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1.
Blood ; 144(16): 1663-1678, 2024 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-38900973

RESUMO

ABSTRACT: A common feature in patients with abdominal aortic aneurysms (AAAs) is the formation of a nonocclusive intraluminal thrombus (ILT) in regions of aortic dilation. Platelets are known to maintain hemostasis and propagate thrombosis through several redundant activation mechanisms, yet the role of platelet activation in the pathogenesis of AAA-associated ILT is still poorly understood. Thus, we sought to investigate how platelet activation affects the pathogenesis of AAA. Using RNA sequencing, we identified that the platelet-associated transcripts are significantly enriched in the ILT compared with the adjacent aneurysm wall and healthy control aortas. We found that the platelet-specific receptor glycoprotein VI (GPVI) is among the top enriched genes in AAA ILT and is increased on the platelet surface of patients with AAAs. Examination of a specific indicator of platelet activity, soluble GPVI (sGPVI), in 2 independent cohorts of patients with AAAs is highly predictive of an AAA diagnosis and associates more strongly with aneurysm growth rate than D-dimer in humans. Finally, intervention with the anti-GPVI antibody (JAQ1) in mice with established aneurysms blunted the progression of AAA in 2 independent mouse models. In conclusion, we show that the levels of sGPVI in humans can predict a diagnosis of AAA and AAA growth rate, which may be critical in the identification of high-risk patients. We also identify GPVI as a novel platelet-specific AAA therapeutic target, with minimal risk of adverse bleeding complications, for which none currently exists.


Assuntos
Aneurisma da Aorta Abdominal , Glicoproteínas da Membrana de Plaquetas , Animais , Humanos , Camundongos , Aneurisma da Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/metabolismo , Plaquetas/metabolismo , Plaquetas/patologia , Modelos Animais de Doenças , Progressão da Doença , Ativação Plaquetária , Glicoproteínas da Membrana de Plaquetas/metabolismo , Glicoproteínas da Membrana de Plaquetas/genética , Trombose/metabolismo , Trombose/patologia , Trombose/etiologia
2.
Circ Res ; 132(6): 775-790, 2023 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-36927182

RESUMO

Platelets are small, anucleate entities that bud from megakaryocytes in the bone marrow. Among circulating cells, platelets are the most abundant cell, traditionally involved in regulating the balance between thrombosis (the terminal event of platelet activation) and hemostasis (a protective response to tissue injury). Although platelets lack the precise cellular control offered by nucleate cells, they are in fact very dynamic cells, enriched in preformed RNA that allows them the capability of de novo protein synthesis which alters the platelet phenotype and responses in physiological and pathological events. Antiplatelet medications have significantly reduced the morbidity and mortality for patients afflicted with thrombotic diseases, including stroke and myocardial infarction. However, it has become apparent in the last few years that platelets play a critical role beyond thrombosis and hemostasis. For example, platelet-derived proteins by constitutive and regulated exocytosis can be found in the plasma and may educate distant tissue including blood vessels. First, platelets are enriched in inflammatory and anti-inflammatory molecules that may regulate vascular remodeling. Second, platelet-derived microparticles released into the circulation can be acquired by vascular endothelial cells through the process of endocytosis. Third, platelets are highly enriched in mitochondria that may contribute to the local reactive oxygen species pool and remodel phospholipids in the plasma membrane of blood vessels. Lastly, platelets are enriched in proteins and phosphoproteins which can be secreted independent of stimulation by surface receptor agonists in conditions of disturbed blood flow. This so-called biomechanical platelet activation occurs in regions of pathologically narrowed (atherosclerotic) or dilated (aneurysmal) vessels. Emerging evidence suggests platelets may regulate the process of angiogenesis and blood flow to tumors as well as education of distant organs for the purposes of allograft health following transplantation. This review will illustrate the potential of platelets to remodel blood vessels in various diseases with a focus on the aforementioned mechanisms.


Assuntos
Plaquetas , Trombose , Humanos , Plaquetas/metabolismo , Micropartículas Derivadas de Células , Células Endoteliais/patologia , Hemostasia , Ativação Plaquetária
3.
Circ Res ; 132(10): 1358-1373, 2023 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-37167358

RESUMO

COVID-19 has become the first modern-day pandemic of historic proportion, affecting >600 million individuals worldwide and causing >6.5 million deaths. While acute infection has had devastating consequences, postacute sequelae of SARS-CoV-2 infection appears to be a pandemic of its own, impacting up to one-third of survivors and often causing symptoms suggestive of cardiovascular phenomena. This review will highlight the suspected pathophysiology of postacute sequelae of SARS-CoV-2, its influence on the cardiovascular system, and potential treatment strategies.


