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1.
N Engl J Med ; 388(3): 203-213, 2023 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-36652352

RESUMO

BACKGROUND: Clinical guidelines recommend low-molecular-weight heparin for thromboprophylaxis in patients with fractures, but trials of its effectiveness as compared with aspirin are lacking. METHODS: In this pragmatic, multicenter, randomized, noninferiority trial, we enrolled patients 18 years of age or older who had a fracture of an extremity (anywhere from hip to midfoot or shoulder to wrist) that had been treated operatively or who had any pelvic or acetabular fracture. Patients were randomly assigned to receive low-molecular-weight heparin (enoxaparin) at a dose of 30 mg twice daily or aspirin at a dose of 81 mg twice daily while they were in the hospital. After hospital discharge, the patients continued to receive thromboprophylaxis according to the clinical protocols of each hospital. The primary outcome was death from any cause at 90 days. Secondary outcomes were nonfatal pulmonary embolism, deep-vein thrombosis, and bleeding complications. RESULTS: A total of 12,211 patients were randomly assigned to receive aspirin (6101 patients) or low-molecular-weight heparin (6110 patients). Patients had a mean (±SD) age of 44.6±17.8 years, 0.7% had a history of venous thromboembolism, and 2.5% had a history of cancer. Patients received a mean of 8.8±10.6 in-hospital thromboprophylaxis doses and were prescribed a median 21-day supply of thromboprophylaxis at discharge. Death occurred in 47 patients (0.78%) in the aspirin group and in 45 patients (0.73%) in the low-molecular-weight-heparin group (difference, 0.05 percentage points; 96.2% confidence interval, -0.27 to 0.38; P<0.001 for a noninferiority margin of 0.75 percentage points). Deep-vein thrombosis occurred in 2.51% of patients in the aspirin group and 1.71% in the low-molecular-weight-heparin group (difference, 0.80 percentage points; 95% CI, 0.28 to 1.31). The incidence of pulmonary embolism (1.49% in each group), bleeding complications, and other serious adverse events were similar in the two groups. CONCLUSIONS: In patients with extremity fractures that had been treated operatively or with any pelvic or acetabular fracture, thromboprophylaxis with aspirin was noninferior to low-molecular-weight heparin in preventing death and was associated with low incidences of deep-vein thrombosis and pulmonary embolism and low 90-day mortality. (Funded by the Patient-Centered Outcomes Research Institute; PREVENT CLOT ClinicalTrials.gov number, NCT02984384.).


Assuntos
Anticoagulantes , Aspirina , Quimioprevenção , Fraturas Ósseas , Heparina de Baixo Peso Molecular , Adulto , Humanos , Pessoa de Meia-Idade , Anticoagulantes/efeitos adversos , Anticoagulantes/uso terapêutico , Aspirina/efeitos adversos , Aspirina/uso terapêutico , Quimioprevenção/métodos , Extremidades/lesões , Fraturas Ósseas/complicações , Fraturas Ósseas/mortalidade , Hemorragia/etiologia , Heparina de Baixo Peso Molecular/efeitos adversos , Heparina de Baixo Peso Molecular/uso terapêutico , Fraturas do Quadril/complicações , Fraturas do Quadril/mortalidade , Ossos Pélvicos/lesões , Ensaios Clínicos Pragmáticos como Assunto , Embolia Pulmonar/etiologia , Embolia Pulmonar/prevenção & controle , Fraturas da Coluna Vertebral/complicações , Fraturas da Coluna Vertebral/mortalidade , Tromboembolia Venosa/etiologia , Tromboembolia Venosa/prevenção & controle , Tromboembolia Venosa/tratamento farmacológico , Trombose Venosa/etiologia , Trombose Venosa/prevenção & controle
2.
Blood ; 143(2): 105-117, 2024 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-37832029

RESUMO

ABSTRACT: Elevated circulating fibrinogen levels correlate with increased risk for both cardiovascular and venous thromboembolic diseases. In vitro studies show that formation of a highly dense fibrin matrix is a major determinant of clot structure and stability. Here, we analyzed the impact of nonpolymerizable fibrinogen on arterial and venous thrombosis as well as hemostasis in vivo using FgaEK mice that express normal levels of a fibrinogen that cannot be cleaved by thrombin. In a model of carotid artery thrombosis, FgaWT/EK and FgaEK/EK mice were protected from occlusion with 4% ferric chloride (FeCl3) challenges compared with wild-type (FgaWT/WT) mice, but this protection was lost, with injuries driven by higher concentrations of FeCl3. In contrast, fibrinogen-deficient (Fga-/-) mice showed no evidence of occlusion, even with high-concentration FeCl3 challenge. Fibrinogen-dependent platelet aggregation and intraplatelet fibrinogen content were similar in FgaWT/WT, FgaWT/EK, and FgaEK/EK mice, consistent with preserved fibrinogen-platelet interactions that support arterial thrombosis with severe challenge. In an inferior vena cava stasis model of venous thrombosis, FgaEK/EK mice had near complete protection from thrombus formation. FgaWT/EK mice also displayed reduced thrombus incidence and a significant reduction in thrombus mass relative to FgaWT/WT mice after inferior vena cava stasis, suggesting that partial expression of nonpolymerizable fibrinogen was sufficient for conferring protection. Notably, FgaWT/EK and FgaEK/EK mice had preserved hemostasis in multiple models as well as normal wound healing times after skin incision, unlike Fga-/- mice that displayed significant bleeding and delayed healing. These findings indicate that a nonpolymerizable fibrinogen variant can significantly suppress occlusive thrombosis while preserving hemostatic potential in vivo.


