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1
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Tang H, Li Z, Zhang Y, Dai M, Wang X, Shao C. Miscarriage, stillbirth, and mortality risk from stroke in women: findings from the PLCO study. Epidemiol Health 2024; 46:e2024093. [PMID: 39638289 PMCID: PMC11840407 DOI: 10.4178/epih.e2024093] [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: 07/04/2024] [Accepted: 11/14/2024] [Indexed: 12/07/2024] Open
Abstract
OBJECTIVES Existing evidence suggests that miscarriage and stillbirth are associated with an increased risk of stroke in women. However, the impact of these events on stroke mortality remains unclear. This study aimed to elucidate the potential association between miscarriage and stillbirth and stroke mortality in women. METHODS We employed a competing risk model using data from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial to assess the relationship between miscarriage/stillbirth and stroke death. Death from other causes was considered as a competing risk, and we conducted a subgroup analysis to explore the potential impact. RESULTS Our study included 68,629 women for miscarriage and 65,343 women for stillbirth. No significant association was observed between miscarriage and stroke mortality (hazard ratio [HR], 0.96; 95% confidence interval [CI], 0.84 to 1.10; p=0.58). While a single stillbirth did not show a significant association (HR, 0.81; 95% CI, 0.57 to 1.15; p=0.23), recurrent stillbirth (≥2) was associated with a significantly increased risk of stroke mortality compared to women with no stillbirths (HR, 2.24; 95% CI, 1.45 to 3.46; p<0.001). CONCLUSIONS Our findings suggest that recurrent stillbirth, but not single events, is associated with an elevated risk of stroke mortality in women. Further research is warranted to clarify the underlying mechanisms and potential long-term health implications of recurrent pregnancy loss.
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Affiliation(s)
- Hui Tang
- Department of Neurosurgery, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong,
China
- Nanchong Institute of Cerebrovascular Diseases, Nanchong,
China
- Sichuan Clinical Research Center for Neurological Disease, Nanchong,
China
| | - Zhou Li
- Department of Neurosurgery, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong,
China
- Nanchong Institute of Cerebrovascular Diseases, Nanchong,
China
- Sichuan Clinical Research Center for Neurological Disease, Nanchong,
China
| | - Yuan Zhang
- Department of Neurosurgery, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong,
China
- Nanchong Institute of Cerebrovascular Diseases, Nanchong,
China
- Sichuan Clinical Research Center for Neurological Disease, Nanchong,
China
| | - Mingjun Dai
- Department of Neurosurgery, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong,
China
| | - Xiaoya Wang
- Department of Pathology, Affiliated Hospital of North Sichuan Medical College, Nanchong,
China
| | - Chuan Shao
- Department of Neurosurgery, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong,
China
- Nanchong Institute of Cerebrovascular Diseases, Nanchong,
China
- Department of Neurosurgery, Chongqing General Hospital, Chongqing University, Chongqing,
China
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2
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Tzang BS, Chin HY, Tzang CC, Chuang PH, Chen DY, Hsu TC. Parvovirus B19 Infection Is Associated with the Formation of Neutrophil Extracellular Traps and Thrombosis: A Possible Linkage of the VP1 Unique Region. Int J Mol Sci 2024; 25:9917. [PMID: 39337405 PMCID: PMC11432092 DOI: 10.3390/ijms25189917] [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: 07/24/2024] [Revised: 09/08/2024] [Accepted: 09/11/2024] [Indexed: 09/30/2024] Open
Abstract
Neutrophil extracellular traps (NETs) formation, namely NETosis, is implicated in antiphospholipid syndrome (APS)-related thrombosis in various autoimmune disorders such as systemic lupus erythematosus (SLE) and APS. Human parvovirus B19 (B19V) infection is closely associated with SLE and APS and causes various clinical manifestations such as blood disorders, joint pain, fever, pregnancy complications, and thrombosis. Additionally, B19V may trigger the production of autoantibodies, including those against nuclear and phospholipid components. Thus, exploring the connection between B19V, NETosis, and thrombosis is highly relevant. An in vitro NETosis model using differentiated HL-60 neutrophil-like cells (dHL-60) was employed to investigate the effect of B19V-VP1u IgG on NETs formation. A venous stenosis mouse model was used to test how B19V-VP1u IgG-mediated NETs affect thrombosis in vivo. The NETosis was observed in the dHL-60 cells treated with rabbit anti-B19V-VP1u IgG and was inhibited in the presence of either 8-Br-cAMP or CGS216800 but not GSK484. Significantly elevated reactive oxygen species (ROS), myeloperoxidase (MPO), and citrullinated histone (Cit-H3) levels were detected in the dHL60 treated with phorbol myristate acetate (PMA), human aPLs IgG and rabbit anti-B19V-VP1u IgG, respectively. Accordingly, a significantly larger thrombus was observed in a venous stenosis-induced thrombosis mouse model treated with PMA, human aPLs IgG, rabbit anti-B19V-VP1u IgG, and human anti-B19V-VP1u IgG, respectively, along with significantly increased amounts of Cit-H3-, MPO- and CRAMP-positive infiltrated neutrophils in the thrombin sections. This research highlights that anti-B19V-VP1u antibodies may enhance the formation of NETosis and thrombosis and implies that managing and treating B19V infection could lower the risk of thrombosis.
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Affiliation(s)
- Bor-Show Tzang
- Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan; (B.-S.T.); (H.-Y.C.); (P.-H.C.)
- Department of Biochemistry, School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
- Department of Clinical Laboratory, Chung Shan Medical University Hospital, Taichung 402, Taiwan
- Immunology Research Center, Chung Shan Medical University, Taichung 402, Taiwan
| | - Hao-Yang Chin
- Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan; (B.-S.T.); (H.-Y.C.); (P.-H.C.)
| | - Chih-Chen Tzang
- School of Medicine, College of Medicine, National Taiwan University, Taipei City 100, Taiwan;
| | - Pei-Hua Chuang
- Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan; (B.-S.T.); (H.-Y.C.); (P.-H.C.)
| | - Der-Yuan Chen
- Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan; (B.-S.T.); (H.-Y.C.); (P.-H.C.)
