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Journal of Thrombosis and Haemostasis :... Apr 2023Antiphospholipid syndrome (APS) is a systemic autoimmune disease, where persistent presence of antiphospholipid antibodies (aPL) leads to thrombotic and obstetric... (Review)
Review
Antiphospholipid syndrome (APS) is a systemic autoimmune disease, where persistent presence of antiphospholipid antibodies (aPL) leads to thrombotic and obstetric complications. APS is a paradigmatic thromboinflammatory disease. Thromboinflammation is a pathophysiological mechanism coupling inflammation and thrombosis, which contributes to the pathophysiology of cardiovascular disease. APS can serve as a model to unravel mechanisms of thromboinflammation and the relationship between innate immune cells and thrombosis. Monocytes are activated by aPL into a proinflammatory and procoagulant phenotype, producing proinflammatory cytokines such as tumor necrosis factor α, interleukin 6, as well as tissue factor. Important cellular signaling pathways involved are the NF-κB-pathway, mammalian target of rapamycin (mTOR) signaling, and the NOD-, LRR-, and pyrin domain-containing protein 3 inflammasome. All of these may serve as future therapeutic targets. Neutrophils produce neutrophil extracellular traps in response to aPL, and this leads to thrombosis. Thrombosis in APS also stems from increased interaction of neutrophils with endothelial cells through P-selectin glycoprotein ligand-1. NETosis can be targeted not only with several experimental therapeutics, such as DNase, but also through the redirection of current therapies such as defibrotide and the antiplatelet agent dipyridamole. Activation of platelets by aPL leads to a procoagulant phenotype. Platelet-leukocyte interactions are increased, possibly mediated by increased levels of soluble P-selectin and soluble CD40-ligand. Platelet-directed future treatment options involve the inhibition of several platelet receptors activated by aPL, as well as mTOR inhibition. This review discusses mechanisms underlying thromboinflammation in APS that present targetable therapeutic options, some of which may be generalizable to other thromboinflammatory diseases.
Topics: Female; Pregnancy; Humans; Antiphospholipid Syndrome; Thromboinflammation; Endothelial Cells; Inflammation; Thrombosis; TOR Serine-Threonine Kinases
PubMed: 36696191
DOI: 10.1016/j.jtha.2022.12.002 -
Seminars in Thrombosis and Hemostasis Apr 2023Antiphospholipid syndrome (APS) is an autoimmune prothrombotic disease characterized by thrombosis and/or pregnancy complications caused by antiphospholipid antibodies...
Antiphospholipid syndrome (APS) is an autoimmune prothrombotic disease characterized by thrombosis and/or pregnancy complications caused by antiphospholipid antibodies (aPL). The history of APS can be traced back to observations made during screening programs for syphilis conducted in the mid-20th century, with identification of patients with the so-called biological false-positive serological reactions for syphilis. Initial observation linking aPL with recurrent miscarriages was first reported more than 40 years ago. Since then, our understanding of the pathogenesis and management of APS has evolved markedly. Although APS is an autoimmune disease, anticoagulation mainly with vitamin K antagonists (VKAs) rather than immunomodulation, is the treatment of choice for thrombotic APS. Direct acting oral anticoagulants are inferior to VKAs, especially those with triple-positive APS and arterial thrombosis. Inflammation, complement activation, and thrombosis in the placenta may contribute to pathogenesis of obstetric APS. Heparin, mainly low-molecular-weight heparin, and low-dose aspirin represent the treatments of choice for women with obstetric complications. Increasingly, immunomodulatory agents such as hydroxychloroquine for thrombotic and obstetric APS are being used, especially in patients who are refractory to present standard treatment.
Topics: Pregnancy; Humans; Female; Antiphospholipid Syndrome; Syphilis; Antibodies, Antiphospholipid; Anticoagulants; Thrombosis; Autoimmune Diseases
PubMed: 36646109
DOI: 10.1055/s-0042-1760333 -
Autoimmunity Reviews Oct 2021To identify and assess the magnitude of effect of pregnancy outcome predictors in women with antiphospholipid syndrome (APS) by means of systematic review and... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
To identify and assess the magnitude of effect of pregnancy outcome predictors in women with antiphospholipid syndrome (APS) by means of systematic review and meta-analysis.
