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1.
Ann Biol Clin (Paris) ; 78(5): 471-481, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-33026344

RESUMO

COVID-19 is associated with disturbances of hemostasis in the laboratory and an increased thrombotic risk. Routine laboratory tests - activated partial thromboplastin time (aPTT), prothrombin time, Clauss fibrinogen and D-dimers levels measurement - are used for the evaluation of the thrombotic risk and the monitoring of hemostasis, but are subject to several drawbacks that may affect the reliability and clinical relevance of the delivered results. Another challenge for the hemostasis laboratory is the monitoring of heparin treatment. For instance, the issue of the monitoring of unfractionated heparin remains debated, the more so when there is a tremendous inflammatory response. This brief review considers the role of laboratory tests of hemostasis in the management of COVID-19 and discusses their main limitations to be kept in mind.


Assuntos
Infecções por Coronavirus/sangue , Infecções por Coronavirus/terapia , Hemostasia/fisiologia , Pneumonia Viral/sangue , Pneumonia Viral/terapia , Trombose/diagnóstico , Trombose/etiologia , Trombose/prevenção & controle , Anticoagulantes/uso terapêutico , Betacoronavirus/fisiologia , Testes de Coagulação Sanguínea , Infecções por Coronavirus/complicações , Infecções por Coronavirus/epidemiologia , Monitoramento de Medicamentos/métodos , Hemostasia/efeitos dos fármacos , Humanos , Laboratórios Hospitalares , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/epidemiologia , Fatores de Risco , Trombose/epidemiologia
5.
Ann Biol Clin (Paris) ; 78(5): 574-580, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32716002

RESUMO

Laboratories need to set up effective overall management of their internal quality control (IQC) and external quality assessment (EQA) results as key elements in statistical process control. Quality targets need to be defined, with methods to ensure durable control with respect to the relevant specifications. The hemostasis laboratory of the Lyon Hospitals Board (HCL, Lyon, France) uses model 3 from the Milan consensus conference, which is the state of the art in terms of quality targets, and uses a common EQA provider supplying as many real patient samples as possible. Giving priority to adopted methods, the lab optimizes the use of manufacturers' prior data: maximum acceptable inter assay coefficient of variation (CV) and prior IQC target values. Bayesian inference brings the method under control with respect to the manufacturers' prior data without the need for a preliminary phase. It links the IQC and EQA plans by the maximum acceptable CVs defined by the manufacturer.


Assuntos
Testes Hematológicos/estatística & dados numéricos , Testes Hematológicos/normas , Laboratórios Hospitalares/estatística & dados numéricos , Garantia da Qualidade dos Cuidados de Saúde , Teorema de Bayes , Testes de Coagulação Sanguínea/instrumentação , Testes de Coagulação Sanguínea/métodos , Testes de Coagulação Sanguínea/normas , Testes de Coagulação Sanguínea/estatística & dados numéricos , Serviços de Laboratório Clínico/organização & administração , Serviços de Laboratório Clínico/normas , Serviços de Laboratório Clínico/estatística & dados numéricos , França/epidemiologia , Testes Hematológicos/instrumentação , Testes Hematológicos/métodos , Hemostasia/fisiologia , Humanos , Laboratórios Hospitalares/organização & administração , Laboratórios Hospitalares/normas , Ensaio de Proficiência Laboratorial/organização & administração , Ensaio de Proficiência Laboratorial/normas , Ensaio de Proficiência Laboratorial/estatística & dados numéricos , Prática Profissional/organização & administração , Prática Profissional/normas , Prática Profissional/estatística & dados numéricos , Garantia da Qualidade dos Cuidados de Saúde/métodos , Garantia da Qualidade dos Cuidados de Saúde/organização & administração , Garantia da Qualidade dos Cuidados de Saúde/normas , Garantia da Qualidade dos Cuidados de Saúde/estatística & dados numéricos , Controle de Qualidade , Estudos Retrospectivos
6.
Crit Care ; 24(1): 364, 2020 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-32560658