- College of Medicine, China Medical University, Taichung 404, Taiwan
- Rheumatology and Immunology Center, China Medical University Hospital, Taichung 404, Taiwan
| | - Tsai-Ching Hsu
- Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan; (B.-S.T.); (H.-Y.C.); (P.-H.C.)
- Department of Clinical Laboratory, Chung Shan Medical University Hospital, Taichung 402, Taiwan
- Immunology Research Center, Chung Shan Medical University, Taichung 402, Taiwan
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3
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Saadalla A, Chen D, Stuart M, Pruthi R, Heikal N, Snyder M, Ashrani A, Seheult J. The lupus anticoagulant titer is associated with elevated antiphosphatidylserine/prothrombin immunoglobulin-M isotype antibody levels. Int J Lab Hematol 2024; 46:695-704. [PMID: 38380742 DOI: 10.1111/ijlh.14251] [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: 09/04/2023] [Accepted: 02/04/2024] [Indexed: 02/22/2024]
Abstract
BACKGROUND Clot based assays used for lupus anticoagulant (LAC) detection are typically interpreted in a qualitative fashion and may not reflect LAC potency. In this cross-sectional study, we describe a method for quantifying the LAC titer using serial (dependent) two-fold dilutions in normal pooled plasma. METHODS Serial dilutions of 51 residual plasma samples from 50 patients were tested using the Russell's viper venom screening time (DRVVT) and activated partial thromboplastin screening time (APTT) methodologies. The measured clotting times and the corresponding dilution factors were then used to derive a four-parameter logistic model. The LAC titer for each patient was interpolated as the sample dilution that corresponds to the upper reference interval limit of the corresponding assay. RESULTS Calculated APTT and DRVVT LAC titers displayed a strong linear correlation (R2 = 0.84) between each other, but not with the degree of prolongation of the APTT/DRVVT screening time in the neat undiluted samples. Using data driven partitioning, patients could be grouped into low (<10) or high (≥10) DRVVT LAC titer. There were no significant differences in anticardiolipin (aCL) or anti-beta 2 glycoprotein 1 (aB2GPI) antibody levels or prevalence of thromboembolic events between low and high LAC titer groups. In contrast, antiphosphatidylserine/prothrombin (aPS/PT) IgM antibody levels, but not IgG, were significantly higher in the high LAC titer group. CONCLUSIONS The degree of prolongation of the APTT/DRVVT screening time is not correlated with the LAC titer. Only aPS/PT IgM antibodies levels were strongly correlated with the LAC titers. Additional studies are warranted to determine clinical implications of high LAC titers.
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Affiliation(s)
- Abdulrahman Saadalla
- Department of Pathology, University of Utah, Salt Lake City, Utah, USA
- ARUP Laboratories, Salt Lake City, Utah, USA
| | - Dong Chen
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Melissa Stuart
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Rajiv Pruthi
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Nahla Heikal
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Melissa Snyder
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Aneel Ashrani
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Jansen Seheult
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
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de Carvalho JF, Brandão Neto RA, Skare TL, Shoenfeld Y. Primary antiphospholipid syndrome with and without limb ischemia: A retrospective observational study. Lupus 2023; 32:1486-1492. [PMID: 37852301 DOI: 10.1177/09612033231208347] [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: 10/20/2023]
Abstract
OBJECTIVE To compare clinical and laboratory data obtained from patients with primary Antiphospholipid Syndrome (PAPS) with and without limb ischemia (LI). METHODS A transverse study with 66 (83.3% female) PAPS patients was performed. All data were evaluated. Patients were subdivided into one of two groups: PAPS with LI and PAPS without LI and compared. RESULTS Sixty-six primary APS were selected. PAPS with LI group exhibited a longer disease duration (p = .012) and more arterial events (p = .002). A lower frequency of venous events was observed in PAPS with LI (p = .007), and deep venous thrombosis (p = .016). Furthermore, PAPS with LI patients had more deficiency of protein C of coagulation (p = .015) than the others. CONCLUSION PAPS and LI have a distinct clinical and laboratory spectra from those without LI and it is characterized by an increased frequency of protein C deficiency, and a lower frequency of venous events, deep venous thrombosis and IgM anticardiolipin.
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Affiliation(s)
| | - Rodrigo A Brandão Neto
- Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | | | - Yehuda Shoenfeld
- Chaim Sheba Medical Center, The Zabludowicz Research Center for Autoimmune Diseases, Tel Hashomer, Israel
- I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow, Russia
- Ariel University in the Shomron, Ari'el, Israel
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5
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Noordermeer T, Chemlal S, Jansma JJ, van der Vegte V, Schutgens REG, Limper M, de Groot PG, Meijers JCM, Urbanus RT. Anti-β2-glycoprotein I and anti-phosphatidylserine/prothrombin antibodies interfere with cleavage of factor V(a) by activated protein C. J Thromb Haemost 2023; 21:2509-2518. [PMID: 37290588 DOI: 10.1016/j.jtha.2023.05.024] [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: 04/13/2023] [Revised: 05/16/2023] [Accepted: 05/26/2023] [Indexed: 06/10/2023]
Abstract
BACKGROUND The acquired thrombotic risk factor known as lupus anticoagulant (LA) interferes with laboratory clotting assays and can be caused by autoantibodies against β2-glycoprotein I (β2GPI) and prothrombin. LA is associated with activated protein C (APC) resistance, which might contribute to thrombotic risk in patients with antiphospholipid syndrome. How antibodies against β2GPI and prothrombin cause APC resistance is currently unclear. OBJECTIVES To investigate how anti-β2GPI and antiphosphatidylserine/prothrombin (PS/PT) antibodies induce APC resistance. METHODS The effects of anti-β2GPI and anti-PS/PT antibodies on APC resistance were studied in plasma (of patients with antiphospholipid syndrome) and with purified coagulation factors and antibodies. RESULTS APC resistance was observed in LA-positive patients with anti-β2GPI or anti-PS/PT antibodies and in normal plasma spiked with monoclonal anti-β2GPI or anti-PS/PT antibodies with LA activity. Analysis of factor (F)V cleavage patterns after APC incubation indicated that anti-β2GPI antibodies attenuated APC-mediated FV cleavage at R506 and R306. APC-mediated cleavage at R506 is required for FV cofactor activity during inactivation of FVIIIa. Assays with purified coagulation factors confirmed that anti-β2GPI antibodies interfered with the cofactor function of FV during FVIIIa inactivation but not with FVa inactivation. Anti-PS/PT antibodies attenuated APC-mediated FVa and FVIIIa inactivation. Analysis of FV(a) cleavage patterns after APC incubation indicated that anti-PS/PT antibodies interfere with APC-mediated cleavage of FV at positions R506 and R306. CONCLUSION Anti-β2GPI antibodies with LA activity contribute to a procoagulant state by causing APC resistance via interference with the cofactor function of FV during FVIIIa inactivation. LA-causing anti-PS/PT antibodies interfere with the anticoagulant function of APC by preventing FV(a) cleavage.