METHODS
PubMed and Embase were searched (13th June 2020) for studies reporting on pre-pregnancy risk factors of pregnancy outcomes in APS patients. Literature screening and data extraction were conducted by two reviewers independently, in a blinded standardized manner. Pooled univariate odds ratios (OR) were computed using a random effects model. Heterogeneity was assessed by I%.
RESULTS
The search yielded 3013 unique results; 27 records were included in this meta-analysis. Previous thrombosis was associated with a decreased live birth risk (OR 0.60, p < 0.01, I = 40%), increased neonatal mortality (OR 15.19, p < 0.01, I = 0%), an increased risk of antenatal or postpartum thrombosis (OR 6.26, p < 0.01, I = 0%) and an increased risk of delivering a small for gestational age neonate (SGA) (OR 2.60, p = 0.01, I = 0%). Patients with an APS laboratory category I (double or triple positivity) profile had a decreased live birth risk (OR 0.66, p < 0.01, I = 0%), an increased risk of SGA (OR 1.86, p = 0.01, I = 43%) and preterm birth (OR 1.35, p < 0.01, I = 49%). Triple positivity was associated with a decreased live birth risk (OR 0.33, p < 0.01, I = 68%), an increased risk of preeclampsia (OR 2.43, p = 0.02, I = 35%) and SGA (OR 2.47, p = 0.04, I = 61%). Patients with lupus anticoagulant positivity had an increased risk of preeclampsia (OR 2.10, p = 0.02, I = 48%), SGA (OR 1.78, p < 0.01, I = 0%) and preterm birth (OR 3.56, p = 0.01, I = 48%). Risk of bias assessment suggested considerable bias on study participation and statistical methods.
CONCLUSIONS
The results of this meta-analysis identified previous thrombosis, laboratory category I, triple positivity and lupus anticoagulant positivity as the most important predictors of adverse pregnancy outcomes. This up-to-date knowledge, can be used in preconception counseling and tailoring of obstetric care.
Topics: Antiphospholipid Syndrome; Female; Humans; Infant, Newborn; Lupus Coagulation Inhibitor; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; Premature Birth
PubMed: 34280554
DOI: 10.1016/j.autrev.2021.102901 -
Current Neurology and Neuroscience... Jun 2021In recent years, the spectrum of neurological manifestations of antiphospholipid syndrome (APS) has been growing. We provide a critical review of the literature with... (Review)
Review
PURPOSE OF REVIEW
In recent years, the spectrum of neurological manifestations of antiphospholipid syndrome (APS) has been growing. We provide a critical review of the literature with special emphasis on presentation, proposed mechanisms of disease, and treatment of neurological involvement in APS.
RECENT FINDINGS
Although stroke is the most common cause of neurological manifestations in patients with APS, other neurological disorders have been increasingly associated with the disease, including cognitive dysfunction, headache, and epilepsy. Direct oral anticoagulants have failed to show non-inferiority compared to vitamin K antagonists for the prevention of major thrombotic events. Antiphospholipid antibodies are often found in patients with acute COVID-19 but clear evidence supporting an association between these antibodies and the risk of thrombotic events, including stroke and cerebral venous thrombosis, is still lacking. APS patients may present with several distinct neurological manifestations. New criteria will facilitate the classification of patients presenting with increasingly recognized non-criteria neurological manifestations.
