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1.
Haemophilia ; 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31583797

RESUMO

INTRODUCTION: Postpartum haemorrhage (PPH) is the major cause of maternal death worldwide. Haemostatic abnormalities are independently associated with a significantly increased risk for severe PPH. In this study, the value of haemostatic evaluation in women with severe PPH was explored. AIM: To investigate the occurrence of previously unknown inherited bleeding disorders in women with severe PPH. METHODS: Women with severe PPH (blood loss of ≥2000 mL) between 2011 and 2017, referred to the haematology outpatient clinic for haemostatic evaluation, were retrospectively included. A bleeding disorder was diagnosed based on (inter)national guidelines, or when having a clear bleeding phenotype, not fulfilling any diagnostic criteria or laboratory abnormalities, this being classified as Bleeding of Unknown Cause (BUC). Logistic regression was used to model the association between diagnosis and obstetrical causes and risk factors for PPH. RESULTS: In total, 85 women with PPH were included. In 23% (n = 16), a mild bleeding disorder was diagnosed, including low von Willebrand factor (Low VWF 8/16), platelet function disorders (PFD 5/16), BUC (2/16) and von Willebrand disease type 1 (1/16). No significant associations were found between obstetrical causes or risk factors for PPH and the presence of a bleeding disorder. CONCLUSION: In 23% of women with severe PPH, a mild bleeding disorder was diagnosed, independent of obstetrical causes or risk factors for PPH. This implies that severe PPH can be the first clinical symptom of an inherited bleeding disorder. Therefore, to optimize clinical management, haemostatic evaluation after severe PPH is recommended.

2.
Infect Immun ; 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31527127

RESUMO

Staphylococcus aureus extracellular DNA (eDNA) plays a crucial role in the structural stability of biofilms during bacterial colonization, on the contrary, host immune responses can be induced by bacterial eDNA. Previously we observed production of S. aureus thermonuclease during the early stages of biofilm formation in a mammalian cell culture medium. Using a fluorescence resonance energy transfer (FRET)-based assay, we detected thermonuclease activity of S. aureus biofilms grown in Iscove's modified Dulbecco's medium (IMDM) earlier compared to widely-studied tryptic soy broth (TSB) grown biofilms. The thermonuclease found was Nuc1, confirmed by mass spectrometry and competitive Luminex assay. These results indicate that biofilm development in IMDM may not rely on eDNA for structural stability. A bacterial viability assay in combination with wheat germ agglutinin (WGA) staining confirmed the accumulation of dead cells and eDNA in biofilms grown in TSB. However, in IMDM-grown biofilms minimal amounts of eDNA were found and instead, polysaccharide intercellular adhesin (PIA) was detected. To investigate if this early production of thermonuclease plays a role in immune modulation by biofilm, we studied the effect of thermonuclease on human neutrophil extracellular traps (NETs) formation using a nuc knockout and complemented strain. We confirmed that thermonuclease produced by early stages biofilms grown in IMDM degraded biofilm-induced NETs. Additionally, neither the presence of biofilms nor thermonuclease stimulated an increase in reactive oxygen species (ROS) production by neutrophils. Our findings indicated that S. aureus, during the early stages of biofilm formation, actively evades the host immune responses by producing thermonuclease.