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Affiliation(s)
- Tessa Noordermeer
- Center for Benign Haematology, Thrombosis and Haemostasis, Van Creveldkliniek, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands; Circulatory Health Research Center, University Medical Center Utrecht, Utrecht, the Netherlands. https://twitter.com/Tessa_Noorder
| | - Soumaya Chemlal
- Center for Benign Haematology, Thrombosis and Haemostasis, Van Creveldkliniek, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands; Circulatory Health Research Center, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Janna J Jansma
- Center for Benign Haematology, Thrombosis and Haemostasis, Van Creveldkliniek, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands; Circulatory Health Research Center, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Vossa van der Vegte
- Center for Benign Haematology, Thrombosis and Haemostasis, Van Creveldkliniek, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands; Circulatory Health Research Center, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Roger E G Schutgens
- Center for Benign Haematology, Thrombosis and Haemostasis, Van Creveldkliniek, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Maarten Limper
- Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | | | - Joost C M Meijers
- Department of Molecular Hematology, Sanquin Research, Amsterdam, the Netherlands; Department of Experimental Vascular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Rolf T Urbanus
- Center for Benign Haematology, Thrombosis and Haemostasis, Van Creveldkliniek, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands; Circulatory Health Research Center, University Medical Center Utrecht, Utrecht, the Netherlands.
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6
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Emerson JS, Gruenewald SM, Gomes L, Lin MW, Swaminathan S. The conundrum of neuropsychiatric systemic lupus erythematosus: Current and novel approaches to diagnosis. Front Neurol 2023; 14:1111769. [PMID: 37025200 PMCID: PMC10070984 DOI: 10.3389/fneur.2023.1111769] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 03/07/2023] [Indexed: 04/08/2023] Open
Abstract
Recognising neuropsychiatric involvement by systemic lupus erythematosus (SLE) is of growing importance, however many barriers to this exist at multiple levels of our currently available diagnostic algorithms that may ultimately delay its diagnosis and subsequent treatment. The heterogeneous and non-specific clinical syndromes, serological and cerebrospinal fluid (CSF) markers and neuroimaging findings that often do not mirror disease activity, highlight important research gaps in the diagnosis of neuropsychiatric SLE (NPSLE). Formal neuropsychological assessments or the more accessible screening metrics may also help improve objective recognition of cognitive or mood disorders. Novel serum and CSF markers, including autoantibodies, cytokines and chemokines have also shown increasing utility as part of diagnosis and monitoring, as well as in distinguishing NPSLE from SLE patients without SLE-related neuropsychiatric manifestations. Novel neuroimaging studies also expand upon our existing strategy by quantifying parameters that indicate microarchitectural integrity or provide an assessment of neuronal function. Some of these novel markers have shown associations with specific neuropsychiatric syndromes, suggesting that future research move away from considering NPSLE as a single entity but rather into its individually recognized neuropsychiatric manifestations. Nevertheless, it is likely that a composite panel of these investigations will be needed to better address the gaps impeding recognition of neuropsychiatric involvement by SLE.
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Affiliation(s)
- Jonathan S. Emerson
- Department of Clinical Immunology and Immunopathology, Westmead Hospital, Sydney, NSW, Australia
- Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
- Centre for Immunology and Allergy Research, The Westmead Institute for Medical Research, Sydney, NSW, Australia
- *Correspondence: Jonathan S. Emerson,
| | - Simon M. Gruenewald
- Department of Nuclear Medicine, PET and Ultrasound, Westmead Hospital, Sydney, NSW, Australia
| | - Lavier Gomes
- Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
- Department of Radiology, Westmead Hospital, Sydney, NSW, Australia
| | - Ming-Wei Lin
- Department of Clinical Immunology and Immunopathology, Westmead Hospital, Sydney, NSW, Australia
- Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
| | - Sanjay Swaminathan
- Department of Clinical Immunology and Immunopathology, Westmead Hospital, Sydney, NSW, Australia
- Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
- Department of Clinical Immunology, Blacktown Hospital, Sydney, NSW, Australia
- School of Medicine, Western Sydney University, Sydney, NSW, Australia
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7
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Addison's Disease in the Course of Recurrent Microangiopathic Antiphospholipid Syndrome-A Clinical Presentation and Review of the Literature. Medicina (B Aires) 2022; 59:medicina59010004. [PMID: 36676628 PMCID: PMC9863237 DOI: 10.3390/medicina59010004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 12/14/2022] [Accepted: 12/16/2022] [Indexed: 12/24/2022] Open
Abstract
The article presents a male patient with adrenocortical insufficiency in the course of antiphospholipid syndrome (APS). It also describes recurrent exacerbations of his clinical status, characteristic of microangiopathic antiphospholipid syndrome (MAPS) which had been misdiagnosed as a disseminated intravascular coagulopathy (DIC) syndrome due to sepsis with multi-organ failure, including heart, kidneys, and liver. Issues related to pathogenesis, clinical symptoms, differential diagnosis, and treatment of APS in the context of presently distinguished subtypes of this syndrome have been addressed. The role of vascular endothelial cell activation and the influence of coagulation patterns on the development of APS continuum clinical symptoms have also been mentioned. In addition, this paper highlights that the diagnosis of APS should be considered in patients with adrenal insufficiency and abdominal pain, even without any prior history of thromboembolic diseases, as well as in the course of DIC, especially without predisposing factors.