Topics: Antibodies, Antiphospholipid; Anticoagulants; Antiphospholipid Syndrome; COVID-19; Humans; SARS-CoV-2
PubMed: 34125304
DOI: 10.1007/s11910-021-01124-z -
Frontiers in Immunology 2020
Topics: Antiphospholipid Syndrome; Biomarkers; Disease Management; Disease Susceptibility; Humans
PubMed: 32983139
DOI: 10.3389/fimmu.2020.01993 -
Journal of Thrombosis and Haemostasis :... Apr 2021Anticoagulation is central to the management of thrombotic antiphospholipid syndrome (APS). The standard anticoagulant treatment for thrombotic APS is life-long warfarin... (Review)
Review
Anticoagulation is central to the management of thrombotic antiphospholipid syndrome (APS). The standard anticoagulant treatment for thrombotic APS is life-long warfarin or an alternative vitamin K antagonist. The role of direct oral anticoagulants for thrombotic APS is not established due to the lack of definitive evidence and has recently been addressed in international guidance. Other anticoagulant options include low molecular weight heparin, unfractionated heparin, and fondaparinux. In APS patients, lupus anticoagulant can affect phospholipid-dependent coagulation monitoring tests, so that they may not reflect true anticoagulation intensity. Accurate assessment of anticoagulation intensity is essential, to optimize anticoagulant dosing and facilitate thrombus resolution; minimize the risk of recurrent thrombosis or bleeding; inform assessment of whether recurrent thrombosis is related to breakthrough thrombosis while on therapeutic anticoagulation, subtherapeutic anticoagulation, non-adherence, or spurious results; and guide the management of bleeding. Knowledge of anticoagulant intensity also informs assessment and comparison of anticoagulation regimens in clinical studies. Considerations regarding anticoagulation dosing and/or monitoring of thrombotic APS patients underpin appropriate management in special situations, notably APS-related severe renal impairment, which can occur in APS or APS/systemic lupus erythematosus-related nephropathy or catastrophic APS; and APS-related thrombocytopenia. Anticoagulant dosing and monitoring in thrombotic APS patients also require consideration in anticoagulant-refractory APS and during pregnancy. In this review, we summarize the tests generally used in monitoring anticoagulant therapy, use of the main anticoagulants considered for thrombotic APS, lupus anticoagulant effects on anticoagulation monitoring tests, and strategies for appropriate anticoagulant monitoring in thrombotic APS.
Topics: Anticoagulants; Antiphospholipid Syndrome; Blood Coagulation; Female; Heparin; Humans; Pregnancy; Thrombosis
PubMed: 33325604
DOI: 10.1111/jth.15217 -
Journal of Thrombosis and Thrombolysis Aug 2023Antiphospholipid antibodies (APLAs) are primarily directed toward phospholipid-binding proteins and are responsible for thrombotic events. APLAs include... (Review)
Review
Antiphospholipid antibodies (APLAs) are primarily directed toward phospholipid-binding proteins and are responsible for thrombotic events. APLAs include anti-β2Glycoprotein I (anti-β2GPI), anticardiolipin (anti-CL) antibodies, and lupus anticoagulant. These antibodies are typical markers of antiphospholipid syndrome (APS) and are a part of its diagnostic criteria. Many data underline the presence of APLAs in other rheumatic diseases (e.g., systemic lupus erythematosus, systemic sclerosis, Sjögren's syndrome, rheumatoid arthritis and Behçet's disease). However, they are also detected in patients with cancer, infection, and neurological disorders. Furthermore, healthy individuals may be carriers of APLAs. Chronic asymptomatic APLAs presence is most common in the elderly and subjects with chronic diseases (including malignancies). Specific kinds of APLAs are considered markers of oncological progression. These antibodies occur in 6% of pregnant women (without diagnosed APS) and are related to many pregnancy complications. Of worth, various types of APLAs are reported to have different prothrombotic properties. The risk of thrombotic events in APLA-positive but clinically naïve patients raises many questions in clinical practice. This manuscript analyses various clinical situations and consequences of the APLAs' presence, particularly in patients without diagnosed APS. The prevalence, etiology, molecular background, and prothrombotic properties of numerous APLAs are broadly discussed. The new management approach in different clinical conditions and organ complications is present in the context of recent recommendations. Discussed data underlines that adequate and timely introduced thromboprophylaxis can decrease the risk of thrombus formation and prevent increased morbidity.
