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Bonisoli GL, Argentino G, Friso S, Tinazzi E. Extracellular Vesicles Analysis as Possible Signatures of Antiphospholipid Syndrome Clinical Features. Int J Mol Sci 2025; 26:2834. [PMID: 40243411 PMCID: PMC11989148 DOI: 10.3390/ijms26072834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2025] [Revised: 03/09/2025] [Accepted: 03/15/2025] [Indexed: 04/18/2025] Open
Abstract
Antiphospholipid syndrome (APS) is a rare autoimmune disease characterized by thrombosis and obstetric complications. Extracellular vesicles (EVs) of either platelet and endothelial origin are recognized to be involved in the pathophysiology of the disease. This study aimed to evaluate the potential role of endothelial- and platelet-derived extracellular vesicles and the clinical features or progression of APS. We enrolled 22 patients diagnosed with APS and 18 age and sex-matched healthy controls. We determined APS-specific antibody positivity and clinical manifestations in APS affected patients, with a focus on neurological, cardiovascular, dermatological, hematological manifestations, and pregnancy-related complications. Platelet-poor plasma was collected from either patients and controls for the analysis of EVs by flow cytometry technology using monoclonal antibodies to specifically identify those derived from either platelets and/or endothelial cells. EVs of endothelial and platelet origins were overall significantly increased in patients as compared to healthy controls. Furthermore, a significant association was also observed between the number of extracellular vesicles and specific organ involvement, particularly central nervous system manifestations, hematological abnormalities, and obstetric complications. An elevated proportion of endothelial-derived EVs in APS and a reduction of resting endothelial cell-derived EVs were observed in APS-affected women with obstetric complications. Our findings highlight the involvement of endothelial cells and platelets in mirroring the activities of endothelial cells and platelets in APS. Additionally, extracellular vesicles may serve as potential predictors of organ involvement and disease-related damage.
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Affiliation(s)
| | | | | | - Elisa Tinazzi
- Department of Medicine, University of Verona, 37134 Verona, Italy
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Sales LP, Souza LVB, Fernandes AL, Murai IH, Santos MD, Vendramini MBG, Oliveira RM, Figueiredo CP, Caparbo VF, Gualano B, Pereira RMR. Effect of vitamin D 3 on antiphospholipid antibodies in hospitalized patients with moderate to severe COVID-19. Clinics (Sao Paulo) 2024; 79:100474. [PMID: 39208655 PMCID: PMC11399608 DOI: 10.1016/j.clinsp.2024.100474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 06/05/2024] [Accepted: 07/21/2024] [Indexed: 09/04/2024] Open
Abstract
OBJECTIVE To investigate the effect of a single oral dose of 200,000 IU of vitamin D3 on antiphospholipid antibodies in hospitalized patients with moderate to severe COVID-19. METHODS This is a post-hoc, exploratory analysis from a double-blind, placebo-controlled, randomized clinical trial performed in two centers in Sao Paulo, Brazil. Hospitalized patients with COVID-19 were randomly assigned to receive either vitamin D3 (n = 97) or placebo (n = 97). In this post-hoc analysis, the endpoints were titers and frequency of anti-β2-Glycoprotein-I (aβ2-GP) and Anticardiolipin (aCL) antibodies [Immunoglobulin G, M and A (IgG, IgM and IgA)]. RESULTS Overall mean (SD) age was 55.3 (13.9) years, Body Mass Index (BMI) was 32.2 (7.1 kg/m2), and 106 participants (54.6 %) were male. There was a significant group by time interaction (p = 0.046) for frequency of aCL IgG, with increased values from baseline to discharge in the placebo group [n (%), from 13 (13.4) to 25 (25.8)] compared to the vitamin D3 [from 25 (25.8) to 29 (29.9)]. However, the frequency of aCL IgG did not change between the groups on discharge. No significant differences between vitamin D3 and placebo groups were found for any other autoantibodies. CONCLUSION These findings do not support the use of a single oral dose of 200,000 IU of vitamin D3 to modulate autoantibodies in hospitalized patients with moderate to severe COVID-19.
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Affiliation(s)
- Lucas P Sales
- Rheumatology Division, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (HCFMUSP), São Paulo, SP, Brazil
| | - Lucas V B Souza
- Rheumatology Division, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (HCFMUSP), São Paulo, SP, Brazil
| | - Alan L Fernandes
- Rheumatology Division, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (HCFMUSP), São Paulo, SP, Brazil
| | - Igor H Murai
- Rheumatology Division, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (HCFMUSP), São Paulo, SP, Brazil
| | - Mayara D Santos
- Rheumatology Division, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (HCFMUSP), São Paulo, SP, Brazil
| | - Margarete B G Vendramini
- Rheumatology Division, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (HCFMUSP), São Paulo, SP, Brazil
| | | | - Camille P Figueiredo
- Rheumatology Division, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (HCFMUSP), São Paulo, SP, Brazil
| | - Valéria F Caparbo
- Rheumatology Division, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (HCFMUSP), São Paulo, SP, Brazil
| | - Bruno Gualano
- Rheumatology Division, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (HCFMUSP), São Paulo, SP, Brazil.
| | - Rosa M R Pereira
- Rheumatology Division, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (HCFMUSP), São Paulo, SP, Brazil
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Dodig S, Čepelak I. Antiphospholipid antibodies in patients with antiphospholipid syndrome. Biochem Med (Zagreb) 2024; 34:020504. [PMID: 38882589 PMCID: PMC11177653 DOI: 10.11613/bm.2024.020504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Accepted: 04/08/2024] [Indexed: 06/18/2024] Open
Abstract
Antiphospholipid syndrome (APS) is a rare systemic autoimmune disease characterized by recurrent pregnancy morbidity or thrombosis in combination with the persistent presence of antiphospholipid antibodies (aPLs) in plasma/serum. Antiphospholipid antibodies are a heterogeneous, overlapping group of autoantibodies, of which anti-β2-glycoprotein I (aβ2GPI), anticardiolipin (aCL) antibodies and antibodies that prolong plasma clotting time in tests in vitro known as lupus anticoagulant (LAC) are included in the laboratory criteria for the diagnosis of APS. The presence of LAC antibodies in plasma is indirectly determined by measuring the length of coagulation in two tests - activated partial thromboplastin time (aPTT) and diluted Russell's viper venom time (dRVVT). The concentration of aβ2GPI and aCL (immunglobulin G (IgG) and immunoglobulin M (IgM) isotypes) in serum is directly determined by solid-phase immunoassays, either by enzyme-linked immunosorbent assay (ELISA), fluoroimmunoassay (FIA), immunochemiluminescence (CLIA) or multiplex flow immunoassay (MFIA). For patient safety, it is extremely important to control all three phases of laboratory testing, i.e. preanalytical, analytical and postanalytical phase. Specialists in laboratory medicine must be aware of interferences in all three phases of laboratory testing, in order to minimize these interferences. The aim of this review was to show the current pathophysiological aspects of APS, the importance of determining aPLs-a in plasma/serum, with an emphasis on possible interferences that should be taken into account when interpreting laboratory findings.
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Affiliation(s)
- Slavica Dodig
- Department of Medical Biochemistry and Hematology, Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb, Croatia
| | - Ivana Čepelak
- Department of Medical Biochemistry and Hematology, Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb, Croatia
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Mathesan M, Ethirajan S. Triumph Over Adversity: A Comprehensive Case Series on Successful Pregnancy Outcomes in Antiphospholipid Antibody (APLA)-Positive Patients. Cureus 2024; 16:e59088. [PMID: 38803763 PMCID: PMC11128359 DOI: 10.7759/cureus.59088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Accepted: 04/26/2024] [Indexed: 05/29/2024] Open
Abstract
The intricate relationship between antiphospholipid antibody (APLA) syndrome and pregnancy outcomes challenges the prevailing notion of inevitable reproductive complications associated with APLA. The introduction provides a comprehensive overview of APLA, its autoimmune thrombophilic nature, and its common association with adverse pregnancy outcomes, emphasizing the need for a nuanced understanding. Here we discuss five case reports to showcase diverse scenarios, each highlighting successful pregnancies in APLA-positive patients, thereby contributing valuable insights into the management of this complex condition. The cases span various clinical presentations, patient demographics, and therapeutic approaches, emphasizing the heterogeneity of APLA-positive pregnancies and the importance of personalized care. The discussion delves into the broader context of APLA's impact on pregnancy, emphasizing recurrent miscarriage and venous thromboembolism (VTE) as severe complications. It underscores the significance of pre-conceptional counseling, a multidisciplinary approach, and regular antenatal monitoring in managing APLA-positive pregnancies. The identification of commonalities among the cases provides a basis for recognizing mitigating factors that contribute to positive outcomes, offering valuable guidance for healthcare providers. The series acknowledges the existence of catastrophic antiphospholipid syndrome (CAPS) and underscores the importance of early recognition and intervention in high-risk cases. Despite the challenges posed by APLA, the cases in the series offer a ray of hope by showcasing instances of successful pregnancies, attributing positive outcomes to optimized therapeutic interventions and vigilant antenatal care. In conclusion, the case series serves as a valuable resource for healthcare professionals, researchers, and policymakers, providing a nuanced perspective on APLA-positive pregnancies. By synthesizing diverse experiences and outcomes, the series contributes to the ongoing dialogue surrounding optimal management strategies, ultimately aiming to improve the quality of care for individuals facing the unique challenges posed by APLA during their reproductive journey.
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Affiliation(s)
- Manju Mathesan
- Obstetrics and Gynecology, Saveetha Institute of Medical and Technical Sciences, Chennai, IND
| | - Shanthi Ethirajan
- Obstetrics and Gynecology, Saveetha Institute of Medical and Technical Sciences, Chennai, IND
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Barbhaiya M, Taghavi M, Zuily S, Domingues V, Chock EY, Tektonidou MG, Erkan D, Seshan SV. Efforts to Better Characterize "Antiphospholipid Antibody Nephropathy" for the 2023 ACR/EULAR Antiphospholipid Syndrome Classification Criteria: Renal Pathology Subcommittee Report. J Rheumatol 2024; 51:150-159. [PMID: 37399462 DOI: 10.3899/jrheum.2022-1200] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/02/2023] [Indexed: 07/05/2023]
Abstract
OBJECTIVE Antiphospholipid antibody (aPL) nephropathy (-N) can be challenging to recognize due to a lack of established classification or diagnostic criteria. As part of efforts to develop new antiphospholipid syndrome (APS) classification criteria (CC), the APS CC Renal Pathology Subcommittee aimed to better characterize the entity of aPL-N. METHODS We used a 4-pronged approach that included (1) administering Delphi surveys to worldwide APS physicians to generate aPL-N terminology; (2) conducting a literature review to demonstrate the association of nephropathy with aPL and identify published aPL-N histopathological terminology and descriptions; (3) evaluating aPL-N terminology used in renal biopsy reports from an international patient registry; and (4) evaluating proposed kidney pathologic features for aPL-N by assessment of international Renal Pathology Society (RPS) members. RESULTS After completing our metaanalysis demonstrating an association between nephropathy and aPL, we used Delphi surveys, a literature review, and international renal biopsy reports to develop a preliminary definition of aPL-N. The preliminary definition included include specific terms associated with acute (ie, thrombotic microangiopathy in glomeruli or arterioles/arteries) and chronic (ie, organized arterial or arteriolar microthrombi with or without recanalization, organized glomerular thrombi, fibrous and fibrocellular [arterial or arteriolar] occlusions, focal cortical atrophy with or without thyroidization, and fibrous intimal hyperplasia) lesions. Most RPS survey respondents agreed with this terminology and the importance of knowing aPL results for histopathological diagnosis. CONCLUSION Our results support the inclusion of aPL-N in the 2023 American College of Rheumatology/European Alliance of Associations for Rheumatology APS CC, and provide the most widely accepted terminology to date for both acute and chronic pathologic lesions of aPL-N.
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Affiliation(s)
- Medha Barbhaiya
- M. Barbhaiya, MD, MPH, D. Erkan, MD, MPH, Hospital for Special Surgery, and Weill Cornell Medicine, New York, New York, USA;
| | - Maxime Taghavi
- M. Taghavi, MD, Department of Nephrology, Centre Hospitalier Universitaire Brugmann, Université Libre de Bruxelles, Belgium
| | - Stephane Zuily
- S. Zuily, MD, PhD, Université de Lorraine, Inserm, Défaillance Cardiovasculaire Aiguë et Chronique, and Centre Hospitalier Régional Universitaire de Nancy, Vascular Medicine Division, and French National Referral Center for Rare Autoimmune Diseases, Nancy, France
| | | | - Eugenia Y Chock
- E.Y. Chock, MD, MPH, Section of Rheumatology, Yale School of Medicine, New Haven, Connecticut, USA
| | - Maria G Tektonidou
- M.G. Tektonidou, First Department of Internal Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Doruk Erkan
- M. Barbhaiya, MD, MPH, D. Erkan, MD, MPH, Hospital for Special Surgery, and Weill Cornell Medicine, New York, New York, USA
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Samarrai R, Rahman K, Parham K. Clinical Biomarkers in Otolaryngology-Head and Neck Surgery: Autoimmune Diseases. EAR, NOSE & THROAT JOURNAL 2024; 103:29-35. [PMID: 34281418 DOI: 10.1177/01455613211033121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
OBJECTIVE The purpose of this article is to review the literature and compile promising and clinically relevant biomarkers in autoimmune disease related to otolaryngology-head and neck surgery. STUDY DESIGN Narrative review. METHODS Pubmed and Google Scholar were queried using combined key words such as "biomarkers" and "otolaryngology." Additional queries were made with combined key words such as "biomarkers" and a particular subspecialty such as "autoimmune" or "Meniere's" to maximize yield of relevant titles. Subsequently, specific biomarkers identified, such as "anti-TPO-antibodies," were used as key words. Relevant titles were reviewed and selected for abstract review. Applicable abstracts were then selected for review of the full text. RESULTS Biomarkers that are currently in clinical use for the management of autoimmune diseases within the field of otolaryngology were included in this review. The compiled biomarkers were then detailed individually regarding their molecular characteristics, function, and clinical significance. CONCLUSIONS Based on this literature review, there are several biomarkers currently in clinical use within the field of otolaryngology relating to autoimmune diseases. The majority of these biomarkers are in the form of proteins such as Cogan peptide and c-ANCA. This survey may serve as a comprehensive resource on biomarkers for autoimmune diseases in clinical otolaryngology.
