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1.
Scand J Clin Lab Invest ; 84(4): 257-267, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38953609

RESUMO

INTRODUCTION: There are important pharmacological differences between direct oral anticoagulants (DOAC) and a deeper knowledge of how they influence different aspects of hemostasis in patients on treatment is desirable. MATERIALS AND METHODS: Blood samples from patients on dabigatran (n = 23), rivaroxaban (n = 26), or apixaban (n = 20) were analyzed with a fibrin network permeability assay, a turbidimetric clotting and lysis assay, the calibrated automated thrombogram (CAT), plasma levels of thrombin-antithrombin complex (TAT) and D-dimer, as well as DOAC concentrations, PT-INR and aPTT. As a comparison, we also analyzed samples from 27 patients on treatment with warfarin. RESULTS: Patients on dabigatran had a more permeable fibrin network, longer lag time (CAT and turbidimetric assay), and lower levels of D-dimer in plasma, compared with patients on rivaroxaban- and apixaban treatment, and a more permeable fibrin network than patients on warfarin. Clot lysis time was slightly longer in patients on dabigatran than in patients on rivaroxaban. Warfarin patients formed a more permeable fibrin network than patients on apixaban, had longer lag time than patients on rivaroxaban (CAT assay), and lower peak thrombin and ETP compared to patients on treatment with both FXa-inhibitors. CONCLUSIONS: Results from this study indicate dabigatran treatment is a more potent anticoagulant than apixaban and rivaroxaban. However, as these results are not supported by clinical data, they are probably more related to the assays used and highlight the difficulty of measuring and comparing the effect of anticoagulants.


Assuntos
Dabigatrana , Fibrina , Fibrinólise , Pirazóis , Piridonas , Rivaroxabana , Trombina , Humanos , Dabigatrana/farmacologia , Rivaroxabana/farmacologia , Pirazóis/farmacologia , Piridonas/farmacologia , Piridonas/uso terapêutico , Trombina/metabolismo , Masculino , Fibrina/metabolismo , Feminino , Idoso , Fibrinólise/efeitos dos fármacos , Pessoa de Meia-Idade , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Permeabilidade/efeitos dos fármacos , Varfarina/farmacologia , Idoso de 80 Anos ou mais , Anticoagulantes/farmacologia
3.
J Intern Med ; 291(3): 327-337, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34820922

RESUMO

BACKGROUND: Recent studies demonstrate that prothrombotic antiphospholipid antibodies (aPL) are overrepresented in patients with myocardial infarction (MI) due to coronary artery disease (MICAD). However, it is not known whether aPL differ between the two subsets of MI: MICAD and MI with nonobstructive coronary arteries (MINOCA). OBJECTIVES: To determine whether aPL are associated with MINOCA or MICAD, or with hypercoagulability as assessed by activated protein C-protein C inhibitor (APC-PCI) complex. METHODS: Well-characterized patients with MINOCA (n = 98), age- and gender-matched patients with MICAD (n = 99), and healthy controls (n = 100) were included in a cross-sectional case-control study. Autoantibodies (IgA/G/M) targeting cardiolipin and ß2 glycoprotein-I and specific nuclear antigens were analyzed by multiplexed bead technology. The concentration of APC-PCI was determined as a measure of hypercoagulability by an immunofluorometric sandwich assay. RESULTS: Both prevalence and titers of aPL of the IgG isotype (anti-cardiolipin and/or anti-ß2 glycoprotein-I) were higher in patients with MINOCA and MICAD than in controls. aPL IgG positivity was twice as frequent among patients with MICAD than MINOCA (11% vs. 6%, nonsignificant). We observed no group differences regarding aPL IgA/M or antibodies targeting specific nuclear antigens. Levels of APC-PCI were elevated in aPL IgG-positive compared to aPL IgG-negative MICAD patients. CONCLUSIONS: aPL IgG, but not IgA/M, are enriched particularly in patients with MICAD but also in patients with MINOCA, as compared to controls. Interestingly, signs of hypercoagulability-measured by increased levels of the APC-PCI complex-were present in aPL IgG-positive MICAD patients, indicating an association with functional disturbances of the coagulation system.


