55 research outputs found
Platelet-primed interactions of coagulation and anticoagulation pathways in flow-dependent thrombus formation
Abstract: In haemostasis and thrombosis, platelet, coagulation and anticoagulation pathways act together to produce fibrin-containing thrombi. We developed a microspot-based technique, in which we assessed platelet adhesion, platelet activation, thrombus structure and fibrin clot formation in real time using flowing whole blood. Microspots were made from distinct platelet-adhesive surfaces in the absence or presence of tissue factor, thrombomodulin or activated protein C. Kinetics of platelet activation, thrombus structure and fibrin formation were assessed by fluorescence microscopy. This work revealed: (1) a priming role of platelet adhesion in thrombus contraction and subsequent fibrin formation; (2) a surface-independent role of tissue factor, independent of the shear rate; (3) a mechanism of tissue factor-enhanced activation of the intrinsic coagulation pathway; (4) a local, suppressive role of the anticoagulant thrombomodulin/protein C pathway under flow. Multiparameter analysis using blood samples from patients with (anti)coagulation disorders indicated characteristic defects in thrombus formation, in cases of factor V, XI or XII deficiency; and in contrast, thrombogenic effects in patients with factor V-Leiden. Taken together, this integrative phenotyping approach of plateletâfibrin thrombus formation has revealed interaction mechanisms of platelet-primed key haemostatic pathways with alterations in patients with (anti)coagulation defects. It can help as an important functional add-on whole-blood phenotyping
Validation of a modified thromboelastometry approach to detect changes in fibrinolytic activity
Risk factors for Coronavirus disease 2019 (Covid-19) death in a population cohort study from the Western Cape province, South Africa
Risk factors for coronavirus disease 2019 (COVID-19) death in sub-Saharan Africa and the effects of human immunodeficiency virus (HIV) and tuberculosis on COVID-19 outcomes are unknown. We conducted a population cohort study using linked data from adults attending public-sector health facilities in the
Western Cape, South Africa. We used Cox proportional hazards models, adjusted for age, sex, location, and comorbidities, to examine the associations between HIV, tuberculosis, and COVID-19 death from 1 March to 9 June 2020 among (1) public-sector âactive patientsâ (â„1 visit in the 3 years before March 2020); (2) laboratory-diagnosed COVID-19 cases; and (3) hospitalized COVID-19
cases. We calculated the standardized mortality ratio (SMR) for COVID-19, comparing adults living with and without HIV using
modeled population estimates.Among 3 460 932 patients (16% living with HIV), 22 308 were diagnosed with COVID-19, of whom 625 died. COVID19 death was associated with male sex, increasing age, diabetes, hypertension, and chronic kidney disease. HIV was associated with
COVID-19 mortality (adjusted hazard ratio [aHR], 2.14; 95% confidence interval [CI], 1.70â2.70), with similar risks across strata of
viral loads and immunosuppression. Current and previous diagnoses of tuberculosis were associated with COVID-19 death (aHR,
2.70 [95% CI, 1.81â4.04] and 1.51 [95% CI, 1.18â1.93], respectively). The SMR for COVID-19 death associated with HIV was 2.39
(95% CI, 1.96â2.86); population attributable fraction 8.5% (95% CI, 6.1â11.1)
A História da Alimentação: balizas historiogråficas
Os M. pretenderam traçar um quadro da HistĂłria da Alimentação, nĂŁo como um novo ramo epistemolĂłgico da disciplina, mas como um campo em desenvolvimento de prĂĄticas e atividades especializadas, incluindo pesquisa, formação, publicaçÔes, associaçÔes, encontros acadĂȘmicos, etc. Um breve relato das condiçÔes em que tal campo se assentou faz-se preceder de um panorama dos estudos de alimentação e temas correia tos, em geral, segundo cinco abardagens Ia biolĂłgica, a econĂŽmica, a social, a cultural e a filosĂłfica!, assim como da identificação das contribuiçÔes mais relevantes da Antropologia, Arqueologia, Sociologia e Geografia. A fim de comentar a multiforme e volumosa bibliografia histĂłrica, foi ela organizada segundo critĂ©rios morfolĂłgicos. A seguir, alguns tĂłpicos importantes mereceram tratamento Ă parte: a fome, o alimento e o domĂnio religioso, as descobertas europĂ©ias e a difusĂŁo mundial de alimentos, gosto e gastronomia. O artigo se encerra com um rĂĄpido balanço crĂtico da historiografia brasileira sobre o tema
Protein C or Protein S deficiency associates with paradoxically impaired platelet-dependent thrombus and fibrin formation under flow
BACKGROUND: Low plasma levels of protein C or protein S are associated with venous thromboembolism rather than myocardial infarction. The high coagulant activity in patients with thrombophilia with a (familial) defect in protein C or S is explained by defective protein C activation, involving thrombomodulin and protein S. This causes increased plasmatic thrombin generation. OBJECTIVE: Assess the role of platelets in the thrombusâ and fibrinâforming potential in patients with familial protein C or protein S deficiency under highâshear flow conditions. PATIENTS/METHODS: Whole blood from 23 patients and 15 control subjects was perfused over six glycoprotein VIâdependent microspot surfaces. By realâtime multicolor microscopic imaging, kinetics of platelet thrombus and fibrin formation were characterized in 49 parameters. RESULTS AND CONCLUSION: Wholeâblood flow perfusion over collagen, collagenâlike peptide, and fibrin surfaces with low or high GPVI dependency indicated an unexpected impairment of platelet activation, thrombus phenotype, and fibrin formation but unchanged platelet adhesion, observed in patients with protein C deficiency and to a lesser extent protein S deficiency, when compared to controls. The defect extended from diminished phosphatidylserine exposure and thrombus contraction to delayed and suppressed fibrin formation. The mechanism was thrombomodulin independent, and may involve negative platelet priming by plasma components. [Image: see text
Increased mortality in SDHB but not in SDHD pathogenic variant carriers
Germline mutations in succinate dehydrogenase subunit B and D (SDHB and SDHD) are predisposed to hereditary paraganglioma (PGL) and pheochromocytoma (PHEO). The phenotype of pathogenic variants varies according to the causative gene. In this retrospective study, we estimate the mortality of a nationwide cohort of SDHB variant carriers and that of a large cohort of SDHD variant carriers and compare it to the mortality of a matched cohort of the general Dutch population. A total of 192 SDHB variant carriers and 232 SDHD variant carriers were included in this study. The Standard Mortality Ratio (SMR) for SDHB mutation carriers was 1.89, increasing to 2.88 in carriers affected by PGL. For SDHD variant carriers the SMR was 0.93 and 1.06 in affected carriers. Compared to the general population, mortality seems to be increased in SDHB variant carriers, especially in those affected by PGL. In SDHD variant carriers, the mortality is comparable to that of the general Dutch population, even if they are affected by PGL. This insight emphasizes the significance of DNA-testing in all PGL and PHEO patients, since different clinical risks may warrant gene-specific management strategies
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