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Affiliation(s)
- Ruwaa Samarrai
- Department of Otolaryngology-Head and Neck Surgery, University of Connecticut Health Center, Farmington, CT, USA
| | - Khalil Rahman
- Department of Otolaryngology-Head and Neck Surgery, University of Connecticut Health Center, Farmington, CT, USA
| | - Kourosh Parham
- Department of Otolaryngology-Head and Neck Surgery, University of Connecticut Health Center, Farmington, CT, USA
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Bradáčová P, Slavík L, Úlehlová J, Kriegová E, Jará E, Bultasová L, Friedecký D, Ullrychová J, Procházková J, Hluší A, Manukyan G, Štefaničková L. Determining Thrombogenicity: Using a Modified Thrombin Generation Assay to Detect the Level of Thrombotic Event Risk in Lupus Anticoagulant-Positive Patients. Biomedicines 2023; 11:3329. [PMID: 38137550 PMCID: PMC10741461 DOI: 10.3390/biomedicines11123329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 12/08/2023] [Accepted: 12/14/2023] [Indexed: 12/24/2023] Open
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.
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Affiliation(s)
- Pavla Bradáčová
- Department Clinical Hematology, Masaryk Hospital Ústí nad Labem, 40113 Ústi nad Labem, Czech Republic; (E.J.); (J.U.)
- Faculty of Medicine and Dentistry, Palacky University Olomouc, 77900 Olomouc, Czech Republic
| | - Luděk Slavík
- Faculty of Medicine and Dentistry, Palacky University Olomouc, 77900 Olomouc, Czech Republic
| | - Jana Úlehlová
- Department of Hemato-Oncology, University Hospital Olomouc, Faculty of Medicine and Dentistry, Palacky University Olomouc, 77900 Olomouc, Czech Republic; (J.Ú.); (J.P.); (A.H.)
| | - Eva Kriegová
- Department of Immunology, University Hospital Olomouc, Faculty of Medicine and Dentistry, Palacky University Olomouc, 77900 Olomouc, Czech Republic; (E.K.); (G.M.)
| | - Eliška Jará
- Department Clinical Hematology, Masaryk Hospital Ústí nad Labem, 40113 Ústi nad Labem, Czech Republic; (E.J.); (J.U.)
| | - Lenka Bultasová
- Department Hematology and Biochemistry, University Hospital, 32300 Plzeň, Czech Republic;
| | - David Friedecký
- Laboratory for Inherited Metabolic Disorders, University Hospital Olomouc, Faculty of Medicine and Dentistry, Palacky University Olomouc, 77900 Olomouc, Czech Republic; (D.F.); (L.Š.)
| | - Jana Ullrychová
- Department Clinical Hematology, Masaryk Hospital Ústí nad Labem, 40113 Ústi nad Labem, Czech Republic; (E.J.); (J.U.)
| | - Jana Procházková
- Department of Hemato-Oncology, University Hospital Olomouc, Faculty of Medicine and Dentistry, Palacky University Olomouc, 77900 Olomouc, Czech Republic; (J.Ú.); (J.P.); (A.H.)
| | - Antonín Hluší
- Department of Hemato-Oncology, University Hospital Olomouc, Faculty of Medicine and Dentistry, Palacky University Olomouc, 77900 Olomouc, Czech Republic; (J.Ú.); (J.P.); (A.H.)
| | - Gayane Manukyan
- Department of Immunology, University Hospital Olomouc, Faculty of Medicine and Dentistry, Palacky University Olomouc, 77900 Olomouc, Czech Republic; (E.K.); (G.M.)
- Laboratory of Molecular and Cellular Immunology, Institute of Molecular Biology NAS RA, Yerevan 0014, Armenia
| | - Lenka Štefaničková
- Laboratory for Inherited Metabolic Disorders, University Hospital Olomouc, Faculty of Medicine and Dentistry, Palacky University Olomouc, 77900 Olomouc, Czech Republic; (D.F.); (L.Š.)
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An R, Yang Y, Liu L, Li P. SAMD1 attenuates antiphospholipid syndrome-induced pregnancy complications. Immun Inflamm Dis 2023; 11:e1006. [PMID: 37904675 PMCID: PMC10614121 DOI: 10.1002/iid3.1006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 06/28/2023] [Accepted: 08/31/2023] [Indexed: 11/01/2023] Open
Abstract
OBJECTIVE This study was intended to investigate the effect of SAMD1 on antiphospholipid syndrome (APS)-induced pregnancy complications in mice. METHODS The mRNA and protein expression of SAMD1 in APS patients and healthy controls was detected by qRT-PCR and western blot. Anti-B2 GPI and ACA levels were tested by ELISA, MMP-9, iNOS, ICAM-1 and MCP-1 mRNA and protein levels determined by qRT-PCR and western blot, cellular senescence detected by β-galactosidase staining, cell proliferation ability detected by CCK-8 assay, cell viability detected by trypan blue staining, cell mobility detected by Transwell, and cell angiogenesis ability detected by matrigel tube formation assay. An APS pregnant mouse model was constructed, and the embryo absorption rate was calculated. RESULTS SAMD1 expression was low in serum of APS patients, which was correlated with the history of thrombosis and the number of adverse pregnancies. Anti-B2 GPI and ACA levels were increased in APS. The expressions of MMP-9, iNOS, ICAM-1, and MCP-1 were also significantly upregulated in HUVECs treated with APS serum. APS promoted HUVEC senescence and inhibited cell proliferation, migration and angiogenesis. Overexpression of SAMD1 reversed the above results. Experiments on the APS pregnant mouse model confirmed that overexpression of SAMD1 reduced the rate of fetal loss. CONCLUSION SAMD1 may reduce APS-induced embryo loss by regulating cellular senescence, proliferation, migration, and angiogenesis.
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Affiliation(s)
- Ran An
- Department of Obstetrics and GynecologyThe Fourth Affiliated Hospital of Harbin Medical UniversityHarbinHeilongjiangP.R. China
| | - Yanqi Yang
- Department of Obstetrics and GynecologyThe Fourth Affiliated Hospital of Harbin Medical UniversityHarbinHeilongjiangP.R. China
| | - Lei Liu
- Department of Obstetrics and GynecologyThe Fourth Affiliated Hospital of Harbin Medical UniversityHarbinHeilongjiangP.R. China
| | - Peiling Li
- Department of Obstetrics and GynecologyThe Second Affiliated Hospital of Harbin Medical UniversityHarbinHeilongjiangP.R. China
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Jang S, Javadov S. Unraveling the mechanisms of cardiolipin function: The role of oxidative polymerization of unsaturated acyl chains. Redox Biol 2023; 64:102774. [PMID: 37300954 PMCID: PMC10363451 DOI: 10.1016/j.redox.2023.102774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 05/26/2023] [Accepted: 06/03/2023] [Indexed: 06/12/2023] Open
Abstract
Cardiolipin is a unique phospholipid of the inner mitochondrial membrane (IMM) as well as in bacteria. It performs several vital functions such as resisting osmotic rupture and stabilizing the supramolecular structure of large membrane proteins, like ATP synthases and respirasomes. The process of cardiolipin biosynthesis results in the production of immature cardiolipin. A subsequent step is required for its maturation when its acyl groups are replaced with unsaturated acyl chains, primarily linoleic acid. Linoleic acid is the major fatty acid of cardiolipin across all organs and tissues, except for the brain. Linoleic acid is not synthesized by mammalian cells. It has the unique ability to undergo oxidative polymerization at a moderately accelerated rate compared to other unsaturated fatty acids. This property can enable cardiolipin to form covalently bonded net-like structures essential for maintaining the complex geometry of the IMM and gluing the quaternary structure of large IMM protein complexes. Unlike triglycerides, phospholipids possess only two covalently linked acyl chains, which constrain their capacity to develop robust and complicated structures through oxidative polymerization of unsaturated acyl chains. Cardiolipin, on the other hand, has four fatty acids at its disposal to form covalently bonded polymer structures. Despite its significance, the oxidative polymerization of cardiolipin has been overlooked due to the negative perception surrounding biological oxidation and methodological difficulties. Here, we discuss an intriguing hypothesis that oxidative polymerization of cardiolipin is essential for the structure and function of cardiolipin in the IMM in physiological conditions. In addition, we highlight current challenges associated with the identification and characterization of oxidative polymerization of cardiolipin in vivo. Altogether, the study provides a better understanding of the structural and functional role of cardiolipin in mitochondria.
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Affiliation(s)
- Sehwan Jang
- Department of Physiology, University of Puerto Rico School of Medicine, San Juan, PR 00936-5067, USA
| | - Sabzali Javadov
- Department of Physiology, University of Puerto Rico School of Medicine, San Juan, PR 00936-5067, USA.
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10
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Meschia JF. Diagnostic Evaluation of Stroke Etiology. Continuum (Minneap Minn) 2023; 29:412-424. [PMID: 37039402 DOI: 10.1212/con.0000000000001206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/12/2023]
Abstract
OBJECTIVE Precise therapies require precise diagnoses. This article provides an evidence-based approach to confirming the diagnosis of ischemic stroke, characterizing comorbidities that provide insights into the pathophysiologic mechanisms of stroke, and identifying targets for treatment to optimize the prevention of recurrent stroke. LATEST DEVELOPMENTS Identifying the presence of patent foramen ovale, intermittent atrial fibrillation, and unstable plaque is now routinely included in an increasingly nuanced workup in patients with stroke, even as ongoing trials seek to clarify the best approaches for treating these and other comorbidities. Multicenter trials have demonstrated the therapeutic utility of patent foramen ovale closure in select patients younger than age 60 years. Insertable cardiac monitors detect atrial fibrillation lasting more than 30 seconds in about one in ten patients monitored for 12 months following a stroke. MRI of carotid plaque can detect unstable plaque at risk of being a source of cerebral embolism. ESSENTIAL POINTS To optimize the prevention of recurrent stroke, it is important to consider pathologies of intracranial and extracranial blood vessels and of cardiac structure and rhythm as well as other inherited or systemic causes of stroke. Some aspects of the stroke workup should be done routinely, while other components will depend on the clinical circumstances and preliminary testing results.
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The APSANTICO Study: A Prospective Observational Study to Evaluate Antiphospholipid Antibody Profiles in Patients with Thromboembolic Antiphospholipid Syndrome (APS) after COVID-19 Infection and/or Vaccination. Int J Mol Sci 2023; 24:ijms24065644. [PMID: 36982716 PMCID: PMC10051980 DOI: 10.3390/ijms24065644] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 02/22/2023] [Accepted: 03/09/2023] [Indexed: 03/18/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new virus discovered in December 2019 that causes coronavirus disease 19 (COVID-19) and various vaccinations have been developed. The extent to which COVID-19 infections and/or COVID-19 vaccinations alter antiphospholipid antibodies (aPL) in patients with thromboembolic antiphospholipid syndrome (APS) remains unclear. Eighty-two patients with confirmed thromboembolic APS were included in this prospective non-interventional trial. Blood parameters including lupus anticoagulants, anticardiolipin IgG- and IgM-antibodies, and anti-ß2-glycoprotein I IgG- and IgM-antibodies were assessed prior to and after COVID-19 vaccination and/or COVID-19 infection. No increases in aPL in the total study population were detected. In fact, low but significant decreases were observed for anticardiolipin IgG- and anti-β2-glycoprotein I IgG-antibodies, while anticardiolipin IgM- and anti-b2-glycoprotein I IgM-antibodies slightly increased only in patients with COVID-19 infection and vaccination. Although the investigated patient group is known to have a high risk of recurrent thrombosis, only one arterial thrombotic event was diagnosed (1.2%, 1/82). This low recurrence rate was probably due to the high vaccination rates prior to infections and a high rate of effective anticoagulation. Our data show that COVID-19 infections and/or vaccinations do not deteriorate the clinical course of anticoagulated thromboembolic APS patients.
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Capozzi A, Manganelli V, Riitano G, Caissutti D, Longo A, Garofalo T, Sorice M, Misasi R. Advances in the Pathophysiology of Thrombosis in Antiphospholipid Syndrome: Molecular Mechanisms and Signaling through Lipid Rafts. J Clin Med 2023; 12:jcm12030891. [PMID: 36769539 PMCID: PMC9917860 DOI: 10.3390/jcm12030891] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 01/17/2023] [Accepted: 01/19/2023] [Indexed: 01/25/2023] Open
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.
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13
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An R, Yang Y, Liu L, Li P. SAMD1 attenuates antiphospholipid syndrome-induced vascular injury and pregnancy complications. Immun Inflamm Dis 2022; 10:e678. [PMID: 36039649 PMCID: PMC9382866 DOI: 10.1002/iid3.678] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 06/22/2022] [Accepted: 07/04/2022] [Indexed: 01/28/2023] Open
Abstract
OBJECTIVE This study was intended to investigate the effect of SAMD1 on antiphospholipid syndrome (APS)-induced vascular injury in human umbilical vein endothelial cells (HUVECs) and pregnancy complications in mice. METHODS The expression of SAMD1 in APS patients and healthy controls was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Anti-B2 GPI and anticardiolipin antibody (ACA) levels were tested by enzyme-linked immunosorbent assay, MMP-9, iNOS, ICAM-1, and MCP-1 mRNA and protein levels determined by qRT-PCR and Western blot, cellular senescence detected by β-galactosidase staining, cell proliferation ability detected by CCK-8 assay, cell viability detected by trypan blue staining, cell mobility detected by Transwell, and cell angiogenesis ability detected by matrigel tube formation assay. An APS pregnant mouse model was constructed, and the embryo absorption rate was calculated. RESULTS SAMD1 expression was low in serum of APS patients, which was correlated with the history of thrombosis and the number of adverse pregnancies. Anti-B2 GPI and ACA levels were increased in APS. The expressions of MMP-9, iNOS, ICAM-1, and MCP-1 were also significantly upregulated in HUVECs treated with APS serum. APS promoted HUVEC senescence and inhibited cell proliferation, migration, and angiogenesis. Overexpression of SAMD1 reversed the above results. Experiments on the APS pregnant mouse model confirmed that overexpression of SAMD1 reduced the rate of fetal loss. CONCLUSION SAMD1 may reduce APS-induced vascular injury and embryo loss by regulating cellular senescence, proliferation, migration, and angiogenesis.