Assuntos
Infarto do Miocárdio , Intervenção Coronária Percutânea , Anticorpos Antifosfolipídeos , Estudos de Casos e Controles , Vasos Coronários , Estudos Transversais , Humanos , Infarto do Miocárdio/complicações , Infarto do Miocárdio/epidemiologia
4.
Stroke ; 52(10): 3082-3087, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34465201

RESUMO

Background and Purpose: The EFFECTS (Efficacy of Fluoxetine­a Randomised Controlled Trial in Stroke) recently reported that 20 mg fluoxetine once daily for 6 months after acute stroke did not improve functional outcome but reduced depression and increased fractures and hyponatremia at 6 months. The purpose of this predefined secondary analysis was to identify if any effects of fluoxetine were maintained or delayed over 12 months. Methods: EFFECTS was an investigator-led, randomized, placebo-controlled, double-blind, parallel group trial in Sweden that enrolled adult patients with stroke. Patients were randomized to 20 mg oral fluoxetine or matching placebo for 6 months and followed for another 6 months. The primary outcome was functional outcome (modified Rankin Scale), at 6 months. Predefined secondary outcomes for these analyses included the modified Rankin Scale, health status, quality of life, fatigue, mood, and depression at 12 months. Results: One thousand five hundred patients were recruited from 35 centers in Sweden between 2014 and 2019; 750 were allocated fluoxetine and 750 placebo. At 12 months, modified Rankin Scale data were available in 715 (95%) patients allocated fluoxetine and 712 (95%) placebo. The distribution of modified Rankin Scale categories was similar in the 2 groups (adjusted common odds ratio, 0.92 [95% CI, 0.76­1.10]). Patients allocated fluoxetine scored worse on memory with a median value of 89 (interquartile range, 75­100) versus 93 (interquartile range, 82­100); P=0.0021 and communication 93 (interquartile range, 82­100) versus 96 (interquartile range, 86­100); P=0.024 domains of the Stroke Impact Scale compared with placebo. There were no other differences in secondary outcomes. Conclusions: Fluoxetine after acute stroke had no effect on functional outcome at 12 months. Patients allocated fluoxetine scored worse on memory and communication on the Stroke Impact Scale compared with placebo, but this is likely to be due to chance. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02683213.


Assuntos
Fluoxetina/uso terapêutico , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Afeto , Idoso , Idoso de 80 Anos ou mais , Depressão/tratamento farmacológico , Depressão/etiologia , Método Duplo-Cego , Fadiga/epidemiologia , Feminino , Nível de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Qualidade de Vida , Recuperação de Função Fisiológica , Acidente Vascular Cerebral/psicologia , Suécia , Resultado do Tratamento
5.
Semin Thromb Hemost ; 47(7): 775-786, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34255337

RESUMO

The earliest assessment of fibrin network porosity used a liquid permeation system and confocal 3D microscopy, which was later replaced by scanning electron microscopy. Although the methods have extensively been applied in studies of health or disease, there remains debate on the choice of a proper clotting trigger. In this review, we assess published data and convey our opinions with regard to several issues. First, when the coagulation process is initiated by recombinant tissue factor (rTF) and phospholipids, the fibrin network porosity is regulated by the endogenous thrombin based on enzymatic activations of multiple coagulants. If purified thrombin (1.0 IU/mL) is employed as the clotting trigger, fibrin network porosity may be affected by exogenous thrombin, which directly polymerizes fibrinogen in plasma, and additionally by endogenous thrombin stemming from a "positive feedback loop" action of the added thrombin. Second, with use of either endogenous or exogenous thrombin, the concentration and clotting property of available fibrinogen both influence the fibrin network porosity. Third, in the assay systems in vitro, exogenous thrombin but not rTF-induced endogenous thrombin seems to be functional enough to activate factor XIII, which then contributes to a decrease in the fibrin network porosity. Fourth, fibrin network porosity determines the transport of fibrinolytic components into/through the clots and therefore serves as an indicator of the fibrinolysis potential in plasma.


Assuntos
Fibrina , Trombina , Coagulação Sanguínea , Fibrinogênio , Fibrinólise , Humanos , Porosidade
6.
Semin Thromb Hemost ; 47(1): 63-73, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33348413