Assuntos
COVID-19 , Sistema Cardiovascular , Humanos , SARS-CoV-2 , Pandemias , Pulmão , Progressão da Doença
4.
Circulation ; 147(14): 1079-1096, 2023 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-37011073

RESUMO

BACKGROUND: Large-scale human and mechanistic mouse studies indicate a strong relationship between the microbiome-dependent metabolite trimethylamine N-oxide (TMAO) and several cardiometabolic diseases. This study aims to investigate the role of TMAO in the pathogenesis of abdominal aortic aneurysm (AAA) and target its parent microbes as a potential pharmacological intervention. METHODS: TMAO and choline metabolites were examined in plasma samples, with associated clinical data, from 2 independent patient cohorts (N=2129 total). Mice were fed a high-choline diet and underwent 2 murine AAA models, angiotensin II infusion in low-density lipoprotein receptor-deficient (Ldlr-/-) mice or topical porcine pancreatic elastase in C57BL/6J mice. Gut microbial production of TMAO was inhibited through broad-spectrum antibiotics, targeted inhibition of the gut microbial choline TMA lyase (CutC/D) with fluoromethylcholine, or the use of mice genetically deficient in flavin monooxygenase 3 (Fmo3-/-). Finally, RNA sequencing of in vitro human vascular smooth muscle cells and in vivo mouse aortas was used to investigate how TMAO affects AAA. RESULTS: Elevated TMAO was associated with increased AAA incidence and growth in both patient cohorts studied. Dietary choline supplementation augmented plasma TMAO and aortic diameter in both mouse models of AAA, which was suppressed with poorly absorbed oral broad-spectrum antibiotics. Treatment with fluoromethylcholine ablated TMAO production, attenuated choline-augmented aneurysm initiation, and halted progression of an established aneurysm model. In addition, Fmo3-/- mice had reduced plasma TMAO and aortic diameters and were protected from AAA rupture compared with wild-type mice. RNA sequencing and functional analyses revealed choline supplementation in mice or TMAO treatment of human vascular smooth muscle cells-augmented gene pathways associated with the endoplasmic reticulum stress response, specifically the endoplasmic reticulum stress kinase PERK. CONCLUSIONS: These results define a role for gut microbiota-generated TMAO in AAA formation through upregulation of endoplasmic reticulum stress-related pathways in the aortic wall. In addition, inhibition of microbiome-derived TMAO may serve as a novel therapeutic approach for AAA treatment where none currently exist.


Assuntos
Aneurisma da Aorta Abdominal , Microbioma Gastrointestinal , Humanos , Camundongos , Animais , Suínos , Camundongos Endogâmicos C57BL , Colina , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/genética , Aneurisma da Aorta Abdominal/prevenção & controle
5.
Vasc Med ; 29(1): 42-47, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38334096

RESUMO

BACKGROUND: Patients with lymphedema and lipedema share physical exam findings that may lead to misdiagnosis. Poor mobility is common in patients with obesity and patients with lymphedema and lipedema. This may constitute a risk factor for venous thromboembolism (VTE). Our objective was to evaluate the association of VTE in obese patients with lymphedema and lipedema. METHODS: The National Inpatient Sample (NIS) was searched from 2016 to 2020 to identify hospital admissions of obese female patients with lymphedema and lipedema. Patients were analyzed in the context of presence or absence of VTE while adjusting for complex cluster sampling techniques. Predictors of VTE were accessed by multivariable regression. RESULTS: Lymphedema was identified in 189,985 patients and lipedema in 50,645 patients. VTE was observed in 3.12% (n = 374,210) of patients with obesity. In patients with obesity, VTE was more common in patients with lymphedema than without (2.6% vs 1.6%; p < 0.01). Similarly, VTE was more common in patients with lipedema than without (0.6% vs 0.4%; p < 0.01). After multivariable logistic regression, VTE events in obese patients with lymphedema were higher versus without (OR 1.6; CI 1.08-2.43; p = 0.02). Similarly, VTE events were more common in obese patients with lipedema versus obese patients without lipedema (OR 1.20; CI 1.03-1.41; p = 0.02). CONCLUSIONS: In this hypothesis-generating study, lymphedema and lipedema show a positive association with VTE after adjusting for baseline patient characteristics such as obesity, which is a known independent risk factor for VTE. Mechanisms whereby lymphedema and lipedema are associated with VTE should be investigated.