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Affiliation(s)
- Ran An
- Department of Obstetrics and Gynecology, the Fourth Affiliated Hospital of Harbin Medical UniversityHarbinHeilongjiangChina
| | - Yanqi Yang
- Department of Obstetrics and Gynecology, the Fourth Affiliated Hospital of Harbin Medical UniversityHarbinHeilongjiangChina
| | - Lei Liu
- Department of Obstetrics and Gynecology, the Fourth Affiliated Hospital of Harbin Medical UniversityHarbinHeilongjiangChina
| | - Peiling Li
- Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Harbin Medical UniversityHarbinHeilongjiangChina
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Determination of Thrombogenicity Levels of Various Antiphospholipid Antibodies by a Modified Thrombin Generation Assay in Patients with Suspected Antiphospholipid Syndrome. Int J Mol Sci 2022; 23:ijms23168973. [PMID: 36012233 PMCID: PMC9409152 DOI: 10.3390/ijms23168973] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 08/05/2022] [Accepted: 08/09/2022] [Indexed: 11/23/2022] Open
Abstract
Antiphospholipid syndrome (APS) is a hypercoagulable state accompanied by the presence of heterogeneous antiphospholipid antibodies (aPL), which nonspecifically affect hemostasis by the presence of lupus anticoagulans (LA), anticardiolipin antibodies (aCL), antibodies against β2-glycoprotein-I (anti-β2GPI), but also non-criteria antibodies such as antibodies against β2-glycoprotein-I domain I (anti-DI), anti-phosphatidylserine/prothrombin (anti-PS/PT), anti-annexin V, and many others. The main target of the antibodies is the activated protein C (APC) system, the elimination of which can manifest itself as a thrombotic complication. The aim of this study was to determine the thrombogenicity of antibodies using a modified protein C-activated thrombin generation assay (TGA) on a group of 175 samples suspected of APS. TGA was measured with/without APC and the ratio of both measurements was evaluated (as for APC resistance), where a cut-off was calculated ≤4.5 (90th percentile) using 21 patients with heterozygous factor V Leiden mutation (FV Leiden heterozygous). Our study demonstrates the well-known fact that multiple positivity of different aPLs is a more severe risk for thrombosis than single positivity. Of the single antibody positivity, LA antibodies are the most serious (p value < 0.01), followed by aCL and their subgroup anti-DI (p value < 0.05). Non-criteria antibodies anti-annexin V and anti-PT/PS has a similar frequency occurrence of thrombogenicity as LA antibodies but without statistical significance or anti-β2GPI1 positivity. The modified TGA test can help us identify patients in all groups who are also at risk for recurrent thrombotic and pregnancy complications; thus, long-term prophylactic treatment is appropriate. For this reason, it is proving increasingly beneficial to include the determination antibodies in combination with modified TGA test.
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McDonnell T, Amarnani R, Spicer C, Jbari H, Pericleous C, Spiteri VA, Wincup C, Artim-Esen B, Mackie I, Botto M, Rahman A, Giles I. Antibodies to FXa and thrombin in patients with SLE differentially regulate C3 and C5 cleavage. Lupus Sci Med 2022; 9:e000738. [PMID: 36007979 PMCID: PMC9422842 DOI: 10.1136/lupus-2022-000738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 08/08/2022] [Indexed: 12/03/2022]
Abstract
OBJECTIVES The significance of antibodies directed against activated factor X (FXa) and thrombin (Thr) in patients with SLE and/or antiphospholipid syndrome (APS) is unknown. FXa and Thr are coregulated by antithrombin (AT) and activate complement. Therefore, we studied the ability of anti activated factor X (aFXa) and/or anti-(a)Thr IgG from patients with SLE±APS to modulate complement activation. METHODS Patients with SLE±APS were selected on the basis of known aThr and/or aFXa IgG positivity, and the effects of affinity-purified aFXa/aThr IgG on FXa and Thr-mediated C3 and C5 activation were measured ±AT. Structural analyses of FXa and Thr and AT-FXa and AT-Thr complexes were analysed in conjunction with the in vitro ability of AT to regulate aFXa-FXa and aThr-Thr-mediated C3/C5 activation. RESULTS Using affinity-purified IgG from n=14 patients, we found that aThr IgG increased Thr-mediated activation of C3 and C5, while aFXa IgG did not increase C3 or C5 activation. Structural analysis identified potential epitopes and predicted a higher likelihood of steric hindrance of AT on FXa by aFXa IgG compared with the AT-Thr-aThr IgG complex that was confirmed by in vitro studies. Longitudinal analysis of 58 patients with SLE (±APS) did not find a significant association between positivity for aFXa or aTHr IgG and C3 levels or disease activity, although there was a trend for patients positive for aFXa IgG alone or both aFXa and aThr IgG to have lower levels of C3 compared with aThr IgG alone during clinical visits. CONCLUSIONS We propose a novel method of complement regulation in patients with SLE±APS whereby aFXa and aThr IgG may have differential effects on complement activation.
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Affiliation(s)
| | - Raj Amarnani
- Department of Rheumatology, University College London, London, UK
| | | | - Hajar Jbari
- Department of Rheumatology, University College London, London, UK
| | - Charis Pericleous
- National Heart and Lung Institute, Imperial College London, London, UK
| | - Valentina A Spiteri
- Department of Structural and Molecular Biology, University College London, London, UK
| | - Chris Wincup
- Department of Rheumatology, University College London, London, UK
| | - Bahar Artim-Esen
- Department of Internal Medicine, Istanbul University, Fatih, Turkey
| | - Ian Mackie
- Department of Haematology, University College London, London, UK
| | - Marina Botto
- National Heart and Lung Institute, Imperial College London, London, UK
- Imperial College Healthcare NHS Trust, London, UK
| | - Anisur Rahman
- Department of Rheumatology, University College London, London, UK
| | - Ian Giles
- Department of Rheumatology, University College London, London, UK
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Zhang Y, Song Y, Xia X, Wang J, Qian Y, Yuan C, Mao Y, Diao F, Liu J, Ma X. A retrospective study on IVF/ICSI outcomes in patients with persisted positive of anticardiolipin antibody: Effects of low-dose aspirin plus low molecular weight heparin adjuvant treatment. J Reprod Immunol 2022; 153:103674. [PMID: 35882076 DOI: 10.1016/j.jri.2022.103674] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 07/08/2022] [Accepted: 07/16/2022] [Indexed: 11/17/2022]
Abstract
Antiphospholipid (aPL) antibodies are more frequently detected among infertile women, but the association between aPL and in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) outcomes and whether need to get routine treatment are still controversial. The present study aims to find out whether infertile population with persistent aPL positive need treatment and which therapy is more effective. This retrospective study included 181 persistent aPL positive women, including 149 cases receiving anticoagulant treatment, either low-dose aspirin, low molecular weight heparin (LMWH) or aspirin plus LMWH adjuvant treatment (treated group), and 32 cases not receiving any treatment (untreated group). The treated group were further divided by combination therapy group (using both aspirin and LMWH，52 cases) and monotherapy group (only using aspirin，76 cases). The live birth rate and other clinical outcomes, including pregnancy rate, implantation rate, ongoing pregnancy rate and miscarriage rate were compared. The results show anticoagulant therapy can significantly improve live birth rate (59.06 % VS 34.48 %, P = 0.019), implantation rate (59.64 % VS 46.15 %, P＜0.001), ongoing pregnancy rate (59.73 % VS 34.38 %, P = 0.016), as well as reduce miscarriage rate (8.25 % VS 31.25 %, P＜0.001). Combination treatment of aspirin and LMWH exerts a higher live birth rate than monotherapy (75.00 % VS 53.95 %, P = 0.026). Infertile women with aPL positive might be classified as high-risk and low-risk aPL profiles. Those high-risk aPL positive infertile populations should be identified during IVF/ICSI and given corresponding thromboprophylaxis, and aspirin plus LMWH adjuvant treatment might be recommended.
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Affiliation(s)
- Yuan Zhang
- State Key Laboratory of Reproductive Medicine, the Center for Clinical Reproductive Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Yunjie Song
- Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Xinru Xia
- State Key Laboratory of Reproductive Medicine, the Center for Clinical Reproductive Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Jing Wang
- State Key Laboratory of Reproductive Medicine, the Center for Clinical Reproductive Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Yi Qian
- State Key Laboratory of Reproductive Medicine, the Center for Clinical Reproductive Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Chun Yuan
- State Key Laboratory of Reproductive Medicine, the Center for Clinical Reproductive Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Yundong Mao
- State Key Laboratory of Reproductive Medicine, the Center for Clinical Reproductive Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Feiyang Diao
- State Key Laboratory of Reproductive Medicine, the Center for Clinical Reproductive Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Jiayin Liu
- State Key Laboratory of Reproductive Medicine, the Center for Clinical Reproductive Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Xiang Ma
- State Key Laboratory of Reproductive Medicine, the Center for Clinical Reproductive Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
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Miao L, Lu Q. Anzi Heji Downregulates DNMT1 to Improve Anticardiolipin Antibody (ACA)-Positive Abortion by Regulating JAK/STAT Pathway. Nat Prod Commun 2022. [DOI: 10.1177/1934578x221112813] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Anzi Heji (AZHJ) is a traditional Chinese medicine compound prepared for long-term treatment of Anticardiolipin Antibody (ACA)-positive abortion, with small side effects and definite curative effect. Abortion was reported to be related to DNMT1, a methylation transferase regulated by JAK2 pathway, so this study aimed to explore whether AZHJ treated ACA-positive abortion by regulating the DNMT1. Cell proliferation estimation employed Cell counting kit-8 (CCK-8) and flow cytometry. Human β2-glycoprotein I (GPI) was used as an inducer to establish ACA-positive mice model. Western blot was applied to examine the expressions of DNMT1, FOXP3, IL-6, and JAK/STAT3 pathway-related proteins. ACA titers and IL-6 levels in peripheral blood were tested by enzyme-linked immunosorbent assay (ELISA). Placental tissue damage was assessed by hematoxylin and eosin (H&E) staining. Based on the findings from experiments, AZHJ could significantly inhibit apoptosis and regulate the proliferation activity of HTR-8/SVneo cells. AZHJ treatment reduced the expression levels of DNMT1, FOXP3, IL-6, and JAK/STAT3 signaling pathways-related proteins in HTR-8/SVneo cells and maternal–fetal interface (uterine decidua and placenta), and the titer of serum ACA was also significantly decreased. In addition, AZHJ effectively alleviated placental tissue damage caused by ACA-positive abortion compared with model group. To sum up, AZHJ may play a therapeutic role by inhibiting DNMT1 activation through Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway, and then promoting FOXP3 expression in maternal–fetal interface of pregnant mice, thereby improving immune tolerance at the maternal–fetal interface, preventing and treating ACA-positive abortion.
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Affiliation(s)
- Li Miao
- Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Provincial Second Traditional Chinese Medicine, Nanjing, China
| | - Qibin Lu
- Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China
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18
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Middeldorp S, Naue C, Köhler C. Thrombophilia, Thrombosis and Thromboprophylaxis in Pregnancy: For What and in Whom? Hamostaseologie 2022; 42:54-64. [PMID: 35196731 DOI: 10.1055/a-1717-7663] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Compared with nonpregnant women, pregnancy carries a four- to fivefold higher risk of venous thromboembolism (VTE). Despite increasing use of heparin prophylaxis in identified high-risk patients, pulmonary embolism still is the leading cause of maternal mortality in the western world. However, evidence on optimal use of thromboprophylaxis is scarce. Thrombophilia, the hereditary or acquired tendency to develop VTE, is also thought to be associated with complications in pregnancy, such as recurrent miscarriage and preeclampsia. In this review, the current evidence on optimal thromboprophylaxis in pregnancy is discussed, focusing primarily on VTE prevention strategies but also discussing the potential to prevent recurrent pregnancy complications with heparin in pregnant women with thrombophilia.
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Affiliation(s)
- Saskia Middeldorp
- Department of Internal Medicine, Radboud Institute of Health Sciences (RIHS), Radboud University Medical Center, Nijmegen, The Netherlands
| | - Christiane Naue
- Division of Hematology, Department of Medicine I, University Hospital "Carl Gustav Carus" Dresden, Dresden, Germany
| | - Christina Köhler
- Division of Hematology, Department of Medicine I, University Hospital "Carl Gustav Carus" Dresden, Dresden, Germany
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19
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Knight JS, Kanthi Y. Mechanisms of immunothrombosis and vasculopathy in antiphospholipid syndrome. Semin Immunopathol 2022; 44:347-362. [PMID: 35122116 PMCID: PMC8816310 DOI: 10.1007/s00281-022-00916-w] [Citation(s) in RCA: 88] [Impact Index Per Article: 29.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 01/19/2022] [Indexed: 12/14/2022]
Abstract
Antiphospholipid syndrome (APS) is an autoimmune thrombophilia propelled by circulating antiphospholipid antibodies that herald vascular thrombosis and obstetrical complications. Antiphospholipid antibodies recognize phospholipids and phospholipid-binding proteins and are not only markers of disease but also key drivers of APS pathophysiology. Thrombotic events in APS can be attributed to various conspirators including activated endothelial cells, platelets, and myeloid-lineage cells, as well as derangements in coagulation and fibrinolytic systems. Furthermore, recent work has especially highlighted the role of neutrophil extracellular traps (NETs) and the complement system in APS thrombosis. Beyond acute thrombosis, patients with APS can also develop an occlusive vasculopathy, a long-term consequence of APS characterized by cell proliferation and infiltration that progressively expands the intima and leads to organ damage. This review will highlight known pathogenic factors in APS and will also briefly discuss similarities between APS and the thrombophilic coagulopathy of COVID-19.