RESUMO

Blood coagulation comprises a series of enzymatic reactions leading to thrombin generation and fibrin formation. This process is commonly illustrated in a waterfall-like manner, referred to as the coagulation cascade. In vivo, this "cascade" is initiated through the tissue factor (TF) pathway, once subendothelial TF is exposed and bound to coagulation factor VII (FVII) in blood. In vitro, a diminutive concentration of recombinant TF (rTF) is used as a clotting trigger in various global hemostasis assays such as the calibrated automated thrombogram, methods that assess fibrin turbidity and fibrin viscoelasticity tests such as rotational thromboelastometry. These assays aim to mimic in vivo global coagulation, and are useful in assessing hyper-/hypocoagulable disorders or monitoring therapies with hemostatic agents. An excess of rTF, a sufficient amount of negatively charged surfaces, various concentrations of exogenous thrombin, recombinant activated FVII, or recombinant activated FIXa are also used to initiate activation of specific sub-processes of the coagulation cascade in vitro. These approaches offer important information on certain specific coagulation pathways, while alterations in pro-/anticoagulants not participating in these pathways remain undetectable by these methods. Reviewing available data, we sought to enhance our knowledge of how choice of clotting trigger affects the outcome of hemostasis assays, and address the call for further investigations on this topic.


Assuntos
Testes de Coagulação Sanguínea/métodos , Coagulação Sanguínea/efeitos dos fármacos , Fibrina/metabolismo , Trombina/metabolismo , Humanos
7.
J Cardiovasc Pharmacol ; 78(4): 551-559, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34269699

RESUMO

ABSTRACT: We have previously shown increased vascular reactivity to angiotensin (Ang) II in familial combined hyperlipidemia. However, this has not been well studied in familial hypercholesterolemia (FH), a condition with incipient endothelial dysfunction. This study aimed to examine microvascular and macrovascular responses to Ang II in FH. Therefore, we investigated the effects of a 3-hour infusion of Ang II on blood pressure and forearm skin microvascular function in 16 otherwise healthy patients with FH and matched healthy controls. Skin microvascular hyperemia was studied by laser Doppler fluxmetry during local heating. Microvascular resistance was determined by the ratio of mean arterial pressure to microvascular hyperemia. Macrovascular reactivity was assessed by changes in brachial blood pressure. Compared with the controls, the FH group had increased baseline systolic blood pressure (127 ± 14 vs. 115 ± 12 mm Hg; P = 0.02), while systolic blood pressure responses were similar (+24 ± 9 vs. +21 ± 7 mm Hg; P = 0.26) after 3 hours of Ang II infusion. At baseline, there were no group differences in microvascular hyperemia or resistance. However, after 3 hours of Ang II infusion, heat-induced microvascular hyperemia was less pronounced in FH (126 ± 95 vs. 184 ± 102 arbitrary units; P = 0.01), while microvascular resistance during heat-induced hyperemia was increased (1.9 ± 0.9 vs. 0.9 ± 0.8, P = 0.01), as compared to controls. Both these responses were further pronounced 1 hour after stopping Ang II. In conclusion, despite similar blood pressure responses to Ang II in the FH group and controls, microvascular dilatation capacity was impaired in the FH group, indicating endothelial dysfunction. These findings and increased microvascular resistance may lead to hypertension and microvascular complications in FH.


Assuntos
Angiotensina II/administração & dosagem , Pressão Arterial/efeitos dos fármacos , Artéria Braquial/efeitos dos fármacos , Hiperlipoproteinemia Tipo II/fisiopatologia , Microcirculação/efeitos dos fármacos , Pele/irrigação sanguínea , Vasodilatação/efeitos dos fármacos , Adulto , Angiotensina II/sangue , Artéria Braquial/fisiopatologia , Estudos de Casos e Controles , Feminino , Antebraço , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/diagnóstico , Infusões Intravenosas , Fluxometria por Laser-Doppler , Masculino , Pessoa de Meia-Idade , Fatores de Tempo
8.
BMC Neurol ; 21(1): 306, 2021 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-34372806

RESUMO

BACKGROUND: Pro-inflammatory processes underlie ischemic stroke, albeit it is largely unknown if they selectively associate with the risk of atherothrombotic or cardioembolic ischemic stroke. Here we analyze whether pro-inflammatory interleukin (IL) 6 trans-signaling, is associated with the risk of ischemic stroke and underlying atrial fibrillation (AF). METHODS: During a 20-year follow-up, 203 incident ischemic strokes were recorded from national registers in the cohort of 60-year-old men and women from Stockholm (n = 4232). The risk of ischemic stroke associated with circulating IL6 trans-signaling, assessed by a ratio between the pro-inflammatory binary IL6:sIL6R complex and the inactive ternary IL6:sIL6R:sgp130 complex (B/T ratio), was estimated by Cox regression and expressed as hazard ratio (HR) with a 95% confidence interval (CI) in the presence or absence of AF. Risk estimates were adjusted for cardiovascular risk factors and anticoagulant treatment. In a secondary analysis, the association of IL6 trans-signaling with the risk of incident AF (n = 279) was analyzed. RESULTS: B/T ratio > median was associated with increased risk of ischemic stroke in study participants without AF (adjusted HR 1.49; 95% CI 1.08-2.06), while an association could not be demonstrated in the presence of AF. Moreover, the B/T ratio was not associated with the risk of AF (HR 0.96; 95% CI 0.75-1.24). CONCLUSIONS: Pro-inflammatory IL6 trans-signaling, estimated by the B/T ratio, is associated with ischemic stroke in individuals without AF. These findings suggest that the B/T ratio could be used to assess the risk of non-AF associated ischemic stroke.