Assuntos
Hemostáticos , Trombose , Trombose Venosa , Animais , Camundongos , Fibrinogênio/metabolismo , Hemostasia , Trombose Venosa/genética , Trombose Venosa/metabolismo , Trombose/metabolismo , Plaquetas/metabolismo
3.
Blood ; 144(5): 477-489, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-38728383

RESUMO

ABSTRACT: Venous thrombosis (VT) is a serious medical condition in which a blood clot forms in deep veins, often causing limb swelling and pain. Current antithrombotic therapies carry significant bleeding risks resulting from targeting essential coagulation factors. Recent advances in this field have revealed that the cross talk between the innate immune system and coagulation cascade is a key driver of VT pathogenesis, offering new opportunities for potential therapeutic interventions without inducing bleeding complications. This review summarizes and discusses recent evidence from preclinical models on the role of inflammation in VT development. We highlight the major mechanisms by which endothelial cell activation, Weibel-Palade body release, hypoxia, reactive oxygen species, inflammasome, neutrophil extracellular traps, and other immune factors cooperate to initiate and propagate VT. We also review emerging clinical data describing anti-inflammatory approaches as adjuncts to anticoagulation in VT treatment. Finally, we identify key knowledge gaps and future directions that could maximize the benefit of anti-inflammatory therapies in VT. Identifying and targeting the inflammatory factors driving VT, either at the endothelial cell level or within the clot, may pave the way for new therapeutic possibilities for improving VT treatment and reducing thromboembolic complications without increasing bleeding risk.


Assuntos
Inflamação , Trombose Venosa , Humanos , Trombose Venosa/etiologia , Trombose Venosa/patologia , Animais , Inflamação/patologia , Coagulação Sanguínea , Células Endoteliais/metabolismo , Células Endoteliais/patologia
4.
Blood ; 143(21): 2190-2200, 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38306657

RESUMO

ABSTRACT: VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome, caused by somatic mutations in UBA1, is an autoinflammatory disorder with diverse systemic manifestations. Thrombosis is a prominent clinical feature of VEXAS syndrome. The risk factors and frequency of thrombosis in VEXAS syndrome are not well described, due to the disease's recent discovery and the paucity of large databases. We evaluated 119 patients with VEXAS syndrome for venous and arterial thrombosis and correlated their presence with clinical outcomes and survival. Thrombosis occurred in 49% of patients, mostly venous thromboembolism (VTE; 41%). Almost two-thirds of VTEs were unprovoked, 41% were recurrent, and 20% occurred despite anticoagulation. The cumulative incidence of VTE was 17% at 1 year from symptom onset and 40% by 5 years. Cardiac and pulmonary inflammatory manifestations were associated with time to VTE. M41L was positively associated specifically with pulmonary embolism by univariate (odds ratio [OR]: 4.58, confidence interval [CI] 1.28-16.21, P = .02) and multivariate (OR: 16.94, CI 1.99-144.3, P = .01) logistic regression. The cumulative incidence of arterial thrombosis was 6% at 1 year and 11% at 5 years. The overall survival of the entire patient cohort at median follow-up time of 4.8 years was 88%, and there was no difference in survival between patients with or without thrombosis (P = .8). Patients with VEXAS syndrome are at high risk of VTE; thromboprophylaxis should administered be in high-risk settings unless strongly contraindicated.


Assuntos
Trombose , Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Trombose/etiologia , Trombose/genética , Trombose/epidemiologia , Adolescente , Enzimas Ativadoras de Ubiquitina/genética , Adulto Jovem , Fatores de Risco , Idoso , Criança , Trombose Venosa/etiologia , Trombose Venosa/epidemiologia , Trombose Venosa/genética , Incidência , Mutação , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/complicações , Pré-Escolar
5.
Blood ; 143(23): 2351-2362, 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38364188

RESUMO

ABSTRACT: Arterial and venous thromboses are classically considered distinct disease states, with arterial thrombosis mediated predominantly by platelets and therefore, treated with antiplatelet therapy, and venous thrombosis mediated by the plasmatic coagulation system and treated with anticoagulation. However, co-occurrence of arterial and venous events is common, and there is increasing evidence of shared risk factors and pathophysiologic overlap. This presents a management challenge: does the patient with venous and arterial thrombosis, require anticoagulation, antiplatelet therapy, or both? Herein, we present a structured approach to the evaluation and management of patients with venous thrombosis who are also at risk for or have a history of an arterial thromboembolic event. We emphasize the importance of defining the indications for antithrombotic therapy, as well as the evaluation of factors that influence both thrombotic and bleeding risk, including disorder-specific and patient-specific factors, as well as the inherent risk balance of antithrombotic therapy regimens. We illustrate this approach in 4 cases, discussing the unique considerations and recent updates in the management of venous thrombosis, acute noncardioembolic ischemic stroke, coronary artery disease and acute myocardial infarction, and peripheral artery disease after revascularization.