RESUMO

COVID-19 is an infection induced by the SARS-CoV-2 coronavirus, and severe forms can lead to acute respiratory distress syndrome (ARDS) requiring intensive care unit (ICU) management. Severe forms are associated with coagulation changes, mainly characterized by an increase in D-dimer and fibrinogen levels, with a higher risk of thrombosis, particularly pulmonary embolism. The impact of obesity in severe COVID-19 has also been highlighted.In this context, standard doses of low molecular weight heparin (LMWH) may be inadequate in ICU patients, with obesity, major inflammation, and hypercoagulability. We therefore urgently developed proposals on the prevention of thromboembolism and monitoring of hemostasis in hospitalized patients with COVID-19.Four levels of thromboembolic risk were defined according to the severity of COVID-19 reflected by oxygen requirement and treatment, the body mass index, and other risk factors. Monitoring of hemostasis (including fibrinogen and D-dimer levels) every 48 h is proposed. Standard doses of LMWH (e.g., enoxaparin 4000 IU/24 h SC) are proposed in case of intermediate thrombotic risk (BMI < 30 kg/m2, no other risk factors and no ARDS). In all obese patients (high thrombotic risk), adjusted prophylaxis with intermediate doses of LMWH (e.g., enoxaparin 4000 IU/12 h SC or 6000 IU/12 h SC if weight > 120 kg), or unfractionated heparin (UFH) if renal insufficiency (200 IU/kg/24 h, IV), is proposed. The thrombotic risk was defined as very high in obese patients with ARDS and added risk factors for thromboembolism, and also in case of extracorporeal membrane oxygenation (ECMO), unexplained catheter thrombosis, dialysis filter thrombosis, or marked inflammatory syndrome and/or hypercoagulability (e.g., fibrinogen > 8 g/l and/or D-dimers > 3 µg/ml). In ICU patients, it is sometimes difficult to confirm a diagnosis of thrombosis, and curative anticoagulant treatment may also be discussed on a probabilistic basis. In all these situations, therapeutic doses of LMWH, or UFH in case of renal insufficiency with monitoring of anti-Xa activity, are proposed.In conclusion, intensification of heparin treatment should be considered in the context of COVID-19 on the basis of clinical and biological criteria of severity, especially in severely ill ventilated patients, for whom the diagnosis of pulmonary embolism cannot be easily confirmed.


Assuntos
Infecções por Coronavirus/terapia , Hemostasia/fisiologia , Hospitalização , Pneumonia Viral/terapia , Trombose/prevenção & controle , Infecções por Coronavirus/fisiopatologia , Humanos , Monitorização Fisiológica , Pandemias , Pneumonia Viral/fisiopatologia , Risco
8.
J Pediatr ; 221S: S29-S36, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32482231

RESUMO

This post hoc study of a plasma proteomic database investigated hemostatic proteins in the context of developmental hemostasis. Twenty-seven hemostatic proteins changed expression with age, and the hemostatic profile of neonates was unique. Appreciating developmental hemostasis through proteomics may lead to more personalized medicine for hospitalized children.


Assuntos
Envelhecimento/sangue , Proteínas Sanguíneas/fisiologia , Hemostasia/fisiologia , Proteômica , Adulto , Coagulação Sanguínea/fisiologia , Plaquetas/fisiologia , Criança , Pré-Escolar , Células Endoteliais/fisiologia , Feminino , Fibrinólise/fisiologia , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Análise de Componente Principal , Adulto Jovem
9.
Br J Radiol ; 93(1111): 20190958, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32356453