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8
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Petersen MMBS, Hartwig TS, Nielsen HS. Pregnancy Loss and Cardiovascular Diseases in Women: Recent Findings and Potential Mechanisms. Curr Atheroscler Rep 2022; 24:889-899. [PMID: 36383292 DOI: 10.1007/s11883-022-01065-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/04/2022] [Indexed: 11/17/2022]
Abstract
PURPOSE OF REVIEW Pregnancy loss (PL) has been acknowledged by the American Heart Association as a risk factor for cardiovascular diseases (CVD) later in life. This review aims to sum up recent findings (< ~ 5 years), concerning the link between PL and CVD. RECENT FINDINGS The association between PL and risk of CVD increased with increasing number of PLs and is inversely correlated to maternal age, indicating that the association concerns euploid PLs. Likely mechanisms leading to PL and an increased risk of CVD include endothelial dysfunction, a pro-inflammatory state, antiphospholipid syndrome, autoimmunity, and genetic predisposition. PL as an independent risk factor for CVD constitutes an obvious gateway for a more targeted approach to future research, prevention, and treatment. Future research should clarify the following questions to which the answers are still unknown: whether PL is (a) directly causing the increased risk of CVD or (b) sharing pathophysiological mechanisms also leading to CVD.
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Affiliation(s)
- Mette Marie Babiel Schmidt Petersen
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen N, Denmark. .,Department of Obstetrics and Gynecology, Copenhagen University Hospital Hvidovre, Kettegaard Alle 30, 2650, Hvidovre, Denmark.
| | - Tanja Schlaikjær Hartwig
- Department of Obstetrics and Gynecology, Copenhagen University Hospital Hvidovre, Kettegaard Alle 30, 2650, Hvidovre, Denmark
| | - Henriette Svarre Nielsen
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen N, Denmark.,Department of Obstetrics and Gynecology, Copenhagen University Hospital Hvidovre, Kettegaard Alle 30, 2650, Hvidovre, Denmark
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9
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Osuorji C, Bilal J, Osuorji I. Recurrent strokes and memory loss in a patient with triple-positive antiphospholipid antibody syndrome. BMJ Case Rep 2022; 15:e246104. [PMID: 35338038 PMCID: PMC8961123 DOI: 10.1136/bcr-2021-246104] [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: 01/21/2022] [Indexed: 11/04/2022] Open
Abstract
Antiphospholipid syndrome may cause recurrent thromboembolic events of the microvasculature, arteries and veins. It is also characterised by a range of neurological and psychiatric dysfunctions, as well as complications during pregnancy. Patients with triple-positive antiphospholipid syndrome have persistently elevated levels of lupus anticoagulant (LA), anti-beta-2-glycoprotein I (B2GPI) and anticardiolipin antibodies (aCL). These patients also have a higher risk of initial or recurrent thrombosis.We report the case of a 36-year-old man who was presented with progressive memory loss and recurrent stroke. He had persistently elevated antiphospholipid antibody titres (LA, aCL-immunoglobulin G and B2GPI antibodies). These features persisted while the patient was receiving low-dose aspirin (LDA), 81mg daily. Vitamin K antagonist (VKA); warfarin, with the international normalised ratio (INR) maintained at 2-3 was then added to his treatment regimen. The VKA dose was maintained at - a higher therapeutic INR while LDA administration was continued to achieve resolution of the patient's symptoms.
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Affiliation(s)
- Chinenye Osuorji
- Internal Medicine, Burrell College of Osteopathic Medicine, Las Cruces, New Mexico, USA
| | - Jawad Bilal
- Rheumatology, University of Arizona, Tucson, Arizona, USA
| | - Ikenna Osuorji
- Haematology/Oncology, Burrell College of Osteopathic Medicine, Las Cruces, New Mexico, USA
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10
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Svenungsson E, Spaak J, Strandberg K, Wallén HN, Agewall S, Brolin EB, Collste O, Daniel M, Ekenbäck C, Frick M, Henareh L, Malmqvist K, Elvin K, Sörensson P, Y-Hassan S, Hofman-Bang C, Tornvall P. Antiphospholipid antibodies in patients with myocardial infarction with and without obstructive coronary arteries. J Intern Med 2022; 291:327-337. [PMID: 34820922 DOI: 10.1111/joim.13409] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
BACKGROUND Recent studies demonstrate that prothrombotic antiphospholipid antibodies (aPL) are overrepresented in patients with myocardial infarction (MI) due to coronary artery disease (MICAD). However, it is not known whether aPL differ between the two subsets of MI: MICAD and MI with nonobstructive coronary arteries (MINOCA). OBJECTIVES To determine whether aPL are associated with MINOCA or MICAD, or with hypercoagulability as assessed by activated protein C-protein C inhibitor (APC-PCI) complex. METHODS Well-characterized patients with MINOCA (n = 98), age- and gender-matched patients with MICAD (n = 99), and healthy controls (n = 100) were included in a cross-sectional case-control study. Autoantibodies (IgA/G/M) targeting cardiolipin and β2 glycoprotein-I and specific nuclear antigens were analyzed by multiplexed bead technology. The concentration of APC-PCI was determined as a measure of hypercoagulability by an immunofluorometric sandwich assay. RESULTS Both prevalence and titers of aPL of the IgG isotype (anti-cardiolipin and/or anti-β2 glycoprotein-I) were higher in patients with MINOCA and MICAD than in controls. aPL IgG positivity was twice as frequent among patients with MICAD than MINOCA (11% vs. 6%, nonsignificant). We observed no group differences regarding aPL IgA/M or antibodies targeting specific nuclear antigens. Levels of APC-PCI were elevated in aPL IgG-positive compared to aPL IgG-negative MICAD patients. CONCLUSIONS aPL IgG, but not IgA/M, are enriched particularly in patients with MICAD but also in patients with MINOCA, as compared to controls. Interestingly, signs of hypercoagulability-measured by increased levels of the APC-PCI complex-were present in aPL IgG-positive MICAD patients, indicating an association with functional disturbances of the coagulation system.
