Thrombosis and haemostasis
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Comparative Study
Potent and specific inhibition of the biological activity of the type-II transmembrane serine protease matriptase by the cyclic microprotein MCoTI-II.
Matriptase is a type-II transmembrane serine protease involved in epithelial homeostasis in both health and disease, and is implicated in the development and progression of a variety of cancers. Matriptase mediates its biological effects both via as yet undefined substrates and pathways, and also by proteolytic cleavage of a variety of well-defined protein substrates, several of which it shares with the closely-related protease hepsin. Development of targeted therapeutic strategies will require discrimination between these proteases. ⋯ Using a model of epithelial cell tight junction assembly, we also found that MCoTI-II could effectively inhibit the re-establishment of tight junctions and epithelial barrier function in MDCK-I cells after disruption, consistent with the role of matriptase in regulating epithelial integrity. Surprisingly, MCoTI-II was unable to inhibit matriptase-dependent proteolytic activation of prostasin, a GPI-anchored serine protease also implicated in epithelial homeostasis. These observations suggest that the unusually high selectivity afforded by MCoTI-II and its biological effectiveness might represent a useful starting point for the development of therapeutic inhibitors, and further highlight the role of matriptase in epithelial maintenance.
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Multicenter Study Comparative Study
A comparative cohort study on personalised antiplatelet therapy in PCI-treated patients with high on-clopidogrel platelet reactivity. Results of the ISAR-HPR registry.
In clopidogrel-treated patients undergoing percutaneous coronary intervention (PCI), high platelet reactivity (HPR) is associated with a higher risk for thrombotic events including stent thrombosis (ST). A personalised therapy with selective intensification of treatment may improve HPR patients´ outcome in this setting although recent randomised trials are against this hypothesis. The aim of the ISAR-HPR registry was to assess whether clopidogrel-treated HPR patients benefit from selective intensification of P2Y12 receptor inhibition. ⋯ The incidence of major bleeding was numerically but not statistically higher in the guided vs the control cohort (1.9 vs 0.7%; p=0.10). In conclusion, present findings are in support for a PF testing guided antiplatelet therapy with selective intensification of P2Y12 receptor inhibition. The issue of personalised antiplatelet treatment warrants further investigation in randomized and well-controlled clinical trials.
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The Calibrated Automated Thrombogram (CAT) assay that measures thrombin generation (TG) in platelet-poor and -rich plasma, is increasingly being recognised as a more sensitive tool to determine the overall function of the haemostatic system. We developed a method enabling the measurement of TG in a small aliquot of blood. The objective was to validate this assay in mouse blood and to examine the rate and extent of TG in a mouse model of premature aging. ⋯ By applying SEM we found that Bmal1 deficient mice display a denser fibrin network with smaller pores compared to WT mice. In conclusion, the whole blood TG assay in mice revealed to be reproducible. As a proof-of-principle we have shown that the whole blood TG assay is capable of detecting a prothrombotic phenotype in Bmal1-KO mice.