RESUMO

OBJECTIVE: Standard treatment for progressive gastric cancer with bleeding includes hemostatic radiotherapy (RT); however, the only prospective study using a fixed dose with fractions during hemostatic RT did not introduce re-irradiation. Therefore, we determined the utility of RT including re-irradiation for gastric cancer. METHODS: In this study, 31 patients with gastric cancer and bleeding were treated with an initial dose of 20 Gy/5 fractions for the whole stomach and a salvage dose of 15 Gy/5 fractions for the partial stomach. Patients achieving hemostasis, defined as a stable hemoglobin level within 30 days following irradiation, were considered responders, whereas those with no cessation of bleeding and those with re-bleeding within 30 days of irradiation were considered non-responders. We evaluated response rate, disease-free survival, overall survival (OS), re-irradiation, and adverse events (AEs). RESULTS: The response rate of initial RT was 80% (25/31). 6 of the 25 patients underwent re-irradiation, and all 6 were responders (100%). The median OS was significantly different among the entire cohort and one-time irradiation and re-irradiation groups (91, 76, and 112 days, respectively). No AEs of grade ≥3 were observed. Initial low-dose RT followed by reirradiation was effective in reducing AEs and did not cause any further AEs. CONCLUSION: Hemostatic RT was an effective approach with low toxicity, and re-irradiation was effective and tolerable, with no patients developing severe AEs. Further, randomized controlled studies are warranted to determine the ideal dose and number of fractions for initial RT in patients with gastric cancer and bleeding. ADVANCES IN KNOWLEDGE: In this prospective study on hemostatic radiotherapy for gastric cancer, the response rate was 80% using a fixed dose of 20 Gy/5 fractions and the salvage dose of 15 Gy for re-bleeding was effective. Future comparative studies should include other doses with 20 Gy as a control.


Assuntos
Hemorragia Gastrointestinal/radioterapia , Neoplasias Gástricas/radioterapia , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Hemostasia/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Planejamento de Assistência ao Paciente , Projetos Piloto , Estudos Prospectivos , Dosagem Radioterapêutica , Reirradiação/estatística & dados numéricos , Recidiva , Resultado do Tratamento
10.
Arterioscler Thromb Vasc Biol ; 40(6): 1441-1453, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32375545

RESUMO

Megakaryocyte-derived platelets and endothelial cells store their hemostatic cargo in α- and δ-granules and Weibel-Palade bodies, respectively. These storage granules belong to the lysosome-related organelles (LROs), a heterogeneous group of organelles that are rapidly released following agonist-induced triggering of intracellular signaling pathways. Following vascular injury, endothelial Weibel-Palade bodies release their content into the vascular lumen and promote the formation of long VWF (von Willebrand factor) strings that form an adhesive platform for platelets. Binding to VWF strings as well as exposed subendothelial collagen activates platelets resulting in the release of α- and δ-granules, which are crucial events in formation of a primary hemostatic plug. Biogenesis and secretion of these LROs are pivotal for the maintenance of proper hemostasis. Several bleeding disorders have been linked to abnormal generation of LROs in megakaryocytes and endothelial cells. Recent reviews have emphasized common pathways in the biogenesis and biological properties of LROs, focusing mainly on melanosomes. Despite many similarities, LROs in platelet and endothelial cells clearly possess distinct properties that allow them to provide a highly coordinated and synergistic contribution to primary hemostasis by sequentially releasing hemostatic cargo. In this brief review, we discuss in depth the known regulators of α- and δ-granules in megakaryocytes/platelets and Weibel-Palade bodies in endothelial cells, starting from transcription factors that have been associated with granule formation to protein complexes that promote granule maturation. In addition, we provide a detailed view on the interplay between platelet and endothelial LROs in controlling hemostasis as well as their dysfunction in LRO related bleeding disorders.


Assuntos
Plaquetas/ultraestrutura , Grânulos Citoplasmáticos/fisiologia , Células Endoteliais/ultraestrutura , Hemostasia/fisiologia , Lisossomos/fisiologia , Transtornos da Coagulação Sanguínea/genética , Transtornos da Coagulação Sanguínea/fisiopatologia , Colágeno/fisiologia , Grânulos Citoplasmáticos/ultraestrutura , Humanos , Lisossomos/ultraestrutura , Corpos de Weibel-Palade/fisiologia , Corpos de Weibel-Palade/ultraestrutura , Fator de von Willebrand/metabolismo
12.
Transfusion ; 60(5): 1069-1077, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32315090

