| 1. |
- Spronk, H. M. H., et al.
(författare)
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Atherothrombosis and Thromboembolism : Position Paper from the Second Maastricht Consensus Conference on Thrombosis
- 2018
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Ingår i: Thrombosis and Haemostasis. - : SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN. - 0340-6245 .- 2567-689X. ; 118:2, s. 229-250
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Forskningsöversikt (refereegranskat)abstract
- Atherothrombosis is a leading cause of cardiovascular mortality and long-term morbidity. Platelets and coagulation proteases, interacting with circulating cells and in different vascular beds, modify several complex pathologies including atherosclerosis. In the second Maastricht Consensus Conference on Thrombosis, this theme was addressed by diverse scientists from bench to bedside. All presentations were discussed with audience members and the results of these discussions were incorporated in the final document that presents a state-of-the-art reflection of expert opinions and consensus recommendations regarding the following five topics:1. Risk factors, biomarkers and plaque instability: In atherothrombosis research, more focus on the contribution of specific risk factors like ectopic fat needs to be considered; definitions of atherothrombosis are important distinguishing different phases of disease, including plaque (in) stability; proteomic and metabolomics data are to be added to genetic information.2. Circulating cells including platelets and atherothrombosis: Mechanisms of leukocyte and macrophage plasticity, migration, and transformation in murine atherosclerosis need to be considered; diseasemechanism-based biomarkers need to be identified; experimental systems are needed that incorporatewhole-blood flow to understand how red blood cells influence thrombus formation and stability; knowledge on platelet heterogeneity and priming conditions needs to be translated toward the in vivo situation.3. Coagulation proteases, fibrin(ogen) and thrombus formation: The role of factor (F) XI in thrombosis including the lower margins of this factor related to safe and effective antithrombotic therapy needs to be established; FXI is a key regulator in linking platelets, thrombin generation, and inflammatory mechanisms in a renin-angiotensin dependent manner; however, the impact on thrombin-dependent PAR signaling needs further study; the fundamental mechanisms in FXIII biology and biochemistry and its impact on thrombus biophysical characteristics need to be explored; the interactions of red cells and fibrin formation and its consequences for thrombus formation and lysis need to be addressed. Platelet-fibrin interactions are pivotal determinants of clot formation and stability with potential therapeutic consequences.4. Preventive and acute treatment of atherothrombosis and arterial embolism; novel ways and tailoring? The role of protease-activated receptor (PAR)-4 vis a vis PAR-1 as target for antithrombotic therapy merits study; ongoing trials on platelet function test-based antiplatelet therapy adjustment support development of practically feasible tests; risk scores for patients with atrial fibrillation need refinement, taking new biomarkers including coagulation into account; risk scores that consider organ system differences in bleeding may have added value; all forms of oral anticoagulant treatment require better organization, including education and emergency access; laboratory testing still needs rapidly available sensitive tests with short turnaround time.5. Pleiotropy of coagulation proteases, thrombus resolution and ischaemia-reperfusion: Biobanks specifically for thrombus storage and analysis are needed; further studies on novelmodified activated protein C-based agents are required including its cytoprotective properties; new avenues for optimizing treatment of patients with ischaemic stroke are needed, also including novel agents that modify fibrinolytic activity (aimed at plasminogen activator inhibitor-1 and thrombin activatable fibrinolysis inhibitor.
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| 3. |
- Neumann, J. T., et al.
