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1.
Rev Med Suisse ; 16(692): 951-954, 2020 May 06.
Artigo em Francês | MEDLINE | ID: mdl-32374544

RESUMO

Since the SARS-CoV-2 pandemic outbreak, growing evidence suggests that patients suffering from COVID-19 are at increased risk of thrombotic events. The sepsis-related activation of the coagulation combined with a high prevalence of common thrombotic risk factors could contribute to this prothrombotic state. Coagulation biomarkers could help in the identification of patients at risk of complications and mortality. The incidence of venous thromboembolic events appears to be increased, especially in severe COVID-19 patients. Based on that knowledge, several societies have provided recommendation on the prevention of venous thromboembolism. In this narrative review, we summarize available epidemiologic data on venous thromboembolism and recommendations on thromboprophylaxis in COVID-19.


Assuntos
Infecções por Coronavirus/complicações , Pneumonia Viral/complicações , Vírus da SARS , Tromboembolia Venosa , Anticoagulantes , Betacoronavirus , Humanos , Pandemias , Prevalência , Risco , Tromboembolia Venosa/etiologia , Tromboembolia Venosa/prevenção & controle
3.
Swiss Med Wkly ; 150: w20210, 2020 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-32329806

RESUMO

Heparin-induced thrombocytopenia (HIT) is an immune-mediated adverse drug effect that occurs in 0.1–5% of heparin treated patients. Management of acute HIT currently involves (1) cessation of heparin exposure, and (2) inhibition of coagulation with an anticoagulant other than heparin. Several anticoagulants can be considered for the treatment of HIT. Anticoagulant monitoring, management of drug-induced adverse events including bleeding, and therapeutic dosing schedules in selected clinical settings represent challenges to the clinician treating HIT patients. Moreover, the fact that not all registered anticoagulants are approved for HIT in Switzerland further complicates the management of HIT. The present recommendations on the anticoagulant treatment of HIT in Switzerland have been elaborated by a panel of Swiss experts belonging to the Working Party Hemostasis (WPH) of the Swiss Society of Hematology (SGH-SSH). They are intended to support clinicians in their decision making when treating HIT patients.

4.
Acta Haematol ; : 1-3, 2020 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-32155618

RESUMO

Acquired hemophilia A (AHA) is a rare but serious condition, usually associated with significant spontaneous or traumatic bleeding and a high mortality rate. In this report, we describe the case of an elderly patient presenting a transient ischemic attack concurrently with AHA. A thrombotic event in AHA is occasionally associated with the use of bypassing agents for treatment, but a spontaneous thrombotic event has not ever been described.

5.
J Thromb Haemost ; 2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-32077582

RESUMO

BACKGROUND: On-clopidogrel platelet reactivity (PR) is associated with the risk of thrombotic or bleeding event in selected populations of high-risk patients. PR is a highly heritable phenotype and a few variants of cytochrome genes, essentially CYP2C19, are associated with PR but only explain 5% to 12% of the variability. OBJECTIVE: The aim of this study is to delineate genetic determinants of on-clopidogrel PR using high-throughput sequencing. METHODS: We performed a whole exome sequencing of 96 low- and matched high-PR patients in a discovery cohort. Exomes from genes with variants significantly associated with PR were sequenced in 96 low- and matched high-PR patients from an independent replication cohort. RESULTS: We identified 585 variants in 417 genes with an adjusted P value < .05. In the replication cohort, all top variants including CYP2C8, CYP2C18, and CYP2C19 from the discovery population were found again. An original network analysis identified several candidate genes of potential interest such as a regulator of PI3K, a key actor in the downstream signaling pathway of the P2Y12 receptor. CONCLUSION: This study emphasizes the role of CYP-related genes as major regulators of clopidogrel response, including the poorly investigated CYP2C8 and CYP2C18.