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Affiliation(s)
- Jason S Knight
- Division of Rheumatology, University of Michigan, 1150 West Medical Center Drive, Ann Arbor, MI, 48109, USA.
| | - Yogendra Kanthi
- Division of Intramural Research National Heart, Lung, and Blood Institute, Bethesda, MD, USA
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20
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Gamal S, Mohamed S, Moghazy A. Thrombocytopenia in a cohort of primary and secondary antiphospholipid syndrome patients: Relation to clinical, laboratory manifestations and damage index. Arch Rheumatol 2022; 37:252-260. [PMID: 36017208 PMCID: PMC9377168 DOI: 10.46497/archrheumatol.2022.9088] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2021] [Accepted: 09/06/2021] [Indexed: 11/24/2022] Open
Abstract
Objectives
This study aims to evaluate the prevalence of thrombocytopenia in a cohort of patients with primary and secondary antiphospholipid syndrome (APS) and to examine the relation of thrombocytopenia to the clinical, laboratory findings, and damage index for antiphospholipid syndrome (DIAPS). Patients and methods
Between August 2018 and February 2019, a total of 168 patients (16 males, 152 females; mean age: 32.5±8.4 years; range, 18 to 59 years) who were followed in our clinic for APS were retrospectively analyzed. Medical records of the patients were screened and clinical data, laboratory investigations, and treatments applied were recorded. The DIAPS was calculated for all patients. The patients were divided into two groups according to the presence or absence of thrombocytopenia and both groups were compared regarding clinical, laboratory findings and DIAPS. Further subgroup analysis was done for patients with primary APS. Results
The most common clinical manifestations in our patients were obstetric manifestations (77.4% in pregnant women), musculoskeletal manifestations (69%) and peripheral vascular thrombosis (54.8%). The prevalence of thrombocytopenia in our study was 42.3%, and it was significantly associated with musculoskeletal manifestations (p=0.043), vascular thrombosis (p=0.043), neurological manifestations (p=0.030), cutaneous manifestations (p=0.006), and use of immunosuppressives (p=0.047). The DIAPS was significantly higher in the thrombocytopenia group (p=0.034). Further subgroup analysis of patients with primary APS revealed that neurological manifestations (p=0.010) were significantly higher in the thrombocytopenia group, while the DIAPS was higher in the thrombocytopenia group, but it did not reach statistical significance (p=0.082). Conclusion
Thrombocytopenia may be associated with a higher incidence of vascular thrombosis, neurological manifestations, musculoskeletal manifestations, use of immunosuppressive treatment, and DIAPS. In primary APS patients, thrombocytopenia may be a risk for neurological manifestations.
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Affiliation(s)
- Sherif Gamal
- Department of Rheumatology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Samar Mohamed
- Department of Rheumatology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Abdelkawy Moghazy
- Department of Rheumatology, Faculty of Medicine, Cairo University, Cairo, Egypt
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21
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Zhang Y, Xia M, Song Y, Wang J, Mao Y, Liu J, Ma X. Long-term pituitary downregulation before frozen embryo transfer improves clinical outcomes in women positive for serum autoantibodies. Eur J Obstet Gynecol Reprod Biol 2021; 265:102-106. [PMID: 34482233 DOI: 10.1016/j.ejogrb.2021.08.018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 08/12/2021] [Accepted: 08/20/2021] [Indexed: 12/24/2022]
Abstract
OBJECTIVE Autoantibodies are associated with worse outcomes in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI), including increasing miscarriage rate, lowering pregnancy rate, and lowering delivery rate. However, little is known about improving IVF/ICSI outcomes for autoantibody-positive women, especially in frozen-thawed embryo transfer (FET) cycles. This study aimed to investigate whether pituitary suppression before FET improves the clinical pregnancy rate (CPR) and live birth rate (LBR) for IVF/ICSI women positive for serum autoantibodies. STUDY DESIGN A total of 181 infertile women positive for serum autoantibodies were recruited, including 65 women receiving GnRHa and hormone replacement therapy protocols (G-HRT group) and 116 women using modified natural cycles (MNC)/mild stimulated cycles (MSC) as FET protocols (MNC/MSC group). The outcomes were compared between two groups, including CPR, implantation rate (IR), miscarriage rate (MR), ongoing pregnancy rate (OPR), LBR, and gestational age (GA). The primary outcome of the study was CPR. RESULTS CPR, OPR, and LBR per embryo transferred in the G-HRT groups were significantly higher than those in the MNC/MSC group. No statistically significant differences were observed in the IR and MR. The CPR, IR, MR, OPR, and LBR was 72.23%, 64.00%, 12.77%, 63.07%, and 63.07% in the G-HRT group, respectively, while that was 56.90%, 53.07%, 10.60%, 50.00%, and 50.00% in the MNC/MSC group, respectively. After adjusting for partial potential confounding factors using multiple logistic regression, the type of endometrial preparation is the factor independently associated with enhanced CPR (OR = 0.48, 95%CI: 0.24-0.96, P = 0.039). CONCLUSIONS The current study showed that prior long-term GnRHa suppression could benefit patients with high serum autoantibody levels during IVF/ICSI FET cycles.
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Affiliation(s)
- Yuan Zhang
- State Key Laboratory of Reproductive Medicine, the Center for Clinical Reproductive Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Meng Xia
- State Key Laboratory of Reproductive Medicine, the Center for Clinical Reproductive Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Yunjie Song
- Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Jing Wang
- State Key Laboratory of Reproductive Medicine, the Center for Clinical Reproductive Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Yundong Mao
- State Key Laboratory of Reproductive Medicine, the Center for Clinical Reproductive Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Jiayin Liu
- State Key Laboratory of Reproductive Medicine, the Center for Clinical Reproductive Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Xiang Ma
- State Key Laboratory of Reproductive Medicine, the Center for Clinical Reproductive Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
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22
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Xi F, Cai Y, Lv M, Jiang Y, Zhou F, Chen Y, Jiang L, Luo Q. Anticardiolipin Positivity Is Highly Associated With Intrauterine Growth Restriction in Women With Antiphospholipid Syndrome. Clin Appl Thromb Hemost 2021; 26:1076029620974455. [PMID: 33296221 PMCID: PMC7731596 DOI: 10.1177/1076029620974455] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
The purpose of our study was to evaluate pregnancy outcomes of women with antiphospholipid antibodies (aPL) positivity and assess risk factors associated with adverse pregnancy outcomes. Pregnant women with aPL positivity were enrolled prospectively in China from January 2017 to March 2020. Treatment of low-dose aspirin and low molecular weight heparin were given. Pregnancy outcomes and coagulation function were recorded and compared with normal pregnancies. Multivariable logistic regression was performed to identify risk factors associated to intrauterine growth restriction (IUGR). 270 pregnant women, including 44 diagnosed as Antiphospholipid syndrome (APS), 91 as non-criteria APS (NCAPS) and 135 normal cases as control, were enrolled in the study. The live birth rate in aPL carriers and APS group was 97% and 95.5%, respectively. Adverse pregnancy outcomes did not show significant difference between aPL carriers and normal pregnancies, and between APS and NCAPS, except for IUGR. The incidence of IUGR was significantly higher in aPL carriers than normal pregnancies, and in APS patients than NCAPS (P < 0.05). After controlling for age, in vitro fertilization (IVF), pregnancy losses related to APS and treatment, anticardiolipin (aCL) positivity was the only variable significantly associated with IUGR, with an adjusted odds ratio of 4.601 (95% CI, 1.205-17.573). Better pregnant outcomes of aPL positive women, include APS and NCAPS, were achieved in our study with treatment based on low-dose aspirin (LDA) plus low molecular weight heparin (LMWH). The incidence of IUGR was still higher in them, and aCL positivity was the only one risk factor associated with IUGR.
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Affiliation(s)
- Fangfang Xi
- Department of Obstetrics, Zhejiang University School of Medicine Women's Hospital, Zhejiang, China
| | - Yuliang Cai
- Department of Obstetrics, Shaoxing Maternity and Child Health Care Hospital, Zhejiang University School of Medicine, Shaoxing, China
| | - Min Lv
- Department of Obstetrics, Zhejiang University School of Medicine Women's Hospital, Zhejiang, China
| | - Ying Jiang
- Department of Obstetrics, Zhejiang University School of Medicine Women's Hospital, Zhejiang, China
| | - Feifei Zhou
- Departments of TCM Gynecology, Zhejiang University School of Medicine Women's Hospital, Hangzhou, China
| | - Yuan Chen
- Department of Obstetrics, Zhejiang University School of Medicine Women's Hospital, Zhejiang, China
| | - Lin Jiang
- Department of Obstetrics, Zhejiang University School of Medicine Women's Hospital, Zhejiang, China
| | - Qiong Luo
- Department of Obstetrics, Zhejiang University School of Medicine Women's Hospital, Zhejiang, China
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23
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Pérez-Crespo A, Gutiérrez-Ortiz C. Retinal arterial and venous obstruction as the first manifestation of an antiphospholipid antibody syndrome. ARCHIVOS DE LA SOCIEDAD ESPANOLA DE OFTALMOLOGIA 2021; 96:380-383. [PMID: 34217476 DOI: 10.1016/j.oftale.2020.06.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Accepted: 06/08/2020] [Indexed: 06/13/2023]
Abstract
CASE REPORT A 34 year-old woman presented with decrease in visual acuity in her right eye (RE). Her past medical history was unremarkable. Dilated fundus examination revealed a central venous occlusion and an obstruction of the cilioretinal artery. Given the patient age, a cardiology and haematology screen was obtained to rule out hypercoagulation disorders and thromboembolic disease. Antiplatelet, anticoagulant, and corticosteroid therapy were started. The laboratory result was positive for anticardiolipin and antiphospholipid antibody. A diagnosis of antiphospholipid syndrome (APS) was made. DISCUSSION Antiphospholipid syndrome may cause thrombosis in any organ. The involvement of the retinal vessels may be the first manifestation of this entity. This diagnosis is important to prevent recurrent thrombotic events.
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Affiliation(s)
- A Pérez-Crespo
- Licenciada en Medicina y Cirugía. Hospital Príncipe de Asturias, Servicio de Oftalmología, Alcalá de Henares, Madrid, Spain
| | - C Gutiérrez-Ortiz
- Doctora en Medicina y Cirugía. Hospital Príncipe de Asturias, Servicio de Oftalmología, Alcalá de Henares, Madrid, Spain.
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Capozzi A, Riitano G, Mancuso S, Recalchi S, Manganelli V, Garofalo T, Alessandri C, Longo A, Misasi R, Conti F, Truglia S, Sorice M. Anti-vimentin/cardiolipin IgA in the anti-phospholipid syndrome: A new tool for 'seronegative' diagnosis. Clin Exp Immunol 2021; 205:326-332. [PMID: 34107056 PMCID: PMC8374216 DOI: 10.1111/cei.13633] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 05/28/2021] [Accepted: 05/28/2021] [Indexed: 12/14/2022] Open
Abstract
Anti-phospholipid syndrome (APS) is a systemic autoimmune disorder defined by the simultaneous presence of vascular clinical events, pregnancy morbidity and anti-phospholipid antibodies (aPL). In clinical practice, it is possible to find patients with APS who are persistently negative for the routine aPL tests (seronegative APS; SN-APS). Recently, the identification of aPL immunoglobulin (Ig)A and/or anti-β2-glycoprotein-I (β2-GPI) IgA was shown to represent a further test in SN-APS patients. In this study we analyzed the presence of anti-vimentin/cardiolipin (aVim/CL) IgA in a large cohort of patients with SN-APS, evaluating their possible association with clinical manifestations of the syndrome. This study includes 60 consecutive SN-APS patients, 30 patients with APS and 40 healthy donors. aVim/CL IgA were detected by enzyme-linked immunosorbent assay (ELISA). Results show that 12 of 30 APS patients (40%) and 16 of 60 SN-APS patients (26.7%) resulted positive for aVim/CL IgA. Interestingly, SN-APS patients who tested positive for aVim/CL IgA showed a higher prevalence of arterial thrombosis (p = 0.017, likelihood positive ratio = 5.7). This study demonstrates for the first time, to our knowledge, the presence of aVim/CL IgA in sera of patients with APS. In particular, they revealed a potential usefulness in identification of a significant proportion of SN-APS patients. Moreover, as patients tested positive for aVim/CL IgA reported a high likelihood ratio to have the clinical features of APS, this test may be considered a suitable approach in the clinical evaluation of SN-APS.