3.
J Thromb Haemost ; 17(11): 1848-1859, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31400072

RESUMO

BACKGROUND: Laboratory analyses of blood samples are essential for diagnostics and therapy monitoring of patients with bleeding and thromboembolic diseases. Following publication of the core curriculum for clinical thrombosis and hemostasis, the International Society on Thrombosis and Haemostasis (ISTH) recognized that thrombosis and hemostasis laboratory specialists require distinct competencies that differ from medical doctors working clinically with patients. To address this gap the ISTH formed a working group of international hemostasis and thrombosis laboratory specialists to develop an evidence-based core curriculum for laboratory specialists. OBJECTIVE: This research sought consensus from the international community on core competencies required for laboratory specialists in thrombosis and hemostasis. METHODS: A draft list of 64 competencies was developed and an online stakeholder survey was circulated electronically to 15 302 ISTH members and contacts in the wider international community. The results were analyzed and used to develop the final approved core curriculum. RESULTS: Three hundred and thirty responses contained meaningful data, with broad international representation of specialists. No draft competencies were excluded, and 58 were rated as "does" or "shows how." The Leik measure of consensus for most competences was "moderate" (n = 30) or "fair" (n = 32). CONCLUSIONS: The development of an international core curriculum for laboratory specialists provides a foundation for the development and enhancement of education and quality management of the laboratory. Although there is no formal designation for laboratory specialists, international governing bodies and regulatory organizations are encouraged to consider the diagnostic core curriculum for development and accreditation of more standardized educational programs and formal assessment across jurisdictions.

4.
PLoS One ; 14(5): e0216222, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31075152

RESUMO

BACKGROUND: Fibrinogen is an essential hemostatic factor and cardiovascular disease risk factor. Early attempts at evaluating the causal effect of fibrinogen on coronary heart disease (CHD) and myocardial infraction (MI) using Mendelian randomization (MR) used single variant approaches, and did not take advantage of recent genome-wide association studies (GWAS) or multi-variant, pleiotropy robust MR methodologies. METHODS AND FINDINGS: We evaluated evidence for a causal effect of fibrinogen on both CHD and MI using MR. We used both an allele score approach and pleiotropy robust MR models. The allele score was composed of 38 fibrinogen-associated variants from recent GWAS. Initial analyses using the allele score used a meta-analysis of 11 European-ancestry prospective cohorts, free of CHD and MI at baseline, to examine incidence CHD and MI. We also applied 2 sample MR methods with data from a prevalent CHD and MI GWAS. Results are given in terms of the hazard ratio (HR) or odds ratio (OR), depending on the study design, and associated 95% confidence interval (CI). In single variant analyses no causal effect of fibrinogen on CHD or MI was observed. In multi-variant analyses using incidence CHD cases and the allele score approach, the estimated causal effect (HR) of a 1 g/L higher fibrinogen concentration was 1.62 (CI = 1.12, 2.36) when using incident cases and the allele score approach. In 2 sample MR analyses that accounted for pleiotropy, the causal estimate (OR) was reduced to 1.18 (CI = 0.98, 1.42) and 1.09 (CI = 0.89, 1.33) in the 2 most precise (smallest CI) models, out of 4 models evaluated. In the 2 sample MR analyses for MI, there was only very weak evidence of a causal effect in only 1 out of 4 models. CONCLUSIONS: A small causal effect of fibrinogen on CHD is observed using multi-variant MR approaches which account for pleiotropy, but not single variant MR approaches. Taken together, results indicate that even with large sample sizes and multi-variant approaches MR analyses still cannot exclude the null when estimating the causal effect of fibrinogen on CHD, but that any potential causal effect is likely to be much smaller than observed in epidemiological studies.

