RESUMEN
BACKGROUND: At present, there is no comprehensive evaluation of the efficacy and safety of low molecular weight heparin (LMWH) for the treatment of thrombophilia during pregnancy in clinical practice. This study aimed to systematically evaluate the efficacy of LMWH in the treatment of patients and its effects on coagulation function, thereby providing a reference for the clinical treatment and prognosis evaluation of thrombophilia during pregnancy. METHODS: Database PubMed, Web of Science and Embase as well as China National Knowledge Infrastructure and Wanfang Database were applied for the search of data. A comparative study on the efficacy of LMWH in the treatment of gestational thrombophilia was enrolled. Stata 16.0 software (Stata, College Station, TX, USA) was utilized to conduct the meta-analysis. RESULTS: A total of 487 relevant articles were retrieved and 14 studies were finally included. Patients in the LMWH combined with the low-dose aspirin group had a significantly higher live birth rate than those in the aspirin or LMWH treat group (OR (odds ratio) = 4.54, 95% CI (confidence interval): 2.76, 7.45). The adverse effects rate was lower in the LMWH combined with the low-dose aspirin group than in the aspirin or LMWH treatment group (OR = 0.40, 95% CI: 0.29, 0.56). After treatment, patients in the LMWH combined with the low-dose aspirin group had significantly lower D-dimer (SMD (standardized mean differences) = -1.50, 95% CI: -2.19, 0.80) and platelet count (PLT; SMD = -0.13, 95% CI: -0.35, 0.09) than those in the aspirin or LMWH treatment group. However, activated partial thromboplastin time (APTT; SMD = 0.16, 95% CI: -0.10, 0.42), thrombin time (TT; SMD = 0.60, 95% CI: -0.14, 1.34), plasma prothrombin time (PT; SMD = 0.42, 95% CI: -0.71, 1.56), and fibrin values (FIB; SMD = -0.92, 95% CI: -2.12, 0.28) were significantly higher in the LMWH combined with low-dose aspirin group than those in the aspirin or LMWH treatment group. CONCLUSIONS: LMWH heparin combined with low-dose aspirin can effectively correct coagulation function in pregnant women, improve prothrombotic state and increase the live birth rate, which has high clinical value.
Asunto(s)
Trombofilia , Trombosis , Humanos , Femenino , Embarazo , Heparina de Bajo-Peso-Molecular/uso terapéutico , Aspirina/uso terapéutico , Anticoagulantes/uso terapéutico , Trombofilia/inducido químicamente , Trombofilia/tratamiento farmacológico , Trombosis/tratamiento farmacológico , Trombosis/inducido químicamenteRESUMEN
Much has evolved over the past 25 years regarding our understanding of the coagulopathy of liver disease. Paradoxically, this form of coagulopathy is relatively hypercoagulability despite the common clinical impression of a hemorrhagic tendency. The latter is largely driven by portal-mesenteric venous pressure (ie, portal hypertension) and has little to do with hemostatic pathways. It cannot be emphasized enough that the INR does not offer a meaningful measure in this situation and may lead to interventions such as fresh frozen plasma that can actually worsen portal pressure and hence pressure-driven bleeding. With regard to procedure-related bleeding, we point out substantial differences in the definition of high-risk procedures and propose a new operational definition dependent on the applicability of local hemostatic measures, although this requires further investigation. The common occurrence of venous thrombosis in these patients requires careful consideration of hemostatic pathways and overall risk and benefit of intervention. The decision regarding anticoagulation therapy needs to be driven not only by a global assessment including history of non-portal hypertensive-related bleeding, but also by fall risk which can result in head trauma in patients prone to encephalopathy. This is probably best estimated by frailty but has yet to be adequately investigated. In the background of these concerns, several superimposed and complex conditions including infections and renal dysfunction should be taken into account. Inherited forms of thrombophilia in the setting of cirrhosis perhaps do not outweigh the thrombophilia inherent to liver disease but warrant further consideration.
Asunto(s)
Trastornos de la Coagulación Sanguínea , Hemostáticos , Hepatopatías , Trombofilia , Trombosis , Humanos , Hemorragia/inducido químicamente , Cirrosis Hepática/complicaciones , Cirrosis Hepática/tratamiento farmacológico , Trombosis/complicaciones , Trastornos de la Coagulación Sanguínea/complicaciones , Hepatopatías/complicaciones , Trombofilia/inducido químicamente , Trombofilia/complicaciones , Trombofilia/tratamiento farmacológico , Hemostáticos/uso terapéutico , Anticoagulantes/efectos adversosRESUMEN
BACKGROUND: Thrombopoietin receptor agonists are frequently used in treating immune thrombocytopenia (ITP) owing to high response rates and good tolerability. ITP is associated with an increased risk of thrombosis. Whether treatment with eltrombopag further increases this risk is controversial. The mechanisms behind the thrombotic risk in ITP are unclear. OBJECTIVES: To assess platelet function and hypercoagulability in patients with ITP and the effect of eltrombopag thereon. METHODS: This prospective multicenter study assessed adult primary patients with ITP who were starting eltrombopag treatment. Platelet (re)activity and hypercoagulability were measured in whole blood or plasma before start and after 2 to 3 weeks of eltrombopag treatment and compared with those of controls. Change over time was assessed by mixed-effects models, and the results were corrected for multiple testing. RESULTS: We included 16 patients and 33 controls. At baseline, patients with ITP exhibited lower expression of glycoprotein VI, more activated platelets, and lower reactivity toward agonists compared with controls. ß-Thromboglobulin levels reduced and thrombin generation peak height increased compared with those of controls. In line with this finding, patients with ITP showed high factor VIII (median, 217%; IQR, 174%-272%) and von Willebrand factor levels (median, 167%; IQR, 109%-198%). Eltrombopag treatment increased thrombin generation potential: lag time decreased and peak height and endogeneous thrombin potential increased. The latter changes were not significant after correction for multiple testing. CONCLUSION: Patients with ITP in this study were in a hypercoagulable state, with preactivated platelets, increased thrombin generation potential, and increased levels of factor VIII and von Willebrand factor. Eltrombopag treatment further increased plasma thrombin generation potential but no other hemostatic parameters.
