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1.
Lancet Haematol ; 7(8): e613-e623, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32735839

RESUMO

Lifelong anticoagulation with warfarin or alternative vitamin K antagonist is the standard anticoagulant treatment for thrombotic antiphospholipid syndrome. Anticoagulant-refractory thrombotic antiphospholipid syndrome can be broadly defined as breakthrough thrombosis while on standard oral anticoagulation treatment and its management is a major challenge given the serious nature of the thrombotic disease observed, which has become refractory to oral anticoagulation. The factors (genetic and cellular) that cause anticoagulant-refractory thrombotic antiphospholipid syndrome are now better understood. However, efforts to use this greater understanding have not yet transformed the capacity to treat it successfully in many patients. In this Viewpoint, we review the factors that are likely to be contributing to the cause of this syndrome and consider how they might be modified or inhibited. We also discuss management, including general strategies to minimise thrombotic risk, intensification of anticoagulation, addition of an antiplatelet agent, adjunctive treatment for thrombosis, immunomodulatory therapy, complement inhibition, vascular options, and future potential therapeutic targets.


Assuntos
Anticoagulantes/farmacologia , Síndrome Antifosfolipídica/terapia , Resistência a Medicamentos/efeitos dos fármacos , Fibrinolíticos/uso terapêutico , Inibidores da Agregação de Plaquetas/uso terapêutico , Terapia Trombolítica , Trombose/prevenção & controle , Síndrome Antifosfolipídica/patologia , Humanos , Trombose/patologia
3.
Int J Mol Med ; 46(3): 903-912, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32588061

RESUMO

The severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2) is a novel ß coronavirus that is the etiological agent of the pandemic coronavirus disease 2019 (COVID­19) that at the time of writing (June 16, 2020) has infected almost 6 million people with some 450,000 deaths. These numbers are still rising daily. Most (some 80%) cases of COVID­19 infection are asymptomatic, a substantial number of cases (15%) require hospitalization and an additional fraction of patients (5%) need recovery in intensive care units. Mortality for COVID­19 infection appears to occur globally between 0.1 and 0.5% of infected patients although the frequency of lethality is significantly augmented in the elderly and in patients with other comorbidities. The development of acute respiratory distress syndrome and episodes of thromboembolism that may lead to disseminated intravascular coagulation (DIC) represent the primary causes of lethality during COVID­19 infection. Increasing evidence suggests that thrombotic diathesis is due to multiple derangements of the coagulation system including marked elevation of D­dimer that correlate negatively with survival. We propose here that the thromboembolic events and eventually the development of DIC provoked by SARS­CoV­2 infection may represent a secondary anti­phospholipid antibody syndrome (APS). We will apply both Baconian inductivism and Cartesian deductivism to prove that secondary APS is likely responsible for coagulopathy during the course of COVID­19 infection. Diagnostic and therapeutic implications of this are also discussed.


Assuntos
Síndrome Antifosfolipídica/patologia , Infecções por Coronavirus/patologia , Coagulação Intravascular Disseminada/patologia , Pneumonia Viral/patologia , Tromboembolia/patologia , Trombose/patologia , Síndrome Antifosfolipídica/imunologia , Antivirais/uso terapêutico , Betacoronavirus , Coagulação Sanguínea/fisiologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Coagulação Intravascular Disseminada/imunologia , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Humanos , Pandemias , Fosfolipídeos/imunologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Tromboembolia/imunologia
4.
Int J Mol Sci ; 21(6)2020 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-32197340

RESUMO

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.