(författare)
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Application of High-Sensitivity Troponin in Suspected Myocardial Infarction
- 2019
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Ingår i: New England Journal of Medicine. - : MASSACHUSETTS MEDICAL SOC. - 0028-4793 .- 1533-4406. ; 380:26, s. 2529-2540
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundData regarding high-sensitivity troponin concentrations in patients presenting to the emergency department with symptoms suggestive of myocardial infarction may be useful in determining the probability of myocardial infarction and subsequent 30-day outcomes. MethodsIn 15 international cohorts of patients presenting to the emergency department with symptoms suggestive of myocardial infarction, we determined the concentrations of high-sensitivity troponin I or high-sensitivity troponin T at presentation and after early or late serial sampling. The diagnostic and prognostic performance of multiple high-sensitivity troponin cutoff combinations was assessed with the use of a derivation-validation design. A risk-assessment tool that was based on these data was developed to estimate the risk of index myocardial infarction and of subsequent myocardial infarction or death at 30 days. ResultsAmong 22,651 patients (9604 in the derivation data set and 13,047 in the validation data set), the prevalence of myocardial infarction was 15.3%. Lower high-sensitivity troponin concentrations at presentation and smaller absolute changes during serial sampling were associated with a lower likelihood of myocardial infarction and a lower short-term risk of cardiovascular events. For example, high-sensitivity troponin I concentrations of less than 6 ng per liter and an absolute change of less than 4 ng per liter after 45 to 120 minutes (early serial sampling) resulted in a negative predictive value of 99.5% for myocardial infarction, with an associated 30-day risk of subsequent myocardial infarction or death of 0.2%; a total of 56.5% of the patients would be classified as being at low risk. These findings were confirmed in an external validation data set. ConclusionsA risk-assessment tool, which we developed to integrate the high-sensitivity troponin I or troponin T concentration at emergency department presentation, its dynamic change during serial sampling, and the time between the obtaining of samples, was used to estimate the probability of myocardial infarction on emergency department presentation and 30-day outcomes.
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| 6. |
- Heestermans, M, et al.
(författare)
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Identification of the factor XII contact activation site enables sensitive coagulation diagnostics
- 2021
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1, s. 5596-
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Tidskriftsartikel (refereegranskat)abstract
- Contact activation refers to the process of surface-induced activation of factor XII (FXII), which initiates blood coagulation and is captured by the activated partial thromboplastin time (aPTT) assay. Here, we show the mechanism and diagnostic implications of FXII contact activation. Screening of recombinant FXII mutants identified a continuous stretch of residues Gln317–Ser339 that was essential for FXII surface binding and activation, thrombin generation and coagulation. Peptides spanning these 23 residues competed with surface-induced FXII activation. Although FXII mutants lacking residues Gln317–Ser339 were susceptible to activation by plasmin and plasma kallikrein, they were ineffective in supporting arterial and venous thrombus formation in mice. Antibodies raised against the Gln317–Ser339 region induced FXII activation and triggered controllable contact activation in solution leading to thrombin generation by the intrinsic pathway of coagulation. The antibody-activated aPTT allows for standardization of particulate aPTT reagents and for sensitive monitoring of coagulation factors VIII, IX, XI.
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| 7. |
- Iglesias, M. J., et al.
(författare)
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Identification of Endothelial Proteins in Plasma Associated With Cardiovascular Risk Factors
- 2021
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Ingår i: Arteriosclerosis Thrombosis and Vascular Biology. - : Ovid Technologies (Wolters Kluwer Health). - 1079-5642 .- 1524-4636. ; 41:12, s. 2990-3004
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Endothelial cell (EC) dysfunction is a well-established response to cardiovascular disease risk factors, such as smoking and obesity. Risk factor exposure can modify EC signaling and behavior, leading to arterial and venous disease development. Here, we aimed to identify biomarker panels for the assessment of EC dysfunction, which could be useful for risk stratification or to monitor treatment response. Approach and Results: We used affinity proteomics to identify EC proteins circulating in plasma that were associated with cardiovascular disease risk factor exposure. Two hundred sixteen proteins, which we previously predicted to be EC-enriched across vascular beds, were measured in plasma samples (N=1005) from the population-based SCAPIS (Swedish Cardiopulmonary Bioimage Study) pilot. Thirty-eight of these proteins were associated with body mass index, total cholesterol, low-density lipoprotein, smoking, hypertension, or diabetes. Sex-specific analysis revealed that associations predominantly observed in female- or male-only samples were most frequently with the risk factors body mass index, or total cholesterol and smoking, respectively. We show a relationship between individual cardiovascular disease risk, calculated with the Framingham risk score, and the corresponding biomarker profiles. Conclusions: EC proteins in plasma could reflect vascular health status.