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Affiliation(s)
- Antonella Capozzi
- Dipartimento di Medicina Sperimentale, Sapienza University, Rome, Italy
| | - Gloria Riitano
- Dipartimento di Medicina Sperimentale, Sapienza University, Rome, Italy
| | - Silvia Mancuso
- Reumatologia, Dipartimento di Scienze Cliniche Internistiche, Anestesiologiche Cardiovascolari, Sapienza University, Rome, Italy
| | - Serena Recalchi
- Dipartimento di Medicina Sperimentale, Sapienza University, Rome, Italy
| | | | - Tina Garofalo
- Dipartimento di Medicina Sperimentale, Sapienza University, Rome, Italy
| | - Cristiano Alessandri
- Reumatologia, Dipartimento di Scienze Cliniche Internistiche, Anestesiologiche Cardiovascolari, Sapienza University, Rome, Italy
| | - Agostina Longo
- Dipartimento di Medicina Sperimentale, Sapienza University, Rome, Italy
| | - Roberta Misasi
- Dipartimento di Medicina Sperimentale, Sapienza University, Rome, Italy
| | - Fabrizio Conti
- Reumatologia, Dipartimento di Scienze Cliniche Internistiche, Anestesiologiche Cardiovascolari, Sapienza University, Rome, Italy
| | - Simona Truglia
- Reumatologia, Dipartimento di Scienze Cliniche Internistiche, Anestesiologiche Cardiovascolari, Sapienza University, Rome, Italy
| | - Maurizio Sorice
- Dipartimento di Medicina Sperimentale, Sapienza University, Rome, Italy
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Wirestam L, Gullstrand B, Jern A, Jönsen A, Linge P, Tydén H, Kahn R, Bengtsson AA. Low Intra-Individual Variation in Mean Platelet Volume Over Time in Systemic Lupus Erythematosus. Front Med (Lausanne) 2021; 8:638750. [PMID: 33959622 PMCID: PMC8093559 DOI: 10.3389/fmed.2021.638750] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 03/23/2021] [Indexed: 12/13/2022] Open
Abstract
Platelets have recently emerged as important immune modulators in systemic lupus erythematosus (SLE), in addition to their role in thrombosis and cardiovascular disease. However, studies investigating mean platelet volume (MPV) in SLE are often scarce, conflicting and cross-sectional. In this study, MPV was measured in clinical routine throughout a defined time-period to quantify both individual MPV fluctuations and investigate if such variations are associated with disease activity and clinical phenotypes of SLE. Of our 212 patients, 34 patients had only one MPV value reported with the remaining 178 patients having between 2 and 19 visits with recorded MPV values. The intra-individual MPV variation was low, with a median variation of 0.7 fL. This was further supported by the finding that 84% of patients stayed within their reference interval category (i.e., small, normal or large) over time. In our cohort, no correlation between disease activity and MPV neither cross-sectionally nor longitudinally was found. Mean platelet volume values were significantly smaller in SLE patients (mean 10.5 fL) compared to controls (mean 10.8 fL), p < 0.0001. Based on the reference interval, 2.4% (n = 5) of patients had large-sized platelets, 84.4% (n = 179) had normal-sized and 13.2% (n = 28) had small-sized. A larger proportion (85.7%) of patients with small-sized platelets met the anti-dsDNA criterion (ACR10b; p = 0.003) compared to patients with normal and large (57.6%) sized platelets. In conclusion, the intra-individual MPV variation was of low magnitude and fluctuations in disease activity did not have any significant impact on MPV longitudinally. This lack of variability in MPV over time indicates that measuring MPV at any time-point is sufficient. Further studies are warranted to evaluate MPV as a possible biomarker in SLE, as well as to determine the underlying mechanisms influencing platelet size in SLE.
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Affiliation(s)
- Lina Wirestam
- Section of Rheumatology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
| | - Birgitta Gullstrand
- Section of Rheumatology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
| | - Andreas Jern
- Section of Rheumatology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
| | - Andreas Jönsen
- Section of Rheumatology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
| | - Petrus Linge
- Section of Rheumatology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
| | - Helena Tydén
- Section of Rheumatology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
| | - Robin Kahn
- Section of Pediatrics, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.,Wallenberg Centre of Molecular Medicine, Lund University, Lund, Sweden
| | - Anders A Bengtsson
- Section of Rheumatology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
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Hasenfuß G, Schellong S. [Less is more in cardiology and angiology]. Internist (Berl) 2021; 62:379-384. [PMID: 33651136 DOI: 10.1007/s00108-021-00982-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/01/2021] [Indexed: 11/26/2022]
Abstract
Cardiovascular medicine is one of the most resource-consuming parts of the healthcare system and many examples of overdiagnostic and overtreatment can be found. The present article presents just three of these, one from cardiology and two from vascular medicine. The topic of chronic coronary heart disease concerns the unequivocal proof of ischemia before a coronary intervention. The sections on Duplex sonography of the cervical blood vessels and the diagnostics of thrombophilia describe which valid clinical problems may justify the performance of these examinations at all. The potential for harm caused by overdiagnostics in both cases lies not only in the unnecessary use of resources but, more importantly, in the subsequent overtreatment. The few appropriate indications are described in detail.
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Affiliation(s)
- G Hasenfuß
- Klinik für Kardiologie und Pneumologie, Herzzentrum Göttingen, Universitätsmedizin Göttingen, Göttingen, Deutschland
| | - S Schellong
- 2. Medizinische Klinik, Städtisches Klinikum Dresden, Friedrichstraße 41, 01069, Dresden, Deutschland.
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Current Promising Biomarkers and Methods in the Diagnostics of Antiphospholipid Syndrome: A Review. Biomedicines 2021; 9:biomedicines9020166. [PMID: 33567576 PMCID: PMC7914732 DOI: 10.3390/biomedicines9020166] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 01/30/2021] [Accepted: 02/02/2021] [Indexed: 12/17/2022] Open
Abstract
Antiphospholipid syndrome (APS) is a hypercoagulation condition associated with the incidence of heterogenic antiphospholipid antibodies (aPLs), which non-specifically affect hemostasis processes. APS is clinically manifested by recurrent arterial and venous thromboses and reproduction losses. The aPL antibodies, which may induce clinical manifestations of APS, include criteria antibodies anti-cardiolipin, anti-β2-glycoprotein-I, and lupus anticoagulant, but also non-criteria antibodies, for example anti-β2-glycoprotein-I domain I, anti-phosphatidylserine/prothrombin, anti-annexin V, and many others. APS occurs mostly in patients of younger and middle age, most frequently in females. Laboratory diagnostics of APS are quite difficult, as they include a wide spectrum of examining methods, which are based on various principles of detection and are performed using various laboratory techniques. The objective of the review is to describe the current state of potentially examined biomarkers and methods in APS diagnostics. The aforementioned biomarkers are lupus anticoagulant, anti-β2-glycoprotein-I, anti-cardiolipin, anti-β2-glycoprotein-I domain I, anti-phosphatidylserine/prothrombin, anti-β2-glycoprotein-I IgA, anti-cardiolipin IgA, anti-annexin V and II, anti-prothrombin, anti-cardiolipin/vimentin, anti-protein S/protein C, and antibodies against phospholipid antigens for whose diagnostics we may use some of the methods established for a long time and some of the modern methods—the coagulation method for the determination of lupus anticoagulant (LA), enzyme-linked imunosorbent assay (ELISA), chemiluminescence analysis (CLIA), multiplex fluorescence flow immunoassay (MFFIA), fluorescence enzyme immunoassay (EliA), line immunoassay (LIA), multiline dot assay (MLDA), and thin-layer chromatography (TLC). Conclusion: Antibodies against phosphatidylethanolamine, phosphatidic acid, phosphatidylserine, phosphatidylinositol, cardiolipin/vimentin complex, and annexin V are currently the most studied new markers. However, these assays have not been standardized until now, both from the laboratory and clinical point of view. In this review we summarize the evidence of the most studied aPL markers and their potential clinical significance in seronegative APS (SN-APS).
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Gasparini G, Canepa P, Verdiani S, Carmisciano L, Cozzani E, De Grazia D, Andrea O, Icardi G, Parodi A. A retrospective study on the prevalence of anti-phospholipid antibodies, thrombotic events and cutaneous signs of vasculopathy in 173 hospitalized COVID-19 patients. Int J Immunopathol Pharmacol 2021; 35:20587384211042115. [PMID: 34541915 PMCID: PMC8460963 DOI: 10.1177/20587384211042115] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Hypercoagulability is a risk factor of thromboembolic events in COVID-19. Anti-phospholipid (aPL) antibodies have been hypothesized to be involved. Typical COVID-19 dermatological manifestations of livedo reticularis and digital ischemia may resemble cutaneous manifestations of anti-phospholipid syndrome (APS). OBJECTIVES To investigate the association between aPL antibodies and thromboembolic events, COVID-19 severity, mortality, and cutaneous manifestations in patients with COVID-19. METHODS aPL antibodies [anti-beta2-glycoprotein-1 (B2GP1) and anti-cardiolipin (aCL) antibodies] were titered in frozen serum samples from hospitalized COVID-19 patients and the patients' clinical records were retrospectively analyzed. RESULTS 173 patients were enrolled. aPL antibodies were detected in 34.7% of patients, anti-B2GP1 antibodies in 30.1%, and aCL antibodies in 10.4%. Double positivity was observed in 5.2% of patients. Thromboembolic events occurred in 9.8% of patients, including 11 pulmonary embolisms, 1 case of celiac tripod thrombosis, and six arterial ischemic events affecting the cerebral, celiac, splenic, or femoral-popliteal arteries or the aorta. aPL antibodies were found in 52.9% of patients with vascular events, but thromboembolic events were not correlated to aPL antibodies (adjusted OR = 1.69, p = 0.502). Ten patients (5.8%) had cutaneous signs of vasculopathy: nine livedo reticularis and one acrocyanosis. No significant association was observed between the presence of cutaneous vasculopathy and aPL antibodies (p = 0.692). CONCLUSIONS Anti-phospholipid antibodies cannot be considered responsible for hypercoagulability and thrombotic events in COVID-19 patients. In COVID-19 patients, livedo reticularis and acrocyanosis do not appear to be cutaneous manifestations of APS.
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Affiliation(s)
- Giulia Gasparini
- Section of Dermatology, Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy
- Dermatology Unit, Ospedale Policlinico San MartinoIRCCS, Genoa, Italy
- Department of Experimental Medicine (DIMES), University of Genoa, Genoa, Italy
| | - Paola Canepa
- Section of Dermatology, Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy
| | - Simonetta Verdiani
- Section of Dermatology, Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy
| | - Luca Carmisciano
- Section of Statistics, Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy
| | - Emanuele Cozzani
- Section of Dermatology, Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy
- Dermatology Unit, Ospedale Policlinico San MartinoIRCCS, Genoa, Italy
| | - Denise De Grazia
- Section of Dermatology, Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy
| | - Orsi Andrea
- Hygiene and Preventive medicine Unit, Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy
- Hygiene and Preventive medicine Unit, Ospedale Policlinico San MartinoIRCCS, Genoa, Italy
| | - Giancarlo Icardi
- Hygiene and Preventive medicine Unit, Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy
- Hygiene and Preventive medicine Unit, Ospedale Policlinico San MartinoIRCCS, Genoa, Italy
| | - Aurora Parodi
- Section of Dermatology, Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy
- Dermatology Unit, Ospedale Policlinico San MartinoIRCCS, Genoa, Italy
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Yu X, He L. Aspirin and heparin in the treatment of recurrent spontaneous abortion associated with antiphospholipid antibody syndrome: A systematic review and meta-analysis. Exp Ther Med 2021; 21:57. [PMID: 33365057 PMCID: PMC7716630 DOI: 10.3892/etm.2020.9489] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Accepted: 03/17/2020] [Indexed: 12/19/2022] Open
Abstract
The present study aimed to review relevant, randomized, controlled trials in order to determine the effects of aspirin and heparin treatment on recurrent spontaneous abortion (RSA) in women with antiphospholipid syndrome (APS). Previous relevant studies were identified using PubMed, Cochrane, Embase, CNKI, VANFUN and VIP by retrieving appropriate key words. Additionally, key relevant sources in the literature were reviewed and articles published before May 2019 were included. The 22 selected studies included 1,515 patients in the treatment group and 1,531 patients in the control group. These previous studies showed that heparin and aspirin significantly improved live birth rate when compared with treatments using intravenous immunoglobulin, aspirin alone or aspirin combined with prednisone. Moreover, heparin and aspirin greatly increased the birth weight compared with placebo and improved vaginal delivery relative to intravenous immunoglobulin. The gestational age at birth was significantly higher in the heparin and aspirin group compared with the placebo group and the incidence of intrauterine growth restriction was lower in the heparin and aspirin group compared with the placebo group. Furthermore, heparin and aspirin markedly reduced the incidence of miscarriage compared with the aspirin group and the placebo group, and the incidence of pre-eclampsia was lower in the heparin and aspirin group than the placebo group. Thus, heparin and aspirin could be further examined for the treatment of RSA in women with APS.
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Affiliation(s)
- Xiaomei Yu
- Department of Obstetrics, Ward 1, Weifang People's Hospital, Weifang, Shandong 261041, P.R. China
| | - Li He
- Department of Women's Health Care, Chongqing Health Center for Women and Children, Yubei, Chongqing 401147, P.R. China
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Misasi R, Longo A, Recalchi S, Caissutti D, Riitano G, Manganelli V, Garofalo T, Sorice M, Capozzi A. Molecular Mechanisms of "Antiphospholipid Antibodies" and Their Paradoxical Role in the Pathogenesis of "Seronegative APS". Int J Mol Sci 2020; 21:ijms21218411. [PMID: 33182499 PMCID: PMC7665122 DOI: 10.3390/ijms21218411] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 10/30/2020] [Accepted: 11/06/2020] [Indexed: 02/06/2023] Open
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.
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Martinez GP, Zabaleta ME, Di Giulio C, Charris JE, Mijares MR. The Role of Chloroquine and Hydroxychloroquine in Immune Regulation and Diseases. Curr Pharm Des 2020; 26:4467-4485. [DOI: 10.2174/1381612826666200707132920] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 05/27/2020] [Indexed: 02/06/2023]
Abstract
Chloroquine (CQ) and hydroxychloroquine (HCQ) are derivatives of the heterocyclic aromatic compound
quinoline. These economical compounds have been used as antimalarial agents for many years. Currently,
they are used as monotherapy or in conjunction with other therapies for the treatment of autoimmune diseases
such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjögren's syndrome (SS) and antiphospholipid
antibody syndrome (APS). Based on its effects on the modulation of the autophagy process, various
clinical studies suggest that CQ and HCQ could be used in combination with other chemotherapeutics for the
treatment of various types of cancer. Furthermore, the antiviral effects showed against Zika, Chikungunya, and
HIV are due to the annulation of endosomal/lysosomal acidification. Recently, CQ and HCQ were approved for
the U.S. Food and Drug Administration (FDA) for the treatment of infected patients with the coronavirus SARSCoV-
2, causing the disease originated in December 2019, namely COVID-2019. Several mechanisms have been
proposed to explain the pharmacological effects of these drugs: 1) disruption of lysosomal and endosomal pH, 2)
inhibition of protein secretion/expression, 3) inhibition of antigen presentation, 4) decrease of proinflammatory
cytokines, 5) inhibition of autophagy, 6) induction of apoptosis and 7) inhibition of ion channels activation. Thus,
evidence has shown that these structures are leading molecules that can be modified or combined with other
therapeutic agents. In this review, we will discuss the most recent findings in the mechanisms of action of CQ and
HCQ in the immune system, and the use of these antimalarial drugs on diseases.