6.
J Thromb Haemost ; 18(3): 732-739, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31750621

RESUMO

BACKGROUND: Careful assessment of bleeding history is the first step in the evaluation of patients with mild/moderate bleeding disorders, and the use of a bleeding assessment tool (BAT) is strongly encouraged. Although a few studies have assessed the utility of the ISTH-BAT in patients with inherited platelet function disorders (IPFD) none of them was sufficiently large to draw conclusions and/or included appropriate control groups. OBJECTIVES: The aim of the present study was to test the utility of the ISTH-BAT in a large cohort of patients with a well-defined diagnosis of inherited platelets disorder in comparison with two parallel cohorts, one of patients with type-1 von Willebrand disease (VWD-1) and one of healthy controls (HC). PATIENTS/METHODS: We enrolled 1098 subjects, 482 of whom had inherited platelet disorders (196 IPFD and 286 inherited platelet number disorders [IT]) from 17 countries. RESULTS: IPFD patients had significantly higher bleeding score (BS; median 9) than VWD-1 patients (median 5), a higher number of hemorrhagic symptoms (4 versus 3), and higher percentage of patients with clinically relevant symptoms (score > 2). The ISTH-BAT showed excellent discrimination power between IPFD and HC (0.9 < area under the curve [AUC] < 1), moderate (0.7 < AUC < 0.9) between IPFD and VWD-1 and between IPFD and inherited thrombocytopenia (IT), while it was inaccurate (AUC ≤ 0.7) in discriminating IT from HC. CONCLUSIONS: The ISTH-BAT allows to efficiently discriminate IPFD from HC, while it has lower accuracy in distinguishing IPFD from VWD-1. Therefore, the ISTH-BAT appears useful for identifying subjects requiring laboratory evaluation for a suspected IPFD once VWD is preliminarily excluded.

7.
Perfusion ; : 267659119890218, 2019 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-31814521

RESUMO

Even if the HeartMate 3TM left ventricular assist device is associated with excellent outcomes, complications, such as pump thrombosis continue to affect patients on hemodynamic support. We report the history of a 68-year-old man who underwent implantation of an HeartMate 3TM as a bridge to transplantation. Nineteen months later, he developed signs of heart failure leading to cardiogenic shock. Neither clinical examination nor parameters from the device allowed a clear-cut diagnosis. Only surgical exploration revealed the presence of clots between the polyethylene terephthalate (Dacron®) and polytetrafluoroethylene tubes. This constitutes a weakness of this device for which we propose to the manufacturer for minimal modifications to overcome the problem.

9.
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.

10.
Endocr Connect ; 8(11): 1447-1454, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31614338

RESUMO

Objective: Vitamin D deficiency is associated with increased risks of arterial and venous cardiovascular events. Hypothetically, supplementation with vitamin D may lead to a less prothrombotic phenotype, as measured by global coagulation assays and fibrin clot structure. Methods: In this prospective cohort study, we enrolled adult outpatients attending the Primary Care Division of the Geneva University Hospitals with a severe vitamin D deficiency (25-hydroxyvitamin-D3 (25-OHD) <25 nmol/L), excluding obese patients or with a recent acute medical event. We evaluated changes in coagulation times, thrombin generation assay, clot formation and clot lysis time, 25-OHD and parathormone before and 1-3 months after cholecalciferol oral supplementation with one-time 300,000 IU then 800 IU daily. Paired t-tests with a two-sided alpha of 0.05 compared absolute mean differences. Results: The 48 participants had a mean age of 43.8 ± 13.8 years. After supplementation, 25-OHD levels increased from 17.9 ± 4.6 nmol/L to 62.5 ± 20.7 nmol/L 6.4 ± 3.0 weeks after inclusion. Endogenous thrombin potential and thrombin generation peak values both decreased significantly (-95.4 nM × min (95%CI -127.9 to -62.8), P < 0.001; -15.1 nM (-23.3 to -6.8), P < 0.001). The maximum absorbance by turbidimetry decreased significantly (P = 0.001) after supplementation. There was no change in clot lysis time, coagulation times or plasminogen activator inhibitor-1 and homocysteine levels. Conclusions: In severe vitamin D deficiency, a high-dose cholecalciferol supplementation was associated with a reduction in thrombin generation and an average decreased number of fibrin protofibrils per fibers and fibrin fiber size measured by turbidimetry. This suggests that severe vitamin D deficiency may be associated with a potentially reversible prothrombotic profile.