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Affiliation(s)
- Elisabet Svenungsson
- Department of Medicine, Solna, Division of Rheumatology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
| | - Jonas Spaak
- Department of Clinical Sciences, Danderyd Hospital, Division of Cardiovascular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Karin Strandberg
- Department of Clinical Chemistry and Pharmacology, Division of Laboratory Medicine, Coagulation Laboratory Malmö, University and Regional Laboratories, Region Skåne, Sweden
| | - Håkan N Wallén
- Department of Clinical Sciences, Danderyd Hospital, Division of Cardiovascular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Stefan Agewall
- Department of Cardiology, Oslo University Hospital and Institute of Clinical Sciences, Oslo University Hospital, University of Oslo, Oslo, Norway
| | - Elin B Brolin
- Department of Clinical Science, Intervention and Technology, Karolinska Institutet and Department of Radiology, Capio S:t Göran's Hospital, Stockholm, Sweden
| | - Olov Collste
- Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden
| | - Maria Daniel
- Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden
| | - Christina Ekenbäck
- Department of Clinical Sciences, Danderyd Hospital, Division of Cardiovascular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Mats Frick
- Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden
| | - Loghman Henareh
- Department of Medicine, Heart and Vascular Theme, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
| | - Karin Malmqvist
- Department of Clinical Sciences, Danderyd Hospital, Division of Cardiovascular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Kerstin Elvin
- Department of Medicine Solna, Division of Immunology and Allergy, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
| | - Peder Sörensson
- Department of Medicine, Solna, Karolinska Institutet, Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden
| | - Shams Y-Hassan
- Coronary Artery Disease Area, Heart and Vascular Theme, Karolinska Institute and Karolinska University Hospital, Stockholm, Sweden
| | - Claes Hofman-Bang
- Department of Clinical Sciences, Danderyd Hospital, Division of Cardiovascular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Per Tornvall
- Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden
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11
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Scheen M, Adedjouma A, Esteve E, Buob D, Abisror N, Planche V, Fain O, Boffa JJ, De Seigneux S, Mekinian A, Haidar F. Kidney disease in antiphospholipid antibody syndrome: Risk factors, pathophysiology and management. Autoimmun Rev 2022; 21:103072. [PMID: 35217200 DOI: 10.1016/j.autrev.2022.103072] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 02/19/2022] [Indexed: 11/02/2022]
Abstract
Antiphospholipid antibody syndrome (APLS) is a rare autoimmune disease characterized by recurrent arterial and venous thromboembolic events, pregnancy related complications as well as the persistent detection of antiphospholipid antibodies at a 12 week interval. Renal complications tend to occur in 3% of APLS patients, with renal artery stenosis being the most common kidney related complication. Renal pathology may be subdivided into macro as well as microvascular thrombotic complications with stenosis, thrombosis and infarction representing the principle macrovascular events and APLS nephropathy representing the predominant microvascular complication. APLS related kidney disease may present with an array of heterogenous manifestations ranging from hematuria and non-nephrotic range proteinuria to hypertension or as part of a severe, life threatening and fulminant multiorgan failure disorder known as catastrophic antiphospholipid antibody syndrome (CAPS). Management of APLS related renal complications depends on the site of vascular injury, the thromboembolic risk profile based on the subtype, isotype and titer of the autoantibodies as well as the severity of the injury. Primary prophylaxis in these patients primarily revolves around the use of low dose aspirin, with prophylactic anticoagulation during events that increase thromboembolic like surgery and hospitalization. Anticoagulation is the cornerstone of treatment of APLS related kidney disease with INR targets varying depending on the associated venous or arterial thrombosis. Immunosuppression with the likes of rituximab, mTOR inhibitors, eculizumab and belimumab have been used with some success, but lack randomized control trial validation for their use. Pulsed corticosteroids with Plasmapheresis and intravenous immunoglobulins is the recommended treatment for CAPS.
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Affiliation(s)
- Marc Scheen
- Hôpitaux universitaires de Genève, Service de Néphrologie, Rue Gabrielle-Perret-Gentil 4, 1205 Genève, Switzerland.
| | - Amir Adedjouma
- Sorbonne Université, AP-HP, Hôpital Saint-Antoine, Service de Médecine Interne, 75012 Paris, France
| | - Emmanuel Esteve
- Sorbonne Université, AP-HP, Hôpital Tenon, Service de Néphrologie, 75020 Paris, France
| | - David Buob
- Sorbonne Université, AP-HP, Hôpital Tenon, Service de Anatomopathologie, 75020 Paris, France
| | - Noémie Abisror
- Sorbonne Université, AP-HP, Hôpital Saint-Antoine, Service de Médecine Interne, 75012 Paris, France
| | - Virginie Planche
- Sorbonne Université, Service de Hématologie biologique, APHP, Hôpital Saint Antoine, 75012, Paris, France
| | - Olivier Fain
- Sorbonne Université, AP-HP, Hôpital Saint-Antoine, Service de Médecine Interne, 75012 Paris, France
| | - Jean Jacques Boffa
- Sorbonne Université, AP-HP, Hôpital Tenon, Service de Néphrologie, 75020 Paris, France
| | - Sophie De Seigneux
- Hôpitaux universitaires de Genève, Service de Néphrologie, Rue Gabrielle-Perret-Gentil 4, 1205 Genève, Switzerland
| | - Arsène Mekinian
- Sorbonne Université, AP-HP, Hôpital Saint-Antoine, Service de Médecine Interne, 75012 Paris, France
| | - Fadi Haidar
- Hôpitaux universitaires de Genève, Service de Néphrologie, Rue Gabrielle-Perret-Gentil 4, 1205 Genève, Switzerland
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12
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The Complex Role of C-Reactive Protein in Systemic Lupus Erythematosus. J Clin Med 2021; 10:jcm10245837. [PMID: 34945133 PMCID: PMC8708507 DOI: 10.3390/jcm10245837] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 11/29/2021] [Accepted: 12/09/2021] [Indexed: 12/12/2022] Open
Abstract
C-reactive protein (CRP) is well-known as a sensitive albeit unspecific biomarker of inflammation. In most rheumatic conditions, the level of this evolutionarily highly conserved pattern recognition molecule conveys reliable information regarding the degree of ongoing inflammation, driven mainly by interleukin-6. However, the underlying causes of increased CRP levels are numerous, including both infections and malignancies. In addition, low to moderate increases in CRP predict subsequent cardiovascular events, often occurring years later, in patients with angina and in healthy individuals. However, autoimmune diseases characterized by the Type I interferon gene signature (e.g., systemic lupus erythematosus, primary Sjögren’s syndrome and inflammatory myopathies) represent exceptions to the general rule that the concentrations of CRP correlate with the extent and severity of inflammation. In fact, adequate levels of CRP can be beneficial in autoimmune conditions, in that they contribute to efficient clearance of cell remnants and immune complexes through complement activation/modulation, opsonization and phagocytosis. Furthermore, emerging data indicate that CRP constitutes an autoantigen in systemic lupus erythematosus. At the same time, the increased risks of cardiovascular and cerebrovascular diseases in patients diagnosed with systemic lupus erythematosus and rheumatoid arthritis are well-established, with significant impacts on quality of life, accrual of organ damage, and premature mortality. This review describes CRP-mediated biological effects and the regulation of CRP release in relation to aspects of cardiovascular disease and mechanisms of autoimmunity, with particular focus on systemic lupus erythematosus.
