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Management, Diagnosis and Pathophysiology of Antiphospholipid Syndrome: Current Updates and Future Approaches

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Immunology".

Deadline for manuscript submissions: closed (28 October 2022) | Viewed by 39781

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Dr. Maria Efthymiou

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Guest Editor

Haemostasis Res Unit, University College London, London, UK
Interests: antiphospholipid syndrome; pregnancy morbidity; antiphospholipid antibodies; resistance to activated protein c; venous thrombosis; stroke
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Special Issue Information

Dear Colleagues,

Antiphospholipid syndrome (APS) is an autoimmune disorder associated with life-threatening complications that, despite therapeutic advances, continues to cause significant mortality and morbidity. APS-associated clinical manifestations are heterogeneous and diverse, varying from venous, arterial thrombosis to catastrophic APS (CAPS) and pregnancy morbidity. APS is often associated with other autoimmune conditions, such as systemic lupus erythematosus, leading to a more severe course of disease. Lifelong anticoagulation with vitamin K antagonists remains the standard treatment for thrombotic APS, but it is often associated with recurrences and failure and not applicable for all manifestations of APS. Unfortunately, the diagnosis and management of APS continue to prove challenging for clinicians.

At the same time and despite various mechanisms having been proposed as key components in the pathophysiology of APS, and many more emerging, their precise contributions in the clinical manifestations of APS remain unknown. This heterogeneity underlying the pathophysiology of APS suggests that a single therapy is unlikely to be effective in all patients.

The scope of this Special Issue, which will include original papers and reviews, is to provide an updated overview of the progress and advances in the treatment and pathophysiology of APS that will aid in the accurate diagnosis and management of this devasting disease to prevent its deleterious consequences.

Dr. Maria Efthymiou
Guest Editor

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Keywords

Antiphospholipid syndrome
Management
Treatment
Pathophysiology
Diagnostic tests

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Published Papers (9 papers)

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15 pages, 1333 KiB

Open AccessArticle

Antiphospholipid Syndrome in Renal Allograft Recipients—A Long-Term Multicenter Analysis

by Agnieszka Furmańczyk-Zawiska, Barbara Bułło-Piontecka, Michał Komorniczak, Alicja Dębska-Ślizień, Hanna Augustyniak-Bartosik and Magdalena Durlik

J. Clin. Med. 2023, 12(2), 667; https://doi.org/10.3390/jcm12020667 - 14 Jan 2023

Cited by 2 | Viewed by 1763

Abstract

Antiphospholipid syndrome (APS) is a devastating autoimmune disease and in renal transplant recipients may result in allograft thrombosis or in extra-renal manifestation, mostly venous thromboembolism. There are many non- and immune risk factors affecting renal allograft in recipients with APS. However, renal allograft outcome in recipients with APS without APS nephropathy remains unknown. Aim: The aim of the study was to assess renal allograft function and survival in recipients with APS. Methods: Retrospective, multicenter study included 19 adult renal recipients with definite APS (primary or lupus-related) from three Polish transplant centers. Renal allograft function was assessed using serum creatinine concentration (SCr1) at 3rd month post-transplant and at the end of the observation (SCr2) and glomerular filtration rate (GFR) was estimated based on modification of diet in renal disease (MDRD) formula. General linear model was used to assess 12 month GFR change over time. Kaplan-Meier curves and restricted mean survival time were used for allograft survival. Matched control group consisted of 21 stable renal recipients without history of thrombosis and without anticoagulation/antiplatelet treatment. Results: The study group differs in induction therapy (p = 0.019), high-urgency procedure (p = 0.04), proteinuria (p = 0.0058), primary disease (lupus) (p < 0.0001), re-transplantation in primary APS (p = 0.0046) and shorter time since engraftment to SCr2 (p = 0.016). Primary APS was more often diagnosed post-transplant (p = 0.0005). Allograft biopsy revealed thrombotic microangiopathy (TMA) with acute rejection (AR) or isolated AR vs AR or chronic rejection in controls but did not reach significance (p = 0.054). Renal allograft function was inferior in the study group but did not reach significance: mean SCr2 (mg/dL) was 2.18 ± 1.41 and 1.5 ± 0.68 in controls, respectively, p = 0.27; mean GFR2 (ml/min/1.73m²) was 39.9 ± 20.83 and 51.23 ± 19.03, respectively, p = 0.102. Renal allograft duration was inferior in patients with APS and was (in years) 11.22 ± 1.44 vs. 14.36 ± 0.42, respectively, p = 0.037, in patients with primary APS (p = 0.021), in patients with APS diagnosed post-transplant (p = 0.012) but not in lupus-related APS (p = ns). Fifteen year renal allograft survival was inferior in APS vs. controls (73,86% vs. 90.48%, respectively, p = 0.049). Conclusions: Recipients with APS are at higher risk for allograft loss due to immune and non-immune causes. Renal allograft survival was inferior in recipients with APS and renal function remains impaired but stable. Full article