Assuntos
Imunidade Adaptativa , Síndrome Antifosfolipídica/imunologia , Imunidade Inata , MicroRNAs/imunologia , Síndrome Antifosfolipídica/patologia , Biomarcadores , Humanos
5.
Mol Med Rep ; 21(3): 1320-1327, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31922220

RESUMO

Human parvovirus B19 (B19V) infection has symptoms similar to those of anti­phospholipid syndrome (APS). Antibodies against B19V­VP1 unique region (VP1u) exhibit activity similar to that of anti­phospholipid antibodies (aPLs) by inducing vascular endothelial cell adhesion factors and APS­like syndrome. Previous studies have identified an effect of aPLs on angiogenesis. However, little is understood regarding the effect of anti­B19V­VP1u antibodies on angiogenesis. The present study investigated the effects of anti­B19V­VP1u antibodies on the expression of adhesion molecules and angiogenic signaling using an aPL­induced human umbilical vein endothelial cell (HUVEC) model, and trypan blue staining and western blotting. The effect of B19V­VP1u antibodies on vascular endothelial growth factor (VEGF) expression in A549 cells, another well­known 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), B19V­VP1u IgG or B19V­NS1 IgG, compared with in the normal human (NH) IgG­treated cells. Conversely, significantly higher vascular cellular adhesion molecule 1 was only detected in HUVECs treated with B19V­VP1u IgG. Significantly increased integrin ß1 was detected in HUVECs treated with aPL IgG or B19V­VP1u IgG, whereas no difference in integrin ß1 was observed in those treated with 10% FCS, NH IgG or B19V­NS1 IgG. No difference in AKT­mTOR­S6 ribosomal protein (S6RP) signaling was observed in HUVECs treated with B19­VP1u IgG or B19V­NS1 IgG, compared with NH IgG­treated cells. Significantly higher human inducible factor­1α was detected in HUVECs treated with 10% FCS, aPL IgG, B19V­VP1u IgG or B19V­NS1 IgG, compared with in NH IgG­treated cells. However, there was no difference in the level of VEGF observed among HUVECs treated with NH IgG, B19V­VP1u IgG or B19V­NS1 IgG. Notably, no difference in VEGF level was observed in A549 cells treated with NH IgG, aPL IgG, B19V­VP1u IgG or B19V­NS1 IgG. These findings suggest that anti­B19V­VP1u antibodies may serve a role in activating adhesion molecules, but not in AKT­mTOR­S6RP signaling.


Assuntos
Anticorpos Antivirais/farmacologia , Síndrome Antifosfolipídica , Eritema Infeccioso , Imunoglobulina G/farmacologia , Neovascularização Fisiológica/efeitos dos fármacos , Parvovirus B19 Humano/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células A549 , Anticorpos Antifosfolipídeos/farmacologia , Síndrome Antifosfolipídica/metabolismo , Síndrome Antifosfolipídica/patologia , Síndrome Antifosfolipídica/virologia , Eritema Infeccioso/metabolismo , Eritema Infeccioso/patologia , Células Endoteliais da Veia Umbilical Humana , Humanos
7.
Lupus ; 29(1): 74-78, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31789127

RESUMO

Indeterminate cell histiocytosis (ICH) is an extremely rare clonal proliferative disorder of dendritic cells which presents with skin lesions in the majority of cases. Although extra-cutaneous manifestations are very rare, ICH may involve the mucosa, cornea, and conjunctiva as well as the visceral organs. Since the clinical appearance of cutaneous lesions of ICH is not distinctive, it is diagnosed with histopathological and immunohistochemical findings after clinical suspicion. Herein, we report a 27-year-old man with a two-year history of asymptomatic reddish papules and papulonecrotic lesions on his face, arms and buttocks. He was previously diagnosed with systemic lupus erythematosus (SLE) and antiphospholipid antibody syndrome (APS), and he had been treated with hydroxychloroquine and low-dose aspirin. Diffuse dermal infiltration of a mixture of histiocytes and lymphocytes accompanied with multinuclear giant cells, the positive CD68 and Factor XIIIa and negative Langerin immunoreactions, along with the positive staining with CD1a and S100, led us to the diagnosis of ICH. To the best of our knowledge, this is the first case of ICH associated with SLE and APS.