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13
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Beyazit F, Ünal Çetin E, Beyazit Y. False-positive results of lupus anticoagulant tests should be kept in mind in pregnant patients receiving low molecular weight heparin. J Turk Ger Gynecol Assoc 2021; 22:334-335. [PMID: 34872234 PMCID: PMC8666997 DOI: 10.4274/jtgga.galenos.2021.2021.0112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Affiliation(s)
- Fatma Beyazit
- Clinic of Obstetrics and Gynecology, Çanakkale Onsekiz Mart University Hospital, Çanakkale, Turkey
| | - Ece Ünal Çetin
- Department of Internal Medicine, Çanakkale Onsekiz Mart University Hospital, Çanakkale, Turkey
| | - Yavuz Beyazit
- Department of Internal Medicine, Çanakkale Onsekiz Mart University Hospital, Çanakkale, Turkey
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14
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Santana LAM, Lessa AFN, Amancio AM, Oliveira EMDE, Barbosa BF, Souza LNDE. Vascular events induced by SARS-CoV-2 and their impact in oral health. AN ACAD BRAS CIENC 2021; 93:e20211178. [PMID: 34787272 DOI: 10.1590/0001-3765202120211178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Accepted: 09/07/2021] [Indexed: 11/22/2022] Open
Affiliation(s)
- Lucas A M Santana
- Federal University of Sergipe (UFS), Department of Dentistry, R. Cláudio Batista, s/n, Santo Antônio, 49060-102 Aracaju, SE, Brazil
| | - Adriele F N Lessa
- Federal University of Minas Gerais (UFMG), Department of Oral Surgery and Pathology, School of Dentistry, Av. Presidente Antônio Carlos, 6627, Pampulha, 31270-901 Belo Horizonte, MG, Brazil
| | - Alice M Amancio
- Muriaé Cancer Hospital, Cristiano Varella Foundation, Av. Cristiano Ferreira Varella, 555, Universitário, 36880-000 Muriaé, MG, Brazil
| | - Eduardo M DE Oliveira
- Federal University of Minas Gerais (UFMG), Department of Oral Surgery and Pathology, School of Dentistry, Av. Presidente Antônio Carlos, 6627, Pampulha, 31270-901 Belo Horizonte, MG, Brazil
| | - Breno F Barbosa
- Ages University Center, Department of Dentistry, Av. Universitária, 23, Parque das Palmeiras, 48430-000 Paripiranga, BA, Brazi
| | - Leandro N DE Souza
- Federal University of Minas Gerais (UFMG), Department of Oral Surgery and Pathology, School of Dentistry, Av. Presidente Antônio Carlos, 6627, Pampulha, 31270-901 Belo Horizonte, MG, Brazil
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15
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de Boysson H, Pagnoux C. Vasculiti del sistema nervoso centrale. Neurologia 2021. [DOI: 10.1016/s1634-7072(21)45782-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
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16
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Lee I, Zickuhr L, Hassman L. Update on ophthalmic manifestations of systemic lupus erythematosus: pathogenesis and precision medicine. Curr Opin Ophthalmol 2021; 32:583-589. [PMID: 34545846 DOI: 10.1097/icu.0000000000000810] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
PURPOSE OF REVIEW Systemic lupus erythematosus (SLE) is an autoimmune disease with manifestations in multiple organs including the eyes. Several ocular manifestations like dry eye, retinopathy, and choroidopathy have been linked with specific systemic manifestations like lupus nephritis or CNS disease. Furthermore, the presence of ocular manifesattions can correlated with the severity of SLE. Finally, some medications used in the treatment of uveitis can present with lupus-like disease. Therefore, communication between the ophthalmologist and rheumatologist is vital. RECENT FINDINGS Ocular and systemic manifestations of SLE can be linked by common pathological processes including immune complex deposition, complement fixation, and vascular injury. Recent research correlating ophthalmic imaging with SLE disease has yielded heterogeneous results likely due to the clinical heterogeneity of SLE, but molecular technologies have and will continue to yield contributions to the emergence of new therapeutics for the treatment of SLE. SUMMARY Ocular manifestations are prevalent in patients with SLE. The association with certain manifestations and other disease manifestations highlights the importance of collaboration between the ophthalmologist and rheumatologist. Additional research utilizing clinico-molecular techniques will likely continue to improve our knowledge in the treatment of SLE in the future.