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Púrpura Trombocitopénica Idiopática , Trombocitopenia , Trombofilia , Adulto , Humanos , Púrpura Trombocitopénica Idiopática/diagnóstico , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Púrpura Trombocitopénica Idiopática/inducido químicamente , Estudios Prospectivos , Factor VIII , Trombina , Factor de von Willebrand , Hidrazinas/efectos adversos , Trombofilia/inducido químicamenteRESUMEN
Findings from the Women's Health Initiative (WHI) randomised placebo-controlled trial (RCT) were published at the beginning of this century. They suggested that hormone replacement therapy (HRT) use increased the risk of cardiovascular disease and venous thromboembolism including pulmonary embolism and deep vein thrombosis The findings led to a decline in HRT prescriptions and negative publicity about the use of HRT for women with significant menopausal symptoms. Subsequent studies have shown that the risk of thrombosis with HRT relates to whether estrogen is combined with a progestogen and the route of administration of estrogen. In healthy women with no background medical problems, transdermal hormone replacement is not associated with an increased risk of thrombosis. However, much less is known about the safety of various HRT preparations in women with a high background risk of thrombosis. These cases can often be challenging for clinicians with uncertainties around testing for thrombophilia, use of anticoagulation and striking a balance between the risks and benefits of prescribing HRT. This article will review the mechanism of thrombosis with differing types of HRT and present the evidence from the relevant trials. The article will also present the evidence that specifically relates to women with a personal history of thrombosis or thrombophilia (heritable and acquired) to enable clinicians to better individualise the risk assessment for each woman requesting HRT and understand the role of thrombophilia screening or concomitant anticoagulation in such situations.
Asunto(s)
Trombofilia , Trombosis , Femenino , Humanos , Terapia de Reemplazo de Estrógeno/efectos adversos , Terapia de Reemplazo de Hormonas/efectos adversos , Trombosis/prevención & control , Trombosis/inducido químicamente , Estrógenos/efectos adversos , Trombofilia/tratamiento farmacológico , Trombofilia/inducido químicamente , Trombofilia/complicaciones , Anticoagulantes , Factores de Riesgo , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Women with a history of venous thromboembolisms (VTEs) and/or thrombophilia are at increased risk of VTE during pregnancy. We analysed our cohort of such women who were treated with a prophylactic doses of dalteparin. 152 pregnant women with 179 pregnancies were classified into 3 groups: (1) previous VTE without thrombophilia (122 pregnancies); (2) previous VTE with thrombophilia (26 pregnancies) and (3) thrombophilia only (31 pregnancies). They were treated with prophylactic dalteparin in the prepartum and postpartum periods or only in the postpartum period. Occurrences of symptomatic VTE and bleeding episodes were followed, as well as dalteparin discontinuation and anti-Xa activity. Symptomatic deep vein thrombosis occurred in 4 women (2.2%) with 2 episodes in group 1 (in the postpartum period) and 2 episodes in group 2 (one in the prepartum and another in the postpartum period). Seven episodes (3.9%) of minor bleeding occurred. Dalteparin was not stopped in any women. Anti-Xa levels were within the prophylactic range. Our real-world data show a low incidence of thrombosis and minor bleeding in pregnant women treated with prophylactic dalteparin. The incidence of recurrent VTE was lower than that reported in women with similar risk, but without prophylactic anticoagulation.
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Trombofilia , Tromboembolia Venosa , Trombosis de la Vena , Femenino , Humanos , Embarazo , Dalteparina/efectos adversos , Tromboembolia Venosa/epidemiología , Mujeres Embarazadas , Factores de Riesgo , Heparina de Bajo-Peso-Molecular/uso terapéutico , Trombofilia/complicaciones , Trombofilia/tratamiento farmacológico , Trombofilia/inducido químicamente , Hemorragia/inducido químicamente , Anticoagulantes/efectos adversosRESUMEN
A turbulent coagulation system is a prominent feature of Coronavirus Disease 2019 (COVID-19), with venous thromboembolism (VTE) a leading cause of death. Our hypothesis is that patients with inherited hypocoagulability, like congenital bleeding disorders (CBD), enjoy a protective effect against COVID-19-induced hypercoagulability and related fatal consequences. Our primary and follow-up observations revealed this effect, at least among patients with moderate to severe congenital bleeding disorders, particularly coagulation factor deficiencies. Theoretically, patients with inherited hypocoagulobility have only a potential protective effect against COVID-19-related hypercoagulability. Yet the lower rate of morbidity and mortality in patients with CBDs suggests that hypercoagulability and thrombotic events are the main cause of death in COVID-19. Therefore, appropriate and timely administration of anticoagulants could significantly decrease the rate of morbidity and mortality in COVID-19.