5.
J Clin Endocrinol Metab ; 104(8): 3203-3212, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30938758

RESUMO

CONTEXT: Mechanisms linking high and high-normal thyroid function to increased cardiovascular risk remain unclear. Hypothetically, coagulation can play a role. OBJECTIVE: To investigate (i) the association of thyroid function with coagulation factors and (ii) whether coagulation factors mediate the association of thyroid function with cardiovascular disease (CVD). DESIGN AND SETTING: Rotterdam Study, a population-based prospective study. PARTICIPANTS AND MAIN OUTCOME MEASURES: In 5918 participants (mean age, 69.1 years), we measured TSH, free T4 (FT4), and coagulation factors [von Willebrand factor antigen (VWF:Ag), ADAMTS13 activity, fibrinogen]. Participants were followed up for the occurrence of cardiovascular events and deaths. Associations of thyroid function with coagulation factors (standardized z scores) and CVD were assessed through linear regression and Cox proportional hazards models, adjusted for potential confounders. We performed causal mediation analyses to evaluate whether the effect of thyroid function on CVD is mediated by coagulation. RESULTS: Higher FT4 levels were associated with higher VWF:Ag (ß = 0.34; 95% CI = 0.22, 0.47), lower ADAMTS13 activity (ß = -0.22; 95%CI = -0.35, -0.09), and higher fibrinogen (ß = 0.26; 95% CI = 0.13, 0.39); 857 incident cardiovascular events and 690 cardiovascular deaths occurred. FT4 levels were positively associated with cardiovascular events and deaths. The effect of FT4 on incident cardiovascular events was minimally mediated by fibrinogen (1.6%) but not by VWF:Ag and ADAMTS13. VWF:Ag and fibrinogen together mediated 10.0% of the effect of FT4 on cardiovascular deaths. CONCLUSIONS: Higher FT4 levels were associated with higher VWF:Ag, lower ADAMTS13 activity, and higher fibrinogen levels, indicating a procoagulant state. VWF:Ag and fibrinogen explained up to 10% of the link between FT4 and CVD.

6.
Clin Chem Lab Med ; 57(8): 1235-1241, 2019 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-30838837

RESUMO

Background Internal quality control (QC) rules for laboratory tests can be derived from analytical performance specifications (APS) using the six-sigma method. We tested the applicability of this paradigm to routine haemostasis measurements. Methods Three laboratories using different instruments and reagents calculated sigma scores for their prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen and antithrombin (AT) measurements. Sigma scores were calculated using biological variation (BV) data from the literature in combination with internal and external QC data. Results Wide ranges in sigma scores for the PT (0.1-6.8), APTT (0.0-4.3), fibrinogen (1.5-8.3) and AT (0.1-2.4) were observed when QC data was combined with the minimum, median and maximum value of BV data, due in particular to a large variation in within-subject and between-subjects coefficients of variation. When the median BV values were applied, most sigma scores were below 3.0, for internal QC data; 75% and for external QC data; 92%. Conclusions Our findings demonstrate that: (1) The sigma scores for common haemostasis parameters are relatively low, and (2) The application of the six-sigma method to BV-derived APS is hampered by the large variation in published BV data. As the six-sigma concept is based on requirements for monitoring, and many haemostasis tests are only designed for diagnostic purposes, a fit-for-purpose APS is needed to achieve clinically relevant quality goals.

7.
Arterioscler Thromb Vasc Biol ; 39(3): 360-372, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30700129

RESUMO

Objectives- The prediction of patients at risk for poor clinical outcome after acute ischemic stroke remains challenging. An imbalance of coagulation factors may play an important role in progression and prognosis of these patients. In this systematic review, we assessed the current literature on hemostasis biomarkers and the association with poor clinical outcome in acute ischemic stroke. Approach and Results- A systematic search of Embase, Medline, Cochrane Library, Web of Science, and Google Scholar was performed on studies reporting on hemostasis biomarkers and clinical outcome after acute ischemic stroke. Studies were considered eligible if blood samples were collected within 72 hours after symptom onset. Additionally, clinical outcome should be assessed using a disability score (Barthel Index or modified Rankin scale). Methodological quality of included studies was assessed with an adapted version of the Quality Assessment of Diagnostic Accuracy Studies questionnaire. A total of 80 articles were read full text, and 41 studies were considered eligible for inclusion, reporting on 37 different hemostasis biomarkers. No single biomarker appeared to be effective in predicting poor clinical outcome in acute ischemic stroke patients. Conclusions- Based on current literature, no clear recommendations can be provided on which hemostasis biomarkers are a predictor of clinical outcome after acute ischemic stroke. However, some biomarkers show promising results and need to be further investigated and validated in large populations with clear defined study designs.