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Affiliation(s)
- Iris Lee
- Division of Rheumatology, Department of Medicine
| | - Lisa Zickuhr
- Division of Rheumatology, Department of Medicine
| | - Lynn Hassman
- Department of Ophthalmology and Visual Sciences, Washington University in St. Louis, St. Louis, USA
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17
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Frodlund M, Walhelm T, Dahle C, Sjöwall C. Longitudinal Analysis of Anti-cardiolipin and Anti-β2-glycoprotein-I Antibodies in Recent-Onset Systemic Lupus Erythematosus: A Prospective Study in Swedish Patients. Front Med (Lausanne) 2021; 8:646846. [PMID: 33732724 PMCID: PMC7959716 DOI: 10.3389/fmed.2021.646846] [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] [Received: 12/28/2020] [Accepted: 02/05/2021] [Indexed: 12/19/2022] Open
Abstract
Background: Anti-phospholipid syndrome (APS) and systemic lupus erythematous (SLE) are autoimmune disorders that often co-occur. Anti-phospholipid antibodies (aPL) are typical of both conditions and may be associated with vascular events and pregnancy-related morbidities. Whereas, aPL-screening is mandatory for individuals with suspected SLE, the clinical value of longitudinal aPL analyses in established SLE is unclear. Methods: We investigated the occurrence and variation of IgG/IgA/IgM anti-cardiolipin (aCL) and anti-β2-glycoprotein-I (anti-β2GPI) antibodies, using both the manufacturer's cut-off and a cut-off based on the 99th percentile of 400 apparently healthy donors, in recent-onset SLE. Furthermore, we evaluated the relationships between aPL levels and SLE/APS manifestations, as well as the pharmacotherapy. Patients with SLE who met validated classification criteria were included in this prospective study (N = 54). Samples were obtained at 0, 6, 12, 24, 36, 48, 60, 72, 84, and 96 months after SLE diagnosis. Results: Depending on the cut-off applied, 61.1 or 44.4% showed a positive result for at least one aPL isotype or the lupus anticoagulant test over time. Median values for all six aPL isotypes numerically decreased from inclusion to last follow-up, but none of the isotypes met statistical significance. Seroconversion (from positive to negative, or the opposite direction) was occasionally seen for both aCL and anti-β2GPI. IgA and IgM anti-β2GPI were the most common isotypes, followed by IgM aCL. Presence of IgG aCL associated significantly with myocardial infarction and miscarriage, and IgG/IgA anti-β2GPI with miscarriage. Conclusion: aPL were common during the first years of SLE. Even though the levels fluctuated over time, the patients tended to remain aPL positive or negative. Repeated aPL testing in the absence of new symptoms seems to be of uncertain value in patients with recent-onset SLE.
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Affiliation(s)
- Martina Frodlund
- Division of Inflammation and Infection/Rheumatology, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Tomas Walhelm
- Division of Inflammation and Infection/Rheumatology, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Charlotte Dahle
- Division of Inflammation and Infection/Clinical Immunology and Transfusion Medicine, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Christopher Sjöwall
- Division of Inflammation and Infection/Rheumatology, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
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18
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Comparison of patients with transient and sustained increments of antiphospholipid antibodies after acute ischemic stroke. J Neurol 2021; 268:2541-2549. [PMID: 33547954 DOI: 10.1007/s00415-021-10432-w] [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: 12/14/2020] [Revised: 01/25/2021] [Accepted: 01/27/2021] [Indexed: 10/22/2022]
Abstract
BACKGROUND AND PURPOSE Antiphospholipid syndrome (APS) is one of the uncommon causes of ischemic stroke, and is associated with young and female patients. However, the significance of antiphospholipid antibody (aPL) in older ischemic stroke patients is uncertain. We aimed to examine the significance of aPLs in ischemic stroke in these older patients. MATERIALS AND METHODS A total of 739 patients with acute ischemic stroke within 7 days of initial symptoms were collected consecutively. Clinical and laboratory data were obtained from medical records. aPLs (lupus anticoagulant, anti-cardiolipin antibody, anti-β2glycoprotein-I antibody) were measured the day after admission and the presence of at least one antibody was regarded as positive aPL. Patients with positive aPL were rechecked after at least 12 weeks for confirmation of APS. RESULT Of the 739 patients, 103 (13.9%) had at least one aPL initially. These patients were older, had more atrial fibrillation and higher levels of inflammatory markers. Among the 103 aPL positive patients, 41 remained positive at 3 months, 23 showed negative conversion, and 39 were not available for follow-up. Patients diagnosed with APS had higher numbers of aPL and had specifically anti-β2glycoprotein-I IgG antibody. The patients with aPLs did not differ significantly from the others in terms of stroke subtype. CONCLUSION aPL was rather common in ischemic stroke patients regardless of age. Although the influence of transient positive aPL on ischemic stroke remains uncertain, two or more aPLs and the presence of anti-β2glycoprotein-I IgG may predict a diagnosis of APS.
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19
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Rhodes JM, Subramanian S, Laird E, Griffin G, Kenny RA. Perspective: Vitamin D deficiency and COVID-19 severity - plausibly linked by latitude, ethnicity, impacts on cytokines, ACE2 and thrombosis. J Intern Med 2021; 289:97-115. [PMID: 32613681 PMCID: PMC7361294 DOI: 10.1111/joim.13149] [Citation(s) in RCA: 150] [Impact Index Per Article: 37.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2020] [Revised: 06/16/2020] [Accepted: 06/23/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND SARS-CoV-2 coronavirus infection ranges from asymptomatic through to fatal COVID-19 characterized by a 'cytokine storm' and lung failure. Vitamin D deficiency has been postulated as a determinant of severity. OBJECTIVES To review the evidence relevant to vitamin D and COVID-19. METHODS Narrative review. RESULTS Regression modelling shows that more northerly countries in the Northern Hemisphere are currently (May 2020) showing relatively high COVID-19 mortality, with an estimated 4.4% increase in mortality for each 1 degree latitude north of 28 degrees North (P = 0.031) after adjustment for age of population. This supports a role for ultraviolet B acting via vitamin D synthesis. Factors associated with worse COVID-19 prognosis include old age, ethnicity, male sex, obesity, diabetes and hypertension and these also associate with deficiency of vitamin D or its response. Vitamin D deficiency is also linked to severity of childhood respiratory illness. Experimentally, vitamin D increases the ratio of angiotensin-converting enzyme 2 (ACE2) to ACE, thus increasing angiotensin II hydrolysis and reducing subsequent inflammatory cytokine response to pathogens and lung injury. CONCLUSIONS Substantial evidence supports a link between vitamin D deficiency and COVID-19 severity but it is all indirect. Community-based placebo-controlled trials of vitamin D supplementation may be difficult. Further evidence could come from study of COVID-19 outcomes in large cohorts with information on prescribing data for vitamin D supplementation or assay of serum unbound 25(OH) vitamin D levels. Meanwhile, vitamin D supplementation should be strongly advised for people likely to be deficient.