(This article belongs to the Special Issue Management, Diagnosis and Pathophysiology of Antiphospholipid Syndrome: Current Updates and Future Approaches)

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15 pages, 2217 KiB

Open AccessArticle

Thromboembolic Antiphospholipid Syndrome (APS): Efficacy and Safety of Different Anticoagulants-Results of the APSantiCO Registry

by Annabel Schulz, Eva Herrmann, Olivia Ott and Edelgard Lindhoff-Last

J. Clin. Med. 2022, 11(16), 4845; https://doi.org/10.3390/jcm11164845 - 18 Aug 2022

Cited by 4 | Viewed by 2281

Abstract

Background: The particular challenge in dealing with patients with thromboembolic antiphospholipid syndrome (APS) is to establish an adequate therapy regime, as patients suffer from an increased risk of relapse despite antithrombotic treatment (ATT). Vitamin K antagonists (VKA) are the standard medication of choice. The current data on the use of direct oral anticoagulants (DOAC) in APS patients remain limited. Methods: The results of the retrospective APSantiCO registry are presented. In 80 patients with APS, the efficacy and safety of different ATT regimens were analyzed. Results: At the time of inclusion, 43.8% of patients were treated with VKA and 36.3% with DOAC. Medication regimes changed several times and 279 treatment phases were further analyzed with a total treatment length of 7529 months. The incidence of recurrent arterial thrombosis was significantly larger in the DOAC group compared with the VKA group (p < 0.001), while the incidence of recurrent venous thrombosis was comparable between both groups, as was the incidence of bleedings. Heavy menstrual bleeding was the most frequently observed bleeding complication. Conclusions: The data suggest that DOAC may be an alternative to VKA for APS patients with venous thromboembolism, while VKA should be used in APS-related arterial thrombosis. Full article

(This article belongs to the Special Issue Management, Diagnosis and Pathophysiology of Antiphospholipid Syndrome: Current Updates and Future Approaches)

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14 pages, 2448 KiB

Open AccessArticle

Comparison of Acquired Activated Protein C Resistance, Using the CAT and ST-Genesia^® Analysers and Three Thrombin Generation Methods, in APS and SLE Patients

by Maria Efthymiou, Philip J. Lane, David Isenberg, Hannah Cohen and Ian J. Mackie

J. Clin. Med. 2022, 11(1), 69; https://doi.org/10.3390/jcm11010069 - 23 Dec 2021

Cited by 3 | Viewed by 2802

Abstract

Background: Acquired activated protein C resistance (APCr) has been identified in antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE). Objective: To assess agreement between the ST-Genesia^® and CAT analysers in identifying APCr prevalence in APS/SLE patients, using three thrombin generation (TG) methods. Methods: APCr was assessed with the ST-Genesia using STG-ThromboScreen and with the CAT using recombinant human activated protein C and Protac^® in 105 APS, 53 SLE patients and 36 thrombotic controls. Agreement was expressed in % and by Cohen’s kappa coefficient. Results: APCr values were consistently lower with the ST-Genesia^® compared to the CAT, using either method, in both APS and SLE patients. Agreement between the two analysers in identifying APS and SLE patients with APCr was poor (≤65.9%, ≤0.20) or fair (≤68.5%, ≥0.29), regardless of TG method, respectively; no agreement was observed in thrombotic controls. APCr with both the ST Genesia and the CAT using Protac^®, but not the CAT using rhAPC, was significantly greater in triple antiphospholipid antibody (aPL) APS patients compared to double/single aPL patients (p < 0.04) and in thrombotic SLE patients compared to non-thrombotic SLE patients (p < 0.05). Notably, the ST-Genesia^®, unlike the CAT, with either method, identified significantly greater APCr in pregnancy morbidity (median, confidence intervals; 36.9%, 21.9–49.0%) compared to thrombotic (45.7%, 39.6–55.5%) APS patients (p = 0.03). Conclusion: Despite the broadly similar methodology used by CAT and ST-Genesia^®, agreement in APCr was poor/fair, with results not being interchangeable. This may reflect differences in the TG method, use of different reagents, and analyser data handling. Full article

(This article belongs to the Special Issue Management, Diagnosis and Pathophysiology of Antiphospholipid Syndrome: Current Updates and Future Approaches)

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6 pages, 435 KiB

Open AccessArticle

Hypercoagulability Evaluation in Antiphospholipid Syndrome without Anticoagulation Treatment with Thrombin Generation Assay: A Preliminary Study

by Paul Billoir, Sébastien Miranda, Herve Levesque, Ygal Benhamou and Véronique Le Cam Duchez