Assuntos
Lipedema , Linfedema , Tromboembolia Venosa , Humanos , Feminino , Lipedema/diagnóstico , Lipedema/epidemiologia , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/epidemiologia , Pacientes Internados , Linfedema/diagnóstico , Linfedema/epidemiologia , Fatores de Risco , Obesidade/complicações , Obesidade/diagnóstico , Obesidade/epidemiologia
6.
Vasc Med ; 29(2): 125-134, 2024 04.
Artigo em Inglês | MEDLINE | ID: mdl-38334067

RESUMO

BACKGROUND: Postacute sequelae of COVID-19 (PASC), also referred to as "Long COVID", sometimes follows COVID-19, a disease caused by SARS-CoV-2. Although SARS-CoV-2 is well known to promote a prothrombotic state, less is known about the thrombosis risk in PASC. Our objective was to evaluate platelet function and thrombotic potential in patients following recovery from SARS-CoV-2, but with clear symptoms of patients with PASC. METHODS: patients with PASC and matched healthy controls were enrolled in the study on average 15 months after documented SARS-CoV-2 infection. Platelet activation was evaluated by light transmission aggregometry (LTA) and flow cytometry in response to platelet surface receptor agonists. Thrombosis in platelet-deplete plasma was evaluated by Factor Xa activity. A microfluidics system assessed thrombosis in whole blood under shear stress conditions. RESULTS: A mild increase in platelet aggregation in patients with PASC through the thromboxane receptor was observed, and platelet activation through the glycoprotein VI (GPVI) receptor was decreased in patients with PASC compared to age- and sex-matched healthy controls. Thrombosis under shear conditions as well as Factor Xa activity were reduced in patients with PASC. Plasma from patients with PASC was an extremely potent activator of washed, healthy platelets - a phenomenon not observed when stimulating healthy platelets after incubation with plasma from healthy individuals. CONCLUSIONS: patients with PASC show dysregulated responses in platelets and coagulation in plasma, likely caused by a circulating molecule that promotes thrombosis. A hitherto undescribed protective response appears to exist in patients with PASC to counterbalance ongoing thrombosis that is common to SARS-CoV-2 infection.


Assuntos
COVID-19 , Trombose , Humanos , COVID-19/complicações , SARS-CoV-2 , Fator Xa , Coagulação Sanguínea , Progressão da Doença , Trombose/etiologia
7.
Pharmacol Rev ; 73(3): 924-967, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34088867

RESUMO

The endothelium, a cellular monolayer lining the blood vessel wall, plays a critical role in maintaining multiorgan health and homeostasis. Endothelial functions in health include dynamic maintenance of vascular tone, angiogenesis, hemostasis, and the provision of an antioxidant, anti-inflammatory, and antithrombotic interface. Dysfunction of the vascular endothelium presents with impaired endothelium-dependent vasodilation, heightened oxidative stress, chronic inflammation, leukocyte adhesion and hyperpermeability, and endothelial cell senescence. Recent studies have implicated altered endothelial cell metabolism and endothelial-to-mesenchymal transition as new features of endothelial dysfunction. Endothelial dysfunction is regarded as a hallmark of many diverse human panvascular diseases, including atherosclerosis, hypertension, and diabetes. Endothelial dysfunction has also been implicated in severe coronavirus disease 2019. Many clinically used pharmacotherapies, ranging from traditional lipid-lowering drugs, antihypertensive drugs, and antidiabetic drugs to proprotein convertase subtilisin/kexin type 9 inhibitors and interleukin 1ß monoclonal antibodies, counter endothelial dysfunction as part of their clinical benefits. The regulation of endothelial dysfunction by noncoding RNAs has provided novel insights into these newly described regulators of endothelial dysfunction, thus yielding potential new therapeutic approaches. Altogether, a better understanding of the versatile (dys)functions of endothelial cells will not only deepen our comprehension of human diseases but also accelerate effective therapeutic drug discovery. In this review, we provide a timely overview of the multiple layers of endothelial function, describe the consequences and mechanisms of endothelial dysfunction, and identify pathways to effective targeted therapies. SIGNIFICANCE STATEMENT: The endothelium was initially considered to be a semipermeable biomechanical barrier and gatekeeper of vascular health. In recent decades, a deepened understanding of the biological functions of the endothelium has led to its recognition as a ubiquitous tissue regulating vascular tone, cell behavior, innate immunity, cell-cell interactions, and cell metabolism in the vessel wall. Endothelial dysfunction is the hallmark of cardiovascular, metabolic, and emerging infectious diseases. Pharmacotherapies targeting endothelial dysfunction have potential for treatment of cardiovascular and many other diseases.