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Affiliation(s)
- J. M. Rhodes
- From theDepartment of Cellular and Molecular PhysiologyInstitute of Translational MedicineUniversity of LiverpoolLiverpoolUK
| | - S. Subramanian
- From theDepartment of Cellular and Molecular PhysiologyInstitute of Translational MedicineUniversity of LiverpoolLiverpoolUK
| | - E. Laird
- The Irish Longitudinal Study on AgeingSchool of MedicineTrinity College DublinDublinIreland
| | - G. Griffin
- Infectious Diseases and MedicineSt George’sUniversity of LondonLondonUK
| | - R. A. Kenny
- Department of Medical GerontologyMercers Institute for AgeingSt James HospitalDublin 8Ireland
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20
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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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21
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Vecchié A, Bonaventura A, Carbone F, Maggi D, Ferraiolo A, Carloni B, Andraghetti G, Affinito Bonabello L, Liberale L, Fetaud V, Pagano S, Dallegri F, Cordera R, Montecucco F, Vuilleumier N. Antiapolipoprotein A-1 Autoantibody Positivity Is Associated with Threatened Abortion. BIOMED RESEARCH INTERNATIONAL 2020; 2020:9309121. [PMID: 32219148 PMCID: PMC7081016 DOI: 10.1155/2020/9309121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Accepted: 02/08/2020] [Indexed: 11/17/2022]
Abstract
BACKGROUND Autoantibodies against apolipoprotein A-1 (anti-ApoA-1 IgG) were demonstrated to be associated with cardiovascular outcomes in several inflammatory diseases. As balanced inflammation is critical for uncomplicated pregnancy, we aimed to investigate the prevalence of anti-ApoA-1 IgG and anti-c-terminal ApoA-1 autoantibodies (Ac-terAA1 IgG) in a cohort of pregnant women and their potential relationship with threatened abortion (TA). METHODS Between 2012 and 2014, 371 consecutive outpatient pregnant women were included in this study and followed until delivery. Anti-ApoA-1 and anti-Ac-terAA1 IgG were measured by ELISA technique on serum samples collected between the 24th and 26th week of pregnancy. Associations with TA were tested using linear regression analysis and C-statistics. RESULTS Median age was 34 with a prevalence of the Caucasian ethnicity (90.5%). TA occurred in 10 women (2.7%). C-statistics indicated that anti-ApoA-1 and anti-Ac-terAA1 IgG levels upon study inclusion were predictive of TA (0.73, 95% confidence interval [CI] 0.69-0.78, p < 0.001 and 0.76, 95% CI 0.71-0.80, p < 0.001 and 0.76, 95% CI 0.71-0.80, p < 0.001 and 0.76, 95% CI 0.71-0.80, p < 0.001 and 0.76, 95% CI 0.71-0.80. CONCLUSION Anti-ApoA-1 and anti-Ac-terAA1 IgG are independently associated with TA during pregnancy with an appealing NPV. The causal biological mechanisms underlying this association as well as the possible clinical relevance of these findings require further investigations.
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Affiliation(s)
- Alessandra Vecchié
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 6 Viale Benedetto XV, 16132 Genoa, Italy
- Virginia Commonwealth University, Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, 1200 East Marshall Street, 23298 Richmond, Virginia, USA
| | - Aldo Bonaventura
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 6 Viale Benedetto XV, 16132 Genoa, Italy
- Virginia Commonwealth University, Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, 1200 East Marshall Street, 23298 Richmond, Virginia, USA
| | - Federico Carbone
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 6 Viale Benedetto XV, 16132 Genoa, Italy
- IRCCS Ospedale Policlinico San Martino Genova-Italian Cardiovascular Network, 10 Largo Benzi, 16132 Genoa, Italy
| | - Davide Maggi
- Diabetology Unit, Department of Internal Medicine, University of Genoa, 6 Viale Benedetto XV, 16132 Genoa, Italy
| | - Antonella Ferraiolo
- Department of Obstetrics and Gynecology, IRCCS Ospedale Policlinico San Martino Genova, 10 Largo Benzi, 16132 Genoa, Italy
| | - Beatrice Carloni
- Diabetology Unit, Department of Internal Medicine, University of Genoa, 6 Viale Benedetto XV, 16132 Genoa, Italy
| | - Gabriella Andraghetti
- Department of Internal Medicine, University of Genoa, 6 Viale Benedetto XV, 16132 Genoa, Italy
| | - Laura Affinito Bonabello
- Diabetology Unit, Department of Internal Medicine, University of Genoa, 6 Viale Benedetto XV, 16132 Genoa, Italy
| | - Luca Liberale
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 6 Viale Benedetto XV, 16132 Genoa, Italy
- Center for Molecular Cardiology, University of Zurich, 12 Wagistrasse, 8952 Schlieren, Switzerland
| | - Vanessa Fetaud
- Division of Laboratory Medicine, Department of Genetics and Laboratory Medicine, Geneva University Hospitals, 4 Rue Gabrielle-Perret-Gentil, 1205 Geneva, Switzerland
- Division of Laboratory Medicine, Department of Medical Specialties, Geneva Faculty of Medicine, Switzerland
| | - Sabrina Pagano
- Division of Laboratory Medicine, Department of Genetics and Laboratory Medicine, Geneva University Hospitals, 4 Rue Gabrielle-Perret-Gentil, 1205 Geneva, Switzerland
- Division of Laboratory Medicine, Department of Medical Specialties, Geneva Faculty of Medicine, Switzerland
| | - Franco Dallegri
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 6 Viale Benedetto XV, 16132 Genoa, Italy
- IRCCS Ospedale Policlinico San Martino Genova-Italian Cardiovascular Network, 10 Largo Benzi, 16132 Genoa, Italy
| | - Renzo Cordera
- Diabetology Unit, Department of Internal Medicine, University of Genoa, 6 Viale Benedetto XV, 16132 Genoa, Italy
| | - Fabrizio Montecucco
- IRCCS Ospedale Policlinico San Martino Genova-Italian Cardiovascular Network, 10 Largo Benzi, 16132 Genoa, Italy
- First Clinic of Internal Medicine, Department of Internal Medicine and Center of Excellence for Biomedical Research (CEBR), University of Genoa, 6 Viale Benedetto XV, 16132 Genoa, Italy
| | - Nicolas Vuilleumier
- Division of Laboratory Medicine, Department of Genetics and Laboratory Medicine, Geneva University Hospitals, 4 Rue Gabrielle-Perret-Gentil, 1205 Geneva, Switzerland
- Division of Laboratory Medicine, Department of Medical Specialties, Geneva Faculty of Medicine, Switzerland
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