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1.
Blood ; 135(5): 351-359, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31917385

RESUMO

Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), is the third most common cause of vascular death after heart attack and stroke. Anticoagulation therapy is the cornerstone of VTE treatment. Despite such therapy, up to 50% of patients with DVT develop postthrombotic syndrome, and up to 4% of patients with PE develop chronic thromboembolic pulmonary hypertension. Therefore, better therapies are needed. Although direct oral anticoagulants are more convenient and safer than warfarin for VTE treatment, bleeding remains the major side effect, particularly in cancer patients. Factor XII and factor XI have emerged as targets for new anticoagulants that may be safer. To reduce the complications of VTE, attenuation of thrombin activatable fibrinolysis inhibitor activity is under investigation in PE patients to enhance endogenous fibrinolysis, whereas blockade of leukocyte interaction with the vessel wall is being studied to reduce the inflammation that contributes to postthrombotic syndrome in DVT patients. Focusing on these novel antithrombotic strategies, this article explains why safer anticoagulants are needed, provides the rationale for factor XII and XI as targets for such agents, reviews the data on the factor XII- and factor XI-directed anticoagulants under development, describes novel therapies to enhance fibrinolysis and decrease inflammation in PE and DVT patients, respectively, and offers insights into the opportunities for these novel VTE therapies.

3.
Eur J Intern Med ; 70: 1-7, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31679885

RESUMO

The achievements with antithrombotic therapy over the past 50 years have been monumental and the disappointments relatively few. In this review, we will discuss, chronologically, the major developments of the two recognized classes of antithrombotics - anticoagulants and antiplatelet agents.

4.
Can J Ophthalmol ; 2019 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-31712009

RESUMO

OBJECTIVES: The aim of this study is to report a case series of atypical presentations of intracranial dysgerminoma in which the diagnosis was delayed due to clinical and radiographic findings initially suggestive of CNS inflammatory or demyelinating diseases, such as MS. DESIGN/PARTICIPANTS/METHODS: This study is a case series detailing the history, clinical presentations, radiographic and laboratory results, and management of three patients with biopsy-proven intracranial dysgerminoma. RESULTS: All three patients demonstrated hyperintense lesions on MRI that were more suggestive of demyelinating or inflammatory diseases, including lesions involving the midbrain and corpus callosum. All three patients were serum positive for oligoclonal bands and negative for both AFP and beta-hCG (these two markers are commonly seen in dysgerminoma cases). One case involved a steroid-responsive tumor whereas the other two cases either did not respond to steroids or steroids were withheld due to uncertainty of etiology. Following biopsy, all three results were consistent with dysgerminoma. CONCLUSION: Clinicians should be aware that dysgerminoma may mimic the clinical and radiographic presentations of demyelinating diseases such as MS. These lesions can cause acute visual loss or diplopia, have MRI and CSF findings that might mimic MS, and have been shown to respond to steroids. Atypical clinical (e.g., headache, dorsal midbrain syndrome, bilateral optic neuropathy) or atypical radiographic features (e.g., mass effect, hydrocephalus) should prompt consideration for repeat imaging and possible biopsy even if serum or CSF tumor markers (beta-hCG and AFP) are negative for dysgerminoma.

5.
J Am Coll Cardiol ; 74(17): 2190-2192, 2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31648712
7.
Br J Ophthalmol ; 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31391182

RESUMO

PURPOSE: To determine the relationship of intraocular pressure (IOP) control with subsequent visual field (VF) deterioration in patients with primary angle closure disease (PACD). METHODS: 419 PACD eyes from 240 Chinese patients were included. Mean IOP and IOP fluctuation were calculated as the average and SD divided by mean IOP, respectively, of all the IOP measured in the initial 18 months for assessment of IOP control. The relationship between IOP control and subsequent VF parameters over time was examined using linear mixed models. VF deterioration was defined as IOP control associated with decreased VF parameters over time with a p value <0.05. We calculated the average of the mean IOPs and IOP fluctuations in the cohort and used these two average values as a cut-off point to define high-threshold (≥average value) or low-threshold (