11.
Artigo em Inglês | MEDLINE | ID: mdl-31504375

RESUMO

AIMS: Clopidogrel is prescribed for the prevention of atherothrombotic events. While investigations have identified genetic determinants of inter-individual variability in on-treatment platelet inhibition (e.g. CYP2C19*2), evidence that these variants have clinical utility to predict major adverse cardiovascular events remains controversial. METHODS AND RESULTS: We assessed the impact of 31 candidate gene polymorphisms on ADP-stimulated platelet reactivity in 3,391 clopidogrel-treated coronary artery disease patients of the International Clopidogrel Pharmacogenomics Consortium (ICPC). The influence of these polymorphisms on cardiovascular events (CVE) was tested in 2,134 ICPC patients (N = 129 events) in whom clinical event data were available. Several variants were associated with on-treatment ADP-stimulated platelet reactivity (CYP2C19*2, P = 8.8x10-54; CES1 G143E, P = 1.3x10-16; CYP2C19*17, P = 9.5x10-10; CYP2B6 1294 + 53C>T, P = 3.0x10-4; CYP2B6 516G>T, P = 1.0x10-3; CYP2C9*2, P = 1.2x10-3; and CYP2C9*3, P = 1.5x10-3). While no individual variant was associated with CVEs, generation of a pharmacogenomic polygenic response score (PgxRS) revealed that patients who carried a greater number of alleles that associated with increased on-treatment platelet reactivity were more likely to experience CVEs (ß = 0.17, SE 0.06, P = 0.01) and cardiovascular-related death (ß = 0.43, SE 0.16, P = 0.007). Patients who carried 8 or more risk alleles were significantly more likely to experience CVEs (OR = 1.78, 95%CI 1.14-2.76, P = 0.01) and cardiovascular death (OR = 4.39, 95%CI 1.35-14.27, P = 0.01) compared to patients who carried 6 or fewer of these alleles. CONCLUSION: Several polymorphisms impact clopidogrel response and PgxRS is a predictor of cardiovascular outcomes. Additional investigations that identify novel determinants of clopidogrel response and validating polygenic models may facilitate future precision medicine strategies.

12.
JACC Cardiovasc Interv ; 12(18): 1867-1868, 2019 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-31537289
13.
Haemophilia ; 25(5): 747-754, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31368232

RESUMO

INTRODUCTION: Hereditary fibrinogen disorders (HFD) are rare quantitative or qualitative fibrinogen anomalies, including afibrinogenaemia (A), hypofibrinogenaemia (H), dysfibrinogenaemia (D) and hypodysfibrinogenaemia (HD). As fibrinogen plays an essential role in pregnancy, we addressed the issue of obstetrical and postpartum complications in women with HFD. METHODS: A systematic literature review, restricted to English manuscripts, was conducted according to the PRISMA guidelines. We searched through the MEDLINE database for English articles, published from January 1985 until November 2018, focusing on pregnancy in A, H, D and HD. A total of 198 articles were identified, 15 articles were added from other sources. Overall, 213 articles were screened and 54 were included in the final analysis. RESULTS: A total of 188 pregnancies from 70 women were analysed. About half of pregnancies resulted in miscarriage; more specifically in 15 (42.9%), 36 (46.8%), 27 (42.9%) and 4 (30.8%) of A, H, D and HD patients, respectively. Preterm complications were also frequent (33.5%). Metrorrhagia, mainly in the first trimester, was observed in 21.7% of the pregnancies. Placenta abruption was reported in 5 (14.3%), 4 (5.2%), 5 (7.9%) and 1 (7.7%) of A, H, D and HD, respectively. A total of 24 (12.7%) deliveries were complicated by postpartum thrombotic events (3.2%) or postpartum haemorrhage (9.6%). A fibrinogen replacement therapy was introduced in 30% of pregnancies, as prophylaxis (81.1%) or on demand (18.9%). CONCLUSION: These results suggest that women with HFD are at high risk of obstetrical and postpartum complications. Prospective international registries may allow to identify more precisely the incidence of obstetrical and postpartum adverse outcomes and their management.