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Trastornos de la Coagulación Sanguínea Heredados , Trastornos de la Coagulación Sanguínea , COVID-19 , Trombofilia , Trombosis , Tromboembolia Venosa , Humanos , COVID-19/complicaciones , SARS-CoV-2 , Trastornos de la Coagulación Sanguínea/complicaciones , Anticoagulantes/uso terapéutico , Trastornos de la Coagulación Sanguínea Heredados/complicaciones , Trombofilia/inducido químicamente , Trombofilia/complicaciones , Tromboembolia Venosa/complicaciones , MorbilidadRESUMEN
Waterpipe tobacco smoking has gained worldwide popularity, particularly among youths. Several clinical and experimental studies have reported that waterpipe smoking (WPS) injures the cardiovascular system. However, the impact of smoking cessation (CS) on the cardiovascular toxicity induced by WPS received scant attention. Hence, we assessed, in C57BL/6 mice, the cardiovascular effects of WPS exposure for 3 months followed by 3 months of SC, as compared with mice exposed for either 3 months to WPS or air (control). WPS exposure induced hypertension, prothrombotic events both in vivo and in vitro and increased the plasma concentrations of tissue factor, fibrinogen and plasminogen activator inhibitor-1. These effects were significantly alleviated by SC. In heart tissue, the levels of troponin I, creatine kinase, lipid peroxidation, 8-isoprostane, tumor necrosis factor α, inteleukin 6, DNA damage and cleaved caspase-3 were significantly increased by WPS exposure. These actions were significantly reduced in the group of mice exposed to WPS followed by SC. Similarly, the increase in the level of nuclear factor κ-ß induced by WPS exposure was significantly mitigated by SC. Immunohistochemical analysis of the hearts showed that WPS exposure increased the expression of nuclear factor erythroid-derived 2-like 2 by cardiomyocytes. The latter effect was significantly reduced by SC. Taken together, our data show that SC is associated with amelioration of WPS induced hypertension, prothrombotic events and cardiac oxidative stress, inflammation, DNA damage and apoptosis.
Asunto(s)
Cardiopatías/terapia , Hipertensión/terapia , Cese del Hábito de Fumar , Trombofilia/terapia , Fumar en Pipa de Agua/efectos adversos , Animales , Apoptosis/efectos de los fármacos , Daño del ADN/efectos de los fármacos , Femenino , Cardiopatías/inducido químicamente , Hipertensión/inducido químicamente , Masculino , Ratones , Ratones Endogámicos C57BL , Estrés Oxidativo/efectos de los fármacos , Trombofilia/inducido químicamenteRESUMEN
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can vary on a spectrum of asymptomatic disease to rarer manifestations like hypercoagulability especially among elderly patients admitted in the intensive care unit (ICU) and those with preexisting comorbidities. The exact mechanism behind this phenomenon is still unclear, however studies have shown an association with elevated cytokines and severe inflammatory response which encompasses this disease. Hypercoagulability can be limited to the lungs, or present as systemic manifestations of arterial and venous thrombosis leading to mortal outcomes. Thus, careful evaluation of risk factors should be performed by physicians and treatment with anticoagulants should be modified accordingly. All Coronavirus Disease 2019 (COVID-19) in-patients should receive thromboprophylactic therapy, with increased dosages administered to patients with increased disease severity or those with a high risk. D-dimer levels and sepsis-induced coagulopathy (SIC) score aid in identifying high risk patients and predicting outcome. This article highlights the pathophysiology behind hypercoagulability, its clinical associations and discusses therapeutic modalities to combat this fatal consequence of SARS-CoV-2.
Asunto(s)
Trastornos de la Coagulación Sanguínea , COVID-19 , Trombofilia , Anciano , Anticoagulantes/uso terapéutico , Trastornos de la Coagulación Sanguínea/etiología , COVID-19/complicaciones , Citocinas , Humanos , SARS-CoV-2 , Trombofilia/inducido químicamente , Trombofilia/etiologíaRESUMEN
BACKGROUND: Alveolar hypercoagulation and fibrinolytic inhibition are important characteristics during acute respiratory distress syndrome (ARDS), and NF-κB p65 signaling pathway is involved to regulate these pathophysiologies. We hypothesize that targeting NF-κB signal pathway could ameliorate alveolar hypercoagulation and fibrinolyitc inhibition, thus attenuating lung injury in ARDS. PURPOSE: We explore the efficacy and the potential mechanism of andrographolide sulfonate (Andro-S) on alveolar hypercoagulation and fibrinolytic inhibition in LPS-induced ARDS in mice. METHODS: ARDS was made by lipopolysaccharide (LPS) inhalation in C57BLmice. Andrographolide sulfonate (2.5, 5 and 10 mg/kg) was intraperitoneally given to the mice (once a day for three consecutive days) before LPS administration. NEMO binding domain peptide (NBD), an inhibitor of NF-κB, was used as the positive control and it replaced Andro-S in mice of NBD group. Mice in normal control received saline instead of LPS. Lung tissues and bronchoalveolar lavage fluid (BALF) were collected for analysis of alveolar coagulation, fibrinolytic inhibition as well as of pulmonary inflammatory response after 8 h of LPS inhalation. NF-κB signal pathway in lung tissue was simultaneously determined. RESULTS: Andro-S dose-dependently inhibited tissue factor (TF) and plasminogen activator inhibitor (PAI)-1 expressions either in mRNA or in protein in lung tissue of ARDS mice, and it also decreased the concentrations of TF, PAI-1, thrombin-antithrombin complex (TAT), procollagen peptide type â ¢ (Pâ ¢P) while promoting the production of activated protein C (APC) in BALF. Meanwhile, Andro-S effectively inhibited inflammatory response (interleukin 1ß and myeloperoxidase) induced by LPS. LPS stimulation dramatically activated NF-κB signal pathway, indicated by increased expressions of phosphorylation of p65 (p-p65), p-IKKα/ß and p-IκBα and the higher p65-DNA binding activity, which were all dose-dependently reversed by Andro-S. Andro-S and NBD presented similar efficacies. CONCLUSIONS: Andro-S treatment improves alveolar hypercoagulation and fibrinolytic inhibition and attenuates pulmonary inflammation in LPS-induced ARDS in mice partly through NF-κB pathway inactivation. The drug is expected to be an effective choice for ARDS.