Assuntos
Anticoagulantes , Inibidores da Agregação Plaquetária , Tromboembolia , Humanos , Inibidores da Agregação Plaquetária/uso terapêutico , Inibidores da Agregação Plaquetária/efeitos adversos , Anticoagulantes/uso terapêutico , Anticoagulantes/efeitos adversos , Tromboembolia/tratamento farmacológico , Tromboembolia/etiologia , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Fatores de Risco , Trombose Venosa/tratamento farmacológico , Tromboembolia Venosa/tratamento farmacológico , Tromboembolia Venosa/etiologia
6.
Circ Res ; 134(10): e93-e111, 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38563147

RESUMO

BACKGROUND: Endothelial activation promotes the release of procoagulant extracellular vesicles and inflammatory mediators from specialized storage granules. Endothelial membrane exocytosis is controlled by phosphorylation. We hypothesized that the absence of PTP1B (protein tyrosine phosphatase 1B) in endothelial cells promotes venous thromboinflammation by triggering endothelial membrane fusion and exocytosis. METHODS: Mice with inducible endothelial deletion of PTP1B (End.PTP1B-KO) underwent inferior vena cava ligation to induce stenosis and venous thrombosis. Primary endothelial cells from transgenic mice and human umbilical vein endothelial cells were used for mechanistic studies. RESULTS: Vascular ultrasound and histology showed significantly larger venous thrombi containing higher numbers of Ly6G (lymphocyte antigen 6 family member G)-positive neutrophils in mice with endothelial PTP1B deletion, and intravital microscopy confirmed the more pronounced neutrophil recruitment following inferior vena cava ligation. RT2 PCR profiler array and immunocytochemistry analysis revealed increased endothelial activation and adhesion molecule expression in primary End.PTP1B-KO endothelial cells, including CD62P (P-selectin) and VWF (von Willebrand factor). Pretreatment with the NF-κB (nuclear factor kappa B) kinase inhibitor BAY11-7082, antibodies neutralizing CD162 (P-selectin glycoprotein ligand-1) or VWF, or arginylglycylaspartic acid integrin-blocking peptides abolished the neutrophil adhesion to End.PTP1B-KO endothelial cells in vitro. Circulating levels of annexin V+ procoagulant endothelial CD62E+ (E-selectin) and neutrophil (Ly6G+) extracellular vesicles were also elevated in End.PTP1B-KO mice after inferior vena cava ligation. Higher plasma MPO (myeloperoxidase) and Cit-H3 (citrullinated histone-3) levels and neutrophil elastase activity indicated neutrophil activation and extracellular trap formation. Infusion of End.PTP1B-KO extracellular vesicles into C57BL/6J wild-type mice most prominently enhanced the recruitment of endogenous neutrophils, and this response was blunted in VWF-deficient mice or by VWF-blocking antibodies. Reduced PTP1B binding and tyrosine dephosphorylation of SNAP23 (synaptosome-associated protein 23) resulting in increased VWF exocytosis and neutrophil adhesion were identified as mechanisms, all of which could be restored by NF-κB kinase inhibition using BAY11-7082. CONCLUSIONS: Our findings show that endothelial PTP1B deletion promotes venous thromboinflammation by enhancing SNAP23 phosphorylation, endothelial VWF exocytosis, and neutrophil recruitment.


Assuntos
Exocitose , Camundongos Knockout , Proteína Tirosina Fosfatase não Receptora Tipo 1 , Trombose Venosa , Fator de von Willebrand , Animais , Proteína Tirosina Fosfatase não Receptora Tipo 1/genética , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 1/deficiência , Humanos , Camundongos , Fator de von Willebrand/metabolismo , Fator de von Willebrand/genética , Trombose Venosa/metabolismo , Trombose Venosa/genética , Trombose Venosa/patologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Inflamação/metabolismo , Inflamação/genética , Camundongos Endogâmicos C57BL , Neutrófilos/metabolismo , Células Endoteliais/metabolismo , Células Cultivadas , Veia Cava Inferior/metabolismo , Veia Cava Inferior/patologia , Masculino , Infiltração de Neutrófilos , NF-kappa B/metabolismo
7.
Brief Bioinform ; 25(1)2023 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-38221905

RESUMO

BACKGROUND: Portal vein thrombosis (PVT) is a significant issue in cirrhotic patients, necessitating early detection. This study aims to develop a data-driven predictive model for PVT diagnosis in chronic hepatitis liver cirrhosis patients. METHODS: We employed data from a total of 816 chronic cirrhosis patients with PVT, divided into the Lanzhou cohort (n = 468) for training and the Jilin cohort (n = 348) for validation. This dataset encompassed a wide range of variables, including general characteristics, blood parameters, ultrasonography findings and cirrhosis grading. To build our predictive model, we employed a sophisticated stacking approach, which included Support Vector Machine (SVM), Naïve Bayes and Quadratic Discriminant Analysis (QDA). RESULTS: In the Lanzhou cohort, SVM and Naïve Bayes classifiers effectively classified PVT cases from non-PVT cases, among the top features of which seven were shared: Portal Velocity (PV), Prothrombin Time (PT), Portal Vein Diameter (PVD), Prothrombin Time Activity (PTA), Activated Partial Thromboplastin Time (APTT), age and Child-Pugh score (CPS). The QDA model, trained based on the seven shared features on the Lanzhou cohort and validated on the Jilin cohort, demonstrated significant differentiation between PVT and non-PVT cases (AUROC = 0.73 and AUROC = 0.86, respectively). Subsequently, comparative analysis showed that our QDA model outperformed several other machine learning methods. CONCLUSION: Our study presents a comprehensive data-driven model for PVT diagnosis in cirrhotic patients, enhancing clinical decision-making. The SVM-Naïve Bayes-QDA model offers a precise approach to managing PVT in this population.