Assuntos
Isquemia Encefálica , AVC Isquêmico , Fibrilação Atrial/complicações , Fibrilação Atrial/epidemiologia , Isquemia Encefálica/epidemiologia , Feminino , Humanos , Incidência , Interleucina-6 , Masculino , Pessoa de Meia-Idade , Medição de Risco , Fatores de Risco
9.
Vasc Med ; 26(1): 3-10, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33350884

RESUMO

Interleukin (IL) 6 contributes to atherosclerotic plaque development through IL6 membrane-bound (IL6R and gp130) and soluble (sIL6R and sgp130) receptors. We investigated IL6 receptor expression in carotid plaques and its correlation with circulating IL6 and soluble receptor levels. Plasma samples and carotid plaques were obtained from 78 patients in the Biobank of Karolinska Endarterectomies study. IL6, sIL6R, and sgp130 were measured in plasma and IL6, IL6R, sIL6R, GP130, and sGP130-RAPS (sGP130) gene expression assessed in carotid plaques. Correlations between plaque IL6 signaling gene expression and plasma levels were determined by Spearman's correlation. Differences in plasma and gene expression levels between patients with (n = 53) and without (n = 25) a history of a cerebral event and statin-treated (n = 65) and non-treated (n = 11), were estimated by Kruskal-Wallis. IL6 and its receptors were all expressed in carotid plaques. There was a positive, borderline significant, moderate correlation between plasma IL6 and sIL6R and the respective gene expression levels (rho 0.23 and 0.22, both p = 0.05). IL6R expression was higher in patients with a history of a cerebrovascular event compared to those without (p = 0.007). Statin-treated had higher IL6R, sIL6R, and sGP130 expression levels and plasma sIL6R compared to non-treated patients (all p < 0.05). In conclusion, all components of the IL6 signaling pathways are expressed in carotid artery plaques and IL6 and sIL6R plasma levels correlate moderately with IL6 and sIL6R. Our data suggest that IL6 signaling in the circulation might mirror the system activity in the plaque, thus adding novel perspectives to the role of IL6 signaling in atherosclerosis.


Assuntos
Artérias Carótidas/metabolismo , Estenose das Carótidas/metabolismo , Receptor gp130 de Citocina/metabolismo , Interleucina-6/metabolismo , Placa Aterosclerótica , Receptores de Interleucina-6/metabolismo , Idoso , Biomarcadores/metabolismo , Artérias Carótidas/cirurgia , Estenose das Carótidas/sangue , Estenose das Carótidas/genética , Estenose das Carótidas/terapia , Estudos Transversais , Receptor gp130 de Citocina/sangue , Receptor gp130 de Citocina/genética , Endarterectomia das Carótidas , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Interleucina-6/sangue , Interleucina-6/genética , Masculino , Receptores de Interleucina-6/sangue , Receptores de Interleucina-6/genética , Transdução de Sinais
10.
Scand Cardiovasc J ; 55(1): 1-8, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32969284

RESUMO

OBJECTIVES: Heart failure (HF) management is suboptimal in Sweden despite available evidence-based guidelines. To improve HF treatment, a comprehensive HF management program (4D project) was implemented in the Stockholm County (>2.1 million inhabitants). Design. A standardized care program centralized at five hospital-based HF clinics was implemented in 2014-2017. We registered from 2012 to 2017: (1) numbers of referrals and visits to HF clinics, (2) numbers of hospital admitted patients per million inhabitants, (3) dispensed HF medications after admission, and (4) covariate-adjusted 1-year all-cause mortality or HF readmission. Results. Yearly visits to the five HF outpatient clinics increased 3.4 times from 3,372 to 11,527. Dispensed HF drug prescriptions increased, in particular, for readmitted patients, compared to 2012 (p<.0001). Total number of hospital admitted HF patients as well as new-onset or readmitted HF patients decreased by 16, 13, and 20%, respectively (p < .0001). The combined 1-year mortality or HF readmission over the period was 48% (n = 17,124/35,880) and improved per year (HR 0.98 [0.97-0.99], p < .001) from 2012. Conclusion. A comprehensive standardized care HF management program including expanded HF clinics was associated with improved evidence-based medication, reduced HF hospitalization, and improvement of the combined outcome of 1-year mortality or HF readmission in Stockholm.


