Essentials
Successful outcome of platelet transfusion depends on specific antiplatelet therapy in use.
We assessed if ticagrelor, clopidogrel or prasugrel impacts on donor platelet activity ex vivo.
...Ticagrelor and/or its active metabolite in plasma or bound to platelets can inhibit donor platelets.
This might compromise the effectiveness of platelet transfusion therapy.
Summary
Background
Platelet transfusion is the conventional approach to restore platelet function during acute bleeds or surgery, but successful outcome depends on the specific antiplatelet therapy. Notably ticagrelor is associated with inadequate recovery of platelet function after platelet transfusion. We examined whether plasma and/or platelets from ticagrelor‐treated patients influence donor platelet function, in comparison with clopidogrel and prasugrel.
Methods
Platelet transfusion was mimicked ex vivo by mixing naïve donor platelet‐rich plasma (PRP) or gel‐filtered platelets (GFP) in defined proportions with PRP, plasma or GFP from cardiovascular patients receiving standard care including medication with prasugrel, clopidogrel or ticagrelor (n = 20 each). Blood was taken 4 h after the previous dose. HLA2/HLA28 haplotyping let us distinguish net (all platelet) and individual patient/donor platelet reactivity in mixtures of patient/donor platelets, measured by flow cytometry analysis of ADP‐induced fibrinogen binding and CD62P expression.
Results
ADP responsiveness of donor platelets was dramatically reduced by even low (10%) concentrations of PRP or plasma from ticagrelor‐treated patients. Clopidogrel and prasugrel were associated with more modest donor platelet inhibition. GFP from ticagrelor‐treated patients but not patients receiving clopidogrel or prasugrel also suppressed donor GFP function upon mixing, suggesting the transfer of ticagrelor from patient platelets to donor platelets. This transfer did not lead to recovery of ADP responsiveness of patient's platelets.
Conclusion
Collectively, these observations support the concept that ticagrelor and/or its active metabolite in plasma or bound to platelets can inhibit donor platelets, which might compromise the effectiveness of platelet transfusion therapy.
Background: Human neutrophil α‐defensins (HNPs) are important constituents of the innate immune system. Beyond their antimicrobial properties, HNPs also have pro‐inflammatory features. While HNPs in ...plasma from healthy individuals are barely detectable, their level is strongly elevated in septic plasma and plasma from patients with acute coronary syndromes.
Objectives: As thrombosis and inflammation are intertwined processes and activation of human polymorphonuclear leukocytes (PMNL) and subsequent degranulation is associated with full activation of surrounding platelets, we studied the effect of HNPs on platelet function.
Methods: The effect of HNPs on platelet activation parameters and apoptosis was investigated via aggregometry, flow cytometry, confocal microscopy and the ELISA technique.
Results: It was found that HNPs activate platelets in pathophysiologically relevant doses, inducing fibrinogen and thrombospondin‐1 binding, aggregation, granule secretion, sCD40L shedding, and procoagulant activity. HNPs bound directly to the platelet membrane, induced membrane pore formation, microparticle formation, mitochondrial membrane depolarization and caspase‐3‐activity. Confocal microscopy revealed the HNP‐induced formation of polymeric fibrinogen and thrombospondin‐1 amyloid‐like structures, which bound microorganisms. Platelets adhered to these structures and formed aggregates. Blocking of glycoprotein IIb/IIIa (GPIIb/IIIa) markedly inhibited HNP‐induced platelet activation. In addition, heparin, heparinoid, serpins and α2‐macroglobulin, which all bind to HNPs, blocked HNP‐1‐induced platelet activation in contrast to direct thrombin inhibitors such as hirudin.
Conclusions: HNPs activate platelets and induce platelet apoptosis by formation of amyloid‐like proteins. As these structures entrapped bacteria and fungi, they might reflect an additional function of HNPs in host defense. The described mechanism links again thrombosis and infection.