9.
Circ Cardiovasc Interv ; 12(5): e007019, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31018667

RESUMO

BACKGROUND: The genetic determinants of response to clopidogrel and aspirin are incompletely characterized. Recently, PEAR1 (platelet endothelial aggregation receptor-1) rs12041331 polymorphism has been shown to influence the platelet reactivity, but its impact on cardiovascular outcomes remains unclear in patients treated with antiplatelet agents. METHODS AND RESULTS: In this prospective cohort study, 2439 Chinese patients with acute coronary syndrome or stable coronary artery disease undergoing coronary stent implantation and receiving clopidogrel and aspirin were consecutively recruited. Their platelet reactivity was determined by light transmission aggregometry at 5 and 30 days after coronary intervention. Genotyping was performed using an improved multiplex ligation detection reaction technique. All patients completed a 30-day follow-up for clinical outcomes. Genotyping for PEAR1 showed 768 (38.3%) GG homozygotes, 941 (46.9%) GA heterozygotes, and 298 (14.8%) AA homozygotes. The 30-day incidence of major adverse cardiovascular events, the composite of cardiovascular death, nonfatal myocardial infarction, and ischemic stroke were significantly higher in AA homozygotes than in non-AA homozygotes (adjusted hazard ratio, 2.78; 95% CI, 1.13-6.82; P=0.026), irrespective of CYP2C19*2 loss-of-function polymorphism and known outcome predictors including age, sex, smoking, and diabetes mellitus. The ADP-induced platelet aggregation was significantly lower in AA homozygotes than that in GG homozygotes at both time points, although no significant difference was found for the arachidonic acid-induced platelet aggregation among the 3 groups. CONCLUSIONS: About 15% of Chinese patients undergoing coronary stent implantation were AA homozygotes for PEAR1 rs12041331. These patients had ≈3-fold increase in short-term major adverse cardiovascular events risk compared with non-AA homozygotes, and the adverse clinical outcome is unlikely to be mediated by suboptimal pharmacological response to aspirin or clopidogrel. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01968499.

12.
Blood ; 133(21): 2269-2278, 2019 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-30926593

RESUMO

Anticoagulant therapy is the most effective strategy to prevent arterial and venous thromboembolism, but treating older individuals is challenging, because increasing age, comorbidities, and polypharmacy increase the risk of both thrombosis and bleeding. Warfarin and non-vitamin K antagonist oral anticoagulants are underused and often underdosed in the prevention of stroke in older patients with atrial fibrillation because of concerns about the risk of bleeding. Poor adherence to anticoagulant therapy is also an issue for older patients with atrial fibrillation and those at risk of recurrent pulmonary embolism. In this review, we present 5 clinical cases to illustrate common challenges with anticoagulant use in older patients and discuss our approach to institute safe and effective antithrombotic therapy.


Assuntos
Anticoagulantes/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Tromboembolia Venosa/tratamento farmacológico , Varfarina/uso terapêutico , Administração Oral , Idoso , Anticoagulantes/efeitos adversos , Fibrilação Atrial/complicações , Fibrilação Atrial/patologia , Feminino , Humanos , Masculino , Fatores de Risco , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/prevenção & controle , Resultado do Tratamento , Tromboembolia Venosa/complicações , Tromboembolia Venosa/patologia , Varfarina/efeitos adversos
13.
Circ Res ; 124(3): 426-436, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30702990

RESUMO

Recent advances in our understanding of the contribution of thrombin generation to arterial thrombosis and the role of platelets in venous thrombosis have prompted new treatment paradigms. Nonetheless, bleeding remains the major side effect of such treatments spurring the quest for new antithrombotic regimens with better benefit-risk profiles and for safer anticoagulants for existing and new indications. The aims of this article are to review the results of recent trials aimed at enhancing the benefit-risk profile of antithrombotic therapy and explain how these findings are changing our approach to the management of arterial and venous thrombosis. Focusing on these 2 aspects of thrombosis management, this article discusses 4 advances: (1) the observation that in some indications, lowering the dose of some direct oral anticoagulants reduces the risk of bleeding without compromising efficacy, (2) the recognition that aspirin is not only effective for secondary prevention of atherothrombosis but also for prevention of venous thromboembolism, (3) the finding that dual pathway inhibition with the combination of low-dose rivaroxaban to attenuate thrombin generation plus aspirin to reduce thromboxane A2-mediated platelet activation is superior to aspirin or rivaroxaban alone for prevention of atherothrombosis in patients with coronary or peripheral artery disease, and (4) the development of inhibitors of factor XI or XII as potentially safer anticoagulants.