Assuntos
Insuficiência Cardíaca , Insuficiência Cardíaca/terapia , Humanos , Suécia , Resultado do Tratamento
11.
J Card Fail ; 26(5): 440-443, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32165346

RESUMO

BACKGROUND: Iron deficiency (ID) is common in patients with chronic heart failure (CHF), but the underlying causes are not fully understood. We investigated whether ID is associated with decreased iron absorption in patients with CHF. METHODS AND RESULTS: We performed an oral iron-absorption test in 30 patients and 12 controls. The patients had CHF with reduced (n = 15) or preserved (n = 15) ejection fraction and ID, defined as s-ferritin < 100 µg/L, or s-ferritin 100-299 µg/L and transferrin saturation < 20%. The controls had no HF or ID and were of similar age and gender. Blood samples were taken before and 2 hours after ingestion of 100 mg ferroglycin sulphate. The primary endpoint was the delta plasma iron at 2 hours. The delta plasma iron was higher in the group with HF than in the control group (median increase 83.8 [61.5;128.5] µg/dL in HF vs 47.5 [30.7;61.5] µg/dL in controls, P = 0.001), indicating increased iron absorption. There was no significant difference between the groups with preserved or reduced ejection fraction (P = 0.46). CONCLUSION: We found increased iron absorption in patients with CHF and ID compared to controls without ID and HF, indicating that reduced iron absorption is not a primary cause of the high prevalence of ID in patients with CHF. CLINICAL TRIAL REGISTRATION: EudraCT 2017-000158-21.


Assuntos
Anemia Ferropriva , Insuficiência Cardíaca , Anemia Ferropriva/diagnóstico , Anemia Ferropriva/epidemiologia , Doença Crônica , Ferritinas , Insuficiência Cardíaca/epidemiologia , Humanos , Ferro
12.
J Card Fail ; 26(12): 1050-1059, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32750486

RESUMO

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF) are associated with metabolic derangements, which may have different pathophysiological implications. METHODS AND RESULTS: In new-onset HFpEF (EF of ≥50%, n = 46) and HFrEF (EF of <40%, n = 75) patients, 109 endogenous plasma metabolites including amino acids, phospholipids and acylcarnitines were assessed using targeted metabolomics. Differentially altered metabolites and associations with clinical characteristics were explored. Patients with HFpEF were older, more often female with hypertension, atrial fibrillation, and diabetes compared with patients with HFrEF. Patients with HFpEF displayed higher levels of hydroxyproline and symmetric dimethyl arginine, alanine, cystine, and kynurenine reflecting fibrosis, inflammation and oxidative stress. Serine, cGMP, cAMP, l-carnitine, lysophophatidylcholine (18:2), lactate, and arginine were lower compared with patients with HFrEF. In patients with HFpEF with diabetes, kynurenine was higher (P = .014) and arginine lower (P = .014) vs patients with no diabetes, but did not differ with diabetes status in HFrEF. Decreasing kynurenine was associated with higher eGFR only in HFpEF (Pinteraction = .020). CONCLUSIONS: Patients with new-onset HFpEF compared with patients with new-onset HFrEF display a different metabolic profile associated with comorbidities, such as diabetes and kidney dysfunction. HFpEF is associated with indices of increased inflammation and oxidative stress, impaired lipid metabolism, increased collagen synthesis, and downregulated nitric oxide signaling. Together, these findings suggest a more predominant systemic microvascular endothelial dysfunction and inflammation linked to increased fibrosis in HFpEF compared with HFrEF. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT03671122 https://clinicaltrials.gov.