Assuntos
Síndrome Antifosfolipídica/diagnóstico , Dermatopatias/diagnóstico , Administração Tópica , Adulto , Síndrome Antifosfolipídica/complicações , Síndrome Antifosfolipídica/tratamento farmacológico , Síndrome Antifosfolipídica/patologia , Humanos , Imunossupressores/administração & dosagem , Lúpus Eritematoso Sistêmico/complicações , Masculino , Dermatopatias/complicações , Dermatopatias/tratamento farmacológico , Dermatopatias/patologia , Tacrolimo/administração & dosagem
8.
Lupus ; 29(2): 105-117, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31829084

RESUMO

Antiphospholipid syndrome is a systemic autoimmune disease associated with obstetric complications along with vascular events affecting multiple organ systems in patients having positive titers of antiphospholipid antibodies. Eight to 20% of infertility cases have an unknown cause, part of which could be due to antiphospholipid syndrome. Although still debatable, many studies have addressed the relation between reproductive failure and antiphospholipid antibodies through the relation between antiphospholipid antibodies and unexplained infertility as well as the effect of antiphospholipid antibodies on the outcome of in vitro fertilization-embryo transfer. Few studies and cases have associated the presence of antiphospholipid antibodies with male infertility, describing morphofunctional penile abnormalities and testicular infarction. There are not enough data to support the routine practice of testing antiphospholipid antibodies in patients with infertility.


Assuntos
Aborto Habitual/imunologia , Anticorpos Antifosfolipídeos/imunologia , Infertilidade Feminina/imunologia , Infertilidade Masculina/imunologia , Aborto Habitual/patologia , Animais , Síndrome Antifosfolipídica/imunologia , Síndrome Antifosfolipídica/patologia , Feminino , Fertilização In Vitro , Humanos , Infertilidade Feminina/patologia , Infertilidade Masculina/patologia , Masculino , Gravidez
9.
Front Immunol ; 10: 2734, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31824510

RESUMO

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.


Assuntos
Síndrome Antifosfolipídica/imunologia , Linfócitos B/imunologia , Comunicação Celular/imunologia , Armadilhas Extracelulares/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Neutrófilos/imunologia , Síndrome Antifosfolipídica/patologia , Linfócitos B/patologia , Citocinas/imunologia , Humanos , Lúpus Eritematoso Sistêmico/patologia , Neutrófilos/patologia
10.
Hematology Am Soc Hematol Educ Program ; 2019(1): 426-432, 2019 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-31808842

RESUMO

Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by thrombosis, pregnancy morbidity, or nonthrombotic manifestations in patients with persistently positive antiphospholipid antibodies (aPL). Conventional APS treatment focuses on antithrombotic strategies, which are usually ineffective for the microvascular and nonthrombotic manifestations of aPL. Using a case-based presentation, this review focuses on the role of immunosuppression in nonobstetric APS, including B-cell inhibition (rituximab, belimumab, and bortezomib), complement inhibition (eculizumab), mechanistic target of rapamycin inhibition (sirolimus), vascular endothelial cell modulation (defibrotide), statins, and traditional rheumatologic disease-modifying agents (hydroxychloroquine, mycophenolate mofetil, azathioprine, and cyclophosphamide).


Assuntos
Síndrome Antifosfolipídica/tratamento farmacológico , Imunossupressão , Imunossupressores/uso terapêutico , Anticorpos Antifosfolipídeos/imunologia , Síndrome Antifosfolipídica/imunologia , Síndrome Antifosfolipídica/patologia , Humanos , Masculino , Pessoa de Meia-Idade
12.
Clin Chest Med ; 40(3): 519-529, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31376888

RESUMO

Systemic lupus erythematosus (SLE) is a systemic inflammatory disease, characterized by an antibody response to nucleic antigens and involvement of any organ system. Pulmonary manifestations are frequent and include pleuritis, acute lupus pneumonitis, chronic interstitial lung disease, alveolar hemorrhage, shrinking lung syndrome, airway disease, pulmonary hypertension (PH), and thromboembolic disease. The antiphospholipid antibody syndrome (APLAS) is a systemic autoimmune disorder where different prothrombotic factors interact to induce arterial and venous thrombosis. The most common pulmonary manifestations are pulmonary thromboembolism and PH. This review will focus on the clinical presentation, diagnosis, and management of the SLE- and APLAS-associated pulmonary conditions.