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Affiliation(s)
- Gricelis P. Martinez
- Institute of Immunology, Faculty of Medicine, Central University of Venezuela, 50109, Los Chaguaramos 1050-A, Caracas, Venezuela
| | - Mercedes E. Zabaleta
- Institute of Immunology, Faculty of Medicine, Central University of Venezuela, 50109, Los Chaguaramos 1050-A, Caracas, Venezuela
| | - Camilo Di Giulio
- Institute of Immunology, Faculty of Medicine, Central University of Venezuela, 50109, Los Chaguaramos 1050-A, Caracas, Venezuela
| | - Jaime E. Charris
- Organic Synthesis Laboratory, Faculty of Pharmacy, Central University of Venezuela, 47206, Los Chaguaramos 1041-A, Caracas, Venezuela
| | - Michael R. Mijares
- Institute of Immunology, Faculty of Medicine, Central University of Venezuela, 50109, Los Chaguaramos 1050-A, Caracas, Venezuela
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Yazıcı A. Definition and treatment approach of non-criteria clinical manifestations of antiphospholipid syndrome. Eur J Rheumatol 2020; 7:180-183. [PMID: 35929896 PMCID: PMC7574762 DOI: 10.5152/eurjrheum.2020.20099] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2020] [Accepted: 08/11/2020] [Indexed: 03/27/2024] Open
Abstract
Antiphospholipid syndrome (APS) is characterized by thrombosis and/or pregnancy morbidity with persistently positive antiphospholipid antibodies. However, in APS, there are several non-thrombotic clinical manifestations such as thrombocytopenia, cardiac valve disease, microthrombotic nephropathy, skin ulcer, or cognitive dysfunction. These non-criteria manifestations are relatively common and usually are non-responsive to anticoagulation. Among the non-criteria manifestations, thrombocytopenia, skin ulcers, migraine, and heart valve lesions are the most frequent manifestations described in APS. Limited data are available on the treatment of non-criteria manifestations of APS, and most therapeutic options are based on case reports or retrospective non-randomized studies. Although there is no consensus on the treatment of non-criteria manifestations of APS, anticoagulant therapy and immunomodulatory drugs could be combined in most patients.
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Affiliation(s)
- Ayten Yazıcı
- Division of Rheumatology, Department of Internal Medicine, Kocaeli University School of Medicine, Kocaeli, Turkey
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Huseynov A, Haselmann V, Kittel M, Bertsch T, Alonso A, Neumaier M, Borggrefe M, Hoffmann U. Lupus Antibody Mimicking Reduced Plasmatic Coagulation in a Patient With Atrial Fibrillation and Ischemic Stroke. Front Neurol 2020; 11:896. [PMID: 32973661 PMCID: PMC7472954 DOI: 10.3389/fneur.2020.00896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Accepted: 07/13/2020] [Indexed: 11/13/2022] Open
Abstract
Background: Lupus anticoagulant (LA) owns procoagulant properties in vivo and prolongs phospholipid-dependent clotting times in vitro. The prolonged in vitro clotting time can be misinterpreted as a bleeding disorder. In some cases, it is necessary to differentiate LA-associated in vitro changes from in vivo coagulation factor deficiency. In this case, we used different laboratory testing in a patient with ischemic stroke and reduced prothrombin time (PT) to identify an in-vitro effect of LA excluding an in-vivo bleeding disorder. Methods: The activity of various coagulation factors was evaluated both with recombinant thromboplastin Innovin (Siemens Healthcare) and reagent tissue extracted thromboplastin Thromborel® (Siemens Healthcare). Moreover, a 1:1 plasma mixing test with standard plasma was performed. In order to exclude the interaction of tromboplastin and LA thromboplastin, an independent global coagulation test, thromboelastography, was used. Diluted-Russel-Viper-Venom (dRVVT) assay was applied to detect the presence of LA detection. Results: The activity of several coagulation factors measured with recombinant thromboplastin Innovin (Siemens Healthcare) showed a reduced activity of the following coagulation factors: Factor V (20.9%), Factor VII (23.8%), Factor X (19.7%) and international normalized ratio (INR) of 2.33. Re-assessment of the factor's activity with another reagent tissue extracted thromboplastin Thromborel® (Siemens Healthcare) showed a normalization of INR and factor's activity in comparison to thromboplastin reagent Innovin®: Factor V (77%), Factor VII (45.4%), Factor X (64.2%), and INR of 1.28. A plasma mixing study with 1:1 standard plasma revealed reduced (<50%) normalization of INR as well as coagulation factor's activity confirming a LA-inhibitor in the patient plasma. Diagnostic LA testing was also performed with dRVVT assay showing a significantly prolonged (112.8 s) test time. Thromboelastography revealed no abnormalities. Conclusions: Different thromboplastin reagents and plasma mixing tests as well as thromboplastin independent coagulation tests may be helpful to differentiate LA and in vitro changes from in vivo factor deficiency in patients with LA.
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Affiliation(s)
- Aydin Huseynov
- First Department of Medicine, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.,DZHK (Deutsches Zentrum für Herz-Kreislauf-Forschung - German Centre for Cardiovascular Research), Mannheim, Germany
| | - Verena Haselmann
- Medical Faculty Mannheim, Institute for Clinical Chemistry, University of Heidelberg, Mannheim, Germany
| | - Maximillian Kittel
- Medical Faculty Mannheim, Institute for Clinical Chemistry, University of Heidelberg, Mannheim, Germany
| | - Thomas Bertsch
- Laboratory Medicine and Transfusion Medicine, Institute of Clinical Chemistry, Nuremberg General Hospital, Paracelsus Medical University, Nuremberg, Germany
| | - Angelika Alonso
- Department of Neurology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Michael Neumaier
- Medical Faculty Mannheim, Institute for Clinical Chemistry, University of Heidelberg, Mannheim, Germany
| | - Martin Borggrefe
- First Department of Medicine, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.,DZHK (Deutsches Zentrum für Herz-Kreislauf-Forschung - German Centre for Cardiovascular Research), Mannheim, Germany
| | - Ursula Hoffmann
- First Department of Medicine, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.,DZHK (Deutsches Zentrum für Herz-Kreislauf-Forschung - German Centre for Cardiovascular Research), Mannheim, Germany
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Bhattacharjee S, Banerjee M. Immune Thrombocytopenia Secondary to COVID-19: a Systematic Review. ACTA ACUST UNITED AC 2020; 2:2048-2058. [PMID: 32984764 PMCID: PMC7501509 DOI: 10.1007/s42399-020-00521-8] [Citation(s) in RCA: 193] [Impact Index Per Article: 38.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/10/2020] [Indexed: 01/08/2023]
Abstract
Immune thrombocytopenia, often known as immune thrombocytopenic purpura (ITP), has emerged as an important complication of COVID-19. A systematic review was done to analyze the clinical profile and outcomes in a total of 45 cases of new-onset ITP in COVID-19 patients described in literature until date. A comprehensive approach is essential for diagnosing COVID-19-associated ITP after excluding several concomitant factors that can cause thrombocytopenia in COVID-19. Majority of ITP cases (71%) were found to be elderly (> 50 years) and 75% cases had moderate-to-severe COVID-19. Three patients (7%) were in the pediatric age group. Reports of ITP in asymptomatic COVID-19 patients (7%) underscore the need for COVID-19 testing in newly diagnosed patients with ITP irrespective of COVID-19 symptoms amid this pandemic. ITP onset occurred in 20% cases 3 weeks after onset of COVID-19 symptoms, with many reports after clinical recovery. SARS-CoV-2-mediated immune thrombocytopenia can be attributed to the underlying immune dysregulation, susceptibility mutations in SOCS 1, and other mechanisms, including molecular mimicry, cryptic antigen expression, and epitope spreading. No bleeding manifestations were reported in 31% cases at diagnosis. Severe life-threatening bleeding was uncommon. One case of mortality was attributed to intracranial hemorrhage. Secondary Evans syndrome was diagnosed in one case. Good initial response to short course of glucocorticoids and intravenous immunoglobulin has been found with the exception of delayed lag response in one case. Thrombopoietin receptor agonist usage as a second-line agent has been noted in few cases for short duration with no adverse events. In the relatively short follow-up period, four relapses of ITP were found.
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Affiliation(s)
- Sukrita Bhattacharjee
- Department of Hematology, Institute of Hematology and Transfusion Medicine, Medical College and Hospital, Kolkata, India
| | - Mainak Banerjee
- Institute of Post Graduate Medical Education and Research, Kolkata, India
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35
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Lettau M, Schrezenmeier EV, Specker C, Dörner T. [Lupus and thrombophilia : Antiphospholipid syndrome]. Z Rheumatol 2020; 79:332-341. [PMID: 32300863 DOI: 10.1007/s00393-020-00786-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Even early on thromboembolic events were observed in patients with systemic lupus erythematosus (SLE) until the antiphospholipid syndrome (APS) was described in the 1980s as an independent disorder. The APS is a systemic autoimmune disease often overlapping with SLE in which antiphospholipid autoantibodies, including lupus anticoagulant, can cause a hypercoagulation state, which clinically by definition is manifested as arterial and venous occlusions or pregnancy complications. The pathophysiology has not yet been entirely delineated and the clinical spectrum of associated concomitant manifestations is large. As the mortality is increased with SLE and simultaneous APS, focused diagnostics and risk assessment are indispensable. According to the recently published recommendations of the European League Against Rheumatism the therapeutic strategy comprises individualized secondary prevention of thromboembolic complications by means of anticoagulation (with unaltered importance of vitamin K antagonists) and thrombocyte aggregation inhibition, usually lifelong. Statins and antimalarial drugs are recommended for vascular protection while immunosuppressive treatment has not so far been sufficiently proven for APS but remains the subject of current research.
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Affiliation(s)
- M Lettau
- Medizinische Klinik mit Schwerpunkt Rheumatologie und Klinische Immunologie, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Deutschland.,Deutsches Rheuma-Forschungszentrum Berlin (DRFZ), 10117, Berlin, Deutschland
| | - E V Schrezenmeier
- Medizinische Klinik mit Schwerpunkt Rheumatologie und Klinische Immunologie, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Deutschland.,Deutsches Rheuma-Forschungszentrum Berlin (DRFZ), 10117, Berlin, Deutschland.,Medizinische Klinik mit Schwerpunkt Nephrologie und Internistische Intensivmedizin, Charité - Universitätsmedizin Berlin, 10117, Berlin, Deutschland
| | - C Specker
- Kliniken Essen-Mitte, Klinik für Rheumatologie und Klinische Immunologie, 45239, Essen, Deutschland
| | - T Dörner
- Medizinische Klinik mit Schwerpunkt Rheumatologie und Klinische Immunologie, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Deutschland. .,Deutsches Rheuma-Forschungszentrum Berlin (DRFZ), 10117, Berlin, Deutschland.
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Abstract
PURPOSE OF REVIEW Antiphospholipid syndrome (APS) is a thrombo-inflammatory disease that is primarily treated with anticoagulation. Better understanding the inflammatory aspects of APS could lead to safer, more effective, and more personalized therapeutic options. To this end, we sought to understand recent literature related to the role of neutrophils and, in particular, neutrophil extracellular traps (NETs) in APS. RECENT FINDINGS Expression of genes associated with type I interferons, endothelial adhesion, and pregnancy regulation are increased in APS neutrophils. APS neutrophils have a reduced threshold for NET release, which likely potentiates thrombotic events and perhaps especially large-vein thrombosis. Neutrophil-derived reactive oxygen species also appear to play a role in APS pathogenesis. There are new approaches for preventing and disrupting NETs that could potentially be leveraged to reduce the risk of APS-associated thrombosis. Neutrophils and NETs contribute to APS pathophysiology. More precisely understanding their roles at a mechanistic level should help identify new therapeutic targets for inhibiting NET formation, enhancing NET dissolution, and altering neutrophil adhesion. Such approaches may ultimately lead to better clinical management of APS patients and thereby reduce the chronic burden of this disease.
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Gul M, Azari Jafari A, Shah M, Mirmoeeni S, Haider SU, Moinuddin S, Chaudhry A. Molecular Biomarkers in Multiple Sclerosis and Its Related Disorders: A Critical Review. Int J Mol Sci 2020; 21:E6020. [PMID: 32825639 PMCID: PMC7547375 DOI: 10.3390/ijms21176020] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 08/10/2020] [Accepted: 08/14/2020] [Indexed: 12/17/2022] Open
Abstract
Multiple sclerosis (MS) is a chronic autoimmune disease affecting the central nervous system (CNS) which can lead to severe disability. Several diseases can mimic the clinical manifestations of MS. This can often lead to a prolonged period that involves numerous tests and investigations before a definitive diagnosis is reached. As well as the possibility of misdiagnosis. Molecular biomarkers can play a unique role in this regard. Molecular biomarkers offer a unique view into the CNS disorders. They help us understand the pathophysiology of disease as well as guiding our diagnostic, therapeutic, and prognostic approaches in CNS disorders. This review highlights the most prominent molecular biomarkers found in the literature with respect to MS and its related disorders. Based on numerous recent clinical and experimental studies, we demonstrate that several molecular biomarkers could very well aid us in differentiating MS from its related disorders. The implications of this work will hopefully serve clinicians and researchers alike, who regularly deal with MS and its related disorders.