Assuntos
Afibrinogenemia/complicações , Hemorragia Pós-Parto/etiologia , Adulto , Feminino , Humanos , Obstetrícia , Gravidez
14.
Hepatol Commun ; 3(7): 855-866, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31304449

RESUMO

Beyond their role in hemostasis, platelets are proposed as key mediators of several physiological and pathophysiological processes of the liver, such as liver regeneration, toxic or viral acute liver injury, liver fibrosis, and carcinogenesis. The effects of platelets on the liver involve interactions with sinusoidal endothelial cells and the release of platelet-contained molecules following platelet activation. Platelets are the major source of circulating extracellular vesicles, which are suggested to play key roles in platelet interactions with endothelial cells in several clinical disorders. In the present review, we discuss the implications of platelet-derived extracellular vesicles in physiological and pathophysiological processes of the liver.

15.
Haemophilia ; 25(5): 731-737, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31294904

RESUMO

INTRODUCTION: Emicizumab (Hemlibra® ) recently became available and requires an adaptation for managing bleeding, suspected bleeding and emergency or scheduled invasive procedures in haemophilia A patients with inhibitor. This implicates a multidisciplinary approach and redaction of recommendations for care that must be regularly adapted to the available data. AIM: The following text aims to provide a guide for the management of people with haemophilia A with inhibitor treated with emicizumab in case of bleeding or invasives procedures. METHODS: The French network on inherited bleeding disorders (MHEMO), the French Reference Centre on Haemophilia (CRH), in collaboration with the French Working Group on Perioperative Haemostasis (GIHP) have been working together to make proposals for the management of these situations. RESULTS: Haemostatic treatment and other medications should be given stepwise, according to the severity and location of the bleeding or the risk of bleeding of the procedure as well as the haemostatic response obtained at each step in order to ensure an optimal benefit/risk ratio. CONCLUSION: The lack of data means that it is only possible to issue proposals rather than recommendations.


Assuntos
Anticorpos Biespecíficos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Hemofilia A/tratamento farmacológico , Anticorpos Biespecíficos/farmacologia , Anticorpos Monoclonais Humanizados/farmacologia , França , Hemostasia , Humanos
16.
Clin Pharmacokinet ; 58(12): 1517-1532, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31250210

RESUMO

Oral anticoagulants and antiplatelet drugs are commonly prescribed to lower the risk of cardiovascular diseases, such as venous and arterial thrombosis, which represent the leading causes of mortality worldwide. A significant percentage of patients taking antithrombotics will nevertheless experience bleeding or recurrent ischemic events, and this represents a major public health issue. Cardiovascular medicine is now questioning the one-size-fits-all policy, and more personalized approaches are increasingly being considered. However, the available tools are currently limited and they are only moderately able to predict clinical events or have a significant impact on clinical outcomes. Predicting concentrations of antithrombotics in blood could be an effective means of personalization as they have been associated with bleeding and recurrent ischemia. Target concentration interventions could take advantage of physiologically based pharmacokinetic (PBPK) and population-based pharmacokinetic (POPPK) models, which are increasingly used in clinical settings and have attracted the interest of governmental regulatory agencies, to propose dosages adapted to specific population characteristics. These models have the benefit of combining parameters from different sources, such as experimental in vitro data and patients' demographic, genetic, and physiological in vivo data, to characterize the dose-concentration relationships of compounds of interest. As such, they can be used to predict individual drug exposure. In the near future, these models could therefore be a valuable means of predicting personalized antithrombotic blood concentrations and, hopefully, of preventing clinical non-response or bleeding in a given patient. Existing approaches for personalization of antithrombotic prescriptions will be reviewed using practical examples for P2Y12 inhibitors and direct oral anticoagulants. The review will additionally focus on the existing PBPK and POPPK models for these two categories of drugs. Lastly, we address potential scenarios for their implementation in clinics, along with the main limitations and challenges.