Assuntos
Síndrome Antifosfolipídica/diagnóstico , Lúpus Eritematoso Sistêmico/diagnóstico , Adolescente , Adulto , Síndrome Antifosfolipídica/patologia , Feminino , Humanos , Lúpus Eritematoso Sistêmico/patologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
13.
J Autoimmun ; 104: 102311, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31378637

RESUMO

Type I Interferon gene expression has been shown to play an important role in the pathogenesis of several systemic autoimmune disorders, paving the way for its potential use as a surrogate marker or a therapeutic tool. While the concept of type I interferon signature and its correlation with clinical phenotypes and disease activity, along with anti-interferon targeted therapy have been vastly investigated in patients with systemic lupus erythematosus, there is a paucity of data concerning antiphospholipid syndrome patients. In this review, we summarize the current knowledge on the pathogenetic and clinical implications of type I interferon expression in antiphospholipid syndrome and discuss the therapeutic possibility of targeting molecules along the interferon signaling pathway. A number of recent studies have shown a type I interferon gene expression induction in patients with primary antiphospholipid syndrome via the plasmacytoid dendritic cell pathway, toll like receptors (TLRs) such as TLR7 and TLR9, anti-beta2glycoprotein I antibody-mediated neutrophil activation and neutrophil extracellular traps (NETs) release in a TLR4-dependent fashion, and a subsequent B cell and plasmablast activation. An association between type I interferon expression and several demographic, clinical and laboratory characteristics including age, gender, pregnancy complications such as eclampsia, anti-beta2glycoprotein I antibodies, and a negative correlation with hydroxychloroquine and/or statin use, has been shown. Correlation of high interferon scores to worse outcomes in prospective studies could direct the initiation for a prompt treatment in high-risk populations. Potential therapeutic approaches targeting type I interferon production and signaling pathway components might include anti-interferon or interferon receptor monoclonal antibodies, or an interferon based therapeutic vaccine as was indicated from previous systemic lupus erythematosus studies, TLR inhibitors including hydroxychloroquine and anti-TLR antibodies, plasmacytoid dendritic cell inhibition, adenosine-receptor agonists, and plasmablast targeting treatments. Well-designed studies are needed to further assess the immunomodulatory potential of the above targets for therapeutic intervention in patients with primary antiphospholipid syndrome.


Assuntos
Síndrome Antifosfolipídica , Regulação da Expressão Gênica/imunologia , Interferon Tipo I/imunologia , Lúpus Eritematoso Sistêmico , Síndrome Antifosfolipídica/imunologia , Síndrome Antifosfolipídica/patologia , Síndrome Antifosfolipídica/terapia , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/terapia
14.
Clin Exp Med ; 19(3): 281-288, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31214910

RESUMO

Catastrophic antiphospholipid syndrome (CAPS) is a rare disorder, characterized by the development of multiple vascular thrombosis over a short period of time, in patients with persistently detectable antiphospholipid antibodies (aPLs). The vascular occlusions predominantly affect small vessels. The overall mortality is 36.9%, despite the recent progress in the therapeutic approach. It has been shown that aPLs are able to induce a hypercoagulability state through different mechanisms of action, including complement activation, which in turn plays a key role in the pathogenesis of some thrombotic microangiopathies. Consequently, complement inhibition may be proposed as a targeted intervention to effectively prevent the progression of the microthrombotic storm. The employment of the complement inhibitor eculizumab has been proposed in CAPS on the basis of occasional reports and expert opinion. We report the case of a 54-year-old woman with a CAPS refractory to conventional therapies, who was successfully treated with eculizumab. The administration of this anti-C5 monoclonal antibody aborted the acute progressive thrombotic events and prevented further clinical episodes of thrombosis in the following year. We also faced our case to a systematic literature review, by analyzing all reported cases of CAPS in which eculizumab was added to conventional therapy. Even if further investigation is needed, our results suggest that the inhibition of one mechanism of aPL-induced organ damage may be an add-on treatment for this condition.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Síndrome Antifosfolipídica/tratamento farmacológico , Síndrome Antifosfolipídica/patologia , Fatores Imunológicos/uso terapêutico , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
15.
Cell Host Microbe ; 26(1): 100-113.e8, 2019 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-31227334