Assuntos
Fibrilação Atrial , Insuficiência Cardíaca , Disfunção Ventricular Esquerda , Feminino , Humanos , Metabolômica , Prognóstico , Volume Sistólico
13.
Haematologica ; 105(1): 218-225, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31048354

RESUMO

Pancreatic cancer is associated with a high incidence of venous thromboembolism. Neutrophils have been shown to contribute to thrombosis in part by releasing neutrophil extracellular traps (NET). A recent study showed that increased plasma levels of the NET biomarker, citrullinated histone H3 (H3Cit), are associated with venous thromboembolism in patients with pancreatic and lung cancer but not in those with other types of cancer, including breast cancer. In this study, we examined the contribution of neutrophils and NET to venous thrombosis in nude mice bearing human pancreatic tumors. We found that tumor-bearing mice had increased circulating neutrophil counts and levels of granulocyte-colony stimulating factor, neutrophil elastase, H3Cit and cell-free DNA compared with controls. In addition, thrombi from tumor-bearing mice contained increased levels of the neutrophil marker Ly6G, as well as higher levels of H3Cit and cell-free DNA. Thrombi from tumor-bearing mice also had denser fibrin with thinner fibers consistent with increased thrombin generation. Importantly, either neutrophil depletion or administration of DNase I reduced the thrombus size in tumor-bearing but not in control mice. Our results, together with clinical data, suggest that neutrophils and NET contribute to venous thrombosis in patients with pancreatic cancer.


Assuntos
Armadilhas Extracelulares , Neoplasias Pancreáticas , Trombose Venosa , Animais , Humanos , Camundongos , Camundongos Nus , Neutrófilos , Trombose Venosa/etiologia
14.
Arterioscler Thromb Vasc Biol ; 39(9): 1724-1738, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31315434

RESUMO

Recent studies have demonstrated a role of neutrophils in both venous and arterial thrombosis. A key prothrombotic feature of neutrophils is their ability to release web-like structures composed of DNA filaments coated with histones and granule proteins referred to as neutrophil extracellular traps (NETs). NETs were discovered over a decade ago as part of our first line of host defense against invading microorganisms. Although NETs have a protective role against pathogens, recent data suggest that an uncontrolled and excessive NET formation within the vasculature may contribute to pathological thrombotic disorders. In vitro studies suggest that NETs promote vessel occlusion by providing a scaffold for platelets, red blood cells, extracellular vesicles, and procoagulant molecules, such as von Willebrand factor and tissue factor. In addition, NET components enhance coagulation by both activating the intrinsic pathway and degrading an inhibitor of the extrinsic pathway (tissue factor pathway inhibitor). NET formation has, therefore, been proposed to contribute to thrombus formation and propagation in arterial, venous, and cancer-associated thrombosis. This review will describe animal and human studies suggesting a role of NETs in the pathogenesis of various thrombotic disorders. Targeting NETs may be a novel approach to reduce thrombosis without affecting hemostasis.


Assuntos
Armadilhas Extracelulares/fisiologia , Neoplasias/complicações , Neutrófilos/fisiologia , Trombose/tratamento farmacológico , Trombose/etiologia , Animais , Aterosclerose/etiologia , Cromatina/química , Desoxirribonuclease I/uso terapêutico , Armadilhas Extracelulares/efeitos dos fármacos , Humanos , Trombose Venosa/etiologia
15.
J Thromb Thrombolysis ; 48(1): 111-118, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30739306

RESUMO

The association between venous thromboembolism (VTE) and occult cancer is well established. However, the benefit of cancer screening in all VTE patients remains controversial. The Registro Informatizado Enfermedad TromboEmbólica (RIETE) score is a recently proposed risk score to identify VTE patients at high risk of occult cancer. We evaluated the performance of the RIETE score in a routine clinical setting comprising patients presenting with VTE between January 1 and December 31, 2014, at Danderyd University hospital. Out of 488 VTE patients, 47 (9.6%) patients received a new cancer diagnosis during a 24-month follow-up. After exclusion of patients with cancer diagnosed at baseline (≤ 10 days after VTE, n = 16), 472 patients were considered eligible for cancer screening. Among these 472 patients, 31 (6.6%) received a cancer diagnosis during follow-up. The cumulative incidence was high after both unprovoked (8.5%) and provoked (4.8%) VTE. The RIETE score was evaluated in 467 of these patients. Interestingly, a high RIETE score was not significantly associated with cancer diagnosis during follow-up (OR 1.78; 95% CI 0.85-3.63), which was mainly due to a poor performance in women (OR 1.04; 95% CI 0.30-2.83). In summary, we observed a relatively high incidence of occult cancer in both unprovoked and provoked VTE. The RIETE score performed poorly in identifying patients at high risk of occult cancer in our VTE population. Additional risk assessment models are warranted to identify VTE patients who would benefit from extensive cancer screening.