Assuntos
Veia Porta , Trombose Venosa , Humanos , Veia Porta/patologia , Fatores de Risco , Teorema de Bayes , Medicina de Precisão , Cirrose Hepática/complicações , Cirrose Hepática/diagnóstico , Fibrose , Trombose Venosa/complicações , Trombose Venosa/diagnóstico
8.
Hepatology ; 79(2): 355-367, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-37505218

RESUMO

BACKGROUND AND AIMS: HCC can increase the risk of nonneoplastic PVT in cirrhosis. However, the natural history of PVT and its prognostic role in HCC patients are unknown. APPROACH AND RESULTS: Consecutive HCC patients with cirrhosis undergoing laparoscopic ablation were retrospectively evaluated and followed up to 36 months. HCC and PVT characteristics and evolution were reviewed. PVT was categorized according to lumen occupancy (≤50%, >50% <100%, and = 100%) and extension to other veins. The evolution of thrombosis was considered at 1 year from diagnosis. Variables associated with the presence of PVT and evolution patterns were analyzed, as well as their impact on survival. In all, 750 patients were included, 88 of whom had PVT. On multivariate analysis, the occurrence of PVT at HCC diagnosis was associated with pretreatment total tumor volume ( p < 0.001) and clinically significant portal hypertension ( p = 0.005). During the follow-up, 46 de novo PVT occurred, 27/46 (58.7%) in the presence of a viable tumor. Among 115 PVT diagnosed in the presence of HCC, 83 had available radiological follow-up, and 22 were anticoagulated. The "complete/progressive" evolution pattern was associated with nonresponse to HCC treatment in non-anticoagulated patients. The presence of PVT was independently associated with lower overall survival, particularly when progressive or occlusive ( p < 0.001). A higher competing risk of death emerged for "complete and progressive" PVT, both for HCC-related ( p < 0.001) and non-HCC-related ( p = 0.002) death. CONCLUSIONS: HCC represents an independent risk factor for the occurrence and progression of PVT in cirrhosis. Since progressive and occlusive PVT seems to be an independent factor associated with mortality, screening and prompt treatment of this complication should be considered.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Trombose Venosa , Humanos , Carcinoma Hepatocelular/patologia , Estudos Retrospectivos , Trombose Venosa/etiologia , Neoplasias Hepáticas/patologia , Veia Porta/patologia , Cirrose Hepática/patologia
9.
Hepatology ; 80(4): 807-815, 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-38358542

RESUMO

BACKGROUND AND AIMS: Systemic treatments are listed as first-line therapies for HCC with portal vein tumor thrombus (PVTT), resulting in modest efficacy. We aimed to evaluate the efficacy and safety of sintilimab plus bevacizumab combined with radiotherapy in HCC with PVTT and to identify prognostic biomarkers. APPROACH AND RESULTS: This open-label, multicenter, single-arm, phase 2 clinical trial was conducted at 3 tertiary hospitals in China. A total of 46 patients with HCC with PVTT were enrolled. All the patients received the first cycle of i.v. sintilimab (200 mg, day 1) plus bevacizumab (15 mg/kg, day 1) within 3 days after enrollment. Radiotherapy (30-50 Gy/10 fractions) was administered after 2 cycles of Sin-Bev. Sin-Bev was disrupted during radiotherapy and resumed 2 weeks after radiotherapy and continued every 3 weeks thereafter until disease progression, unacceptable toxicity, or withdrawal of consent. The primary end point was objective response rate. Patients obtained an objective response rate of 58.7% and a disease control rate of 100%. After a median follow-up time of 26.0 months (95% CI: 24.0-26.0), the median OS was 24.0 months (95% CI: 19.0 to not applicable) and the median progression-free survival was 13.8 months (95% CI: 12.0-21.0), respectively. No unexpected adverse events or treatment-related deaths occurred. Mutations of PCTMD1 were predictive of shorter OS and progression-free survival. CONCLUSIONS: Sintilimab plus bevacizumab combined with radiotherapy provides favorable treatment response and survival outcomes along with an acceptable safety profile in the first-line setting for patients with HCC with PVTT (ClinicalTrials.gov Identifier: NCT05010434).


Assuntos
Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Bevacizumab , Carcinoma Hepatocelular , Neoplasias Hepáticas , Veia Porta , Humanos , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/radioterapia , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Bevacizumab/administração & dosagem , Bevacizumab/uso terapêutico , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/radioterapia , Masculino , Pessoa de Meia-Idade , Feminino , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Adulto , Trombose Venosa/etiologia , Trombose Venosa/tratamento farmacológico , Quimiorradioterapia/métodos , Quimiorradioterapia/efeitos adversos , China
10.
Blood ; 141(19): 2390-2401, 2023 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-36701760