Assuntos
Aspirina/uso terapêutico , Inibidores do Fator Xa/administração & dosagem , Inibidores da Agregação de Plaquetas/uso terapêutico , Rivaroxabana/administração & dosagem , Trombose/tratamento farmacológico , Administração Oral , Anticoagulantes/administração & dosagem , Anticoagulantes/efeitos adversos , Antitrombinas/administração & dosagem , Antitrombinas/efeitos adversos , Fibrilação Atrial/complicações , Ensaios Clínicos como Assunto , Doença das Coronárias/complicações , Quimioterapia Combinada , Fator XI/antagonistas & inibidores , Fator XII/antagonistas & inibidores , Hemorragia/induzido quimicamente , Hemorragia/prevenção & controle , Humanos , Doença Arterial Periférica/complicações , Placa Aterosclerótica/complicações , Agregação Plaquetária , Prevenção Primária , Medição de Risco , Prevenção Secundária , Trombina/metabolismo , Trombose/etiologia , Trombose/prevenção & controle , Trombose Venosa/prevenção & controle
14.
Future Cardiol ; 15(2): 63-77, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30779598

RESUMO

Until recently, heparins and vitamin K antagonists (VKAs) were the cornerstones for prevention and treatment of venous thromboembolism (VTE). This situation changed with the introduction of the direct oral anticoagulants, which are now replacing low-molecular-weight heparin for thromboprophylaxis after elective hip or knee arthroplasty and VKAs for VTE treatment. Rivaroxaban, an oral factor Xa inhibitor, was the first direct oral anticoagulant licensed for VTE prevention and treatment. This paper provides the rationale for factor Xa as a target for anticoagulants, describes the development of rivaroxaban, reviews its pharmacological profile, discusses the clinical trials with rivaroxaban for VTE prevention and treatment and highlights areas of uncertainty.


Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Rivaroxabana/administração & dosagem , Tromboembolia Venosa/tratamento farmacológico , Administração Oral , Inibidores do Fator Xa/administração & dosagem , Humanos , Tromboembolia Venosa/sangue , Tromboembolia Venosa/prevenção & controle
15.
Thromb Haemost ; 119(5): 689-694, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30808045

RESUMO

Many patients with venous thromboembolism (VTE) are at risk of recurrence if anticoagulant therapy is stopped. Whereas 3 months of anticoagulation treatment is sufficient for patients with VTE provoked by major surgery or trauma, in many cases a longer course is needed. Extended therapy with vitamin K antagonists (VKAs) requires frequent coagulation monitoring and dose adjustments to ensure that the international normalized ratio (INR) remains within the therapeutic range; furthermore, there is a risk of major bleeding even if a therapeutic INR is maintained. Therefore, more convenient and safer anticoagulants are needed.The non-VKA oral anticoagulants (NOACs)-apixaban, dabigatran, edoxaban and rivaroxaban-simplify extended therapy because they can be given in fixed doses without routine coagulation monitoring. Randomized clinical trials have demonstrated the efficacy and safety of NOACs for extended VTE treatment, but bleeding remains a concern. Patients and physicians may, therefore, be reluctant to continue anticoagulation beyond 3 to 6 months except in patients at high risk of recurrence. Acetylsalicylic acid (ASA) is often prescribed instead of an anticoagulant because of its perceived lower risk of bleeding; however, the recent EINSTEIN CHOICE trial demonstrated that once-daily rivaroxaban at a dose of either 20 or 10 mg reduced the risk of recurrent VTE by 70% compared with ASA without significantly increasing the risk of bleeding. In this review, we discuss the EINSTEIN CHOICE trial in the context of previous trials for extended VTE treatment and examine some of the lessons that can be applied to clinical practice.


Assuntos
Anticoagulantes/uso terapêutico , Aspirina/uso terapêutico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Hemorragia/epidemiologia , Rivaroxabana/uso terapêutico , Tromboembolia Venosa/tratamento farmacológico , Canadá/epidemiologia , Ensaios Clínicos como Assunto , Hemorragia/etiologia , Humanos , Recidiva , Risco , Resultado do Tratamento , Tromboembolia Venosa/epidemiologia
16.
Thromb Haemost ; 119(4): 668-674, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30699447

RESUMO

BACKGROUND: Systematic reviews reporting time trends in mortality following major orthopaedic surgery are few and have limitations. They reported on only a fraction (< 15%) of the available data and did not investigate potential causes of the reduction in mortality. METHODS: We searched PubMed for randomized trials and observational studies, published between 1950 and 2016, reporting on mortality within 3 months of elective total hip and knee replacement (THR/TKR). Mortality risks were estimated for each 5-year interval using a Poisson regression model and presented by study design and mode of prophylaxis. To estimate the mortality reduction unrelated to anti-thrombotic use, we performed a pooled analysis of four thromboprophylaxis strategies for which data spanned five decades. RESULTS: We identified 255 eligible studies, which documented 31,604 deaths among 6,293,954 patients, and found a consistent decline in mortality irrespective of study design and mode of prophylaxis. Mortality declined from 1.15% pre-1980 to 0.24% post-2000, a 78.7% relative risk reduction (95% confidence interval [CI]: 74.7-82.1%) in randomized and cohort studies. Furthermore, our data showed a 74.4% (95% CI: 68.7-79.0%) relative reduction in mortality independent of the methods of prophylaxis, thereby indicating that improvements in peri-operative care unrelated to anti-thrombotic prophylaxis played a major role in such reduction. CONCLUSION: Mortality following elective THR/TKR has markedly declined over the past 50 years and is now low irrespective of which prophylactic agent is being used. Although anti-thrombotic prophylaxis may have contributed, other improvements in peri-operative care played a major role in the mortality reduction.


