (n = 133)			LA screen (n = 86)
Antibodies n (%)	anti-β2GPI	Positive (>14.4 U/ml)	Equivocal (10–14.4 U/ml)	Negative (<10 U/ml)	Positive (>7.2 U/ml)	Equivocal (5–7.2 U/ml)	Negative (<5 U/ml)	Positive (>44 s)	Negative (31–44 s)
anti-β2GPI
Positive (>24 U/ml)	10	8	0	2	6	4	2	6	1
Equivocal (16–24 U/ml)	15	8	0	7	7	4	5	9	2
Negative (<16 U/ml)	108	18	7	83	24	2	79	22	46

anti-β2GPI: anti-β2glycoprotein-1; aCL: anticardiolipin; IgG: immunoglobulin G; IgM: Immunoglobulin M; LA: lupus anticoagulant.

Association between aPL antibodies with gender and clinical manifestations

A statistically significant correlation was observed between female gender and the presence of aCL IgG (p-value 0.023), aCL IgM (p-value 0.024), and LA screen (p-value 0.029). However, no statistically significant association was discerned between anti-β2GPI and either of the two genders (p-value 0.427).

On the chi-squared test to assess the association with clinical characteristics, a significant correlation was identified between the presence of anti-β2GPI and the incidence of DVT and other manifestations of VTE. Conversely, a significant association was noted between aCL IgG and peripheral artery occlusion (PAO) or the development of gangrene in the extremities. In contrast, both LA screen and aCL IgM demonstrated statistically significant associations with various clinical features, elucidated comprehensively in Table 3.

Table 3.

Association of anti-phospholipid antibodies with clinical manifestations.

Clinical manifestations	LA screen (n = 86)		aCL IgG (n = 133)		aCL IgM (n = 133)		anti-β2GPI (n = 133)
Clinical manifestations	Positive	p-value	Positive	p-value	Positive	p-value	Positive	p-value
Thrombotic
Stroke	3	0.076	7	0.428	7	0.002*	7	0.118
TIA	7	0.694	11	0.820	11	0.220	11	0.747
PE	3	0.575	4	0.667	4	0.008*	4	0.091
CVP	3	1.000	4	0.090	4	0.176	4	0.160
Raynaud’s	8	0.010*	12	0.235	12	0.125	12	0.501
PAO or gangrene of limbs	5	0.013*	5	0.043*	5	0.111	5	0.236
Livedo reticularis	2	0.182	4	0.490	4	1.000	4	0.324
DVT	12	0.026*	18	0.730	18	0.022*	18	0.022*
Other VTE**	7	0.039*	11	0.564	11	0.320	11	0.034*
Obstetric
Unexplained miscarriage >10 weeks	52	0.037*	77	0.130	77	0.095	77	0.154
Preterm before 34 weeks	2	0.040	4	0.252	4	0.173	4	0.258
IUGR	5	0.022*	8	0.355	8	0.094	8	0.213
>3 unexplained consecutive miscarriage <10 weeks of gestation	14	0.043*	24	0.572	24	0.022*	24	0.286
Adverse pregnancy outcome: abruptio, Eclampsia	8	0.038*	11	0.497	11	0.051	11	0.249

TIA: transient ischemic attack; PE: pulmonary embolism; CVP: cardiac valve pathology; PAO: peripheral artery occlusion; DVT: deep venous thrombosis; VTE: venous thromboembolic events; IUGR: intrauterine growth restriction.

Shows significant (p-value <0.05) association between positive aPL and the clinical manifestation observed.

These comprised of recurrent hepatic, splenic, and other visceral venous thromboembolism.