RESUMO

C1 inhibitor (C1INH) is a multifunctional serine protease inhibitor that functions as a major negative regulator of several biological pathways, including the contact pathway of blood coagulation. In humans, congenital C1INH deficiency results in a rare episodic bradykinin-mediated swelling disorder called hereditary angioedema (HAE). Patients with C1INH deficiency-associated HAE (C1INH-HAE) have increased circulating markers of activation of coagulation. Furthermore, we recently reported that patients with C1INH-HAE had a moderate but significant increased risk of venous thromboembolism. To further investigate the impact of C1INH deficiency on activation of coagulation and thrombosis, we conducted studies using patient samples and mouse models. Plasmas from patients with C1INH-HAE had significantly increased contact pathway-mediated thrombin generation. C1INH-deficient mice, which have been used as a model of C1INH-HAE, had significantly increased baseline circulating levels of prothrombin fragment 1+2 and thrombin-antithrombin complexes. In addition, whole blood from C1INH-deficient mice supported significantly increased contact pathway-mediated thrombin generation. Importantly, C1INH-deficient mice exhibited significantly enhanced venous, but not arterial, thrombus formation. Furthermore, purified human C1INH normalized contact pathway-mediated thrombin generation and venous thrombosis in C1INH-deficient mice. These findings highlight a key role for endogenous C1INH as a negative regulator of contact pathway-mediated coagulation in humans and mice. Further, this work identifies endogenous C1INH as an important negative regulator of venous thrombus formation in mice, complementing the phenotype associated with C1INH-HAE.


Assuntos
Angioedemas Hereditários , Trombose , Trombose Venosa , Humanos , Animais , Camundongos , Angioedemas Hereditários/genética , Trombina , Proteína Inibidora do Complemento C1/genética , Coagulação Sanguínea , Trombose/etiologia , Trombose Venosa/etiologia
11.
Am J Respir Crit Care Med ; 209(12): 1477-1485, 2024 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-38470220

RESUMO

Rationale: Chronic thromboembolic pulmonary hypertension involves the formation and nonresolution of thrombus, dysregulated inflammation, angiogenesis, and the development of a small-vessel vasculopathy. Objectives: We aimed to establish the genetic basis of chronic thromboembolic pulmonary hypertension to gain insight into its pathophysiological contributors. Methods: We conducted a genome-wide association study on 1,907 European cases and 10,363 European control subjects. We coanalyzed our results with existing results from genome-wide association studies on deep vein thrombosis, pulmonary embolism, and idiopathic pulmonary arterial hypertension. Measurements and Main Results: Our primary association study revealed genetic associations at the ABO, FGG, F11, MYH7B, and HLA-DRA loci. Through our coanalysis, we demonstrate further associations with chronic thromboembolic pulmonary hypertension at the F2, TSPAN15, SLC44A2, and F5 loci but find no statistically significant associations shared with idiopathic pulmonary arterial hypertension. Conclusions: Chronic thromboembolic pulmonary hypertension is a partially heritable polygenic disease, with related though distinct genetic associations with pulmonary embolism and deep vein thrombosis.


Assuntos
Estudo de Associação Genômica Ampla , Hipertensão Pulmonar , Embolia Pulmonar , Humanos , Embolia Pulmonar/genética , Embolia Pulmonar/complicações , Hipertensão Pulmonar/genética , Masculino , Feminino , Pessoa de Meia-Idade , Doença Crônica , Genômica , Predisposição Genética para Doença , Adulto , Estudos de Casos e Controles , Idoso , Trombose Venosa/genética
12.
Curr Opin Hematol ; 31(3): 122-129, 2024 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-38359323

RESUMO

PURPOSE OF REVIEW: This review summarizes recent advances in developing targeted diagnostics for venous thromboembolism (VTE) and unaddressed knowledge gaps in patient management. Without addressing these critical data needs, the morbidity in VTE patients will persist. RECENT FINDINGS: Recent studies investigating plasma protein profiles in VTE patients have identified key diagnostic targets to address the currently unmet need for low-cost, confirmatory, point-of-care VTE diagnostics. These studies and a growing body of evidence from animal model studies have revealed the importance of inflammatory and vascular pathology in driving VTE, which are currently unaddressed targets for VTE therapy. To enhance the translation of preclinical animal studies, clinical quantification of thrombus burden and comparative component analyses between modeled VTE and clinical VTE are necessary. SUMMARY: Lead candidates from protein profiling of VTE patients' plasma offer a promising outlook in developing low cost, confirmatory, point-of-care testing for VTE. Additionally, addressing the critical knowledge gap of quantitatively measuring clinical thrombi will allow for an array of benefits in VTE management and informing the translatability of experimental therapeutics.


Assuntos
Tromboembolia Venosa , Trombose Venosa , Humanos , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/tratamento farmacológico , Anticoagulantes/uso terapêutico
13.
Circulation ; 148(21): 1665-1676, 2023 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-37638968