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Affiliation(s)
- Maryam Gul
- Precision Rheumatology INC, 2050 South Euclid Street, Anaheim, CA 92802, USA
| | - Amirhossein Azari Jafari
- Student Research Committee, School of Medicine, Shahroud University of Medical Sciences, Shahroud 3614773947, Iran; (A.A.J.); (S.M.)
| | - Muffaqam Shah
- Deccan College of Medical Sciences, P.O. Kanchanbagh, DMRL ‘X’ Road, Santhosh Nagar, Hyderabad 500058, Telangana State, India;
| | - Seyyedmohammadsadeq Mirmoeeni
- Student Research Committee, School of Medicine, Shahroud University of Medical Sciences, Shahroud 3614773947, Iran; (A.A.J.); (S.M.)
| | - Safee Ullah Haider
- Shaikh Khalifa Bin Zayed Al-Nahyan Medical College, Shaikh Zayed Medical Complex, Lahore 54000, Pakistan;
| | - Sadia Moinuddin
- Department of Internal Medicine, San Antonio Regional Medical Center, 999 San Bernardino Rd, Upland, CA 91786, USA;
| | - Ammar Chaudhry
- Department of Radiology, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010, USA;
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Hillarp A, Strandberg K, Gustafsson KM, Lindahl TL. Unveiling the complex effects of direct oral anticoagulants on dilute Russell's viper venom time assays. J Thromb Haemost 2020; 18:1866-1873. [PMID: 32294291 DOI: 10.1111/jth.14829] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 04/02/2020] [Accepted: 04/02/2020] [Indexed: 12/24/2022]
Abstract
INTRODUCTION Dilute Russell viper venom time (dRVVT) assays can be affected by direct oral anticoagulants (DOACs), which may cause false-positive results. However, there are conflicting results indicating significant differences between different reagents and DOACs. OBJECTIVES To evaluate the effect of DOACs on dRVVT assays. MATERIAL AND METHODS Samples were prepared by adding DOAC (dabigatran, rivaroxaban, apixaban, or edoxaban) to pooled normal plasma in the concentration range 0 to 800 µg/L. Six integrated dRVVT reagents were used, all composed of a screen assay (low phospholipid content) and a confirm assay (high phospholipid content). The screen/confirm dRVVT results were expressed as normalized ratios. To further evaluate the observed differences between tests and DOACs, addition of synthetic phospholipids was used. RESULTS The dRVVT ratios increased dose dependently for all DOACs, with four of the six tests and the DOAC rivaroxaban having the greatest effect. With one test, the ratios were almost unaffected with increasing DOAC concentration, whereas another test revealed a negative dose dependency for all DOACs. Variable DOAC effects can be explained by different effects on dRVVT screen and confirm clotting time. Adding synthetic phospholipids to samples containing rivaroxaban resulted in greatly reduced screen clotting times and thereby lower calculated dRVVT ratios. CONCLUSIONS There is a great variability in the dRVVT test result with different DOACs. The dRVVT ratios are unaffected for some reagents and this can be explained by an equal dose-dependent effect on both screen and confirm assays. The phospholipid type and content of the different reagents may contribute to the observed differences.
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Affiliation(s)
- Andreas Hillarp
- Department of Clinical Chemistry and Transfusion Medicine, Halland County Hospital, Halmstad, Sweden
| | - Karin Strandberg
- Clinical Chemistry, University and Regional Laboratories Region Skåne, Malmö, Sweden
| | - Kerstin M Gustafsson
- Department of Biomedical and Clinical Sciences, Clinical Chemistry, Linköping University, Linköping, Sweden
| | - Tomas L Lindahl
- Department of Biomedical and Clinical Sciences, Clinical Chemistry, Linköping University, Linköping, Sweden
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Saito M, Makino Y, Inoue K, Watanabe Y, Hoshi O, Kubota T. Anti-DNA antibodies cross-reactive with β 2-glycoprotein I induce monocyte tissue factor through the TLR9 pathway. Immunol Med 2020; 44:124-135. [PMID: 32701417 DOI: 10.1080/25785826.2020.1796285] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Antibodies specific for cardiolipin (CL)-β2-glycoprotein I (β2GPI) are known to induce tissue factor (TF) expression by monocytes and endothelial cells which leads to a prothrombotic state in antiphospholipid syndrome (APS), but the mechanism is not fully elucidated. Previously, we reported that the mouse monoclonal anti-CL-β2GPI antibody WB-6 cross-reacts with DNA, enters monocytes via binding to cell surface DNA, and induces TF expression. The current study aimed to identify the intracellular signaling pathways involved in this process. The binding of WB-6 to CL-β2GPI or DNA, and endocytosis was not prevented by chloroquine, but pre-treatment of the cells with chloroquine significantly suppressed TF expression. TLR9 inhibitory oligodeoxynucleotide also suppressed the WB-6-induced TF expression, suggesting a pivotal role of the TLR9 pathway in TF production. Serum antibodies obtained from a patient with APS accompanying systemic lupus erythematosus (SLE) bound to both CL-β2GPI and DNA, and induced TF in normal monocytes. This effect was suppressed by chloroquine, and abolished by removal of the DNA-binding activity. These results suggest that induction of TF expression results from TLR9 activation by DNA which was internalized together with cross-reactive antibodies produced in secondary APS accompanying SLE.
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Affiliation(s)
- Masumi Saito
- Department of Immunopathology, Tokyo Medical and Dental University (TMDU) Graduate School of Medical and Dental Sciences, Tokyo, Japan.,Laboratory for Clinical Research, Nippon Medical School, Tokyo, Japan
| | - Yumi Makino
- Department of Immunopathology, Tokyo Medical and Dental University (TMDU) Graduate School of Medical and Dental Sciences, Tokyo, Japan
| | - Kumi Inoue
- Department of Immunopathology, Tokyo Medical and Dental University (TMDU) Graduate School of Medical and Dental Sciences, Tokyo, Japan.,Department of Anatomical and Physiological Science, TMDU Graduate School of Medical and Dental Sciences, Tokyo, Japan
| | - Yoshino Watanabe
- Department of Immunopathology, Tokyo Medical and Dental University (TMDU) Graduate School of Medical and Dental Sciences, Tokyo, Japan
| | - Osamu Hoshi
- Department of Anatomical and Physiological Science, TMDU Graduate School of Medical and Dental Sciences, Tokyo, Japan
| | - Tetsuo Kubota
- Department of Immunopathology, Tokyo Medical and Dental University (TMDU) Graduate School of Medical and Dental Sciences, Tokyo, Japan.,Department of Anatomical and Physiological Science, TMDU Graduate School of Medical and Dental Sciences, Tokyo, Japan.,Department of Medical Technology, Tsukuba International University, Ibaraki, Japan
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40
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Parodi A, Gasparini G, Cozzani E. Could antiphospholipid antibodies contribute to coagulopathy in COVID-19? J Am Acad Dermatol 2020; 83:e249. [PMID: 32505779 PMCID: PMC7271853 DOI: 10.1016/j.jaad.2020.06.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Revised: 05/28/2020] [Accepted: 06/01/2020] [Indexed: 12/13/2022]
Affiliation(s)
- Aurora Parodi
- Section of Dermatology, Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy; Ospedale Policlinico San Martino IRCCS, Genoa, Italy
| | - Giulia Gasparini
- Section of Dermatology, Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy; Department of Experimental Medicine, University of Genoa, Genoa, Italy.
| | - Emanuele Cozzani
- Section of Dermatology, Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy; Ospedale Policlinico San Martino IRCCS, Genoa, Italy
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41
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Mahdian S, Zarrabi M, Moini A, Movahedi M, Shahhoseini M. In silico identification of new inhibitors for βeta-2-glycoprotein I as a major antigen in antiphospholipid antibody syndrome. J Mol Model 2020; 26:156. [PMID: 32458176 DOI: 10.1007/s00894-020-04406-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Accepted: 04/29/2020] [Indexed: 02/06/2023]
Abstract
Beta 2 glycoprotein I (β2GPI) is a major antigen for autoantibodies present in antiphospholipid antibody syndrome (APS). β2GPI is a single polypeptide with five repeated domains and different conformations. The activated J-shaped conformation of β2GPI binds to negatively charged phospholipids in the membrane via the fifth domain and causes blood clotting reactions. We applied a drug repurposing strategy using virtual screening and molecular dynamics to find the best FDA drugs against the fifth domain of β2GPI. In the first phase, FDA drugs that had the most favorable ΔG with the fifth domain of β2GPI were selected by virtual screening. Among these drugs that had the most favorable ΔG, Vorapaxar and Antrafenine were selected for molecular dynamics (MD) simulation studies. MD simulation was performed to evaluate the stability of Vorapaxar and Antrafenine complexes and the effect of the two drugs on protein conformation. Also, MD simulation was done to investigate the effect of Antrafenine and Vorapaxar on the binding of β2GPI to the platelet model membrane. According to the results, Vorapaxar and Antrafenine were bound to the protein with the favorable binding energy (Vorapaxar and Antrafenine binding energies are - 49.641 and - 38.803 kcal/mol, respectively). In this study, it was shown that unlike protein alone and protein in the Antrafenine complex, the protein in the Vorapaxar complex was completely separated from the model membrane after 350 ns. Moreover, Vorapaxar led to more changes in the activated J-shape of β2GPI. Thus, Vorapaxar can be a suitable candidate for further investigations on the treatment of APS.
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Affiliation(s)
- Soodeh Mahdian
- Department of Biochemistry, Faculty of Biological Sciences, North Tehran Branch, Islamic Azad University, Tehran, Iran
| | - Mahboobeh Zarrabi
- Department of Biotechnology, Biological Faculty, Alzahra University, Tehran, Iran
| | - Ashraf Moini
- Department of Endocrinology and Female Infertility, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran.,Disease Research Center (BDRC), Tehran University of Medical Sciences, Tehran, Iran.,Department of Gynecology and Obstetrics, Arash Women's Hospital, Tehran, University of Medical Sciences, Tehran, Iran
| | - Monireh Movahedi
- Department of Biochemistry, Faculty of Biological Sciences, North Tehran Branch, Islamic Azad University, Tehran, Iran.
| | - Maryam Shahhoseini
- Reproductive Epidemiology Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran. .,Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran. .,Department of Cell and Molecular Biology, School of Biology, College of Science, University of Tehran, Tehran, Iran.
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42
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Sarecka-Hujar B, Kopyta I. Antiphospholipid syndrome and its role in pediatric cerebrovascular diseases: A literature review. World J Clin Cases 2020; 8:1806-1817. [PMID: 32518771 PMCID: PMC7262698 DOI: 10.12998/wjcc.v8.i10.1806] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2019] [Revised: 04/10/2020] [Accepted: 04/26/2020] [Indexed: 02/05/2023] Open
Abstract
Antiphospholipid syndrome (APS) or Hughes syndrome is an acquired thromboinflammatory disorder. Clinical criteria of APS diagnosis are large- and small-vessel thrombosis as well as obstetric problems; laboratory criteria are the presence of antiphospholipid antibodies (lupus anticoagulant, anticardiolipin antibodies and anti-β2-glycoprotein-1). The presence of at least 1 clinical and 1 laboratory criterion allows definitive diagnosis of APS. Primary APS is diagnosed in patients without features of connective tissue disease; secondary APS is diagnosed in patients with clinical signs of autoimmune disease. A high frequency of catastrophic APS as well as a high tendency to evolve from primary APS to secondary syndrome during the course of lupus and lupus-like disease is a feature of pediatric APS. The most characteristic clinical presentation of APS in the pediatric population is venous thrombosis, mainly in the lower limbs, and arterial thrombosis causing ischemic brain stroke. Currently, no diagnostic criteria for pediatric APS exist, which probably results in an underestimation of the problem. Similarly, no therapeutic procedures for APS specific for children have yet been established. In the present literature review, we discussed data concerning APS in children and its role in cerebrovascular diseases, including pediatric arterial ischemic stroke, migraine and cerebral venous thrombosis.
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Affiliation(s)
- Beata Sarecka-Hujar
- Department of Basic Biomedical Science, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia in Katowice, Sosnowiec 41200, Poland
| | - Ilona Kopyta
- Department of Paediatric Neurology, School of Medicine in Katowice, Medical University of Silesia in Katowice, Sosnowiec 41200, Poland
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43
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Wei A, Xiao H, Xu G, Yu X, Guo J, Jing Z, Shi S, Song Y. Hyperoside Protects Human Umbilical Vein Endothelial Cells Against Anticardiolipin Antibody-Induced Injury by Activating Autophagy. Front Pharmacol 2020; 11:762. [PMID: 32508661 PMCID: PMC7253676 DOI: 10.3389/fphar.2020.00762] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Accepted: 05/07/2020] [Indexed: 12/28/2022] Open
Abstract
Anticardiolipin antibody (aCL), an important characterization of antiphospholipid syndrome, shows an intense association with vascular endothelial injury. Hyperoside is a flavonoid extracted from medicinal plants traditionally used in Chinese medicines, displaying anti-inflammatory, anti-cancer, and anti-oxidative properties in various diseases. Recent studies have shifted the focus on the protective effects of hyperoside on vascular endothelial injury. However, little is known about the mechanisms involved. In the present study, we investigated the effect of hyperoside on aCL-induced injury of human umbilical vein endothelial cells (HUVECs) in vitro. Our data illustrated that aCL induced HUVEC injury via inhibiting autophagy. Hyperoside reduced aCL-induced secretion of proinflammatory cytokines IL-1β and IL-8 and endothelial adhesion cytokines TF, ICAM1, and VCAM1 in HUVECs. Additionally, hyperoside activated autophagy and suppressed the mTOR/S6K and TLR4/Myd88/NF-κB signaling transduction pathways in aCL-induced HUVECs. To the best of our knowledge, this is the first study to investigate the effect of hyperoside on aCL-induced injury, as well as offer insights into the involved mechanisms, which is of great significance for the treatment of antiphospholipid syndrome.