Assuntos
Aterosclerose , Tratamento Farmacológico da COVID-19 , COVID-19 , Fármacos Cardiovasculares , Doenças Cardiovasculares , Endotélio Vascular , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Aterosclerose/fisiopatologia , COVID-19/metabolismo , COVID-19/fisiopatologia , Fármacos Cardiovasculares/classificação , Fármacos Cardiovasculares/farmacologia , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Descoberta de Drogas , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Humanos , Terapia de Alvo Molecular/métodos , Terapia de Alvo Molecular/tendências , SARS-CoV-2
8.
J Biol Chem ; 298(4): 101832, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35304099

RESUMO

Protein lysine carbamylation is an irreversible post-translational modification resulting in generation of homocitrulline (N-ε-carbamyllysine), which no longer possesses a charged ε-amino moiety. Two distinct pathways can promote protein carbamylation. One results from urea decomposition, forming an equilibrium mixture of cyanate (CNO-) and the reactive electrophile isocyanate. The second pathway involves myeloperoxidase (MPO)-catalyzed oxidation of thiocyanate (SCN-), yielding CNO- and isocyanate. Apolipoprotein A-I (apoA-I), the major protein constituent of high-density lipoprotein (HDL), is a known target for MPO-catalyzed modification in vivo, converting the cardioprotective lipoprotein into a proatherogenic and proapoptotic one. We hypothesized that monitoring site-specific carbamylation patterns of apoA-I recovered from human atherosclerotic aorta could provide insights into the chemical environment within the artery wall. To test this, we first mapped carbamyllysine obtained from in vitro carbamylation of apoA-I by both the urea-driven (nonenzymatic) and inflammatory-driven (enzymatic) pathways in lipid-poor and lipidated apoA-I (reconstituted HDL). Our results suggest that lysine residues within proximity of the known MPO-binding sites on HDL are preferentially targeted by the enzymatic (MPO) carbamylation pathway, whereas the nonenzymatic pathway leads to nearly uniform distribution of carbamylated lysine residues along the apoA-I polypeptide chain. Quantitative proteomic analyses of apoA-I from human aortic atheroma identified 16 of the 21 lysine residues as carbamylated and suggested that the majority of apoA-I carbamylation in vivo occurs on "lipid-poor" apoA-I forms via the nonenzymatic CNO- pathway. Monitoring patterns of apoA-I carbamylation recovered from arterial tissues can provide insights into both apoA-I structure and the chemical environment within human atheroma.


Assuntos
Aorta , Apolipoproteína A-I , Aterosclerose , Lisina , Carbamilação de Proteínas , Aorta/metabolismo , Aorta/patologia , Apolipoproteína A-I/metabolismo , Aterosclerose/metabolismo , Aterosclerose/patologia , Humanos , Isocianatos , Lipoproteínas HDL/metabolismo , Lisina/metabolismo , Placa Aterosclerótica/patologia , Proteômica , Ureia
9.
Circ Res ; 128(8): 1214-1236, 2021 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-33856918

RESUMO

A pandemic of historic impact, coronavirus disease 2019 (COVID-19) has potential consequences on the cardiovascular health of millions of people who survive infection worldwide. Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), the etiologic agent of COVID-19, can infect the heart, vascular tissues, and circulating cells through ACE2 (angiotensin-converting enzyme 2), the host cell receptor for the viral spike protein. Acute cardiac injury is a common extrapulmonary manifestation of COVID-19 with potential chronic consequences. This update provides a review of the clinical manifestations of cardiovascular involvement, potential direct SARS-CoV-2 and indirect immune response mechanisms impacting the cardiovascular system, and implications for the management of patients after recovery from acute COVID-19 infection.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/virologia , Doenças Cardiovasculares/virologia , Miócitos Cardíacos/virologia , SARS-CoV-2/fisiologia , Internalização do Vírus , Biomarcadores/metabolismo , COVID-19/complicações , COVID-19/epidemiologia , COVID-19/terapia , Cardiomiopatias/virologia , Expressão Gênica , Humanos , Sistema Imunitário/fisiologia , Miocárdio/enzimologia , Miócitos Cardíacos/enzimologia , Neuropilina-1/metabolismo , Ativação Plaquetária , RNA Mensageiro/metabolismo , Sistema Renina-Angiotensina/fisiologia , Volta ao Esporte , Fatores de Risco , SARS-CoV-2/ultraestrutura , Glicoproteína da Espícula de Coronavírus/metabolismo , Troponina/metabolismo , Remodelação Ventricular , Ligação Viral , Internalização do Vírus/efeitos dos fármacos
11.
J Thromb Thrombolysis ; 55(3): 499-505, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36662443