Discussions

The aPL antibodies play a crucial role in the pathogenesis of APS and are associated with disease severity. Where the presence of anti-β2GPI are a firm classification and diagnostic criterion in APS diagnosis, our study aims to explore their prevalence and utility in the Pakistani population, which, to our knowledge, has not been specifically addressed in this context. The utility of anti-β2GPI was evident as they successfully identified two patients with suspected APS that had been missed by other aPL antibodies. In the current study, the mean age of the patients was determined to be 31.3 ± 8.8 years, indicating a relatively young cohort. Based on our study findings, among the referred patients, we observed a higher proportion of females compared to males (90.7% vs 9.2%). Similar findings were reported by Santiago Álvarez-López et al., who included all the suspected APS patients, the median age of the cohort was 37.5 years and 86% were female.¹⁰

In the present study, out of the three aPL antibodies, anti-β2GPI had the lowest prevalence (7.6%) that could be due to adaptation from the manufacturer’s recommendation as these cut-offs may not account for variations in assay performance, demographics, or disease prevalence in the local population. Comparing the prevalence of anti-β2GPI by gender in our study proved challenging due to the limited availability of local studies specifically reporting its prevalence. However, contrasting findings were reported in the study conducted by Stojanovich et al., which included 162 individuals with APS, the prevalence of anti-β2GPI IgG was reported as 32.1%, and anti-β2GPI IgM was 44.4%.¹¹ Similarly, Fujieda et al., while studying arterial thrombosis events in a Japanese population with APS, found a prevalence of 31.3% for anti-β2GPI IgG and 7.1% for anti-β2GPI IgM.¹² These variations in anti-β2GPI positivity may be due to dissimilar genetic compositions within the two populations. Additionally, the elevated female-to-male ratio in the current study could contribute to the observed differences in antibody prevalence. In concordance with our investigation, LA screen emerged as the predominantly detected aPL antibody, aligning with findings from Martin et al.’s study. They reported an overall aPL antibody positivity rate of 17.9%, with LA positivity observed in 15.3% of patients.¹³

Regarding clinical manifestations, our study found that the most prevalent outcome was unexplained miscarriages occurring after the 10th week of gestation (57.7%). Additionally, we observed that DVT emerged as the primary non-obstetric thrombotic event (13.5%). Remarkably, these findings align with previous research conducted by Singh et al. in a cohort of 231 patients with APS, where they reported that 54.18% (n = 97) of the patients experienced fetal loss occurring after the 10th week of gestation.¹⁴ Moreover, another study by Pons-Estel et al., focusing on a cohort of 1000 APS patients secondary to systemic lupus erythematosus, also highlighted DVT as the primary thrombotic complication.¹⁵

In the present study, we observed a significant association between anti-β2GPI and the occurrence of DVT and other VTE. Similar findings were reported by a comprehensive study conducted by Martinuzzo et al., where the presence and clinical associations of anti-β2GPI of IgG isotype were investigated in a cohort of 169 patients with aCL and/or LA.¹⁶ They observed a statistically significant association between the presence of anti-β2GPI and VTE. In another study conducted by de Groot et al., the presence of anti-β2GPI significantly increases the risk of DVT.¹⁷ However, in a systematic review conducted by Jiang et al. to assess the relationship between anti-β2GPI and APS manifestations, it was found that the presence anti-β2GPI was only weakly and inconsistently associated with thrombosis and obstetric complications.¹⁸

Our study also displayed a significant association between aCL IgG and PAO or the development of gangrene in the limbs. Similar findings were reported in a study conducted by Puisieux et al., which reported that aCL IgG were significantly more prevalent in patients with PAO compared to the control group.¹⁹ Lastly, our study revealed significant associations of LA screen with multiple clinical features. Similar findings were observed in a study conducted by Sevim et al., which involved 804 persistently aPL antibody-positive patients and within this cohort, the presence of LA emerged as a key factor influencing clinical events.²⁰