RESUMO

BACKGROUND: The optimal duration of anticoagulation therapy for isolated distal deep vein thrombosis in patients with cancer is clinically relevant, but the evidence is lacking. The prolonged anticoagulation therapy could have a potential benefit for prevention of thrombotic events; however, it could also increase the risk of bleeding. METHODS: In a multicenter, open-label, adjudicator-blinded, randomized clinical trial at 60 institutions in Japan, we randomly assigned patients with cancer with isolated distal deep vein thrombosis, in a 1-to-1 ratio, to receive either a 12-month or 3-month edoxaban treatment. The primary end point was a composite of a symptomatic recurrent venous thromboembolism (VTE) or VTE-related death at 12 months. The major secondary end point was major bleeding at 12 months, according to the criteria of the International Society on Thrombosis and Haemostasis. The primary hypothesis was that a 12-month edoxaban treatment was superior to a 3-month edoxaban treatment with respect to the primary end point. RESULTS: From April 2019 through June 2022, 604 patients were randomized, and after excluding 3 patients who withdrew consent, 601 patients were included in the intention-to-treat population: 296 patients in the 12-month edoxaban group and 305 patients in the 3-month edoxaban group. The mean age was 70.8 years, 28% of the patients were men, and 20% of the patients had symptoms of deep vein thrombosis at baseline. The primary end point of a symptomatic recurrent VTE event or VTE-related death occurred in 3 of the 296 patients (1.0%) in the 12-month edoxaban group and in 22 of the 305 patients (7.2%) in the 3-month edoxaban group (odds ratio, 0.13; 95% CI, 0.03-0.44). The major secondary end point of major bleeding occurred in 28 of the 296 patients (9.5%) in the 12-month edoxaban group and in 22 of the 305 patients (7.2%) in the 3-month edoxaban group (odds ratio, 1.34; 95% CI, 0.75-2.41). The prespecified subgroups did not affect the estimates on the primary end point. CONCLUSIONS: In patients with cancer with isolated distal deep vein thrombosis, 12 months was superior to 3 months for an edoxaban treatment with respect to the composite outcome of a symptomatic recurrent VTE or VTE-related death. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03895502.


Assuntos
Neoplasias , Trombose , Tromboembolia Venosa , Trombose Venosa , Masculino , Humanos , Idoso , Feminino , Anticoagulantes/efeitos adversos , Tromboembolia Venosa/tratamento farmacológico , Tromboembolia Venosa/complicações , Hemorragia/complicações , Trombose/complicações , Trombose Venosa/complicações , Neoplasias/complicações , Neoplasias/tratamento farmacológico
14.
Stroke ; 55(3): e77-e90, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38284265

RESUMO

Cerebral venous thrombosis accounts for 0.5% to 3% of all strokes. The most vulnerable populations include young individuals, women of reproductive age, and patients with a prothrombotic state. The clinical presentation of cerebral venous thrombosis is diverse (eg, headaches, seizures), requiring a high level of clinical suspicion. Its diagnosis is based primarily on magnetic resonance imaging/magnetic resonance venography or computed tomography/computed tomographic venography. The clinical course of cerebral venous thrombosis may be difficult to predict. Death or dependence occurs in 10% to 15% of patients despite intensive medical treatment. This scientific statement provides an update of the 2011 American Heart Association scientific statement for the diagnosis and management of cerebral venous thrombosis. Our focus is on advances in the diagnosis and management decisions of patients with suspected cerebral venous thrombosis. We discuss evidence for the use of anticoagulation and endovascular therapies and considerations for craniectomy. We also provide an algorithm to optimize the management of patients with cerebral venous thrombosis and those with progressive neurological deterioration or thrombus propagation despite maximal medical therapy.


Assuntos
Trombose Intracraniana , Trombose dos Seios Intracranianos , Trombose Venosa , Humanos , Feminino , American Heart Association , Trombose Intracraniana/diagnóstico por imagem , Trombose Intracraniana/terapia , Angiografia por Ressonância Magnética , Cavidades Cranianas , Trombose Venosa/diagnóstico por imagem , Trombose Venosa/terapia , Trombose dos Seios Intracranianos/tratamento farmacológico
15.
Stroke ; 55(4): 934-942, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38527140

RESUMO

BACKGROUND: The importance of thromboembolism in the pathogenesis of lacunar stroke (LS), resulting from cerebral small vessel disease (cSVD), is debated, and although antiplatelets are widely used in secondary prevention after LS, there is limited trial evidence from well-subtyped patients to support this approach. We sought to evaluate whether altered anticoagulation plays a causal role in LS and cSVD using 2-sample Mendelian randomization. METHODS: From a recent genome-wide association study (n=81 190), we used 119 genetic variants associated with venous thrombosis at genome-wide significance (P<5*10-8) and with a linkage disequilibrium r2<0.001 as instrumental variables. We also used genetic associations with stroke from the GIGASTROKE consortium (62 100 ischemic stroke cases: 10 804 cardioembolic stroke, 6399 large-artery stroke, and 6811 LS). In view of the lower specificity for LS with the CT-based phenotyping mainly used in GIGASTROKE, we also used data from patients with magnetic resonance imaging-confirmed LS (n=3199). We also investigated associations with more chronic magnetic resonance imaging features of cSVD, namely, white matter hyperintensities (n=37 355) and diffusion tensor imaging metrics (n=36 533). RESULTS: Mendelian randomization analyses showed that genetic predisposition to venous thrombosis was associated with an increased odds of any ischemic stroke (odds ratio [OR], 1.19 [95% CI, 1.13-1.26]), cardioembolic stroke (OR, 1.32 [95% CI, 1.21-1.45]), and large-artery stroke (OR, 1.41 [95% CI, 1.26-1.57]) but not with LS (OR, 1.07 [95% CI, 0.99-1.17]) in GIGASTROKE. Similar results were found for magnetic resonance imaging-confirmed LS (OR, 0.94 [95% CI, 0.81-1.09]). Genetically predicted risk of venous thrombosis was not associated with imaging markers of cSVD. CONCLUSIONS: These findings suggest that altered thrombosis plays a role in the risk of cardioembolic and large-artery stroke but is not a causal risk factor for LS or imaging markers of cSVD. This raises the possibility that antithrombotic medication may be less effective in cSVD and underscores the necessity for further trials in well-subtyped cohorts with LS to evaluate the efficacy of different antithrombotic regimens in LS.