RESUMO

Given the immense antigenic load present in the microbiome, we hypothesized that microbiota mimotopes can be a persistent trigger in human autoimmunity via cross-reactivity. Using antiphospholipid syndrome (APS) as a model, we demonstrate cross-reactivity between non-orthologous mimotopes expressed by a common human gut commensal, Roseburia intestinalis (R. int), and T and B cell autoepitopes in the APS autoantigen ß2-glycoprotein I (ß2GPI). Autoantigen-reactive CD4+ memory T cell clones and an APS-derived, pathogenic monoclonal antibody cross-reacted with R. int mimotopes. Core-sequence-dependent anti-R. int mimotope IgG titers were significantly elevated in APS patients and correlated with anti-ß2GPI IgG autoantibodies. R. int immunization of mice induced ß2GPI-specific lymphocytes and autoantibodies. Oral gavage of susceptible mice with R. int induced anti-human ß2GPI autoantibodies and autoimmune pathologies. Together, these data support a role for non-orthologous commensal-host cross-reactivity in the development and persistence of autoimmunity in APS, which may apply more broadly to human autoimmune disease.


Assuntos
Anticorpos Antibacterianos/imunologia , Antígenos de Bactérias/imunologia , Autoimunidade , Linfócitos B/imunologia , Clostridiales/imunologia , Reações Cruzadas , Linfócitos T/imunologia , Adulto , Idoso , Animais , Síndrome Antifosfolipídica/patologia , Autoanticorpos/sangue , Autoanticorpos/imunologia , Feminino , Trato Gastrointestinal/microbiologia , Humanos , Imunoglobulina G/sangue , Masculino , Camundongos , Pessoa de Meia-Idade , Modelos Animais , Adulto Jovem , beta 2-Glicoproteína I/imunologia
16.
Clin Exp Immunol ; 197(3): 376-386, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31091357

RESUMO

Anti-phospholipid syndrome (APS) is characterized by recurrent pathological pregnancy, arterial or venous thrombosis in the presence of anti-phospholipid antibody (aPL). Complement activation is recognized as an intermediate link leading to placental thrombosis and placental inflammation in APS model mice. Decay accelerating factor (DAF, CD55), MAC-inhibitory protein (MAC-IP, CD59) and membrane co-factor protein (MCP, CD46) are important complement inhibitory proteins (CIPs) highly expressed in normal placenta to curb excessive complement activation and its mediated injuries. Anti-ß2 glycoprotein I (anti-ß2GPI) antibody is an important aPL. We found that placental DAF and CD46 decreased in ß2GPI passively immunized APS model mice, accompanied by C3 deposition, neutrophil infiltration and increased proinflammatory cytokine levels detected in its placenta. Progesterone supplement can up-regulate DAF but not CD46 expression, curb C3 activation and decrease proinflammatory cytokines levels to reduce fetal loss frequency. Progesterone receptor antagonist (mifepristone) or knock-down DAF with specific siRNA, above the protective effects of progesterone, were significantly weakened. Another sex hormone, oestrogen, has no significant effect on placental DAF and C3 contents and fetal loss frequency in the APS mice model. This may be an important mechanism by which progesterone induces maternal-fetal immune tolerance. At the same time, it may provide evidence for the use of progesterone in APS abortion patients.