RESUMO

High-risk pulmonary embolism (PE) patients can be managed with systemic lysis, catheter-based therapies, or surgical embolectomy. Despite the advent of newer therapies, patients with high-risk PE remain with a 50-60% short-term mortality risk. In such patients, extracorporeal membrane oxygenation (ECMO) is increasingly utilized for hemodynamic support. To evaluate the outcomes of the use of ECMO in patients with high-risk PE. Using the National Inpatient Sample (NIS) database, we identified patients with high-risk PE using ICD 10 codes and compared in-hospital outcomes of patients with and without ECMO support. We identified 38,035 patients with high-risk PE, of whom 820 had undergone ECMO placement. Most patients who underwent ECMO were male (54%), white (65%), and with a mean age of 53.7 years. ECMO use was not associated with a meaningful difference in patient mortality when comparing treatment groups (OR, 1.32 ± 0.39; 0.74-2.35; p = 0.35). Rather, ECMO use was associated with a higher frequency of inpatient complications. ECMO use was not associated with a significant difference in patient mortality in patients with high-risk PE.


Assuntos
Oxigenação por Membrana Extracorpórea , Embolia Pulmonar , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Oxigenação por Membrana Extracorpórea/efeitos adversos , Embolectomia , Terapia Trombolítica , Bases de Dados Factuais , Estudos Retrospectivos
12.
J Thromb Thrombolysis ; 55(3): 426-431, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36653575

RESUMO

Vaccination against COVID-19 reduces infection-related mortality. Unfortunately, reports of vaccine-induced immune thrombotic thrombocytopenia (VITT) in individuals administered adenovirus-vector-based vaccines (ChAdOx1 nCoV-19 and Ad26.COV2.S) have spurred side effect concerns. To address vaccine hesitancy related to this, it is essential to determine the incidence of VITT (defined by a 50% decrease in platelet count and positive anti-PF4 immunoassay within 4-28 days after vaccination) among patients administered two doses of an mRNA-based COVID-19 vaccination. We identified a retrospective cohort of 223,345 patients in the Cleveland Clinic Enterprise administered a COVID-19 vaccine at any location in Northeast Ohio and Florida from 12/4/2020 to 6/6/2021. 97.3% of these patients received an mRNA-based vaccination. Patients with: (1) a serial complete blood count both before and after vaccination and (2) a decrease in platelet count of ≥ 50% were selected for chart review. The primary outcome was the incidence of thrombotic events, including venous thromboembolism (VTE) and arterial thrombosis, 4-28 days post vaccination. Of 74 cohort patients with acute thrombosis, 72 (97.3%) demonstrated clear etiologies, such as active malignancy. Of two patients with unprovoked thrombosis, only one had findings concerning for VITT, with a strongly positive anti-PF4 antibody assay. In this large, multi-state, retrospective cohort, of 223,345 patients (97.2% of whom received the mRNA-based mRNA-1273 or BNT162b2 vaccines), we detected a single case that was concerning for VITT in a patient who received an mRNA vaccine. The overwhelming majority of patients with a thrombotic event 4-28 days following vaccination demonstrated clear etiologies.


Assuntos
COVID-19 , Púrpura Trombocitopênica Idiopática , Trombocitopenia , Humanos , Vacinas contra COVID-19/efeitos adversos , Ad26COVS1 , Vacina BNT162 , ChAdOx1 nCoV-19 , Estudos Retrospectivos , COVID-19/prevenção & controle , Vacinação/efeitos adversos , Trombocitopenia/induzido quimicamente
13.
Arterioscler Thromb Vasc Biol ; 41(1): 390-400, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33176447