17.
Thromb Haemost ; 119(5): 797-806, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30822809

RESUMO

BACKGROUND: The anti-phospholipid syndrome (APS) is characterized by thrombosis and/or pregnancy morbidity with persistent presence of anti-phospholipid antibodies (aPL). Laboratory criteria include aPL detection by coagulation tests for lupus anticoagulant (LAC) or solid phase assays measuring anti-ß2 glycoprotein I (aß2GPI) or anti-cardiolipin (aCL) immunoglobulin (Ig) G/IgM antibodies. External quality control programs illustrate that commercially available aPL assays produce variable results. OBJECTIVE: We aimed to investigate the agreement and diagnostic accuracy of solid phase assays. MATERIALS AND METHODS: In this multi-centre study, 1,168 patient samples were tested on one site for aCL and aß2GPI IgG/IgM antibodies by four solid phase test systems. Samples included APS patients, controls and monoclonal antibodies (MoAB) against different epitopes of ß2GPI. LAC was determined by the local centre. RESULTS: aCL IgM assays resulted in the most discrepancies (60%), while aCL IgG and aß2GPI IgM assays resulted in lower discrepancies (36%), suggesting better agreement. Discrepant samples displayed lower median aPL titers. Dependent on the solid phase test system, odds ratios (ORs) for thrombosis and pregnancy morbidity ranged from 1.98 to 2.56 and 3.42 to 4.78, respectively. Three platforms showed lower sensitivity for MoAB directed against the glycine (Gly) 40-arginine (Arg) 43 epitope of domain I of ß2GPI. CONCLUSION: Poor agreement was observed between different commercially available aCL and aß2GPI IgG/IgM assays, hampering uniformity in the identification of aPL-positive patients. Clinical association was globally concordant between solid phase test systems considering results of the four aPL together. An assay sensitive in detecting the MoAB against Gly40-Arg43 of domain I of ß2GPI reached the highest OR for thrombosis.


Assuntos
Síndrome Antifosfolipídica/diagnóstico , Autoanticorpos/sangue , Cardiolipinas/imunologia , Ensaio de Imunoadsorção Enzimática/métodos , Trombose/diagnóstico , beta 2-Glicoproteína I/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Gravidez , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Adulto Jovem
18.
Arch Cardiovasc Dis ; 112(3): 199-216, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30621917

RESUMO

The French Working Group on Perioperative Haemostasis (GIHP) and the French Study Group on Haemostasis and Thrombosis (GFHT), in collaboration with the French Society for Anaesthesia and Intensive Care (SFAR), drafted up-to-date proposals on the management of antiplatelet therapy for non-elective invasive procedures or bleeding complications. The proposals were discussed and validated by a vote; all proposals could be assigned with a high strength. Management of oral antiplatelet agents in emergency settings requires knowledge of their pharmacokinetic and pharmacodynamic parameters, evaluation of the degree of alteration of haemostatic competence and the associated bleeding risk. Platelet function testing may be considered. When antiplatelet agent-induced bleeding risk may worsen the prognosis, measures should be taken to neutralize antiplatelet therapy, by considering not only the efficacy of available means (which can be limited for prasugrel and even more for ticagrelor), but also the risks that these means expose the patient to. The measures include platelet transfusion at the appropriate dose and haemostatic agents (tranexamic acid; recombinant activated factor VII for ticagrelor). When possible, postponing non-elective invasive procedures at least for a few hours until the elimination of the active compound (which could compromise the effect of transfused platelets) or, if possible, for a few days (reduction of the effect of antiplatelet agents) should be considered.


Assuntos
Perda Sanguínea Cirúrgica/prevenção & controle , Assistência Perioperatória/métodos , Inibidores da Agregação de Plaquetas/administração & dosagem , Hemorragia Pós-Operatória/prevenção & controle , Administração Oral , Consenso , Esquema de Medicação , Monitoramento de Medicamentos/normas , Humanos , Inibidores da Agregação de Plaquetas/efeitos adversos , Inibidores da Agregação de Plaquetas/farmacocinética , Testes de Função Plaquetária/normas , Transfusão de Plaquetas , Hemorragia Pós-Operatória/sangue , Hemorragia Pós-Operatória/induzido quimicamente , Medição de Risco , Fatores de Risco , Sociedades Médicas/normas , Resultado do Tratamento
19.
Thromb Haemost ; 119(2): 254-263, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30602197