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Affiliation(s)
- Aiwu Wei
- Department of Reproductive Medicine, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China
| | - Huidongzi Xiao
- Department of Reproductive Medicine, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China
| | - Guangli Xu
- Department of Reproductive Medicine, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China
| | - Xile Yu
- Department of Reproductive Medicine, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China
| | - Jingjing Guo
- Department of Reproductive Medicine, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China
| | - Zhuqing Jing
- Department of Reproductive Medicine, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China
| | - Shaoqi Shi
- Department of Reproductive Medicine, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China
| | - Yanli Song
- Department of Reproductive Medicine, Henan Province Hospital of Traditional Chinese Medicine, Zhengzhou, China
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44
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Wahl U, Hirsch T. The importance of antiphospholipid syndrome testing in venous thromboembolism after varicose vein surgery. J Vasc Surg Venous Lymphat Disord 2020; 8:1097-1101. [PMID: 32381473 DOI: 10.1016/j.jvsv.2020.03.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Accepted: 03/13/2020] [Indexed: 10/24/2022]
Abstract
Anticoagulation treatment after a venous thromboembolism event is usually managed on a case-by-case basis. The risk of thrombosis must be weighed against the risk of bleeding. Identifying patients who could benefit from anticoagulation therapy requires the thromboembolism event to be assessed with respect to its presentation and the severity of the triggering factors. A case report is employed to explain the important aspects of practical approaches to venous thromboembolism events after vein surgery. The Trial on Rivaroxaban in AntiPhospholipid Syndrome (TRAPS) study has prompted new considerations for anticoagulation management. Patients with antiphospholipid syndrome need to be identified early to lower the risk of thromboembolism also during anticoagulation treatment.
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Affiliation(s)
- Uwe Wahl
- Department of Internal Medicine, BG Hospital Bergmannstrost Halle, Halle, Germany.
| | - Tobias Hirsch
- Practice for Internal Medicine and Vascular Diseases, Vein Competence Centre Halle, Halle, Germany
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45
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Giemza-Stokłosa J, Islam MA, Kotyla PJ. Hyperferritinaemia: An Iron Sword of Autoimmunity. Curr Pharm Des 2020; 25:2909-2918. [PMID: 31686632 DOI: 10.2174/1381612825666190709202804] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2019] [Accepted: 06/30/2019] [Indexed: 01/01/2023]
Abstract
BACKGROUND Ferritin is a molecule that plays many roles being the storage for iron, signalling molecule, and modulator of the immune response. METHODS Different electronic databases were searched in a non-systematic way to find out the literature of interest. RESULTS The level of ferritin rises in many inflammatory conditions including autoimmune disorders. However, in four inflammatory diseases (i.e., adult-onset Still's diseases, macrophage activation syndrome, catastrophic antiphospholipid syndrome, and sepsis), high levels of ferritin are observed suggesting it as a remarkable biomarker and pathological involvement in these diseases. Acting as an acute phase reactant, ferritin is also involved in the cytokine-associated modulator of the immune response as well as a regulator of cytokine synthesis and release which are responsible for the inflammatory storm. CONCLUSION This review article presents updated information on the role of ferritin in inflammatory and autoimmune diseases with an emphasis on hyperferritinaemic syndrome.
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Affiliation(s)
| | - Md Asiful Islam
- Department of Haematology, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia
| | - Przemysław J Kotyla
- Department of Internal Medicine, Rheumatology and Clinical Immunology, Faculty in Katowice, Medical University of Silesia, 40-635 Katowice, Poland
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46
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Song JC, Liu SY, Zhu F, Wen AQ, Ma LH, Li WQ, Wu J. Expert consensus on the diagnosis and treatment of thrombocytopenia in adult critical care patients in China. Mil Med Res 2020; 7:15. [PMID: 32241296 PMCID: PMC7118900 DOI: 10.1186/s40779-020-00244-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Accepted: 03/20/2020] [Indexed: 01/14/2023] Open
Abstract
Thrombocytopenia is a common complication of critical care patients. The rates of bleeding events and mortality are also significantly increased in critical care patients with thrombocytopenia. Therefore, the Critical Care Medicine Committee of Chinese People's Liberation Army (PLA) worked with Chinese Society of Laboratory Medicine, Chinese Medical Association to develop this consensus to provide guidance for clinical practice. The consensus includes five sections and 27 items: the definition of thrombocytopenia, etiology and pathophysiology, diagnosis and differential diagnosis, treatment and prevention.
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Affiliation(s)
- Jing-Chun Song
- Department of Critical Care Medicine, the 908th Hospital of Joint Logistics Support Forces of Chinese PLA, Nanchang, 360104, China.
| | - Shu-Yuan Liu
- Emergency Department, the Sixth Medical Center, Chinese PLA General Hospital, Beijing, 100048, China
| | - Feng Zhu
- Burns and Trauma ICU, Changhai Hospital, Naval Medical University, Shanghai, 200003, China
| | - Ai-Qing Wen
- Department of Blood Transfusion, Daping Hospital of Army Medical University, Chongqing, 400042, China
| | - Lin-Hao Ma
- Department of Emergency and Critical Care Medicine, Changzheng Hospital, Naval Medical University, Shanghai, 200003, China
| | - Wei-Qin Li
- Surgery Intensive Care Unit, Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, China.
| | - Jun Wu
- Department of Clinical Laboratory, Peking University Fourth School of Clinical Medicine, Beijing Jishuitan Hospital, Beijing, 100035, China.
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Kotyla PJ, Islam MA. MicroRNA (miRNA): A New Dimension in the Pathogenesis of Antiphospholipid Syndrome (APS). Int J Mol Sci 2020; 21:ijms21062076. [PMID: 32197340 PMCID: PMC7139820 DOI: 10.3390/ijms21062076] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 03/15/2020] [Accepted: 03/16/2020] [Indexed: 12/11/2022] Open
Abstract
MicroRNAs (miRNAs) are single-stranded, endogenous RNA molecules that play a significant role in the regulation of gene expression as well as cell development, differentiation, and function. Recent data suggest that these small molecules are responsible for the regulation of immune responses. Therefore, they may act as potent modulators of the immune system and play an important role in the development of several autoimmune diseases. Antiphospholipid syndrome (APS) is an autoimmune systemic disease characterized by venous and/or arterial thromboses and/or recurrent fetal losses in the presence of antiphospholipid antibodies (aPLs). Several lines of evidence suggest that like other autoimmune disorders, miRNAs are deeply involved in the pathogenesis of APS, interacting with the function of innate and adaptive immune responses. In this review, we characterize miRNAs in the light of having a functional role in the immune system and autoimmune responses focusing on APS. In addition, we also discuss miRNAs as potential biomarkers and target molecules in treating APS.
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Affiliation(s)
- Przemysław J. Kotyla
- Department of Internal Medicine, Rheumatology and Clinical Immunology, Faculty in Katowice, Medical University of Silesia, 40-635 Katowice, Poland
- Correspondence: (P.J.K.); (M.A.I.)
| | - Md Asiful Islam
- Department of Haematology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia
- Correspondence: (P.J.K.); (M.A.I.)
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Su CC, Hsu TC, Hsiao CH, Chiu CC, Tzang BS. Effects of antibodies against human parvovirus B19 on angiogenic signaling. Mol Med Rep 2020; 21:1320-1327. [PMID: 31922220 DOI: 10.3892/mmr.2020.10921] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Accepted: 11/18/2019] [Indexed: 11/05/2022] Open
Abstract
Human parvovirus B19 (B19V) infection has symptoms similar to those of anti‑phospholipid syndrome (APS). Antibodies against B19V‑VP1 unique region (VP1u) exhibit activity similar to that of anti‑phospholipid antibodies (aPLs) by inducing vascular endothelial cell adhesion factors and APS‑like syndrome. Previous studies have identified an effect of aPLs on angiogenesis. However, little is understood regarding the effect of anti‑B19V‑VP1u antibodies on angiogenesis. The present study investigated the effects of anti‑B19V‑VP1u antibodies on the expression of adhesion molecules and angiogenic signaling using an aPL‑induced human umbilical vein endothelial cell (HUVEC) model, and trypan blue staining and western blotting. The effect of B19V‑VP1u antibodies on vascular endothelial growth factor (VEGF) expression in A549 cells, another well‑known model used to study angiogenesis, was also examined. Significantly higher intracellular adhesion molecule 1 expression was observed following treatments with 10% fetal calf serum (FCS), aPL immunoglobulin G (IgG), B19V‑VP1u IgG or B19V‑NS1 IgG, compared with in the normal human (NH) IgG‑treated cells. Conversely, significantly higher vascular cellular adhesion molecule 1 was only detected in HUVECs treated with B19V‑VP1u IgG. Significantly increased integrin β1 was detected in HUVECs treated with aPL IgG or B19V‑VP1u IgG, whereas no difference in integrin β1 was observed in those treated with 10% FCS, NH IgG or B19V‑NS1 IgG. No difference in AKT‑mTOR‑S6 ribosomal protein (S6RP) signaling was observed in HUVECs treated with B19‑VP1u IgG or B19V‑NS1 IgG, compared with NH IgG‑treated cells. Significantly higher human inducible factor‑1α was detected in HUVECs treated with 10% FCS, aPL IgG, B19V‑VP1u IgG or B19V‑NS1 IgG, compared with in NH IgG‑treated cells. However, there was no difference in the level of VEGF observed among HUVECs treated with NH IgG, B19V‑VP1u IgG or B19V‑NS1 IgG. Notably, no difference in VEGF level was observed in A549 cells treated with NH IgG, aPL IgG, B19V‑VP1u IgG or B19V‑NS1 IgG. These findings suggest that anti‑B19V‑VP1u antibodies may serve a role in activating adhesion molecules, but not in AKT‑mTOR‑S6RP signaling.
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Affiliation(s)
- Chia-Cheng Su
- Department of Urology, Chi Mei Medical Center, Tainan 710, Taiwan, R.O.C
| | - Tsai-Ching Hsu
- Institute of Biochemistry, Microbiology and Immunology, College of Medicine, Chung Shan Medical University, Taichung 402, Taiwan, R.O.C
| | - Chao-Hsiang Hsiao
- Institute of Biochemistry, Microbiology and Immunology, College of Medicine, Chung Shan Medical University, Taichung 402, Taiwan, R.O.C
| | - Chun-Ching Chiu
- Institute of Biochemistry, Microbiology and Immunology, College of Medicine, Chung Shan Medical University, Taichung 402, Taiwan, R.O.C
| | - Bor-Show Tzang
- Institute of Biochemistry, Microbiology and Immunology, College of Medicine, Chung Shan Medical University, Taichung 402, Taiwan, R.O.C
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Fazili M, Stevens SM, Woller SC. Direct oral anticoagulants in antiphospholipid syndrome with venous thromboembolism: Impact of the European Medicines Agency guidance. Res Pract Thromb Haemost 2020; 4:9-12. [PMID: 31989078 PMCID: PMC6971326 DOI: 10.1002/rth2.12287] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2019] [Revised: 10/25/2019] [Accepted: 10/29/2019] [Indexed: 12/25/2022] Open
Affiliation(s)
- Masarret Fazili
- Department of MedicineIntermountain Medical CenterMurrayUtah
| | - Scott M. Stevens
- Department of MedicineIntermountain Medical CenterMurrayUtah
- Division of General Internal MedicineUniversity of Utah School of MedicineSalt Lake CityUtah
| | - Scott C. Woller
- Department of MedicineIntermountain Medical CenterMurrayUtah
- Division of General Internal MedicineUniversity of Utah School of MedicineSalt Lake CityUtah
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Wirestam L, Arve S, Linge P, Bengtsson AA. Neutrophils-Important Communicators in Systemic Lupus Erythematosus and Antiphospholipid Syndrome. Front Immunol 2019; 10:2734. [PMID: 31824510 PMCID: PMC6882868 DOI: 10.3389/fimmu.2019.02734] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Accepted: 11/07/2019] [Indexed: 12/15/2022] Open
Abstract
Systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) are two autoimmune diseases that can occur together or separately. Insights into the pathogenesis have revealed similarities, such as development of autoantibodies targeting subcellular antigens as well as a shared increased risk of cardiovascular morbidity, potentially due to mutual pathologic mechanisms. In this review, we will address the evidence implicating neutrophils in the pathogenesis of these conditions, highlighting their shared features. The neutrophil is the most abundant leukocyte, recognized for its role in infectious and inflammatory diseases, but dysregulation of neutrophil effector functions, including phagocytosis, oxidative burst and formation of neutrophil extracellular traps (NETs) may also contribute to an autoimmune process. The phenotype of neutrophils in SLE and APS differs from neutrophils of healthy individuals, where neutrophils in SLE and APS are activated and prone to aggregate. A specific subset of low-density neutrophils with different function compared to normal-density neutrophils can also be found within the peripheral blood mononuclear cell (PBMC) fraction after density gradient centrifugation of whole blood. Neutrophil phagocytosis is required for regular clearance of cell remnants and nuclear material. Reactive oxygen species (ROS) released by neutrophils during oxidative burst are important for immune suppression and impairment of ROS production is seen in SLE. NETs mediate pathology in both SLE and APS via several mechanisms, including exposure of autoantigens, priming of T-cells and activation of autoreactive B-cells. NETs are also involved in cardiovascular events by forming a pro-thrombotic scaffolding surface. Lastly, neutrophils communicate with other cells by producing cytokines, such as Interferon (IFN) -α, and via direct cell-cell contact. Physiological neutrophil effector functions are necessary to prevent autoimmunity, but in SLE and APS these are altered.
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Affiliation(s)
- Lina Wirestam
- Section of Rheumatology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
| | - Sabine Arve
- Section of Rheumatology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
| | - Petrus Linge
- Section of Rheumatology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
| | - Anders A Bengtsson
- Section of Rheumatology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
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