RESUMO

OBJECTIVE: The platelet phenotype in certain patients and clinical contexts may differ from healthy conditions. We evaluated platelet activation through specific receptors in healthy men and women, comparing this to patients presenting with ST-segment-elevation myocardial infarction and non-ST-segment-elevation myocardial infarction. Approach and Results: We identified independent predictors of platelet activation through certain receptors and a murine MI model further explored these findings. Platelets from healthy women and female mice are more reactive through PARs (protease-activated receptors) compared with platelets from men and male mice. Multivariate regression analyses revealed male sex and non-ST-segment-elevation myocardial infarction as independent predictors of enhanced PAR1 activation in human platelets. Platelet PAR1 signaling decreased in women and increased in men during MI which was the opposite of what was observed during healthy conditions. Similarly, in mice, thrombin-mediated platelet activation was greater in healthy females compared with males, and lesser in females compared with males at the time of MI. CONCLUSIONS: Sex-specific signaling in platelets seems to be a cross-species phenomenon. The divergent platelet phenotype in males and females at the time of MI suggests a sex-specific antiplatelet drug regimen should be prospectively evaluated.


Assuntos
Plaquetas/metabolismo , Infarto do Miocárdio sem Supradesnível do Segmento ST/sangue , Ativação Plaquetária , Receptor PAR-1/sangue , Infarto do Miocárdio com Supradesnível do Segmento ST/sangue , Idoso , Animais , Plaquetas/efeitos dos fármacos , Estudos de Casos e Controles , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Fenótipo , Ativação Plaquetária/efeitos dos fármacos , Fatores Sexuais , Transdução de Sinais , Trombina/farmacologia
14.
J Thromb Thrombolysis ; 53(3): 616-625, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34586572

RESUMO

The decision by pulmonary embolism response teams (PERTs) to utilize anticoagulation (AC) with or without systemic thrombolysis (ST) or catheter-directed therapies (CDT) for pulmonary embolism (PE) is a balance between the desire for a positive outcome and safety. Our primary aim was to develop a predictive model of in-hospital mortality for patients with high- or intermediate-risk PE managed by PERT while externally validating this model. Our secondary aim was to compare the relative safety and efficacy of ST and CDT in this cohort. Consecutive patients hospitalized between June 2014 and January 2020 at the Cleveland Clinic Foundation and The University of Rochester with acute high- or intermediate-risk PE managed by PERT were retrospectively evaluated. Groups were stratified by treatment strategy. The primary outcome was in-hospital mortality, and secondary outcome was major bleeding. A logistic regression model to predict the primary outcome was built using the derivation cohort, with 100-fold bootstrapping for internal validation. External validation was performed and the area under the receiver operating curve (AUC) was calculated. Of 549 included patients, 421 received AC alone, 71 received ST, and 64 received CDT. Predictors of major bleeding include ESC risk category, PESI score, hypoxia, hemodynamic instability, and serum lactate. CDT trended towards lower mortality but with an increased risk of bleeding relative to ST (OR = 0.42; 95% CI [0.15, 1.17] and OR = 2.14; 95% CI [0.9, 5.06] respectively). In the multivariable logistic regression model in the derivation institution cohort, predictors of in-hospital mortality were age, cancer, hemodynamic instability requiring vasopressors, and elevated NT-proBNP (AUC = 0.86). This model was validated using the validation institution cohort (AUC = 0.88). We report an externally-validated model for predicting in-hospital mortality in patients with PE managed by PERT. The decision by PERT to initiate CDT or ST for these patients had no impact on mortality or major bleeding, yet the long-term efficacy of these interventions needs to be elucidated.


Assuntos
Embolia Pulmonar , Terapia Trombolítica , Catéteres/efeitos adversos , Fibrinolíticos/uso terapêutico , Hemorragia/induzido quimicamente , Humanos , Prognóstico , Embolia Pulmonar/tratamento farmacológico , Embolia Pulmonar/terapia , Estudos Retrospectivos , Terapia Trombolítica/efeitos adversos , Resultado do Tratamento
15.
J Card Surg ; 37(1): 214-222, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34779523