J. Clin. Med. 2021, 10(12), 2728; https://doi.org/10.3390/jcm10122728 - 21 Jun 2021

Cited by 9 | Viewed by 2131

Abstract

Antiphospholipid syndrome (APS) is associated with thrombotic events (tAPS) and/or obstetrical morbidity (oAPS), with persisting antiphospholipid antibodies (aPL). Despite an update of aPL in 2006, several patients had typical clinical events without the classical biological criteria. The aim of our study was to evaluate the hypercoagulability state with both thrombin generation (TG) profiles and activated protein C resistance (aPCR) in different types of APS. Methods: We retrospectively included 41 patients with Sydney criteria classification (tAPS, oAPS) and no clinical manifestation of APS with persistent aPL (biological APS). A thrombin generation assay was performed with a Fluoroskan Ascent fluorometer in platelet-poor plasma (PPP). Activated protein C resistance was measured as a ratio: ETP_+aPC/ETP_-aPC × 100. Results: Thrombotic APS and oAPS had an increase of global thrombin generation (ETP_control = 808 nM.min (756–853) vs. 1265 nM.min (956–1741) and 1863 nM.min (1434–2080), respectively) (Peak_control = 78 nM (74–86) vs. 153 nM (109–215) and 254 nM.min (232–289), respectively). Biological APS had only a lag time increase (T_control = 4.89 ± 1.65 min vs. 13.6 ± 3.9 min). An increased aPCR was observed in tAPS (52.7 ± 16.4%), oAPS (64.1 ± 14.6%) as compared to the control group (27.2 ± 13.8%). Conclusion: Our data suggest an increase of thrombin generation in thrombotic and obstetrical APS and no hypercoagulable states in patients with biological APS. The study of a prospective and a larger controlled cohort could determine the TGA useful for APS monitoring and could confirm an aPCR evaluation in PPP. Full article

(This article belongs to the Special Issue Management, Diagnosis and Pathophysiology of Antiphospholipid Syndrome: Current Updates and Future Approaches)

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Review

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16 pages, 3173 KiB

Open AccessReview

Advances in the Pathophysiology of Thrombosis in Antiphospholipid Syndrome: Molecular Mechanisms and Signaling through Lipid Rafts

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

J. Clin. Med. 2023, 12(3), 891; https://doi.org/10.3390/jcm12030891 - 23 Jan 2023

Cited by 6 | Viewed by 3070

Abstract

The pathological features of antiphospholipid syndrome (APS) are related to the activity of circulating antiphospholipid antibodies (aPLs) associated with vascular thrombosis and obstetric complications. Indeed, aPLs are not only disease markers, but also play a determining pathogenetic role in APS and exert their effects through the activation of cells and coagulation factors and inflammatory mediators for the materialization of the thromboinflammatory pathogenetic mechanism. Cellular activation in APS necessarily involves the interaction of aPLs with target receptors on the cell membrane, capable of triggering the signal transduction pathway(s). This interaction occurs at specific microdomains of the cell plasma membrane called lipid rafts. In this review, we focus on the key role of lipid rafts as signaling platforms in the pathogenesis of APS, and propose this pathogenetic step as a strategic target of new therapies in order to improve classical anti-thrombotic approaches with “new” immunomodulatory drugs. Full article

(This article belongs to the Special Issue Management, Diagnosis and Pathophysiology of Antiphospholipid Syndrome: Current Updates and Future Approaches)

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13 pages, 6025 KiB

Open AccessReview

B-Cells and BAFF in Primary Antiphospholipid Syndrome, Targets for Therapy?

by Lucas L. van den Hoogen and Radjesh J. Bisoendial

J. Clin. Med. 2023, 12(1), 18; https://doi.org/10.3390/jcm12010018 - 20 Dec 2022

Cited by 11 | Viewed by 2408

Abstract

Primary antiphospholipid syndrome (PAPS) is a systemic autoimmune disease characterized by thrombosis, pregnancy morbidity, and the presence of antiphospholipid antibodies (aPL). Anticoagulants form the mainstay of treatment in PAPS. A growing number of studies suggest a previously underappreciated role of the immune system in the pathophysiology of PAPS. Although B-cells are strongly implicated in the pathophysiology of other autoimmune diseases such as systemic lupus erythematosus (SLE), little is known about the role of B-cells in PAPS. Shifts in B-cell subsets including increases in plasmablasts and higher levels of BAFF are present in patients with PAPS. However, while treatment with rituximab and belimumab may ameliorate thrombotic and non-thrombotic manifestations of PAPS, these treatments do not reduce aPL serum levels, suggesting that B-cells contribute to the pathophysiology of APS beyond the production of autoantibodies. Full article

(This article belongs to the Special Issue Management, Diagnosis and Pathophysiology of Antiphospholipid Syndrome: Current Updates and Future Approaches)