Assuntos
Artroplastia de Quadril/mortalidade , Artroplastia do Joelho/mortalidade , Procedimentos Cirúrgicos Eletivos/mortalidade , Procedimentos Ortopédicos/mortalidade , Anticoagulantes/uso terapêutico , Humanos , Estudos Observacionais como Assunto , Período Perioperatório , Distribuição de Poisson , Período Pós-Operatório , Embolia Pulmonar/mortalidade , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa , Tromboembolia Venosa/mortalidade
17.
Thromb Haemost ; 119(1): 14-38, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30597497

RESUMO

Non-vitamin K antagonist oral anticoagulants (NOACs) include dabigatran, which inhibits thrombin, and apixaban, betrixaban, edoxaban and rivaroxaban, which inhibit factor Xa. In large clinical trials comparing the NOACs with the vitamin K antagonist (VKA) warfarin, dabigatran, apixaban, rivaroxaban and edoxaban were at least as effective for stroke prevention in atrial fibrillation and for treatment of venous thromboembolism, but were associated with less intracranial bleeding. In addition, the NOACs are more convenient to administer than VKAs because they can be given in fixed doses without routine coagulation monitoring. Consequently, the NOACs are now replacing VKAs for these indications, and their use is increasing. Although, as a class, the NOACs have a favourable benefit-risk profile compared with VKAs, choosing among them is complicated because they have not been compared in head-to-head trials. Therefore, selection depends on the results of the individual trials, renal function, the potential for drug-drug interactions and preference for once- or twice-daily dosing. In addition, several 'special situations' were not adequately studied in the dedicated clinical trials. For these situations, knowledge of the unique pharmacological features of the various NOACs and judicious cross-trial comparison can help inform prescription choices. The purpose of this position article is therefore to help clinicians choose the right anticoagulant for the right patient at the right dose by reviewing a variety of special situations not widely studied in clinical trials.


Assuntos
Anticoagulantes/uso terapêutico , Cardiopatias/complicações , Trombina/antagonistas & inibidores , Vitamina K/antagonistas & inibidores , Administração Oral , Anticorpos Monoclonais Humanizados/uso terapêutico , Arginina/análogos & derivados , Arginina/uso terapêutico , Fibrilação Atrial/prevenção & controle , Benzamidas/uso terapêutico , Biomarcadores/metabolismo , Coagulação Sanguínea , Ensaios Clínicos como Assunto , Dabigatrana/uso terapêutico , Esquema de Medicação , Fator Xa/uso terapêutico , Cardiopatias/tratamento farmacológico , Humanos , Piperazinas/uso terapêutico , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Piridonas/uso terapêutico , Proteínas Recombinantes/uso terapêutico , Risco , Rivaroxabana/uso terapêutico , Acidente Vascular Cerebral/prevenção & controle , Tiazóis/uso terapêutico , Tromboembolia Venosa/tratamento farmacológico , Varfarina/uso terapêutico
18.
Arterioscler Thromb Vasc Biol ; 39(1): 7-12, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30580558

RESUMO

Thrombosis remains a major cause of morbidity and mortality. Consequently, advances in antithrombotic therapy are needed to reduce the disease burden. This article focuses on 2 such advances. First, the prevention of atherothrombosis in patients with coronary or peripheral artery disease, which has been enhanced by the finding that the combination of low-dose rivaroxaban plus aspirin is superior to aspirin alone for prevention of recurrent ischemic events. However, this benefit comes at the cost of increased bleeding albeit not fatal bleeding. To overcome this problem, the second advance is the identification of factor XI as a target for new anticoagulants that are potentially safer than those currently available.