Assuntos
Doenças de Pequenos Vasos Cerebrais , AVC Embólico , Acidente Vascular Cerebral Lacunar , Acidente Vascular Cerebral , Trombose , Trombose Venosa , Humanos , Doenças de Pequenos Vasos Cerebrais/diagnóstico por imagem , Doenças de Pequenos Vasos Cerebrais/genética , Doenças de Pequenos Vasos Cerebrais/complicações , Imagem de Tensor de Difusão , AVC Embólico/complicações , Fibrinolíticos , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral Lacunar/diagnóstico por imagem , Acidente Vascular Cerebral Lacunar/genética , Acidente Vascular Cerebral Lacunar/complicações , Trombose/complicações , Trombose Venosa/diagnóstico por imagem , Trombose Venosa/epidemiologia , Trombose Venosa/genética
16.
Stroke ; 55(4): 999-1005, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38299332

RESUMO

INTRODUCTION: Infertility treatment with assisted reproductive technologies (ARTs) has been associated with adverse vascular events in some but not all previous studies. Endothelial damage, prothrombotic factor release, and a higher prevalence of cardiovascular risk factors in those receiving ART have been invoked to explain this association. We sought to explore the relationship between ART and stroke risk using population-level data. METHODS: We conducted a retrospective cohort study using data from the National Inpatient Sample registry from 2015 to 2020, including all delivery hospitalizations for patients aged 15 to 55 years. The study exposure was use of ART. The primary end point was any stroke defined as ischemic stroke, subarachnoid hemorrhage, intracerebral hemorrhage, or cerebral venous thrombosis during index delivery hospitalization. Individual stroke subtypes (ischemic stroke, subarachnoid hemorrhage, intracerebral hemorrhage, and cerebral venous thrombosis) were evaluated as secondary end points. Standard International Classification of Diseases, Tenth Revision, Clinical Modification algorithms were used to define study exposure, comorbidities, and prespecified end points. In addition to reporting population-level estimates, propensity score adjustment by inverse probability weighting was used to mimic the effects of randomization by balancing baseline clinical characteristics associated with stroke between ART and non-ART users. RESULTS: Among 19 123 125 delivery hospitalizations identified, patients with prior ART (n=202 815, 1.1%) experienced significantly higher rates of any stroke (27.1/100 000 versus 9.1/100 000), ischemic stroke (9.9/100 000 versus 3.3/100 000), subarachnoid hemorrhage (7.4/100 000 versus 1.6/100 000), intracerebral hemorrhage (7.4/100 000 versus 2.0/100 000), and cerebral venous thrombosis (7.4/100 000 versus 2.7/100 000) in comparison to non-ART users (all P<0.001 for all unadjusted comparisons). Following inverse probability weighting analysis, ART was associated with increased odds of any stroke (adjusted odds ratios, 2.14 (95% CI, 2.02-2.26); P<0.001). CONCLUSIONS: Using population-level data among patients hospitalized for delivery in the United States, we found an association between ART and stroke after adjustment for measured confounders.


Assuntos
AVC Isquêmico , Acidente Vascular Cerebral , Hemorragia Subaracnóidea , Trombose Venosa , Humanos , Estados Unidos/epidemiologia , Estudos Retrospectivos , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/terapia , Hemorragia Cerebral/epidemiologia , Hemorragia Subaracnóidea/epidemiologia , Hospitalização , Prevalência , Técnicas de Reprodução Assistida/efeitos adversos , Trombose Venosa/epidemiologia
17.
Am J Transplant ; 24(6): 1087-1090, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38219868

RESUMO

Atezolizumab plus bevacizumab is the preferred first-line treatment regimen for patients with advanced hepatocellular carcinoma. Limited data have shown promising results with the use of immune checkpoint inhibitors like nivolumab to downstage these patients for liver transplantation (LT). Here, we describe the first case of successful downstaging with atezolizumab plus bevacizumab in a patient with multifocal hepatocellular carcinoma and main portal vein tumoral thrombosis, followed by ABO-incompatible live donor LT. This illustrated case highlights that atezolizumab plus bevacizumab therapy may be a potential bridging tool for curative LT.


Assuntos
Anticorpos Monoclonais Humanizados , Bevacizumab , Carcinoma Hepatocelular , Neoplasias Hepáticas , Transplante de Fígado , Veia Porta , Trombose Venosa , Humanos , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/complicações , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/complicações , Bevacizumab/uso terapêutico , Bevacizumab/administração & dosagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Veia Porta/patologia , Masculino , Trombose Venosa/etiologia , Trombose Venosa/tratamento farmacológico , Trombose Venosa/terapia , Pessoa de Meia-Idade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Prognóstico
18.
J Hepatol ; 81(3): 451-460, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38679069