RESUMO

BACKGROUND: Phlebotomy is among the main determinants of anemia of prematurity. Blood sparing policies endorsed umbilical cord blood (here called placental) as an alternative source for laboratory testing. Little is known on the suitability of placental blood to evaluate neonatal hemostasis of newborn infants. We aimed to compare the hemostatic profile of paired placental and infant venous blood, by means of prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen, antithrombin, protein C, thromboelastography (TEG) and thrombin generation assay (TGA). STUDY DESIGN: This was an observational single-center study. METHODS: We collected at birth venous citrated blood from both placental and infant venous source and performed PT, APTT, fibrinogen, antithrombin, protein C, TEG (reaction time-R; kinetics-K alpha angle-α, maximum amplitude-MA and lysis at 30 minutes-LY30), and TGA (endogenous thrombin potential-ETP). RESULTS: We enrolled 60 neonates with a median gestational age (range) of 37 weeks (28+1 -41) and birth-weight 2417 g (950-4170). Based on TEG and TGA, placental blood showed a procoagulant imbalance as indicated by lower median R (4.0 vs. 6.1 min; p < 0.001) and K (1.3 vs. 2.2 min; p < 0.001); higher α-angle (69.7 vs. 57.4°; p < 0.001) and ETP (1260 vs. 1078; p = 0.002) than those observed for infant venous blood. PT and APTT did not differ significantly between the two groups. CONCLUSIONS: While placental and neonatal blood samples are equally suitable to measure the standard coagulation tests PT and APTT, placental blood leads to a procoagulant imbalance when testing is performed with TEG or TGA. These effects should be considered when interpreting results stemming from investigation of neonatal hemostasis.


Assuntos
Transtornos da Coagulação Sanguínea/diagnóstico , Hemostasia/fisiologia , Doenças do Recém-Nascido/diagnóstico , Triagem Neonatal/métodos , Placenta/irrigação sanguínea , Transtornos da Coagulação Sanguínea/sangue , Testes de Coagulação Sanguínea , Feminino , Sangue Fetal/fisiologia , Fibrinogênio/análise , Idade Gestacional , Humanos , Recém-Nascido , Doenças do Recém-Nascido/sangue , Masculino , Tempo de Tromboplastina Parcial , Parto/sangue , Flebotomia/métodos , Flebotomia/normas , Gravidez , Tempo de Protrombina , Reprodutibilidade dos Testes , Trombina/análise
13.
Haemophilia ; 26(2): 306-313, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32166871

RESUMO

INTRODUCTION: Advances in genomic sequencing have facilitated the sequencing of genes associated with disorders of haemostasis. The identification of variants within genes and access to curated data incorporating structural, functional, evolutionary as well as phenotypic data has become increasingly important in order to ascribe pathogenicity. AIM: The European Association for Haemophilia and Allied Disorders (EAHAD) Coagulation Factor Variant Database Project aims to provide a single port of entry to a web-accessible resource for variants in genes involved in clinical bleeding disorders. RESULTS: New databases have evolved from previously developed single gene variant coagulation database projects, incorporating new data, new analysis tools and a new common database architecture with new interfaces and filters. These new databases currently present information about the genotype, phenotype (laboratory and clinical) and structural and functional effects of variants described in the genes of factor (F) VII (F7), FVIII (F8), FIX (F9) and von Willebrand factor (VWF). CONCLUSION: The project has improved the quality and quantity of information available to the haemostasis research and clinical communities, thereby enabling accurate classification of disease severity in order to make assessments of likely pathogenicity.