Asunto(s)
Antiinflamatorios/farmacología , Diterpenos/farmacología , Fibrinólisis/efectos de los fármacos , Fibrinolíticos/farmacología , FN-kappa B/metabolismo , Alveolos Pulmonares/efectos de los fármacos , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Trombofilia/tratamiento farmacológico , Animales , Factores de Coagulación Sanguínea/metabolismo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Mediadores de Inflamación/metabolismo , Lipopolisacáridos , Masculino , Ratones Endogámicos C57BL , Fosforilación , Alveolos Pulmonares/metabolismo , Síndrome de Dificultad Respiratoria/sangre , Síndrome de Dificultad Respiratoria/inducido químicamente , Transducción de Señal , Trombofilia/sangre , Trombofilia/inducido químicamenteRESUMEN
BACKGROUND: Alveolar hypercoagulation and fibrinolysis inhibition were associated with the refractory hypoxemia and the high mortality in patient with acute respiratory distress syndrome (ARDS), and NF-κB pathway was confirmed to contribute to the process. Triptolide (TP) significantly inhibited NF-κB pathway and thus depressed accessive inflammatory response in ARDS. We speculate that TP could improve alveolar hypercoagulation and fibrinolytic inhibition in LPS-induced ARDS via NF-κB inactivation. PURPOSE: The aim of this experiment was to explore the efficacy and potential mechanism of TP on alveolar hypercoagulation and fibrinolysis inhibition in LPS-induced ARDS in mice. METHODS: 50⯵l of LPS (5â¯mg/ml) was inhalationally given to C57BL/6 mice to set up ARDS model. Male mice were randomly accepted with LPS, LPS + TP (1⯵g/kg, 10⯵g/kg, 50⯵g/kg respectively), or with NEMO Binding domain peptide (NBD), an inhibitor of NF-κB. TP (1⯵g/kg, 10⯵g/kg, 50⯵g/kg) were intraperitoneally injected or 10⯵g/50⯵l of NBD solution were inhaled 30â¯min before LPS inhalation. A same volume of normal saline (NS) substituted for TP in mice in control. The endpoint of experiment was at 8â¯hours after LPS stimulation. Pulmonary tissues were taken for hematoxylin-eosin (HE) staining, wet / dry ratio and for lung injury scores (LIS). Tissue factor (TF) and plasminogen activator inhibitor (PAI)-1 in lung tissue were detected by Western-blotting and by quantitative Real-time PCR(qPCR) respectively. Concentrations of TF, PAI-1, thrombin-antithrombin complex (TAT), procollagen peptide type â ¢ (Pâ ¢P) and activated protein C (APC) in bronchoalveolar lavage fluid (BALF) were measured by ELISA. NF-κB activation and p65-DNA binding activity in pulmonary tissue were simultaneously determined. RESULTS: LPS stimulation resulted in pulmonary edema, neutrophils infiltration, obvious alveolar collapse, interstitial congestion, with high LIS, which were all dose-dependently ameliorated by Triptolide. LPS also dramatically promoted the expressions of TF and PAI-1 either in mRNA or in protein in lung tissue, and significantly stimulated the secretions of TF, PAI-1, TAT, Pâ ¢P but inhibited APC production in BALF, which were all reversed by triptolide treatment in dose-dependent manner. TP dose-dependently inhibited the activation of NF-κB pathway induced by LPS, indicated by the changes of phosphorylations of p65 (p-p65), p-IKKα/ß and p-IκBα, and weakened p65-DNA binding activity. TP and NBD had same efficacies either on alveolar hypercoagulation and fibrinolysis inhibition or on NF-κB signalling pathway in ARDS mice. CONCLUSIONS: TP dose-dependently improves alveolar hypercoagulation and fibrinolysis inhibition in ARDS mice through inhibiting NF-κB signaling pathway. Our data demonstrate that TP is expected to be an effective selection in ARDS.
Asunto(s)
Diterpenos/farmacología , Fibrinólisis/efectos de los fármacos , Lipopolisacáridos/farmacología , Pulmón/efectos de los fármacos , FN-kappa B/metabolismo , Fenantrenos/farmacología , Trombofilia/inducido químicamente , Trombofilia/tratamiento farmacológico , Animales , Modelos Animales de Enfermedad , Compuestos Epoxi/farmacología , Pulmón/metabolismo , Lesión Pulmonar/tratamiento farmacológico , Lesión Pulmonar/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Síndrome de Dificultad Respiratoria , Transducción de Señal/efectos de los fármacos , Trombofilia/metabolismo , Tromboplastina/metabolismoRESUMEN
In recent years a variety of metals (cadmium, chromium, copper, iron) have been demonstrated to modulate coagulation in vitro and in vivo. One group of metals, the platinoids, have not been assessed, and such investigation is justified given the thromboembolic phenomena associated with platinum-based chemotherapy. Thus, the goal of the present investigation was to assess the effects of carboplatin, cisplatin (platinum compounds), NAMI-A, and ruthenium chloride (ruthenium compounds) on human plasmatic coagulation. Human plasma was exposed to clinically relevant, equimolar concentrations of the aforementioned platinum and ruthenium compounds, with changes in plasmatic coagulation assessed via thrombelastography. The first series of experiments demonstrated no significant modulation of coagulation by the platinum compounds, while NAMI-A demonstrated mild hypercoagulability and ruthenium chloride exerted marked hypercoagulability. A second series of experiments utilizing a variety of specialized modifications of thrombelastography focused on ruthenium chloride revealed that this compound enhances prothrombin activation. While the hypercoagulability associated with platinum compounds in vivo do not appear to have a basis in plasmatic biochemistry, it appears that ruthenium compounds can exert procoagulant properties by enhancing the common pathway of human plasmatic coagulation. Future investigation of Ru based chemotherapeutic agents in development to assess procoagulant activity as part of evaluating their potential clinical safety is warranted.