RESUMO

BACKGROUND: Emergency surgery, blood transfusion, and reoperation for bleeding have been associated with increased operative morbidity and mortality. The recent increased use of direct oral anticoagulants and antiplatelet medications has made the above more challenging. In addition, cardiopulmonary bypass (CPB), with its associated hemodilution, fibrinolysis, and platelet consumption, may exacerbate the pre-existing coagulopathy and increase the risk of bleeding. AIM: The aim of this study was to examine available literature with regard to treating patients who are on the above medications and require emergency cardiac surgery. RESULTS: Management decisions are typically made on a case-by-case basis. Surgery is delayed when possible, and less invasive percutaneous options should be considered if feasible. Attention is paid to exercising meticulous techniques, avoiding excessive hypothermia, and treating coexisting issues such as sepsis. Ensuring a dry operative field upon entry by correcting the coagulopathy with reversal agents is offset by the concern of potentially hindering efforts to anticoagulate the patient (heparin resistance) in preparation for CPB, in addition to possibly increasing the risk of thromboembolism. CONCLUSION: Proper knowledge of anticoagulants, their reversal agents, and the usefulness of laboratory testing are all essential. Platelet transfusion remains the mainstay for antiplatelet medications. Four-factor prothrombin complex concentrate is considered in patients on oral anticoagulants if CPB needs to be instituted quickly. Specific reversal agents such as idarucizumab and andexanet alfa can be considered if significant tissue dissection is anticipated, such as redo sternotomy, but are costly and may lead to heparin resistance and anticoagulant rebound.


Assuntos
Transtornos da Coagulação Sanguínea , Procedimentos Cirúrgicos Cardíacos , Administração Oral , Anticoagulantes/uso terapêutico , Hemorragia/tratamento farmacológico , Humanos , Inibidores da Agregação Plaquetária/uso terapêutico
16.
Vasc Med ; 26(6): 626-632, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34010070

RESUMO

Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 is an ongoing viral pandemic marked by increased risk of thrombotic events. However, the role of platelets in the elevated observed thrombotic risk in COVID-19 and utility of antiplatelet agents in attenuating thrombosis is unknown. We aimed to determine if the antiplatelet effect of aspirin may mitigate risk of myocardial infarction, cerebrovascular accident, and venous thromboembolism in COVID-19. We evaluated 22,072 symptomatic patients tested for COVID-19. Propensity-matched analyses were performed to determine if treatment with aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) affected thrombotic outcomes in COVID-19. Neither aspirin nor NSAIDs affected mortality in COVID-19. Thus, aspirin does not appear to prevent thrombosis and death in COVID-19. The mechanisms of thrombosis in COVID-19, therefore, appear distinct and the role of platelets as direct mediators of SARS-CoV-2-mediated thrombosis warrants further investigation.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Aspirina/administração & dosagem , COVID-19/complicações , Pacientes Internados , Trombose/prevenção & controle , Adulto , Idoso , Anti-Inflamatórios não Esteroides/efeitos adversos , Aspirina/efeitos adversos , Feminino , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , SARS-CoV-2 , Trombose/virologia
17.
Platelets ; 32(1): 138-140, 2021 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-32141372

RESUMO

Venous thromboembolism (VTE) whether provoked or not can be life-threatening due to an acute increase in load on the right ventricle (RV) from obstruction of the pulmonary artery (PA). Treatment for and prevention of VTE involves anti-thrombotic agents; more specifically, medications targeting the anticoagulation cascade. In spite of the widespread acceptance of anticoagulants in the treatment of VTE, there appears to be an ongoing belief that platelet reactivity contributes to thrombus burden in patients with acute pulmonary embolism (PE). This investigation of 398 patients presenting with acute PE evaluated whether anti-platelet medication use, which consisted mostly of aspirin therapy, at the time of presentation, affects PA thrombus burden, RV load, or short-term patient outcomes. We conclude that platelets may have been erroneously incriminated as direct thrombotic mediators in patients with acute PE since aspirin neither decreased PA thrombus burden, nor did aspirin improve short-term mortality following acute PE.


Assuntos
Inibidores da Agregação Plaquetária/uso terapêutico , Embolia Pulmonar/complicações , Embolia Pulmonar/tratamento farmacológico , Tromboembolia Venosa/tratamento farmacológico , Doença Aguda , Humanos , Embolia Pulmonar/patologia , Estudos Retrospectivos , Fatores de Risco
18.
Blood ; 132(25): 2619-2628, 2018 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-30228233

RESUMO

Abdominal aortic aneurysm (AAA) is a degenerative vascular pathology resulting in significant morbidity and mortality in older adults due to rupture and sudden death. Despite 150 000 new cases and nearly 15 000 deaths annually, the only approved treatment of AAA is surgical or endovascular intervention when the risk for aortic rupture is increased. The goal of the scientific community is to develop novel pharmaceutical treatment strategies to reduce the need for surgical intervention. Because most clinically relevant AAAs contain a complex structure of fibrin, inflammatory cells, platelets, and red blood cells in the aneurysmal sac known as an intraluminal thrombus (ILT), antithrombotic therapies have emerged as potential pharmaceutical agents for the treatment of AAA progression. However, the efficacy of these treatments has not been shown, and the effects of shrinking the ILT may be as detrimental as they are beneficial. This review discusses the prospect of anticoagulant and antiplatelet (termed collectively as antithrombotic) therapies in AAA. Herein, we discuss the role of the coagulation cascade and platelet activation in human and animal models of AAA, the composition of ILT in AAA, a possible role of the ILT in aneurysm stabilization, and the implications of antithrombotic drugs in AAA treatment.