Assuntos
Síndrome Antifosfolipídica/imunologia , Antígenos CD55/imunologia , Placenta/imunologia , Placenta/lesões , Complicações na Gravidez/imunologia , Progesterona/farmacologia , Regulação para Cima/efeitos dos fármacos , Animais , Síndrome Antifosfolipídica/patologia , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Placenta/patologia , Gravidez , Complicações na Gravidez/tratamento farmacológico , Complicações na Gravidez/patologia , Regulação para Cima/imunologia
17.
Methods Mol Biol ; 1967: 275-283, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31069777

RESUMO

ß2-Glycoprotein I is the major autoantigen in the antiphospholipid syndrome (APS), a prothrombotic disorder characterized by the occurrence of either venous or arterial thrombosis. In women it is also associated with an increased risk of obstetric complications such as recurrent miscarriages. We have identified that the plasma protein ß2-glycoprotein I in healthy individuals exists in an optimal ratio between two distinct forms, an oxidized and free thiol, reduced form. This ratio is disrupted in pathophysiological conditions associated with increased oxidative stress such as the APS, but also in the setting of age-related macular degeneration and gram-negative sepsis. We have developed assays that quantify plasma/serum levels of total and free thiol ß2-glycoprotein I which can potentially be used for risk stratification and prognostic purposes in the early stages of the aforementioned conditions.


Assuntos
Síndrome Antifosfolipídica/sangue , Testes Diagnósticos de Rotina/métodos , Trombose/sangue , beta 2-Glicoproteína I/sangue , Aborto Habitual/sangue , Aborto Habitual/patologia , Síndrome Antifosfolipídica/patologia , Feminino , Humanos , Gravidez , Prognóstico , Compostos de Sulfidrila/sangue , Compostos de Sulfidrila/química , Trombose/patologia , beta 2-Glicoproteína I/isolamento & purificação
18.
Nat Commun ; 10(1): 1916, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015489

RESUMO

Potentiation of neutrophil extracellular trap (NET) release is one mechanism by which antiphospholipid antibodies (aPL Abs) effect thrombotic events in patients with antiphospholipid syndrome (APS). Surface adenosine receptors trigger cyclic AMP (cAMP) formation in neutrophils, and this mechanism has been proposed to regulate NETosis in some contexts. Here we report that selective agonism of the adenosine A2A receptor (CGS21680) suppresses aPL Ab-mediated NETosis in protein kinase A-dependent fashion. CGS21680 also reduces thrombosis in the inferior vena cavae of both control mice and mice administered aPL Abs. The antithrombotic medication dipyridamole is known to potentiate adenosine signaling by increasing extracellular concentrations of adenosine and interfering with the breakdown of cAMP. Like CGS21680, dipyridamole suppresses aPL Ab-mediated NETosis via the adenosine A2A receptor and mitigates venous thrombosis in mice. In summary, these data suggest an anti-inflammatory therapeutic paradigm in APS, which may extend to thrombotic disease in the general population.


Assuntos
Agonistas do Receptor A2 de Adenosina/farmacologia , Adenosina/análogos & derivados , Síndrome Antifosfolipídica/tratamento farmacológico , Armadilhas Extracelulares/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Fenetilaminas/farmacologia , Trombose Venosa/tratamento farmacológico , Adenosina/imunologia , Adenosina/metabolismo , Adenosina/farmacologia , Animais , Anticorpos Antifosfolipídeos/sangue , Síndrome Antifosfolipídica/genética , Síndrome Antifosfolipídica/imunologia , Síndrome Antifosfolipídica/patologia , AMP Cíclico/imunologia , AMP Cíclico/metabolismo , Dipiridamol/farmacologia , Modelos Animais de Doenças , Armadilhas Extracelulares/imunologia , Armadilhas Extracelulares/metabolismo , Fibrinolíticos/farmacologia , Regulação da Expressão Gênica , Humanos , Imunoglobulina G/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/imunologia , Receptor A2A de Adenosina/genética , Receptor A2A de Adenosina/imunologia , Transdução de Sinais , Veia Cava Inferior/efeitos dos fármacos , Veia Cava Inferior/imunologia , Veia Cava Inferior/metabolismo , Trombose Venosa/genética , Trombose Venosa/imunologia , Trombose Venosa/patologia
19.
Front Immunol ; 10: 449, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30923524