Asunto(s)
Coagulación Sanguínea , Carboplatino/farmacología , Cisplatino/farmacología , Dimetilsulfóxido/análogos & derivados , Compuestos Organometálicos/farmacología , Protrombina/metabolismo , Compuestos de Rutenio/farmacología , Tromboelastografía/métodos , Antineoplásicos/farmacología , Coagulación Sanguínea/efectos de los fármacos , Coagulación Sanguínea/fisiología , Pruebas de Coagulación Sanguínea/métodos , Dimetilsulfóxido/farmacología , Humanos , Compuestos de Platino/farmacología , Trombofilia/sangre , Trombofilia/inducido químicamenteRESUMEN
Hereditary hemorrhagic telangiectasia (HHT) management is evolving because of the emergence and development of antiangiogenic therapies to eliminate bleeding telangiectasias and achieve hemostasis. This progress is reflected in recent clinical recommendations published in the Second International Guidelines for the Diagnosis and Treatment of HHT, in which systemic therapies including antiangiogenics and antifibrinolytics are now recommended as standard treatment options for bleeding. This review highlights the new recommendations especially relevant to hematologists in managing bleeding, anticoagulation, and anemia in patients with HHT.
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Guías de Práctica Clínica como Asunto , Nivel de Atención/tendencias , Telangiectasia Hemorrágica Hereditaria/terapia , Anemia/epidemiología , Anemia/etiología , Inhibidores de la Angiogénesis/efectos adversos , Inhibidores de la Angiogénesis/uso terapéutico , Anticoagulantes/efectos adversos , Anticoagulantes/uso terapéutico , Antifibrinolíticos/efectos adversos , Antifibrinolíticos/uso terapéutico , Ensayos Clínicos como Asunto , Manejo de la Enfermedad , Epistaxis/tratamiento farmacológico , Epistaxis/etiología , Epistaxis/prevención & control , Transfusión de Eritrocitos , Predicción , Hemorragia Gastrointestinal/tratamiento farmacológico , Hemorragia Gastrointestinal/etiología , Hemorragia Gastrointestinal/prevención & control , Humanos , Factores Inmunológicos/uso terapéutico , Deficiencias de Hierro , Inhibidores de Agregación Plaquetaria/efectos adversos , Inhibidores de Agregación Plaquetaria/uso terapéutico , Prevalencia , Telangiectasia Hemorrágica Hereditaria/complicaciones , Trombofilia/inducido químicamente , Trombofilia/tratamiento farmacológico , Trombofilia/etiología , Ácido Tranexámico/uso terapéuticoRESUMEN
INTRODUCTION: Zucker diabetic fatty (ZDF) rats are used widely as an animal model of metabolic syndrome and insulin resistance. Our study focused on the effects of high versus low dietary fat on the development of Type 2 diabetes in obese male ZDF rats (fa/fa), including biomarkers to detect early signs of hypercoagulability and vascular injury in the absence of overt thrombosis. METHODS: In this study, male (5/group) 10-week-old CRL:ZDF370(obese) rats were fed low (LFD, 16.7% fat) or high fat (HFD, 60% fat) diet for 12 or 15 weeks. Cohorts of 5 rats within diet groups were scheduled for sample collection after weeks 12 and 15. RESULTS: HFD-fed ZDF rats had oily coats, lower rates of food consumption, more accelerated weight gain and increased serum cholesterol (+15%) and triglyceride concentrations (+75%) vs. LFD-fed ZDF rats. Urinary ketones were observed only in HFD-fed ZDF rats and greater urine glucose and protein concentrations in HFD-fed ZDF vs. LFD-fed ZDF rats were seen. Hemostasis testing showed ~2-fold greater fibrinogen concentration, increased von Willebrand factor concentration, and high thrombin generation in HFD-fed ZDF vs LFD-fed ZDF rats. Increased mortality in the HFD-fed ZDF rat was attributed to exacerbations of altered carbohydrate metabolism as evidenced by ketonuria and nephropathy leading to renal failure. DISCUSSION: This characterization shows that the ZDF rat at the age, sex and weight used in this study is highly sensitive to dietary fat content that can exacerbate prothrombotic, metabolic and renal disturbances and increase mortality.