Assuntos
Fator XI/antagonistas & inibidores , Fibrinolíticos/uso terapêutico , Trombose/prevenção & controle , Aspirina/administração & dosagem , Aspirina/uso terapêutico , Ensaios Clínicos como Assunto , Fator XI/fisiologia , Fator XII/fisiologia , Humanos , Rivaroxabana/administração & dosagem , Rivaroxabana/uso terapêutico , Trombose/etiologia
19.
Semin Thromb Hemost ; 45(2): 187-195, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30566971

RESUMO

The highest risk of adverse events for patients with acute venous thromboembolism (VTE) is during the early anticoagulation period. However, no established model exists for early clinical monitoring of patients treated with non-vitamin K antagonist oral anticoagulants (NOACs). The authors' aim was to evaluate the utility of a nurse-led pathway to minimize adverse events in acute VTE patients starting on rivaroxaban. The rivaroxaban VTE treatment pathway is a prospective cohort study of consecutive patients with objectively confirmed VTE between July 2015 and May 2017. Primary outcome was the proportion of patients identified at major risk of adverse events (bleeding or recurrent VTE). Secondary outcomes were rates of interventions, major or clinically relevant nonmajor bleeding (CRNMB), recurrent VTE, and all-cause mortality at 90 days. Among 304 participants, 5% (n = 15) were identified to be at major and 9% (n = 28) at possible risk for adverse events. Appropriate interventions to prevent harm were required in 40 patients. Rates of major bleeding, CRNMB, recurrence, and all-cause mortality were 0.3% (95% confidence interval [CI]: 0.1-1.8), 7.2% (95% CI: 4.8-10.7), 1.0 (95% CI: 0.3-2.9), and 1.6% (95% CI: 0.7-3.8), respectively. In conclusion, following discharge of acute VTE patients, a nurse-led pathway identified one in seven (14%) patients at major or possible risk of adverse events. Preemptive interventions to reduce harm translated into the low rates of bleeding and recurrence. The authors' experience highlights the feasibility and importance of a structured clinical surveillance pathway for acute VTE patients initiating NOAC therapy.


Assuntos
Procedimentos Clínicos , Relações Enfermeiro-Paciente , Rivaroxabana/uso terapêutico , Tromboembolia Venosa/prevenção & controle , Doença Aguda , Adulto , Idoso , Inibidores do Fator Xa/efeitos adversos , Inibidores do Fator Xa/uso terapêutico , Feminino , Hemorragia/induzido quimicamente , Hemorragia/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Monitorização Fisiológica/métodos , /estatística & dados numéricos , Estudos Prospectivos , Recidiva , Fatores de Risco , Rivaroxabana/efeitos adversos
20.
Thromb Haemost ; 118(11): 1895-1901, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30332695

RESUMO

BACKGROUND: Ticagrelor is an anti-platelet agent that is indicated for prevention of thrombosis after acute coronary syndrome or intra-coronary artery stent implantation, but it increases the risk of bleeding. Platelet transfusion has the potential to treat or prevent bleeding in patients taking ticagrelor, but the optimal quantity of platelets and timing of administration have not been fully defined. METHODS AND RESULTS: Ten healthy subjects took ticagrelor in combination with acetylsalicylic acid for 5 days, and had blood collected prior to treatment and at 2, 10, 24, 48, 72 and 96 hours after the last doses. The potential of platelet transfusion to prevent or reverse bleeding was evaluated by mixing subject and donor platelet-rich plasma in vitro in nine different proportions, and measuring adenosine diphosphate-mediated aggregation by light transmission aggregometry. Spontaneous offset of the anti-aggregant effect of ticagrelor occurred gradually and was complete at 72 hours after the last dose. The addition of donor platelets enhanced the recovery. The addition of the equivalent of six apheresis platelet units produced a 50% relative reversal at 10 hours, and > 90% reversal at 24 hours. CONCLUSION: Donor platelets enhance reversal of the anti-aggregant effect of ticagrelor in vitro. Donor platelets given in clinically relevant amounts partially reversed ticagrelor at 10 hours after the last dose, and almost fully reversed ticagrelor at 24 hours. The results inform on the potential to reverse ticagrelor in patients who develop bleeding or require emergency surgery.


Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Plaquetas/efeitos dos fármacos , Hemorragia/tratamento farmacológico , Inibidores da Agregação de Plaquetas/uso terapêutico , Trombose/tratamento farmacológico , Ticagrelor/uso terapêutico , Síndrome Coronariana Aguda/cirurgia , Difosfato de Adenosina/metabolismo , Adulto , Plaquetas/fisiologia , Células Cultivadas , Feminino , Voluntários Saudáveis , Humanos , Masculino , Agregação Plaquetária/efeitos dos fármacos , Transfusão de Plaquetas , Plasma Rico em Plaquetas/metabolismo , Risco , Adulto Jovem
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