8.
Scand J Clin Lab Invest ; 79(1-2): 32-38, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30727759

RESUMO

Haemostatic treatment in women experiencing postpartum haemorrhage is increasingly based on point-of-care devices such as ROTEM® thromboelastometry. Recently, a fully automated successor of the ROTEM® Delta device, the ROTEM® Sigma was introduced. To determine whether these devices provide similar results, we compared ROTEM® parameters using the ROTEM® Delta and Sigma devices in women experiencing postpartum haemorrhage. Prospective observational cohort study of 23 women experiencing postpartum haemorrhage. ROTEM® INTEM, EXTEM, FIBTEM and APTEM measurements handled by the ROTEM® Delta and Sigma devices were compared. ROTEM® FIBTEM values were also related to Clauss fibrinogen values. A correlation of Spearman's r (rs) varying between 0.76 and 0.95 was displayed between clot firmness measured in millimeters at 5 (A5), 10 (A10) and 20 (A20) minutes after start of clot formation measured by EXTEM, INTEM and APTEM assays executed on both devices; A5, A10 and A20 of FIBTEM correlated less well (rS between 0.71 and 0.74), especially after five and ten minutes. Correlation between both devices regarding clotting time (CT) was poor. The observed correlation between levels of Clauss fibrinogen and FIBTEM A5 was rs = 0.70, (95% confidence interval (CI): 0.38 to 0.87) for Delta and rs = 0.85, (CI 0.65 to 0.94) for Sigma. A5, A10 and A20 measured in EXTEM, INTEM and APTEM obtained from ROTEM® Delta and Sigma devices were similar. EXTEM, FIBTEM and APTEM CT values from both devices showed no correlation. Substantial variation was found between FIBTEM assays of the devices. Consequently, results of FIBTEM assays should always be interpreted in the context of device-specific reference values. Correlation with Clauss fibrinogen was better in the ROTEM® Sigma device.


Assuntos
Coagulação Sanguínea , Fibrinogênio/metabolismo , Hemorragia Pós-Parto/diagnóstico , Tromboelastografia/instrumentação , Adulto , Feminino , Humanos , Sistemas Automatizados de Assistência Junto ao Leito , Hemorragia Pós-Parto/sangue , Gravidez , Estudos Prospectivos , Tromboelastografia/métodos , Tromboelastografia/normas
9.
Blood ; 133(9): 967-977, 2019 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-30642921

RESUMO

Factor VII (FVII) is an important component of the coagulation cascade. Few genetic loci regulating FVII activity and/or levels have been discovered to date. We conducted a meta-analysis of 9 genome-wide association studies of plasma FVII levels (7 FVII activity and 2 FVII antigen) among 27 495 participants of European and African ancestry. Each study performed ancestry-specific association analyses. Inverse variance weighted meta-analysis was performed within each ancestry group and then combined for a trans-ancestry meta-analysis. Our primary analysis included the 7 studies that measured FVII activity, and a secondary analysis included all 9 studies. We provided functional genomic validation for newly identified significant loci by silencing candidate genes in a human liver cell line (HuH7) using small-interfering RNA and then measuring F7 messenger RNA and FVII protein expression. Lastly, we used meta-analysis results to perform Mendelian randomization analysis to estimate the causal effect of FVII activity on coronary artery disease, ischemic stroke (IS), and venous thromboembolism. We identified 2 novel (REEP3 and JAZF1-AS1) and 6 known loci associated with FVII activity, explaining 19.0% of the phenotypic variance. Adding FVII antigen data to the meta-analysis did not result in the discovery of further loci. Silencing REEP3 in HuH7 cells upregulated FVII, whereas silencing JAZF1 downregulated FVII. Mendelian randomization analyses suggest that FVII activity has a positive causal effect on the risk of IS. Variants at REEP3 and JAZF1 contribute to FVII activity by regulating F7 expression levels. FVII activity appears to contribute to the etiology of IS in the general population.