Asunto(s)
Diabetes Mellitus Tipo 2 , Trombofilia , Animales , Grasas de la Dieta/efectos adversos , Masculino , Obesidad/inducido químicamente , Ratas , Ratas Zucker , Trombofilia/inducido químicamenteRESUMEN
BACKGROUND: Alveolar hypercoagulation and pulmonary inflammation are important characteristics and they regulate each other in acute respiratory distress syndrome (ARDS). NF-κB pathway has been confirmed to be involved in regulation of this crosstalk. Emodin, a traditional Chinese herb, shows potent inhibitory effect on NF-κB pathway, but whether it is effective in alveolar hypercoagulation and pulmonary inflammation in ARDS remains to be elucidated. PURPOSE: The aim of this experiment was to evaluate the efficacy of emodin on LPS-provoked alveolar hypercoagulation and excessive pulmonary inflammation in ARDS, and its potential mechanism. METHODS: Mice ARDS was set up through LPS (40 µl, 4 mg/ml) inhalation. Male mice were randomly received with BPS, LPS only, LPS+ emodin (5 mg/kg, 10 mg/kg, 20 mg/kg, respectively) and BAY65-1942, an inhibitor of IKKß. After 48 h of LPS stimulation, pulmonary pathological injury, expressions of Tissue factor (TF), plasminogen activator inhibitor (PAI)-1, activated protein C (APC), collagen â , collagen III, interleukin (IL) 8, IL-1ß and tumor necrosis factor (TNF)-α in lung tissues, as well as concentrations of antithrombin III (AT III), procollagen peptide type III (PIIIP), soluble thrombomodulin (sTM), thrombin antithrombin complex (TAT), myeloperoxidase (MPO) and the percentage of inflammatory cells in bronchoalveolar lavage fluid (BALF) were all determined. NF-κB pathway activation as well as NF-κB DNA binding activity in pulmonary tissue were simultaneously checked. RESULTS: LPS stimulation resulted in obvious lung injury, excessive inflammatory cells infiltration, which all were dose-dependently ameliorated by emodin. Expressions of TF, PAI-1, collagen â and collagen III as well as IL-8, IL-1ß and TNF-α in pulmonary tissue were all elevated while APC decreased under LPS provocation, which were all reversed by emodin treatment in dose-dependent manner. LPS promoted the secretions of PIIIP, sTM, TAT and inhibited AT III production in BALF, and resulted in high levels of MPO and the percentage of inflammatory cells in BALF, all of which were significantly and dose-dependently attenuated while AT III production was increased by emodin. Meanwhile, emodin effectively inhibited NF-κB pathway activation and attenuated p65 DNA binding activity induced by LPS inhalation. Emodin and BAY-65-1942 had similar impacts in this experiment. CONCLUSIONS: Emodin improves alveolar hypercoagulation and fibrinolytic inhibition and depresses excessive pulmonary inflammation in ARDS mice in dose-dependent manner via NF-κB inactivation. Our data demonstrate that emodin is expected to be an effective drug in alveolar hypercoagulation and pulmonary inflammation in ARDS.
Asunto(s)
Emodina/uso terapéutico , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Lipopolisacáridos/toxicidad , FN-kappa B/metabolismo , Síndrome de Dificultad Respiratoria/inducido químicamente , Animales , Regulación de la Expresión Génica/efectos de los fármacos , Ratones , FN-kappa B/genética , Alveolos Pulmonares/efectos de los fármacos , Alveolos Pulmonares/patología , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Trombofilia/inducido químicamente , Trombofilia/tratamiento farmacológicoRESUMEN
Tamoxifen shows efficacy in reducing breast cancer-related mortality but clinically, is associated with increased risk for thromboembolic events. We aimed to determine whether breast tumour sub-phenotype could predict propensity for thrombosis. We present two ex vivo Models of Tamoxifen-therapy, Model 1 in which treatment recapitulates accumulation within breast tissue, by treating MCF7 and T47D cells directly prior to exposure to blood constituents; and Model 2 in which we recreate circulating Tamoxifen by treating blood constituents prior to exposure to cancer cells. Blood constituents included whole blood, platelet-rich plasma and platelet-poor plasma. Hypercoagulation was assessed as a function of thrombin activity, expression of CD62P and CD63 activation markers defined as an index of platelet activation, and platelet morphology; while oestrogen receptor expression was assessed using immunocytochemistry with quantitative analysis. We determined, in concert with clinical studies and contrary to selected laboratory investigations, that Tamoxifen induces hypercoagulation, dependent on sub-phenotypes, with the T47D cell line capacity most enhanced. We determined a weak positive correlation between oestrogen receptor expression, and CD62P and CD63; indicating an association between tumour invasion profiles and hypercoagulation, however, other yet unknown factors may play a predictive role in defining hypercoagulation.
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Neoplasias de la Mama , Receptor alfa de Estrógeno/sangre , Receptor beta de Estrógeno/sangre , Proteínas de Neoplasias/sangre , Tamoxifeno/efectos adversos , Trombofilia , Adulto , Neoplasias de la Mama/sangre , Neoplasias de la Mama/tratamiento farmacológico , Femenino , Humanos , Células MCF-7 , Tamoxifeno/farmacología , Trombofilia/sangre , Trombofilia/inducido químicamenteRESUMEN
Newly diagnosed multiple myeloma (NDMM) patients treated with immunomodulatory drugs are at high risk of venous thromboembolism (VTE), but data are lacking from large prospective cohorts. We present thrombosis outcome data from Myeloma IX (n = 1936) and Myeloma XI (n = 4358) phase 3 randomized controlled trials for NDMM that treated transplant-eligible and transplant-ineligible patients before and after publication of thrombosis prevention guidelines. In Myeloma IX, transplant-eligible patients randomly assigned to cyclophosphamide, vincristine, doxorubicin, and dexamethasone (CVAD) induction had higher risk of VTE compared with patients treated with cyclophosphamide, thalidomide, and dexamethasone (CTD) (22.5% [n = 121 of 538] vs 16.1% [n = 89 of 554]; adjusted hazard ratio [aHR],1.46; 95% confidence interval [95% CI], 1.11-1.93). For transplant-ineligible patients, those randomly assigned to attenuated CTD (CTDa) induction had a higher risk of VTE compared with those treated with melphalan and prednisolone (MP) (16.0% [n = 68 of 425] vs 4.1% [n = 17 of 419]; aHR, 4.25; 95% CI, 2.50-7.20). In Myeloma XI, there was no difference in risk of VTE (12.2% [n = 124 of 1014] vs 13.2% [n = 133 of 1008]; aHR, 0.92; 95% CI, 0.72-1.18) or arterial thrombosis (1.2% [n = 12 of 1014] vs 1.5% [n = 15 of 1008]; aHR, 0.80; 95% CI, 0.37-1.70) between transplant-eligible pathways for patients treated with cyclophosphamide, lenalidomide, and dexamethasone (CRD) or CTD. For transplant-ineligible patients, there was no difference in VTEs between attenuated CRD (CRDa) and CTDa (10.4% [n = 95 of 916] vs 10.7% [n = 97 of 910]; aHR, 0.97; 95% CI, 0.73-1.29). However, arterial risk was higher with CRDa than with CTDa (3.1% [n = 28 of 916] vs 1.6% [n = 15 of 910]; aHR, 1.91; 95% CI, 1.02-3.57). Thrombotic events occurred almost entirely within 6 months of treatment initiation. Thrombosis was not associated with inferior progression-free survival (PFS) or overall survival (OS), apart from inferior OS for patients with arterial events (aHR, 1.53; 95% CI, 1.12-2.08) in Myeloma XI. The Myeloma XI trial protocol incorporated International Myeloma Working Group (IMWG) thrombosis prevention recommendations and compared with Myeloma IX, more patients received thromboprophylaxis (80.5% vs 22.3%) with lower rates of VTE for identical regimens (CTD, 13.2% vs 16.1%; CTDa, 10.7% vs 16.0%). However, thrombosis remained frequent in spite of IMWG-guided thromboprophylaxis, suggesting that new approaches are needed.