RESUMO

The antiphospholipid syndrome (APS) is characterized by thrombosis and pregnancy morbidity in the presence of antiphospholipid antibodies (aPL). Complement is a system of enzymes and regulatory proteins of the innate immune system that plays a key role in the inflammatory response to pathogenic stimuli. The complement and coagulation pathways are closely linked, and expanding data indicate that complement may be activated in patients with aPL and function as a cofactor in the pathogenesis of aPL-associated clinical events. Complement activation by aPL generates C5a, which induces neutrophil tissue factor-dependent procoagulant activity. Beta-2-glycoprotein I, the primary antigen for pathogenic aPL, has complement regulatory effects in vitro. Moreover, aPL induce fetal loss in wild-type mice but not in mice deficient in specific complement components (C3, C5). Antiphospholipid antibodies also induce thrombosis in wild type mice and this effect is attenuated in C3 or C6 deficient mice, or in the presence of a C5 inhibitor. Increased levels of complement activation products have been demonstrated in sera of patients with aPL, though the association with clinical events remains unclear. Eculizumab, a terminal complement inhibitor, has successfully been used to treat catastrophic APS and prevent APS-related thrombotic microangiopathy in the setting of renal transplant. However, the mechanisms of complement activation in APS, its role in the pathogenesis of aPL related complications in humans, and the potential of complement inhibition as a therapeutic target in APS require further study.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Síndrome Antifosfolipídica , Ativação do Complemento , Proteínas do Sistema Complemento/imunologia , Complicações na Gravidez , Microangiopatias Trombóticas , Animais , Anticorpos Antifosfolipídeos/imunologia , Síndrome Antifosfolipídica/tratamento farmacológico , Síndrome Antifosfolipídica/imunologia , Síndrome Antifosfolipídica/patologia , Feminino , Humanos , Camundongos , Gravidez , Complicações na Gravidez/tratamento farmacológico , Complicações na Gravidez/imunologia , Complicações na Gravidez/patologia , Microangiopatias Trombóticas/tratamento farmacológico , Microangiopatias Trombóticas/imunologia , Microangiopatias Trombóticas/patologia
20.
PLoS One ; 14(3): e0212614, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30870459

RESUMO

Antiphospholipid antibodies (aPL) promote endothelial dysfunction, inflammation and procoagulant state. We investigated the effect of hydroxychloroquine (HCQ) on prothrombotic state and endothelial function in mice and in human aortic endothelial cells (HAEC). Human aPL were injected to C57BL/6 mice treated or not with HCQ. Vascular endothelial function and eNOS were assessed in isolated mesenteric arteries. Thrombosis was assessed both in vitro by measuring thrombin generation time (TGT) and tissue factor (TF) expression and in vivo by the measurement of the time to occlusion in carotid and the total thrombosis area in mesenteric arteries. TGT, TF, and VCAM1 expression were evaluated in HAEC. aPL increased VCAM-1 expression and reduced endothelium dependent relaxation to acetylcholine. In parallel, aPL shortened the time to occlusion and extended thrombus area in mice. This was associated with an overexpression of TF and an increased TGT in mice and in HAEC. HCQ reduced clot formation as well as TGT, and improved endothelial-dependent relaxations. Finally, HCQ increased the p-eNOS/eNOS ratio. This study provides new evidence that HCQ improves procoagulant status and vascular function in APS by modulating eNOS, leading to an improvement in the production of NO.


Assuntos
Síndrome Antifosfolipídica/tratamento farmacológico , Hidroxicloroquina/farmacologia , Trombose/prevenção & controle , Animais , Anticorpos Antifosfolipídeos/imunologia , Síndrome Antifosfolipídica/imunologia , Síndrome Antifosfolipídica/patologia , Modelos Animais de Doenças , Células Endoteliais/imunologia , Células Endoteliais/patologia , Endotélio Vascular/imunologia , Endotélio Vascular/patologia , Feminino , Humanos , Masculino , Camundongos , Óxido Nítrico Sintase Tipo III/imunologia , Trombina/imunologia , Tromboplastina/imunologia , Trombose/imunologia , Trombose/patologia , Molécula 1 de Adesão de Célula Vascular/imunologia
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