10.
Eur Heart J Cardiovasc Pharmacother ; 5(2): 91-99, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30608563

RESUMO

AIMS: Effective anticoagulation in patients undergoing electrical cardioversion (ECV) for symptomatic atrial fibrillation is important to prevent adverse events. High medication adherence is a requirement. In patients with newly diagnosed atrial fibrillation (n = 169) who were intended to undergo ECV, the aim of this study was to measure self-reported short- and long-term adherence, evaluate whether dabigatran plasma concentrations reflect adherence, measure treatment satisfaction and assess whether adherence and treatment satisfaction are correlated. METHODS AND RESULTS: Plasma concentrations (liquid-chromatography tandem mass spectrometry), the 8-point Morisky Medication Adherence Scale (MMAS-8) and the Anti-Clot Treatment Scale (ACTS) were measured after 3 weeks and 7 weeks of treatment. Combined mean peak (1-3 h after intake) and trough (10-16 h after intake) plasma concentrations were 175 (SD 109) ng/mL and 75 (SD 45) ng/mL, respectively. There was no relationship between short-term adherence (last 3 days) or long-term adherence (last 3-4 weeks) and plasma concentrations, unless the last intake was more than 48 h ago. After 7 weeks high, moderate, and low adherence, according to the MMAS-8, was seen in 74%, 21%, and 5% of patients, respectively. Treatment satisfaction was high (median ACTS score 68.5, range 46-75 points). Treatment satisfaction and adherence were not correlated. CONCLUSION: The percentage of patients in the high adherence group (74%) was lower than expected, which is a matter of concern. Dabigatran plasma concentrations could not detect short- or long-term non-adherence, unless the drug was last taken more than 48 h ago. Treatment satisfaction did not correlate with adherence.


Assuntos
Antitrombinas/administração & dosagem , Fibrilação Atrial/terapia , Dabigatrana/administração & dosagem , Cardioversão Elétrica , Adesão à Medicação , Idoso , Antitrombinas/sangue , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/fisiopatologia , Cromatografia Líquida , Dabigatrana/sangue , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Masculino , Satisfação do Paciente , Estudos Prospectivos , Autorrelato , Espectrometria de Massas em Tandem , Fatores de Tempo , Resultado do Tratamento
11.
Thromb Res ; 175: 8-12, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30660948

RESUMO

INTRODUCTION: Heparins exert their anticoagulant effect through activation of antithrombin. Whether antithrombin deficiency leads to clinically relevantly reduced anti-Xa activity of heparins is unknown. We investigated the relation between antithrombin deficiency and anti-Xa activity measurements of plasma samples spiked with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). MATERIALS AND METHODS: Plasma samples from 34 antithrombin-deficient subjects and 17 family controls were spiked with UFH and LMWH (nadroparin) aimed to correspond with an anti-Xa activity of 0.8 IU/mL. Antithrombin, ß-antithrombin and anti-Xa activities were measured. RESULTS: Mean anti-Xa activity with LWMH was 0.55 IU/mL (0.30-0.74) (recovery 69%, 38-93%) in antithrombin-deficient subjects and 0.82 (0.71-0.89) IU/mL in controls (recovery 103%, 89-111%). Expected anti-Xa measurements after LMWH spiking were found in 17/17 non-deficient subjects and in 8/34 antithrombin-deficient subjects. Anti-Xa measurements in the expected range (0.6-1.0 IU/mL) after UFH spiking were found in 17/17 non-deficient subjects and in 1/22 antithrombin-deficient subjects. Antithrombin activity correlated with anti-Xa activity of UFH (R = 0.77) and LMWH (R = 0.66). Mixing studies of pooled normal plasma and antithrombin-deficient plasma showed that anti-Xa recovery was linearly reduced with antithrombin activity decreasing below 100%. CONCLUSIONS: Reduced antithrombin activity causes significantly reduced anti-Xa levels. Standard LWMH- or UFH-doses are likely to lead to under treatment in antithrombin-deficient individuals.