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Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Factores Inmunológicos/efectos adversos , Mieloma Múltiple/complicaciones , Trombofilia/inducido químicamente , Trombosis/etiología , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Dexametasona/administración & dosificación , Dexametasona/efectos adversos , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Femenino , Trasplante de Células Madre Hematopoyéticas , Humanos , Factores Inmunológicos/uso terapéutico , Incidencia , Estimación de Kaplan-Meier , Lenalidomida/administración & dosificación , Lenalidomida/efectos adversos , Masculino , Melfalán/administración & dosificación , Melfalán/efectos adversos , Persona de Mediana Edad , Mieloma Múltiple/sangre , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/terapia , Prednisolona/administración & dosificación , Prednisolona/efectos adversos , Supervivencia sin Progresión , Medición de Riesgo , Talidomida/administración & dosificación , Talidomida/efectos adversos , Trombofilia/tratamiento farmacológico , Trombosis/epidemiología , Trombosis/prevención & control , Trasplante Autólogo , Tromboembolia Venosa/epidemiología , Tromboembolia Venosa/etiología , Vincristina/administración & dosificación , Vincristina/efectos adversosRESUMEN
Osteoporosis is a chronic condition that reflects reduced bone strength and an associated increased risk for fracture. As a chronic condition, osteoporosis generally requires sustained medical intervention(s) to limit the risks for additional bone loss, compromise of skeletal integrity, and fracture occurrence. Further complicating this issue is the fact that the abrupt cessation of some therapies can be associated with an increased risk for harm. It is in this context that the COVID-19 pandemic has brought unprecedented disruption to the provision of health care globally, including near universal requirements for social distancing. In this Perspective, we provide evidence, where available, regarding the general care of patients with osteoporosis in the COVID-19 era and provide clinical recommendations based primarily on expert opinion when data are absent. Particular emphasis is placed on the transition from parenteral osteoporosis therapies. It is hoped that these recommendations can be used to safely guide care for patients with osteoporosis until a return to routine clinical care standards is available. © 2020 American Society for Bone and Mineral Research.
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Infecciones por Coronavirus , Osteoporosis/terapia , Pandemias , Neumonía Viral , Absorciometría de Fotón , Biomarcadores/sangre , Densidad Ósea , Conservadores de la Densidad Ósea/administración & dosificación , Conservadores de la Densidad Ósea/efectos adversos , Conservadores de la Densidad Ósea/uso terapéutico , COVID-19 , Continuidad de la Atención al Paciente , Infecciones por Coronavirus/sangre , Infecciones por Coronavirus/complicaciones , Denosumab/efectos adversos , Denosumab/uso terapéutico , Manejo de la Enfermedad , Esquema de Medicación , Terapia de Reemplazo de Estrógeno/efectos adversos , Fracturas Espontáneas/prevención & control , Fracturas Espontáneas/terapia , Servicios de Atención de Salud a Domicilio , Humanos , Terapia de Inmunosupresión/efectos adversos , Osteoporosis/sangre , Osteoporosis/diagnóstico por imagen , Osteoporosis/tratamiento farmacológico , Neumonía Viral/sangre , Neumonía Viral/complicaciones , Clorhidrato de Raloxifeno/efectos adversos , Clorhidrato de Raloxifeno/uso terapéutico , Recurrencia , Telemedicina , Trombofilia/inducido químicamente , Trombofilia/etiología , Procedimientos InnecesariosRESUMEN
BACKGROUND: It has been confirmed that NF-κB p65 signaling pathway is involved in the regulation of alveolar hypercoagulation and fibrinolysis inhibition in acute respiratory distress syndrome (ARDS). Whether SN50, a NF-κB cell permeable inhibitor, could attenuate alveolar hypercoagulation and fibrinolysis inhibition in ARDS remains to be elucidated. PURPOSE: We explored the efficacy and potential mechanism of SN50 on alveolar hypercoagulation and fibrinolysis inhibition in ARDS in mice. MATERIALS AND METHODS: Mouse ARDS was made by 50 µl of lipopolysaccharide (LPS) (4 mg/ml) inhalation. Male BALB/c mice were intraperitoneally injected with different does of SN50 1 h before LPS inhalation. Lung tissues were collected for hematoxylin-eosin (HE) staining, wet/dry ratio. Pulmonary expressions of tissue factor (TF), plasminogen activator inhibitor-1 (PAI-1), collagen III, as well as phosphorylated p65 (p-p65), p65 in nucleus (p'-p65), IκBα and IKKα/ß were measured. Bronchoalveolar lavage fluid (BALF) was gathered to test the concentrations of TF, PAI-1, activated protein C (APC) and thrombinantithrombin complex (TAT). DNA binding activity of NF-κB p65 was also determined. RESULTS: After LPS stimulation, pulmonary edema and exudation and alveolar collapse occured. LPS also stimulated higher expressions of TF and PAI-1 