Platelets bind to Candida albicans, the major cause of candidiasis. But in contrast to other microorganisms the fungus does not aggregate platelets. Gliotoxin (GT), which possesses immunosuppressive ...properties, is produced by various fungi, including the opportunistic pathogens Aspergillus fumigatus and C. albicans . Its mode of action involves the formation of mixed disulfides with host proteins. Disulfide exchanges play an important role in platelet activation. Therefore, the effect of C. albicans and GT on platelet function was tested. C. albicans yeast cells (5,000–10,000 cells/μl) and GT, in pathophysiologically relevant concentrations (0.05–0.5 μM), inhibited platelet fibrinogen binding, anti gp IIb/IIIa antibody PAC-1 binding, aggregation and procoagulant activity in a dose-dependent manner. Alpha granule release, measured via CD62P surface expression, was not affected. Addition of reduced glutathione partially counteracted the effect of C. albicans and GT on platelet fibrinogen binding and platelet aggregation. The C. albicans metabolite GT features antithrombotic properties in addition to its immunosuppressive functions. Since treatment with reduced glutathione partially counteracted the inhibitory effect of C. albicans yeast cells and GT on platelet fibrinogen binding, the antithrombotic activity is likely to depend on the disulfide bridge of this mycotoxin. GT production by C. albicans could contribute to its survival in the blood stream during vascular infections. The knowledge of the underlying mechanisms of the antithrombotic properties might help to treat fungal infections as well as thrombosis.
In cftr(tmIHGU/m1HGU) mice, an animal model designed to study pathophysiologic alterations due to the CFTR defect found in cysticfibrosis, surfactant phospholipids of bronchoalveolar lavage fluid ...(BALF) are increased. To study the metabolical basis of such increases, we intraperitoneally injected cft(tm1HGU/tm1HGU) mice methyl-3Hcholine and measured methyl-3Hcholine incorporation into phosphatidylcholine (PC) molecular species of lung tissue and BALF after 1.5 to 24 hours. MF1 and MF1 x cftr(tm1HGU/tm1HGU) hybrid mice served as controls. In tissue methyl-3Hcholine incorporation into total PC was constant for 24 hours and identical in control and cftr(tmIHGU/m1HGU) mice. However, from 7.5 to 24 hours there was a shift of methyl-3Hcholine incorporation from palmitoyloleoyl-PC and palmitoyllinoleoyl-PC towards PC species enriched in surfactant, dipalmitoyl-PC, palmitoylmyristoyl-PC, and palmitoylpalmitoleoyl-PC. The relative and absolute 3H-labels of PC species were identical for cftr(tmIHGU/m1HGU) compared to control mice. In BALF methyl-3Hcholine of total PC increased from 1.5 to 24 hours (R2 > .98), mainly due to methyl-3Hcholine-labelled dipalmitoyl-PC, in all experimental groups. In BALF from cftr(tmIHGU/m1HGU) mice, the methyl-3Hcholine label of total PC and individual PC species was significantly increased over control values after 24 hours, but not after 1.5 to 6 hours. Numbers and composition of BALF cells were not different between controls and cftr(tmIHGU/m1HGU) mice. We, conclude that increased alveolar phospholipid in cftr(tmIHGU/m1HGU) mice is likely due to decreased reuptake of surfactant.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The process of solid formation during spray drying has been described many times in the literature, however, a detailed mathematical description of the time‐dependent process concerning the structure ...of the particles as a function of substance and process parameters is still not available. In the present work, a time‐dependent and local modeling of the mass and energy transport processes during solid formation inside the droplet was carried out. The model was validated against reproducible experiments performed in a vertical pipe with single drop generation.
Gearbox has proven to be a major contributor toward downtime in wind turbines. The majority of failures in the gearbox originate from the gearbox bearings. An early indication of possible wear and ...tear in the gearbox bearings may be used for effective predictive maintenance, thereby reducing the overall cost of maintenance. This paper introduces a self-evolving maintenance scheduler framework for maintenance management of wind turbines. Furthermore, an artificial neural network (ANN)-based condition monitoring approach using data from supervisory control and data acquisition system is proposed. The ANN-based condition monitoring approach is applied to gearbox bearings with real data from onshore wind turbines, rated 2 MW, and located in the south of Sweden. The results demonstrate that the proposed ANN-based condition monitoring approach is capable of indicating severe damage in the components being monitored in advance.
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