Assuntos
Deficiência de Antitrombina III/tratamento farmacológico , Heparina de Baixo Peso Molecular/uso terapêutico , Estudos Transversais , Feminino , Heparina de Baixo Peso Molecular/sangue , Heparina de Baixo Peso Molecular/farmacologia , Humanos , Masculino , Estudos Retrospectivos
12.
Circulation ; 139(5): 620-635, 2019 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-30586737

RESUMO

BACKGROUND: Factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are associated with risk of arterial and venous thrombosis and with hemorrhagic disorders. We aimed to identify and functionally test novel genetic associations regulating plasma FVIII and VWF. METHODS: We meta-analyzed genome-wide association results from 46 354 individuals of European, African, East Asian, and Hispanic ancestry. All studies performed linear regression analysis using an additive genetic model and associated ≈35 million imputed variants with natural log-transformed phenotype levels. In vitro gene silencing in cultured endothelial cells was performed for candidate genes to provide additional evidence on association and function. Two-sample Mendelian randomization analyses were applied to test the causal role of FVIII and VWF plasma levels on the risk of arterial and venous thrombotic events. RESULTS: We identified 13 novel genome-wide significant ( P≤2.5×10-8) associations, 7 with FVIII levels ( FCHO2/TMEM171/TNPO1, HLA, SOX17/RP1, LINC00583/NFIB, RAB5C-KAT2A, RPL3/TAB1/SYNGR1, and ARSA) and 11 with VWF levels ( PDHB/PXK/KCTD6, SLC39A8, FCHO2/TMEM171/TNPO1, HLA, GIMAP7/GIMAP4, OR13C5/NIPSNAP, DAB2IP, C2CD4B, RAB5C-KAT2A, TAB1/SYNGR1, and ARSA), beyond 10 previously reported associations with these phenotypes. Functional validation provided further evidence of association for all loci on VWF except ARSA and DAB2IP. Mendelian randomization suggested causal effects of plasma FVIII activity levels on venous thrombosis and coronary artery disease risk and plasma VWF levels on ischemic stroke risk. CONCLUSIONS: The meta-analysis identified 13 novel genetic loci regulating FVIII and VWF plasma levels, 10 of which we validated functionally. We provide some evidence for a causal role of these proteins in thrombotic events.

14.
Haemophilia ; 2018 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-30488994

RESUMO

BACKGROUND: Both one-stage (OSA) and chromogenic substrate assays (CSA) are used to measure factor VIII (FVIII) activity. Factors explaining analytical variation in FVIII activity levels are still to be completely elucidated. AIM: The aim of this study was to investigate and quantify the analytical variation in OSA and CSA. METHODS: Factors determining analytical variation were studied in sixteen lyophilized plasma samples (FVIII activity <0.01-1.94 IU/mL) and distributed by the ECAT surveys. To elucidate the causes of OSA variation, we exchanged deficient plasma between three company set-ups. RESULTS: On average, 206 (range 164-230) laboratories used the OSA to measure FVIII activity and 30 (range 12-51) used CSA. The coefficient of variation of OSA and CSA increased with lower FVIII levels (FVIII <0.05 IU/mL). This resulted in misclassification of a severe haemophilia A sample into a moderate or mild haemophilia A sample in 4/30 (13.3%) of CSA measurements, while this was 37/139 (26.6%) for OSA. OSA measurements performed with reagents and equipment from Werfen showed slightly lower FVIII activity (0.93, IQR 0.88-0.98 IU/mL) compared to measurements with Stago (1.07, IQR 1.02-1.14 IU/mL) and Siemens (1.03, IQR 0.97-1.07 IU/mL). Part of this difference is explained by the value of the calibrator. For CSA, the measured FVIII levels were similar using the different kits. CONCLUSIONS: In the lower range (<0.05 IU/mL), analytical variation of FVIII measurements is high in both OSA and CSA measurements. The variation in FVIII activity levels was partly explained by specific manufacturers. Further standardization of FVIII measurements and understanding of analytical variation is required.