in lung tissues, and higher secretions of TF, PAI-1, TAT and low level of APC in BALF. Pulmonary collagen III expression was obviously enhanced after LPS inhalation. At same time, NF-κB signaling pathway was activated with LPS injury, shown by higher expressions of p-p65, p'-p65, p-IKKα/ß, p-Iκα in pulmonary tissue and higher level p65 DNA binding activity. SN50 dose-dependently inhibited TF, PAI-1 and collagen IIIexpressions, and decreased TF, PAI-1, TAT but increased APC in BALF. SN50 treatment attenuated pulmonary edema, exudation and reduced lung tissue damage as well. SN50 application significantly reduced p'-p65 expression and weakened p65 DNA binding activity, but expressions of p-p65, p-IKKα/ß, p-Iκα in cytoplasm of pulmonary tissue were not affected. CONCLUSIONS: SN 50 attenuates alveolar hypercoagulation and fibrinolysis inhibition in ARDS via inhibition of NF-κB p65 translocation. Our data demonstrates that NF-κB p65 pathway is a viable new therapeutic target for ARDS treatment.
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Fibrinólisis/efectos de los fármacos , Péptidos/uso terapéutico , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Trombofilia/tratamiento farmacológico , Factor de Transcripción ReIA/antagonistas & inhibidores , Translocación Genética/efectos de los fármacos , Animales , Fibrinólisis/fisiología , Lipopolisacáridos/toxicidad , Masculino , Ratones , Ratones Endogámicos BALB C , Péptidos/farmacología , Alveolos Pulmonares/efectos de los fármacos , Alveolos Pulmonares/metabolismo , Distribución Aleatoria , Síndrome de Dificultad Respiratoria/inducido químicamente , Síndrome de Dificultad Respiratoria/metabolismo , Trombofilia/inducido químicamente , Trombofilia/metabolismo , Factor de Transcripción ReIA/metabolismo , Translocación Genética/fisiologíaRESUMEN
Managing severe valvular heart disease with mechanical valve replacement necessitates lifelong anticoagulation with a vitamin K antagonist. Optimal anticoagulation intensity for patients with mechanical valves remains uncertain; current recommendations are inconsistent across guideline bodies and largely based on expert opinion. In this review, we outline the history of anticoagulation therapy in patients with mechanical heart valves and critically evaluate current antithrombotic guidelines for these patients. We conclude that randomized trials evaluating optimal anticoagulation intensity in patients with mechanical valves are needed, and that future guidelines must better justify antithrombotic treatment recommendations.
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Anticoagulantes/historia , Implantación de Prótesis de Válvulas Cardíacas/historia , Complicaciones Posoperatorias/prevención & control , Anticoagulantes/administración & dosificación , Anticoagulantes/efectos adversos , Anticoagulantes/uso terapéutico , Fibrilación Atrial/etiología , Monitoreo de Drogas , Necesidades y Demandas de Servicios de Salud , Prótesis Valvulares Cardíacas/efectos adversos , Prótesis Valvulares Cardíacas/historia , Hemorragia/inducido químicamente , Hemorragia/prevención & control , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Estudios Multicéntricos como Asunto , Complicaciones Posoperatorias/inducido químicamente , Complicaciones Posoperatorias/etiología , Guías de Práctica Clínica como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , Trombofilia/inducido químicamente , Vitamina K/antagonistas & inhibidoresRESUMEN
This study aimed to investigate the risks of thromboembolic vascular disease following androgen deprivation therapy (ADT) administered to prostate cancer (PCa) patients. A total of 24,464 men with newly diagnosed PCa during 2000-2008 were recruited through a longitudinal health insurance database in Taiwan. All PCa patients were stratified into two: ADT and non-ADT groups. Patients with ADT treatment were grouped into three: surgical castration, chemical castration, and anti-androgen alone. The risks of pulmonary embolism (PE), peripheral arterial occlusion disease (PAOD), and deep vein thrombosis (DVT) were assessed in multiple Cox proportional-hazards regression with time-dependent covariates. During the 12-year follow-up period, incidence rates per 1000 person-years in ADT and non-ADT groups were 2.87 and 1.62 for DVT, 1.00 and 0.52 for PE, and 1.03 and 0.70 for PAOD, respectively. The DVT and PE risks were significantly increased in patients receiving combined androgen blockade (CAB) compared with the counterpart ADT non-recipients. After adjusting for potential risk factors, PCa patients receiving CAB had the highest PE risk (HR = 3.11), followed by DVT risk (HR = 2.53). The DVT risk remained elevated throughout the entire duration of chemical castration. However, high PE risk was observed in patients with ≤720-day treatment duration. No association was found between ADT and PAOD risks. Overall, the risks of PE and DVT were considerably heightened in Asian men subjected to CAB for PCa, whereas PAOD risk was unrelated to such treatments.