Limitations and recommendations: The study has several limitations that warrant acknowledgment. Due to its cross-sectional design and logistical constraints, patients were not tested for antibodies 12 weeks apart, as required by the ICS criteria to confirm APS, limiting the ability to establish causality or temporal relationships between antibodies and clinical manifestations. The relatively small sample size may restrict the generalizability of findings and underscores the need for further research in larger South Asian cohorts using updated criteria, such as the ACR/EULAR APS classification criteria.²¹ Additionally, the study did not differentiate between IgG and IgM anti-β2GPI isotypes, preventing a detailed assessment of their specific associations with APS manifestations and alignment with ACR/EULAR criteria, where IgG titres hold greater diagnostic weight. Cut-offs for aCL and anti-β2GPI antibodies were based on manufacturer recommendations and may not account for assay performance, demographic variability, or local disease prevalence. Incorporating locally derived cut-offs, aligned with International Society on Thrombosis and Haemostasis guidelines or based on the 99th percentile among healthy controls, could improve diagnostic accuracy. Lastly, limitations in the LA testing approach, including the absence of confirmatory tests and locally validated reference ranges, further highlight the need for standardized and comprehensive testing in future research.

Conclusion

This study highlights the prevalence and clinical relevance of anti-β2GPI in a cohort of patients suspected of APS in Pakistan. Anti-β2GPI identified APS cases missed by other aPL, underscoring its diagnostic utility in this cohort. Significant associations were observed between anti-β2GPI positivity and key thrombotic manifestations, such as DVT and other VTE. However, limitations, including study’s cross-sectional design and lack of confirmatory APS testing (e.g. 12-week interval antibody testing) limit causal inferences. Additionally, small sample size, absence of locally derived cut-offs, and incomplete LA testing highlight the need for broader, standardized studies in diverse populations.

Supplemental Material

sj-docx-1-iji-10.1177_03946320251316724 – Supplemental material for Unveiling the clinical spectrum: Exploring the role of anti-β2glycoprotein-1 antibodies (anti-β2GPI) in antiphospholipid syndrome suspects

Supplemental material, sj-docx-1-iji-10.1177_03946320251316724 for Unveiling the clinical spectrum: Exploring the role of anti-β2glycoprotein-1 antibodies (anti-β2GPI) in antiphospholipid syndrome suspects by Muhammad Umer Naeem Effendi, Hafsa Majid, Bushra Moiz, Lena Jafri, Nawazish Zehra and Aysha Habib Khan in International Journal of Immunopathology and Pharmacology

Footnotes

Acknowledgements

This project’s proposal was awarded a grant by the Resident Research Grant Cycle 2021–2022 by the Department of Pathology and Laboratory Medicine, Aga Khan University, and ‘MBBS ‘88 Student and Trainee Initiated Research (STIR 2021-22) round#2 by Aga Khan University, Karachi, Pakistan.

Author’s note

Presentation in Conferences: Abstract presented at XXV WorldLab–EuroMedLab Congress Rome 2023, held in Rome, Italy from 21st to 25th May 2023.

Author contributions

Muhammad Umer Naeem Effendi: Acquisition, analysis, and interpretation of data, drafting of the work, and critical revision for important intellectual content.

Hafsa Majid: Conception and design of the work, acquisition, analysis, and interpretation of data, drafting of the work, and critical revision for important intellectual content.

Bushra Moiz: Analysis and interpretation of data, and critical revision for important intellectual content.

Lena Jafri: Analysis and interpretation of data, and critical revision for important intellectual content.

Nawazish Zehra: Acquisition, analysis, and interpretation of data, drafting of the work.

Aysha Habib Khan: Conception and design of the work, interpretation of data, and critical revision for important intellectual content.

Data availability

The dataset generated and analyzed during the current study is available in the Harvard Dataverse repository.²² https://dataverse.harvard.edu/dataset.xhtml?persistentId=doi:10.7910/DVN/BU4Q3Z&version=DRAFT

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Ethical approval

Ethical approval was obtained from the Ethical Review Committee of Aga Khan University (ERC ID: 2021-6404-19580).

Informed consent to participate and publish data

Verbal informed consent was obtained from the patients for their participation in the study and anonymized information to be published in this article.

Trial registration

Not applicable.

ORCID iD

Hafsa Majid

Supplemental material

Supplemental material for this article is available online.

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