15.
Blood Adv ; 2(19): 2433-2442, 2018 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-30266818

RESUMO

We describe the pattern of change in coagulation parameters during the course of severe postpartum hemorrhage in a retrospective cohort study among 1312 women experiencing severe postpartum hemorrhage necessitating blood transfusion. Levels of hemoglobin, hematocrit, platelet count, fibrinogen, activated partial thromboplastin time (aPTT) and prothrombin time (PT) per categorized volume of blood loss during severe postpartum hemorrhage were described and compared between women with and without the composite adverse outcome. Need for surgical intervention, severe acute maternal morbidity, and maternal mortality were jointly considered the composite adverse outcome. Of the 1312 women, 463 (35%) developed the composite adverse outcome. The incidence of a fibrinogen level <2 g/L was 26% (342 per 1312). Low fibrinogen and prolonged aPTT during the first 2 L of hemorrhage were associated with a subsequent composite adverse outcome; median fibrinogen and aPTT among women with and without the composite end point after 1.5 to 2 L of hemorrhage were 1.5 g/L (interquartile range [IQR], 1.0-1.9) vs 2.7 g/L (IQR, 1.9-3.4) and 39 s (IQR, 30-47) vs 32 s (IQR, 28-36), respectively. PT and platelet count as assessed during the first 2 L of hemorrhage were not associated with morbidity or mortality. Our results suggest that detection of low levels of fibrinogen and elevated aPTT levels during early postpartum hemorrhage can contribute to the identification of women that may benefit from targeted hemostatic treatment. Essential in this identification process is the moment of reaching a level of fibrinogen of <2 g/L during the course of postpartum hemorrhage.

16.
J Am Heart Assoc ; 7(13)2018 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-29934420

RESUMO

BACKGROUND: Currently, acute ischemic stroke is still a leading cause of mortality and morbidity. Approximately 2 years ago, mechanical thrombectomy was proven beneficial as a revolutionary new therapy for stroke in the MR-CLEAN trial (A Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands). However, the mechanisms by which the thrombectomy device, or stent-retriever, interacts with the thrombus are largely unknown. A better understanding could lead to improved efficacy of mechanical thrombectomy devices. METHODS AND RESULTS: Seven stent-retrievers with thrombi still entrapped were collected directly after thrombectomy. The stent-retrievers were studied using micro computed tomography, followed by scanning electron microscopy and light microscopy. Two independent observers rated interaction type and thrombus surface structure (porous filamentous or dense) at the interaction sites.A total of 79 interaction sites between thrombus and stent-retriever were categorized. Thrombus-stent-retriever interaction was found to be adhesive (n=44; 56%) or mechanical (n=35; 44%). Adhesive interaction was most frequently observed at interaction sites with a dense surface, compared with interaction sites with a porous filamentous fibrin surface (38/58; 66% versus 6/21; 29%, P=0.011). CONCLUSIONS: The interaction between thrombus and stent-retriever was predominantly adhesive, not mechanical. Adhesive interaction was strongly associated with the presence of a dense thrombus surface without a porous filamentous fibrin network.

18.
Front Immunol ; 9: 165, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29459871

RESUMO

Staphylococcus aureus are strong inducers of neutrophil extracellular traps (NETs), a defense mechanism of neutrophils against pathogens. Our aim was to explore the role of Protein A in S. aureus-induced NETosis. We determined the Protein A production of four different S. aureus strains and found a direct relationship between the degree of NETosis induction and Protein A production: strains producing higher concentrations of Protein A evoke significantly more NETs. A S. aureus strain in which Protein A as well as a second binding protein for immunoglobulins (Sbi) have been knocked-out (ΔSpA ΔSbi) induced significantly less NETosis than the wild-type strain. NETosis induction by this knockout strain can be rescued by the addition of purified Protein A. Dead S. aureus did not induce NETosis. In conclusion, Protein A is a determinant for NETosis induction by S. aureus.