Assuntos
Hemofilia A/epidemiologia , Hemostasia/fisiologia , Pesquisa Biomédica , Bases de Dados Factuais , Europa (Continente) , Humanos
14.
Cardiovasc Intervent Radiol ; 43(5): 714-720, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32043200

RESUMO

PURPOSE: Upper extremity and tibiopedal arterial access are increasingly used during endovascular therapies. Balloon compression hemostasis devices in these anatomic locations have been described, but most utilize a compression surface extending well beyond the puncture site. We report single-center experience with an arterial puncture-focused compression device following upper extremity and tibiopedal access. PATIENTS AND METHODS: A series of 249 focused compression hemostasis devices (VasoStat, Forge Medical, Bethlehem, Pennsylvania, USA) were used in 209 patients following lower extremity (n = 63) and upper extremity (n = 186; radial: 90%) arterial access procedures using 4-7 French sheaths. Demographic, operative, and follow-up data were collected. Logistic regression was used to evaluate potential association between patient/operative variables and time to hemostasis. RESULTS: Primary hemostasis was achieved in 97.2% (242/249) following sheath removal; in 7 cases (2.8%) puncture site oozing occurred after initial device removal and required reapplication. Secondary hemostasis was 100% (249/249). Seven complications (2.8%) were recorded: 5 minor hematomas (2%) and 2 transient access artery occlusions (0.8%). Mean time to hemostasis enabling device removal was 55 ± 28 min. Elevated body mass index (BMI) was not associated with increased time to hemostasis (p = 0.31). Accessed artery, sheath size, and heparin dose were also not associated with time to hemostasis (p = 0.64; p = 0.74; p = 0.75, respectively). CONCLUSIONS: The focused compression hemostasis device enabled rapid hemostasis with a low complication rate. Time to hemostasis was independent of BMI, access site, sheath size, or heparin dose.


Assuntos
Hemostasia/fisiologia , Técnicas Hemostáticas/instrumentação , Dispositivos de Compressão Pneumática Intermitente , Procedimentos Cirúrgicos Vasculares/métodos , Feminino , Humanos , Extremidade Inferior/irrigação sanguínea , Extremidade Inferior/cirurgia , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do Tratamento , Extremidade Superior/irrigação sanguínea , Extremidade Superior/cirurgia
15.
Vet Clin North Am Equine Pract ; 36(1): 53-71, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31987707

RESUMO

Horses with clinical signs of unprovoked or excessive hemorrhage should be evaluated for underlying platelet defects or coagulopathies. This article provides an overview of preliminary screening and definitive tests to assess coagulation and identify hemostatic defects in horses, as well as a review of the hemostatic disorders most frequently encountered in clinical practice.


Assuntos
Transtornos da Coagulação Sanguínea/veterinária , Doenças dos Cavalos/sangue , Cavalos/sangue , Animais , Coagulação Sanguínea , Transtornos da Coagulação Sanguínea/sangue , Fibrinólise/fisiologia , Hemorragia/sangue , Hemorragia/veterinária , Hemostasia/fisiologia , Doenças dos Cavalos/diagnóstico
16.
Anesth Analg ; 130(2): 416-425, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31567472