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| 9. |
- Konrath, S, et al.
(författare)
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Intrinsic coagulation pathway-mediated thrombin generation in mouse whole blood
- 2022
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Ingår i: Frontiers in cardiovascular medicine. - : Frontiers Media SA. - 2297-055X. ; 9, s. 1008410-
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Tidskriftsartikel (refereegranskat)abstract
- Calibrated Automated Thrombography (CAT) is a versatile and sensitive method for analyzing coagulation reactions culminating in thrombin generation (TG). Here, we present a CAT method for analyzing TG in murine whole blood by adapting the CAT assay used for measuring TG in human plasma. The diagnostically used artificial and physiologic factor XII (FXII) contact activators kaolin, ellagic acid and polyphosphate (polyP) stimulated TG in murine blood in a dose-dependent manner resulting in a gradual increase in endogenous thrombin potential and peak thrombin, with shortened lag times and times to peak. The activated FXII inhibitor rHA-Infestin-4 and direct oral anticoagulants (DOACs) interfered with TG triggered by kaolin, ellagic acid and polyP and TG was completely attenuated in blood of FXII- (F12−/−) and FXI-deficient (F11−/−) mice. Moreover, reconstitution of blood from F12−/− mice with human FXII restored impaired contact-stimulated TG. HEK293 cell-purified polyP also initiated FXII-driven TG in mouse whole blood and addition of the selective inhibitor PPX_Δ12 ablated natural polyP-stimulated TG. In conclusion, the data provide a method for analysis of contact activation-mediated TG in murine whole blood. As the FXII-driven intrinsic pathway of coagulation has emerged as novel target for antithrombotic agents that are validated in mouse thrombosis and bleeding models, our novel assay could expedite therapeutic drug development.
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| 14. |
- Larsson, M, et al.
(författare)
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When Life-Saving Is Life-Threatening
- 2014
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Ingår i: SCIENCE TRANSLATIONAL MEDICINE. - 1946-6234. ; 6:222
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 16. |
- Merle, Renaud, 1976-, et al.
(författare)
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Mt Bambouto Volcano, Cameroon Line : Mantle Source and Differentiation of Within-plate Alkaline Rocks
- 2017
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Ingår i: Journal of Petrology. - : Oxford University Press (OUP). - 0022-3530 .- 1460-2415. ; 58:5, s. 933-962
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Tidskriftsartikel (refereegranskat)abstract
- The Late Cretaceous–Quaternary Cameroon Volcanic Line (CVL) is a 1600 km long chain of volcanoes that straddles the continent–ocean boundary and extends from the Gulf of Guinea to the interior of the African continent. The magmatic activity started at 70 Ma and has continued until the present. The products of this magmatic activity are distinctive in terms of petrology and isotope geochemistry, the variety of volcanic rocks ranging from ultrabasic, alkaline to sub-alkaline lavas to highly evolved alkaline lavas with isotopic compositions indicating complex combinations of both sub-lithospheric (HIMU, EM, DMM) and lithospheric components (sub-continental lithospheric mantle and crust). We conducted a petrological and geochemical study of a set of volcanic rocks, sampled from the rim and interior of the Miocene Mt Bambouto caldera, one of the 12 main volcanic centres of the CVL. The rocks were analysed for their whole-rock major and trace element contents, 40Ar/39Ar ages and whole-rock Sr–Nd–Pb–Os isotopic compositions. Phonolites and quartz-trachytes of the Mt Bambouto caldera are derived by fractional crystallization of highly alkaline and moderately alkaline parental basic magmas, respectively. Assimilation of the shallow crust has affected both alkaline and subalkaline magmas, suggesting that the petrogenesis of the differentiated rocks cannot be explained by crustal contamination alone. Only minor amounts (usually less than 5%) of assimilation of upper crustal silicic rocks from the local Pan-African basement are required to produce the most differentiated compositions. The rocks with the highest crustal contribution are Q-normative trachytes from peripheral cones, as well as one Ne-trachyte. Mt Bambouto basic–ultrabasic rocks, including basanites and alkali-basalts