19.
Thromb Res ; 164: 32-39, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29475179

RESUMO

BACKGROUND: Issues with laboratory measurement of dabigatran include: 1. Do coagulation assays reflect dabigatran plasma concentrations? 2. Do samples from patients treated with dabigatran have the same coagulability as dabigatran-spiked samples from healthy volunteers? 3. What is the long-term stability of dabigatran after storage at -80 °C? This study aims to evaluate these questions. MATERIALS AND METHODS: Ecarin chromogenic assay (ECA), a laboratory-developed diluted thrombin time (LD-dTT), prothrombin time (PT) and activated partial thromboplastin time (APTT) and ROTEM® were used to measure dabigatran anticoagulant activity and liquid chromatography-tandem mass spectrometry (LC-MS/MS) to measure dabigatran plasma concentrations. ROTEM® (EXTEM, INTEM, FIBTEM) was performed in whole blood and the other assays in platelet poor plasma (PPP), both in samples spiked with dabigatran (0, 25, 50, 100, 250, 500 and 1000 ng/mL) from healthy donors and in ex vivo samples from patients treated with dabigatran etexilate. Citrated PPP samples were frozen and stored at -80 °C, 1, 3, 6 and 12 months until analysis. RESULTS: EXTEM and FIBTEM clotting time (CT), ECA and LD-dTT correlate well with dabigatran plasma concentrations. With the exception of few ROTEM® parameters, there were no differences between spiked and patient samples. Samples were stable for at least 12 months at -80 °C. CONCLUSIONS: EXTEM and FIBTEM CT, ECA and LD-dTT are suitable for measuring the effect of dabigatran in treated patients. In general, results from spiked plasma samples are similar to those of patient samples. Storage of dabigatran plasma samples for up to 12 months does not influence measured levels.


Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Adolescente , Adulto , Idoso , Anticoagulantes/farmacologia , Anticoagulantes/uso terapêutico , Dabigatrana/farmacologia , Dabigatrana/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
20.
Atherosclerosis ; 269: 144-150, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29366986

RESUMO

BACKGROUND AND AIMS: It is as yet unknown whether antithrombin levels are associated with arterial thromboembolism (ATE) at a young age. To investigate the association between antithrombin levels and premature and recurrent ATE, we performed a case-control study and a subsequent nested cohort study of premature coronary heart disease (CHD) patients. METHODS: In the case-control study, we included 571 patients who had a recent premature ATE, including CHD and ischemic stroke (IS), and 461 healthy controls. The association between antithrombin levels (dichotomized: ≤median vs. >median) and ATE was investigated. Subsequently we studied the association between antithrombin levels and recurrent cardiac events, ATE or death in a nested cohort of 323 CHD patients. RESULTS: Low antithrombin levels (≤median, 1.04 IU/mL) are associated with an increased risk of ATE (OR 1.46; 95% CI:1.09-1.96), after adjustment for classical cardiovascular risk factors. This was observed in the subgroups of CHD patients (1.43; 1.01-2.02) and IS patients (1.48; 1.01-2.19). CHD patients with low antithrombin levels had a higher risk of recurrent cardiac events (HR 2.16, 95% CI:1.07-4.38). Especially in women with low antithrombin levels, the risk of recurrent cardiac events was high (HR 5.97, 95% CI 1.31-27.13) as was the risk of recurrent ATE or death (HR 4.22, 95% CI 1.19-15.00). CONCLUSIONS: Individuals with relatively low antithrombin levels have an increased risk for ATE at a younger age. CHD patients with low antithrombin levels, especially women, have a higher risk of recurrent cardiac events.

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