RESUMO

BACKGROUND: Rapid assessment of hemostasis during postpartum hemorrhage (PPH) is essential to allow characterization of coagulopathy, to estimate bleeding severity, and to improve outcome. Point of care (POC) coagulation monitors could be of great interest for early diagnosis and treatment of coagulation disorders in PPH. METHODS: Women with ongoing PPH >500 mL who clinically required an assessment of coagulation with thromboelastography (TEG) were included. The primary aim of this retrospective observational cohort study was to assess the predictive accuracy of TEG parameters for the diagnosis of coagulation disorders (hypofibrinogenemia ≤2 g/L, thrombocytopenia ≤80,000/mm, prothrombin ratio ≤50%, or activated partial thromboplastin time ratio ≥1.5) during PPH. The analyzed TEG parameters were Kaolin-maximum amplitude (K-MA), Kaolin-maximum rate of thrombus generation using G (K-MRTGG), functional fibrinogen-maximum amplitude (FF-MA), and functional fibrinogen-maximum rate of thrombus generation using G (FF-MRTGG). Secondary aims of this study were (1) comparison of the time delay between classical parameters and velocity curve-derived parameters (K-MA versus K-MRTGG and FF-MA versus FF-MRTGG) and (2) evaluation of the accuracy of TEG parameters to predict severe hemorrhage estimated by calculated blood losses. RESULTS: Ninety-eight patients were included with 98 simultaneous TEG analyses and laboratory assays. All parameters had an excellent predictive performance. For the Kaolin assay, no significant difference was evidenced between K-MA and K-MRTGG for the predictive performance for hypofibrinogenemia ≤2 g/L and/or thrombocytopenia ≤80,000/mm (respective area under the curve [AUC], 0.970 vs 0.981). For the functional fibrinogen assay, no significant difference was evidenced between FF-MA and FF-MRTGG for the predictive performance for hypofibrinogenemia ≤2 g/L (respective AUC, 0.988 vs 0.974). For both assays, the time to obtain results was shorter for the velocity parameters (K-MRTGG: 7.7 minutes [2.4 minutes] versus K-MA: 24.7 minutes [4.2 minutes], P < .001; FF-MRTGG: 2.7 minutes [2.7 minutes] versus FF-MA: 14.0 minutes [4.3 minutes], P < .001). All TEG parameters derived from the Kaolin and functional fibrinogen assays and Clauss fibrinogen were significantly predictive of severe PPH >2500 mL. CONCLUSIONS: During PPH, when coagulation assessment is indicated, TEG provides a rapid and reliable detection of hypofibrinogenemia ≤2 g/L and/or thrombocytopenia ≤80,000/mm. No difference in performance was evidenced between the velocity-derived parameters (K-MRTGG and FF-MRTGG) and the classical parameters (K-MA and FF-MA). However, velocity-derived parameters offer the advantage of a shorter time to obtain results: FF-MRTGG parameter is available within ≤5 minutes. POC assessment of hemostasis during PPH management may help physicians to diagnose clotting disorders and to provide appropriate hemostatic support.


Assuntos
Transtornos da Coagulação Sanguínea/diagnóstico , Coagulação Sanguínea/fisiologia , Hemorragia Pós-Parto/diagnóstico , Tromboelastografia/métodos , Adulto , Transtornos da Coagulação Sanguínea/sangue , Transtornos da Coagulação Sanguínea/fisiopatologia , Estudos de Coortes , Feminino , Hemostasia/fisiologia , Humanos , Hemorragia Pós-Parto/sangue , Hemorragia Pós-Parto/fisiopatologia , Gravidez , Estudos Retrospectivos , Tromboelastografia/normas
18.
Nat Commun ; 10(1): 5562, 2019 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-31804481

RESUMO

Hemostatic materials are of great importance in medicine. However, their successful implementation is still challenging as it depends on two, often counteracting, attributes; achieving blood coagulation rapidly, before significant blood loss, and enabling subsequent facile wound-dressing removal, without clot tears and secondary bleeding. Here we illustrate an approach for achieving hemostasis, rationally targeting both attributes, via a superhydrophobic surface with immobilized carbon nanofibers (CNFs). We find that CNFs promote quick fibrin growth and cause rapid clotting, and due to their superhydrophobic nature they severely limit blood wetting to prevent blood loss and drastically reduce bacteria attachment. Furthermore, minimal contact between the clot and the superhydrophobic CNF surface yields an unforced clot detachment after clot shrinkage. All these important attributes are verified in vitro and in vivo with rat experiments. Our work thereby demonstrates that this strategy for designing hemostatic patch materials has great potential.