RESUMO

BACKGROUND: Platelets are an abundant source of micro-ribonucleic acids (miRNAs) that may play a role in the regulation of platelet function. Some miRNAs, such as miR-126-3p, have been noted as potential biomarkers of platelet reactivity and the recurrence of cardiovascular events. However, the biological relevance of these associations remains uncertain, and the functional validation of candidate miRNAs on human-derived cells is lacking. OBJECTIVE: This article functionally validates miR-126-3p as a regulator of platelet reactivity in platelet-like structures (PLS) derived from human haematopoietic stem cells. MATERIALS AND METHODS: CD34+-derived megakaryocytes were transfected with miR-126-3p and differentiated in PLS. PLS reactivity was assessed using perfusion in a fibrinogen-coated flow chamber. miR-126-3p's selected gene targets were validated using quantitative polymerase chain reaction, protein quantification and a reporter gene assay. RESULTS: CD34+-derived megakaryocytes transfected with miR-126-3p generated PLS exhibiting 156% more reactivity than the control. These functional data were in line with those obtained analysing CD62P expression. Moreover, miR-126-3p transfection was associated with the down-regulation of a disintegrin and metalloproteinase-9 (ADAM9) messenger RNA (mRNA), a validated target of miR-126-3p, and of Plexin B2 (PLXNB2) mRNA and protein, an actin dynamics regulator. Silencing PLXNB2 led to similar functional results to miR-126-3p transfection. Finally, using a reporter gene assay, we validated PLXNB2 as a direct target of miR-126-3p. CONCLUSION: We functionally validated miR-126-3p as a regulator of platelet reactivity in PLS derived from human haematopoietic stem cells. Moreover, PLXNB2 was validated as a new gene target of miR-126-3p in human cells, suggesting that miR-126-3p mediates its effect on platelets, at least in part, through actin dynamics regulation.


Assuntos
Células-Tronco Hematopoéticas/citologia , Megacariócitos/citologia , MicroRNAs/sangue , Proteínas ADAM/sangue , Animais , Antígenos CD34/metabolismo , Biomarcadores/metabolismo , Plaquetas/citologia , Técnicas de Cultura de Células , Diferenciação Celular , Proliferação de Células , Perfilação da Expressão Gênica , Humanos , Proteínas de Membrana/sangue , Camundongos , MicroRNAs/genética , Proteínas do Tecido Nervoso/sangue , Transfecção
20.
J Proteomics ; 192: 258-266, 2019 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-30240925

RESUMO

Diabetes is a major risk factor for cardiovascular diseases. Although aspirin is considered a cornerstone of the prevention and treatment of atherothrombotic-related ischemic events, this antiplatelet drug appears to be less effective in patients with poorly controlled diabetes. It has been suggested that the glycation of platelet proteins plays a pivotal role in poor responsiveness to aspirin. However, a direct effect on the critical residue (serine 529, or Ser 529) of the catalytic pocket of cyclooxygenase 1 (COX-1) has never been demonstrated. This pilot study aimed to elucidate the impact of hyperglycaemia on aspirin acetylation of COX-1 using a targeted mass spectrometry approach. We observed that high glucose concentration had a direct impact on the level of acetylation of the COX-1 Ser 529 residue, whereas it's overall acetylation level remained unchanged. Moreover, the functional aspirin-induced inhibition of COX-1 was dose-dependently impaired as glucose concentrations increased. These in vitro findings were in line with data obtained using platelets from diabetic patients. These data provide new insights into the interplay between glucose and aspirin on platelet proteins and their effects on platelet COX-1. They also suggest a potential mechanistic explanation for the phenomenon of poor response to aspirin in diabetic patients. Data are available via ProteomeXchange with identifier PXD011204. SIGNIFICANCE: Deciphering the mutual interplay between glucose and aspirin-mediated acetylation on platelet COX-1, might be of great interest as there is still a lack of information of the mechanism underlying this process that may contribute to the less-than expected response of platelets to aspirin, often observed in diabetes.


Assuntos
Aspirina/administração & dosagem , Glicemia/metabolismo , Plaquetas/enzimologia , Ciclo-Oxigenase 1/sangue , Diabetes Mellitus/sangue , Acetilação/efeitos dos fármacos , Adulto , Diabetes Mellitus/tratamento farmacológico , Feminino , Humanos , Masculino , Projetos Piloto , Serina
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