Assuntos
Aneurisma da Aorta Abdominal/tratamento farmacológico , Ruptura Aórtica/prevenção & controle , Fibrinolíticos/uso terapêutico , Inibidores da Agregação Plaquetária/urina , Animais , Aneurisma da Aorta Abdominal/sangue , Aneurisma da Aorta Abdominal/patologia , Ruptura Aórtica/sangue , Ruptura Aórtica/patologia , Coagulação Sanguínea/efeitos dos fármacos , Fibrinolíticos/efeitos adversos , Humanos , Inibidores da Agregação Plaquetária/efeitos adversos , Trombose/sangue , Trombose/tratamento farmacológico , Trombose/patologia
19.
Thromb J ; 18: 16, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32905282

RESUMO

BACKGROUND: Patients infected with SARS-CoV-2 often develop venous and arterial thrombosis. The high patient mortality is partly attributed to thrombotic events. An emerging trend is the presence of immunological phenomena including antiphospholipid antibodies which may promote thrombosis. The mechanism for these observations is not clear though many patients with SARS-CoV-2 develop thrombocytopenia. CASE PRESENTATION: We describe a patient with SARS-CoV-2 pneumonitis who presented with intermediate risk pulmonary embolism (PE). Careful attention to his daily platelet count suggested the possibility of immune mediated heparin-induced thrombocytopenia (HIT) which was confirmed by laboratory testing and resolved when anticoagulation was switched to a direct thrombin inhibitor. CONCLUSIONS: Since excessive platelet activation and in situ thrombosis occur in HIT, this case underscores the need to consider that thrombocytopenia in patients with SARS-CoV-2-most of whom receive heparinoids-may be unrecognized HIT. A central role for the platelet in the etiology of thrombosis during the COVID-19 pandemic should be explored.

20.
J Thromb Thrombolysis ; 49(1): 34-41, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31375993

RESUMO

Several risk stratification tools are available to predict short-term mortality in patients with acute pulmonary embolism (PE). The presence of right ventricular (RV) dysfunction is an independent predictor of mortality and may be a more efficient way to stratify risk for patients assessed by a Pulmonary Embolism Response Team (PERT). We evaluated 571 patients presenting with acute PE, then stratified them by the pulmonary embolism severity index (PESI), by the BOVA score, or categorically as low risk (no RV dysfunction by imaging), intermediate risk/submassive (RV dysfunction by imaging), or high risk/massive PE (RV dysfunction with sustained hypotension). Using imaging data to firstly define the presence of RV strain, and plasma cardiac biomarkers as additional evidence for myocardial dysfunction, we evaluated whether PESI, BOVA, or RV strain by imaging were more appropriate for determining patient risk by a PERT where rapid decision making is important. Cardiac biomarkers poorly distinguished between PESI classes and BOVA stages in patients with acute PE. Cardiac TnT and NT-proBNP easily distinguished low risk from submassive PE with an area under the curve (AUC) of 0.84 (95% CI 0.73-0.95, p < 0.0001), and 0.88 (95% CI 0.79-0.97, p < 0.0001), respectively. Cardiac TnT and NT-proBNP easily distinguished low risk from massive PE with an area under the curve (AUC) of 0.89 (95% CI 0.78-1.00, p < 0.0001), and 0.89 (95% CI 0.82-0.95, p < 0.0001), respectively. In patients with RV dysfunction, the predicted short-term mortality by PESI score or BOVA stage was lower than the observed mortality by a two-fold order of magnitude. The presence of RV dysfunction alone in the context of acute PE is sufficient for the purposes of risk stratification. More complicated risk stratification tools which require the consideration of multiple clinical variables may under-estimate short-term mortality risk.


Assuntos
Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Índice de Gravidade de Doença , Troponina T/sangue , Disfunção Ventricular Direita , Idoso , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Embolia Pulmonar/sangue , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/fisiopatologia , Estudos Retrospectivos , Medição de Risco , Disfunção Ventricular Direita/sangue , Disfunção Ventricular Direita/diagnóstico , Disfunção Ventricular Direita/fisiopatologia
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