Topics: Humans; Female; Pregnancy; Aged; Anticoagulants; Venous Thromboembolism; Antibodies, Antiphospholipid; Antiphospholipid Syndrome; Lupus Erythematosus, Systemic; Thrombosis
PubMed: 37264223
DOI: 10.1007/s11239-023-02834-6 -
Haematologica Mar 2020Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by arterial and venous thrombotic manifestations and/or pregnancy-related complications in... (Review)
Review
Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by arterial and venous thrombotic manifestations and/or pregnancy-related complications in patients with persistently high antiphospholipid antibodies (aPL), the most common being represented by anticardiolipin antibodies (aCL), anti-beta 2 glycoprotein-I (aβ2GPI), and lupus anticoagulant (LAC). A growing number of studies have showed that, in some cases, patients may present with clinical features of APS but with temporary positive or persistently negative titers of aPL. For these patients, the definition of seronegative APS (SN-APS) has been proposed. Nevertheless, the negativity to classic aPL criteria does not imply that other antibodies may be present or involved in the onset of thrombosis. The diagnosis of SN-APS is usually made by exclusion, but its recognition is important to adopt the most appropriate anti-thrombotic strategy to reduce the rate of recurrences. This research is in continuous development as the clinical relevance of these antibodies is far from being completely clarified. The most studied antibodies are those against phosphatidylethanolamine, phosphatidic acid, phosphatidylserine, phosphatidylinositol, vimentin/cardiolipin complex, and annexin A5. Moreover, the assays to measure the levels of these antibodies have not yet been standardized. In this review, we will summarize the evidence on the most studied non-criteria aPL, their potential clinical relevance, and the antithrombotic therapeutic strategies available in the setting of APS and SN-APS.
Topics: Antibodies, Anticardiolipin; Antibodies, Antiphospholipid; Antiphospholipid Syndrome; Female; Humans; Lupus Coagulation Inhibitor; Pregnancy; beta 2-Glycoprotein I
PubMed: 32001534
DOI: 10.3324/haematol.2019.221945 -
Kidney & Blood Pressure Research 2023Antiphospholipid syndrome (APS) is an autoimmune disease characterized by the development of autoantibodies and the impairment of the coagulation system. Knowledge about... (Review)
Review
BACKGROUND
Antiphospholipid syndrome (APS) is an autoimmune disease characterized by the development of autoantibodies and the impairment of the coagulation system. Knowledge about this syndrome is increasing over time, but kidney involvement, especially APS nephropathy, still represents a challenge for physicians.
SUMMARY
A "two hit" model has been hypothesized to explain APS pathophysiology, and the role played by some factors, such as the complement system, is becoming more and more clear. From a clinical point of view, along with thrombosis in any site and/or obstetric morbidities, that are the hallmarks of APS, a constellation of several other clinical symptoms is related to APS. These symptoms alone are not sufficient to fulfill Sydney criteria for APS and this could potentially lead to omitting some diagnoses. The mainstay of management of APS is antithrombotic therapy, but there are expectations for new drugs that regulate the immune system. APS could affect the kidneys in many ways and among them, APS nephropathy is an intriguing entity that has been overlooked in recent years. Novel studies on APS nephropathy are lacking.
KEY MESSAGES
In this review, we discuss what we currently know about APS and its relationship with the kidney, with an eye toward the future perspectives. Multicenter studies on APS nephropathy are necessary in order to develop targeted therapies.
Topics: Female; Pregnancy; Humans; Antiphospholipid Syndrome; Antibodies, Antiphospholipid; Kidney; Kidney Diseases; Thrombosis
PubMed: 37734329
DOI: 10.1159/000529229 -
Progress in Cardiovascular Diseases 2009The antiphospholipid syndrome (APS) is an autoimmune systemic disease that is diagnosed when there is vascular thrombosis and/or pregnancy morbidity occurring with... (Review)
Review
The antiphospholipid syndrome (APS) is an autoimmune systemic disease that is diagnosed when there is vascular thrombosis and/or pregnancy morbidity occurring with persistently positive antiphospholipid antibodies (aPL) (lupus anticoagulant test, anticardiolipin antibodies, and/or anti-beta(2)-glycoprotein I antibodies). Although International APS Classification Criteria have been formulated to provide a uniform approach to APS research, aPL may cause a spectrum of clinical manifestations, some of which are not included in these criteria. The main aPL-related cardiac manifestations include valve abnormalities (vegetations and/or thickening), myocardial infarction (MI), intracardiac thrombi, and myocardial microthrombosis. In this article, we will review the definition, etiopathogenesis, clinical manifestations, diagnosis, and treatment of aPL-related clinical events with emphasis on cardiac manifestations.
Topics: Antibodies, Antiphospholipid; Antiphospholipid Syndrome; Aspirin; Comorbidity; Female; Humans; Lupus Coagulation Inhibitor; Myocardial Infarction; Platelet Aggregation Inhibitors; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Thrombosis
PubMed: 19732604
DOI: 10.1016/j.pcad.2009.06.005