RESUMO

BACKGROUND & AIMS: One-third of non-cirrhotic portal vein thrombosis (NCPVT) cases are associated with local factors. The risk of rethrombosis after anticoagulation withdrawal is unknown. We aimed to determine factors associated with new splanchnic or extrasplanchnic thrombotic events in this setting. METHODS: We performed a retrospective study including cases of recent NCPVT associated with local factors. High- and low-risk prothrombotic factors, prespecified according to RIPORT study criteria, were assessed. Univariate and multivariate Cox models assessed the influence of different variables on the occurrence of new thrombotic events. RESULTS: At baseline, 83/154 (53.9%) patients had at least one prothrombotic factor including 50 (32.5%) with a high-risk and 33 (21.4%) with a low-risk prothrombotic factor. Oestrogen-containing contraception was discontinued in all patients. During follow-up, 63/140 (45%) patients had at least one prothrombotic factor, including 47 (33.6%) with a high-risk and 16 (11.4%) with a low-risk prothrombotic factor. Seventeen new thrombotic events occurred after a median follow-up of 52 (IQR 14-62) (min-max 3.0-69.0) months. New thromboses were associated with high-risk factors (hazard ratio [HR] 3.817, 95% CI 1.303-11.180, p = 0.015), but were inversely related to recanalization (HR 0.222, 95% CI 0.078-0.635, p = 0.005) and anticoagulation (HR 0.976, 95% CI 0.956-0.995, p = 0.016). When a high-risk factor was present a new thrombotic event occurred in 7.4%, 14.6%, 14.6% and 28.8% of patients at 1, 3, 5 and 7 years under anticoagulants, respectively, compared to 21.2%, 21.2%, 58% and 58% without anticoagulants, respectively. CONCLUSIONS: In cases of recent NCPVT associated with local factors, high-risk factors for thrombosis are associated with new thrombotic events. Permanent anticoagulation appears beneficial in this high-risk situation. IMPACT AND IMPLICATIONS: In non-cirrhotic portal vein thrombosis (NCPVT) associated with local factors, systematic screening for prothrombotic factors is recommended, but the prevalence of the latter is not clearly established, and the risk of recurrent intra or extrasplanchnic thromboembolism is poorly described. Thus, interest in permanent anticoagulation remains. NCPVT associated with local factors is a matter of concern for hepatologists, gastroenterologists and digestive surgeons. Due to a lack of knowledge, practices are heterogeneous. Our findings highlight that systematic screening for prothrombotic factors in NCPVT is needed even when associated with local factors, as it may justify long-term anticoagulation for the prevention of new intra or extrasplanchnic thrombotic events in at least one-third of cases. The interest in long-term anticoagulation should be investigated prospectively in the absence of high-risk prothrombotic factors. CLINICAL TRIAL NUMBER: NCT0536064.


Assuntos
Veia Porta , Recidiva , Trombose Venosa , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Anticoagulantes/efeitos adversos , Anticoagulantes/administração & dosagem , Estudos Retrospectivos , Fatores de Risco , Circulação Esplâncnica , Trombose Venosa/epidemiologia , Trombose Venosa/etiologia , Trombose Venosa/tratamento farmacológico
19.
Mol Med ; 30(1): 84, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38867168

RESUMO

BACKGROUND: Deep vein thrombosis (DVT) is a common vascular surgical disease caused by the coagulation of blood in the deep veins, and predominantly occur in the lower limbs. Endothelial progenitor cells (EPCs) are multi-functional stem cells, which are precursors of vascular endothelial cells. EPCs have gradually evolved into a promising treatment strategy for promoting deep vein thrombus dissolution and recanalization through the stimulation of various physical and chemical factors. METHODS: In this study, we utilized a mouse DVT model and performed several experiments including qRT-PCR, Western blot, tube formation, wound healing, Transwell assay, immunofluorescence, flow cytometry analysis, and immunoprecipitation to investigate the role of HOXD9 in the function of EPCs cells. The therapeutic effect of EPCs overexpressing HOXD9 on the DVT model and its mechanism were also explored. RESULTS: Overexpression of HOXD9 significantly enhanced the angiogenesis and migration abilities of EPCs, while inhibiting cell apoptosis. Additionally, results indicated that HOXD9 specifically targeted the HRD1 promoter region and regulated the downstream PINK1-mediated mitophagy. Interestingly, intravenous injection of EPCs overexpressing HOXD9 into mice promoted thrombus dissolution and recanalization, significantly decreasing venous thrombosis. CONCLUSIONS: The findings of this study reveal that HOXD9 plays a pivotal role in stimulating vascular formation in endothelial progenitor cells, indicating its potential as a therapeutic target for DVT management.


Assuntos
Modelos Animais de Doenças , Células Progenitoras Endoteliais , Proteínas de Homeodomínio , Mitofagia , Neovascularização Fisiológica , Trombose Venosa , Animais , Células Progenitoras Endoteliais/metabolismo , Camundongos , Trombose Venosa/metabolismo , Trombose Venosa/genética , Trombose Venosa/terapia , Proteínas de Homeodomínio/metabolismo , Proteínas de Homeodomínio/genética , Mitofagia/genética , Neovascularização Fisiológica/genética , Movimento Celular , Masculino , Apoptose , Humanos , Angiogênese
20.
Br J Haematol ; 205(1): 71-87, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38664942

RESUMO

A shared decision on the most appropriate agent for the treatment of cancer-associated thrombosis should consider the following factors, which should be reassessed as patients continue along their cancer care pathway: risk of bleeding; tumour site; suitability of oral medications; potential for drug-drug interactions; and patient preference and values regarding choice of drug. Continuing anticoagulation beyond 6 months in patients with cancer-associated venous thromboembolism and active cancer is recommended.


Assuntos
Anticoagulantes , Neoplasias , Trombose Venosa , Humanos , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Trombose Venosa/etiologia , Anticoagulantes/uso terapêutico , Adulto , Reino Unido , Hemorragia/etiologia , Hemorragia/induzido quimicamente , Tromboembolia Venosa/etiologia
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