Assuntos
Detecção Precoce de Câncer/métodos , Neoplasias Primárias Desconhecidas/etiologia , Medição de Risco/métodos , Tromboembolia Venosa/complicações , Detecção Precoce de Câncer/estatística & dados numéricos , Humanos , Masculino , Neoplasias Primárias Desconhecidas/diagnóstico , Valor Preditivo dos Testes , Medição de Risco/normas , Fatores Sexuais
16.
Platelets ; 30(3): 348-355, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-29547014

RESUMO

Diabetes mellitus (DM) is associated with prothrombotic alterations, and postprandial hyperglycemia is an independent risk factor for cardiovascular complications. We therefore investigated whether a standardized mixed meal alters circulating microparticles (MPs) and their procoagulant activity in DM patients. Patients with DM type 1 (T1DM, n = 11) and type 2 (T2DM; n = 9) were studied before and 90 min after a standardized meal (without premeal insulin). MPs in plasma derived from platelets (PMPs), endothelial cells (EMPs), or monocytes (MMPs) were measured by flow cytometry. MP-induced thrombin generation in plasma was assessed by a calibrated automated thrombogram. In the fasting state, MPs did not differ significantly between T1DM and T2DM. Meal intake increased the following microparticles: PMPs expressing phosphatidylserine (by 55%, on average), P-selectin (by 86%), and tissue factor (TF; by 112%); EMPs expressing E-selectin (by 96%) and MMPs expressing TF (by 164%), with no significant group differences between T1DM and T2DM. There were no increments in EMPs expressing phosphatidylserine or TF. Meal intake increased MP-induced thrombin generation similarly in T1DM and T2DM with increased endogenous thrombin potential (p = 0.02) and peak thrombin (p = 0.03) and shortened time to peak (p = 0.02). Phosphatidylserine inhibition by lactadherin completely abolished MP-induced thrombin generation, while an anti-TF antibody had no effect. In conclusion, meal intake increased several types of circulating MPs in patients with diabetes mellitus. These MPs have a procoagulant potential, which is related to phosphatidylserine expression and negatively charged MP surfaces rather than to TF.


Assuntos
Micropartículas Derivadas de Células/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Refeições/fisiologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
17.
Scand J Clin Lab Invest ; 79(7): 507-512, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31502883

RESUMO

Microvesicles (MVs) released from leukocytes, platelets and endothelial cells are elevated in patients with acute coronary syndrome (ACS). In the present study, we assessed the potential pro-aggregatory properties of MVs obtained from ACS patients. Thus, we divided the patients into two groups based on clopidogrel-responsiveness, i.e. high on-treatment platelet reactivity (HPR; n = 16), and low or normal on-treatment platelet reactivity (non-HPR; n = 14), respectively. MVs from patients were obtained by high-speed centrifugation, and the pro-aggregatory effect of MVs added to fresh isolated platelets from healthy subjects were analyzed by 96-well microplate aggregometry. MVs from HPR patients significantly enhanced spontaneous platelet aggregation around two times more than MVs from non-HPR patients. The pro-aggregatory effect of three out of four MV phenotypes correlated to MV-concentrations as determined by flow cytometry. Furthermore, MVs from patients with diabetes mellitus (n = 9) had a stronger pro-aggregatory effect compared to MVs from those without diabetes (n = 21; p = .025 between groups). In conclusion, MVs from ACS patients with clopidogrel non-responsiveness enhance platelet aggregation, as do MVs from ACS patients with diabetes. Thus, MVs from patients with hyperreactive platelets boost platelet aggregation. Blocking MV-formation may reduce platelet hyperreactivity.


Assuntos
Síndrome Coronariana Aguda/sangue , Micropartículas Derivadas de Células/patologia , Agregação Plaquetária/fisiologia , Idoso , Clopidogrel/farmacologia , Diabetes Mellitus/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/farmacologia
18.
BMC Nephrol ; 20(1): 71, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30823870