Assuntos
Coagulação Sanguínea/fisiologia , Hemostasia/fisiologia , Hemostáticos/química , Nanofibras/química , Animais , Aderência Bacteriana/efeitos dos fármacos , Bandagens , Coagulação Sanguínea/efeitos dos fármacos , Ensaio de Imunoadsorção Enzimática , Feminino , Fibrina/metabolismo , Hemostasia/efeitos dos fármacos , Hemostáticos/farmacologia , Humanos , Interações Hidrofóbicas e Hidrofílicas , Ratos Sprague-Dawley , Suínos
19.
Thromb Res ; 183: 56-62, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31669824

RESUMO

BACKGROUND: Hemostasis is a tightly regulated physiological process to rapidly induce hemostatic plugs at sites of vascular injury. Inappropriate activation of this process may lead to thrombosis, i.e. pathological blood clot formation in uninjured vessels or on atherosclerotic lesions. ATP release through Pannexin1 (Panx1) membrane channels contributes to collagen-induced platelet aggregation in vitro. OBJECTIVE: To investigate the effects of genetic and pharmacological inhibition of Panx1 on hemostasis and thrombosis in vivo. RESULTS: Bleeding time after tail clipping was increased by 2.5-fold in Panx1-/- mice compared to wild-type controls, suggesting that Panx1 deficiency impairs primary hemostasis. Wire myography on mesenteric arteries revealed diminished vasoconstriction in response to phenylephrine or U446619 in Panx1-/- mice. Mice with platelet-specific deletion of Panx1 (Panx1PDel) displayed 2-fold longer tail bleeding times than Panx1fl/fl controls. Moreover, venous thromboembolism (VTE) after injection of collagen/epinephrine in the jugular vein was reduced in Panx1-/- and Panx1PDel mice. Panx1PDel mice also showed reduced FeCl3-induced thrombosis in mesenteric arteries. BrilliantBlue-FCF, a Panx1 channel inhibitor, decreased collagen-induced platelet aggregation in vitro, increased tail bleeding time and reduced VTE in wild-type mice. Furthermore, we developed a specific Panx1 blocking antibody targeting a Panx1 extracellular loop, which reduced ATP release from platelets in vitro. Treating wild-type mice with this antibody increased tail bleeding time and decreased VTE compared to control antibody. CONCLUSIONS: Panx1 channel deletion or inhibition diminishes clot formation during hemostasis and thrombosis in vivo. Blocking Panx1 channels may be an attractive strategy for modulating platelet aggregation in thrombotic disease.


Assuntos
Conexinas/antagonistas & inibidores , Hemostasia/fisiologia , Proteínas do Tecido Nervoso/antagonistas & inibidores , Trombose/terapia , Animais , Humanos , Masculino , Camundongos
20.
Nutrients ; 11(9)2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31484340

RESUMO

A pro-coagulative state is related to increased risk of cardiovascular diseases but also certain cancers. Since experimental and smaller human studies suggest that diet, physical activity, and body weight may all affect coagulation, we evaluated associations between these lifestyle factors and hemostatic biomarkers in a population-based study. Cross-sectional baseline data from 2267 randomly selected participants of EPIC-Heidelberg (age range 35-65 years) was used. Fibrinogen, glycoprotein IIb/IIIa, P-selectin, thrombomodulin (TM), and thrombopoietin (TPO) were measured in baseline plasma samples. A score reflecting adherence to the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) recommendations for cancer prevention was created. Associations between the WCRF/AICR score as well as its individual components and hemostatic biomarkers were analyzed by linear regression models. Multivariable-adjusted geometric means (95% confidence intervals) of TM and TPO were higher with greater adherence to the WCRF/AICR recommendations (TM, lowest vs. highest score category: 2.90 (2.7,3.1) vs. 3.10 (2.9,3.3) ng/mL, plinear trend = 0.0001; TPO: 328 (302,356) vs. 348 (321,378) pg/mL, plinear trend = 0.0007). These associations were driven by lower alcohol and meat consumption among persons with higher WCRF/AICR scores. Our results indicate that lifestyle factors favorably affect TM and TPO, two hemostatic factors implicated in chronic disease development.


Assuntos
Dieta , Hemostasia/fisiologia , Estilo de Vida , Neoplasias/prevenção & controle , Trombomodulina/sangue , Trombopoetina/sangue , Academias e Institutos , Adulto , Biomarcadores , Estudos Transversais , Coleta de Dados , Feminino , Guias como Assunto , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Inquéritos e Questionários , Estados Unidos
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