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13 pages, 690 KiB

Open AccessReview

Anticoagulant Therapy in Patients with Antiphospholipid Syndrome

by Marco Capecchi, Maria Abbattista, Alessandro Ciavarella, Mario Uhr, Cristina Novembrino and Ida Martinelli

J. Clin. Med. 2022, 11(23), 6984; https://doi.org/10.3390/jcm11236984 - 26 Nov 2022

Cited by 12 | Viewed by 7827

Abstract

Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by the persistent positivity of antiphospholipid antibodies (aPLA) together with thrombosis or obstetrical complications. Despite their recognized predominant role, aPLA are not sufficient to induce the development of thrombosis and a second hit has been proposed to be necessary. The mainstay of treatment of APS is anticoagulant therapy. However, its optimal intensity in different presentations of the disease remains undefined. Moreover, decision on which patients with aPLA would benefit from an antithrombotic prophylaxis and its optimal intensity are challenging because of the lack of stratification tools for the risk of thrombosis. Finally, decision on the optimal type of anticoagulant drug is also complex because the central pathway responsible for the development of thrombosis is so far unknown and should be carried out on an individual basis after a careful evaluation of the clinical and laboratory features of the patient. This review addresses the epidemiology, physiopathology, diagnosis and management of thrombosis and obstetrical complications in APS, with a special focus on the role of direct oral anticoagulants. Full article

(This article belongs to the Special Issue Management, Diagnosis and Pathophysiology of Antiphospholipid Syndrome: Current Updates and Future Approaches)

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26 pages, 1039 KiB

Open AccessReview

Laboratory Diagnosis of Antiphospholipid Syndrome: Insights and Hindrances

by Arne Vandevelde and Katrien M. J. Devreese

J. Clin. Med. 2022, 11(8), 2164; https://doi.org/10.3390/jcm11082164 - 13 Apr 2022

Cited by 35 | Viewed by 9903

Abstract

Diagnosis of antiphospholipid syndrome (APS) requires the presence of a clinical criterion (thrombosis and/or pregnancy morbidity), combined with persistently circulating antiphospholipid antibodies (aPL). Currently, laboratory criteria aPL consist of lupus anticoagulant (LAC), anticardiolipin antibodies (aCL) IgG/IgM, and anti-β2 glycoprotein I antibodies (aβ2GPI) IgG/IgM. Diagnosis and risk stratification of APS are complex and efforts to standardize and optimize laboratory tests have been ongoing since the initial description of the syndrome. LAC detection is based on functional coagulation assays, while aCL and aβ2GPI are measured with immunological solid-phase assays. LAC assays are especially prone to interference by anticoagulation therapy, but strategies to circumvent this interference are promising. Alternative techniques such as thrombin generation for LAC detection and to estimate LAC pathogenicity have been suggested, but are not applicable yet in routine setting. For aCL and aβ2GPI, a lot of different assays and detection techniques such as enzyme-linked immunosorbent and chemiluminescent assays are available. Furthermore, a lack of universal calibrators or standards results in high variability between the different solid-phase assays. Other non-criteria aPL such as anti-domain I β2 glycoprotein I and antiphosphatidylserine/prothrombin antibodies have been suggested for risk stratification purposes in APS, while their added value to diagnostic criteria seems limited. In this review, we will describe laboratory assays for diagnostic and risk evaluation in APS, integrating applicable guidelines and classification criteria. Current insights and hindrances are addressed with respect to both laboratory and clinical implications. Full article

(This article belongs to the Special Issue Management, Diagnosis and Pathophysiology of Antiphospholipid Syndrome: Current Updates and Future Approaches)

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13 pages, 292 KiB

Open AccessReview

Clinical Management of Thrombotic Antiphospholipid Syndrome

by Nor Rafeah Tumian and Beverley J. Hunt

J. Clin. Med. 2022, 11(3), 735; https://doi.org/10.3390/jcm11030735 - 29 Jan 2022

Cited by 16 | Viewed by 6274

Abstract

Thrombotic manifestations of antiphospholipid syndrome are often a therapeutic dilemma and challenge. Despite our increasing knowledge of this relatively new disease, many issues remain widely unknown and controversial. In this review, we summarise the latest literature and guidelines on the management of thrombotic antiphospholipid syndrome. These include the laboratory assays involved in antiphospholipid antibodies (aPL) testing, the use of direct oral anticoagulants in secondary prevention, management of recurrent thrombosis, individuals with isolated aPL, and catastrophic antiphospholipid syndrome. Treatment aims to prevent the potentially fatal and often disabling complications of APS with antithrombotic and cardiovascular risks prevention strategies. Some insights and updates on topical issues in APS are provided. We also include our current practice, which we believe is the pragmatic approach based on the currently available evidence. Full article

(This article belongs to the Special Issue Management, Diagnosis and Pathophysiology of Antiphospholipid Syndrome: Current Updates and Future Approaches)

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