RESUMO

BACKGROUND: Patients with chronic kidney disease (CKD) have a high risk of recurring thrombotic events following acute myocardial infarction (AMI). Microparticles (MPs) are circulating small vesicles shed from various cells. Platelet microparticles (PMPs) reflect platelet activation and endothelial microparticles (EMPs) reflect endothelial activation or dysfunction. Both increase following AMI, and may mediate important biological effects. We hypothesized that AMI patients with CKD have further elevated PMPs and EMPs compared with non-CKD patients, despite concurrent antithrombotic treatment. METHODS: We performed a descriptive study of patients with AMI. Fasting blood samples were acquired from 47 patients on dual antiplatelet treatment. Patients were stratified by renal function: normal (H; n = 19) mean eGFR 88; moderate CKD (CKD3; n = 15) mean eGFR 47, and severe CKD (CKD4-5; n = 13) mean eGFR 20 mL/min/1.73 m2. MPs were measured by flow-cytometry and phenotyped according to size (< 1.0 µm) and expression of CD41 (GPIIb; PMPs) and CD62E (E-selectin; EMPs). In addition, expression of platelet activation markers P-selectin (CD62P) and CD40ligand (CD154) were also investigated. RESULTS: PMPs expressing CD40 ligand were higher in CKD4-5: 210 /µl (174-237); median and interquartile range; vs. group H; 101 /µl (71-134; p < 0.0001) and CKD 3: 142 /µl (125-187; p = 0.006). PMPs expressing P-selectin were higher in CKD4-5 compared with H, but not in CKD3. EMPs were higher in CKD4-5; 245 /µl (189-308) compared with H; 83 /µl (53-140; p < 0.0001) and CKD3; 197 /µl (120-245; p < 0.002). CONCLUSIONS: In AMI patients, PMPs and EMPs from activated platelets and endothelial cell are further elevated in CKD patients. This indicate impaired endothelial function and higher platelet activation in CKD patients, despite concurrent antiplatelet treatment.


Assuntos
Micropartículas Derivadas de Células/fisiologia , Endotélio Vascular/fisiopatologia , Infarto do Miocárdio , Ativação Plaquetária , Inibidores da Agregação Plaquetária/farmacologia , Insuficiência Renal Crônica , Coagulação Sanguínea , Plaquetas/efeitos dos fármacos , Plaquetas/fisiologia , Correlação de Dados , Células Endoteliais/fisiologia , Feminino , Citometria de Fluxo/métodos , Taxa de Filtração Glomerular , Humanos , Testes de Função Renal/métodos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/sangue , Infarto do Miocárdio/complicações , Infarto do Miocárdio/diagnóstico , Ativação Plaquetária/efeitos dos fármacos , Ativação Plaquetária/fisiologia , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/diagnóstico
20.
Clin Endocrinol (Oxf) ; 84(5): 729-35, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26252432

RESUMO

OBJECTIVE: Graves' disease (GD) is an autoimmune disease characterized by the presence of circulating autoantibodies against thyroid-stimulating hormone (TSH) receptor. Despite extensive research, the pathogenic mechanisms remain unclear. Immune responses associated with the disease may lead to cell activation/apoptosis and the release of microvesicles (MVs) into the circulation. MVs can display biological activities which may aggravate GD further. We studied immune mechanisms in GD by investigating the numbers and phenotype of circulating MVs in patients before and after antithyroid therapy with thiamazole. PATIENTS AND MEASUREMENTS: Samples were obtained from 15 patients with GD in the acute phase of hyperthyroidism and following 17-26 months treatment and 14 healthy controls. MVs from platelets, endothelial cells and monocytes exposing inflammation/activation markers (P-selectin, CD40 ligand, E-selectin and HMGB1) and MVs containing nuclear molecules were measured with flow cytometry. RESULTS: Patients had elevated baseline values of MVs (P < 0·001 for all types of MVs), while the levels decreased during thiamazole treatment (P < 0·05 for all types of MVs). The majority of MV populations remained, however, significantly higher in patients after treatment compared to levels in controls. CONCLUSIONS: GD patients have elevated levels of MVs that carry molecules with potential biological activities. MVs are significantly reduced after antithyroid treatment with thiamazole but still higher compared to levels in healthy controls. Assessment of MV levels and pattern may therefore provide additional information on underlying immune disturbances not obtained by measurements of hormone levels alone.


Assuntos
Vesículas Extracelulares/efeitos dos fármacos , Doença de Graves/sangue , Doença de Graves/tratamento farmacológico , Metimazol/uso terapêutico , Adulto , Antitireóideos/uso terapêutico , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Ligante de CD40/metabolismo , Micropartículas Derivadas de Células/efeitos dos fármacos , Micropartículas Derivadas de Células/metabolismo , Selectina E/metabolismo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Vesículas Extracelulares/metabolismo , Feminino , Citometria de Fluxo , Proteína HMGB1/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Selectina-P/metabolismo , Fatores de Tempo , Resultado do Tratamento
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