with high 187Os/188Osi, might have experienced some crustal contamination, but it must have been a limited process. Some Mt Bambouto ultrabasic to basic rocks show large ion lithophile element enrichment, notably of Sr, Ba and P compared with Zr. These samples also have relatively radiogenic Sr and unradiogenic Pb isotopic compositions. Such compositions are similar to those of the high-Sr group identified by previous studies. Most of the basic rocks do not show such characteristics and are identified as a low-Sr group. We interpret the geochemical characteristics of the high-Sr group as resulting from the partial melting of a depleted mantle (DMM-like) peridotite source containing pyroxenite veins that had interacted with carbonatitic fluids. To test this hypothesis, we used a new modelling approach based on Monte Carlo simulation; this method has the advantage of deciphering how different mantle components interacted through time. Our modelling confirms the plausibility of a three-component source. In addition, it suggests that the carbonatitic fluid first mixed with the pyroxenititic component and the resulting melt interacted with a DMM-like mantle. Both high-Sr and low-Sr groups can be produced by such a mixing scenario but with a stronger contribution of the carbonatitic fluid for the high-Sr group. At the time of melting, these source components could have been located in a metasomatized region of the sublithospheric mantle (uppermost section of the asthenosphere) or in the sub-continental lithospheric mantle.
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| 17. |
- Mueller, FE, et al.
(författare)
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Mechanism and therapy of fat embolism
- 2011
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Ingår i: JOURNAL OF THROMBOSIS AND HAEMOSTASIS. - 1538-7933. ; 9, s. 739-740
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)
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| 19. |
- Peate, I U, et al.
(författare)
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Volcanic stratigraphy of large-volume silicic pyroclastic eruptions during Oligocene Afro-Arabian flood volcanism in Yemen
- 2005
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Ingår i: Bulletin of Volcanology. - : Springer Science and Business Media LLC. - 0258-8900 .- 1432-0819. ; 68:2, s. 135-156
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Tidskriftsartikel (refereegranskat)abstract
- A new stratigraphy for bimodal Oligocene flood volcanism that forms the volcanic plateau of northern Yemen is presented based on detailed field observations, petrography and geochemical correlations. The > 1 km thick volcanic pile is divided into three phases of volcanism: a main basaltic stage ( 31 to 29.7 Ma), a main silicic stage ( 29.7 to 29.5 Ma), and a stage of upper bimodal volcanism ( 29.5 to 27.7 Ma). Eight large-volume silicic pyroclastic eruptive units are traceable throughout northern Yemen, and some units can be correlated with silicic eruptive units in the Ethiopian Traps and to tephra layers in the Indian Ocean. The silicic units comprise pyroclastic density current and fall deposits and a caldera-collapse breccia, and they display textures that unequivocally identify them as primary pyroclastic deposits: basal vitrophyres, eutaxitic fabrics, glass shards, vitroclastic ash matrices and accretionary lapilli. Individual pyroclastic eruptions have preserved on-land volumes of up to similar to 850 km(3). The largest units have associated co-ignimbrite plume ash fall deposits with dispersal areas > 1 x 10(7) km(2) and estimated maximum total volumes of up to 5,000 km(3), which provide accurate and precisely dated marker horizons that can be used to link litho-, bio- and magnetostratigraphy studies. There is a marked change in eruption style of silicic units with time, from initial large-volume explosive pyroclastic eruptions producing ignimbrites and near-globally distributed tuffs, to smaller volume (< 50 km(3)) mixed effusive-explosive eruptions emplacing silicic lavas intercalated with tuffs and ignimbrites. Although eruption volumes decrease by an order of magnitude from the first stage to the last, eruption intervals within each phase remain broadly similar. These changes may reflect the initiation of continental rifting and the transition from pre-break-up thick, stable crust supporting large-volume magma chambers, to syn-rift actively thinning crust hosting small-volume magma chambers.
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