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Response: platelets do not generate activated factor XII--how inappropriate experimental models have led to misleading conclusions
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
Sahlgrenska Academy, University of Gothenburg, Sweden.
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2014 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, no 10, 1692-1694 p.Article in journal, Letter (Other academic) Published
Place, publisher, year, edition, pages
American Society of Hematology , 2014. Vol. 124, no 10, 1692-1694 p.
National Category
Clinical Medicine
Identifiers
URN: urn:nbn:se:liu:diva-111531DOI: 10.1182/blood-2014-04-566067ISI: 000342762300027PubMedID: 25190755OAI: oai:DiVA.org:liu-111531DiVA: diva2:757405
Available from: 2014-10-22 Created: 2014-10-22 Last updated: 2017-12-05Bibliographically approved
In thesis
1. Studies on interfaces between primary and secondary hemostasis
Open this publication in new window or tab >>Studies on interfaces between primary and secondary hemostasis
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Our conceptual understanding of hemostasis is still heavily influenced by outdated experimental models wherein the hemostatic activity of platelets and coagulation factors are understood and studied in isolation. Although perhaps convenient for researchers and clinicians, this reductionist view is negated by an ever increasing body of evidence pointing towards an intimate relationship between the two phases of hemostasis, marked by strong interdependence. In this thesis, I have focused on factual and proposed interfaces between primary and secondary hemostasis, and on how these interfaces can be studied.

In my first project, we zoomed in on the mechanisms behind the well-known phenomenon of thrombin-induced platelet activation, an important event linking secondary to primary hemostasis. In our study, we examined how thrombin makes use of certain domains for high-affinity binding to substrates, called exosite I and II, to activate platelets via PAR4. We show that thrombin-induced platelet activation via PAR4 is critically dependent on exosite II, and that blockage of exosite II with different substances virtually eliminates PAR4 activation. Apart from providing new insights into the mechanisms by which thrombin activates PAR4, these results expand our knowledge of the antithrombotic actions of various endogenous proteins such as members of the serpin superfamily, which inhibit interactions with exosite II. Additionally, we show that inhibition of exosite II could be a feasible pharmacological strategy for achieving selective blockade of PAR4.

In my second project, we examined the controversial issue of whether platelets can initiate the coagulation cascade by means of contact activation, a hypothesis which, if true, could provide a direct link between primary and secondary hemostasis. In contrast to previous results, our findings falsify this hypothesis, and show that some of the erroneous conclusions drawn from earlier studies can be explained by inappropriate experimental models unsuitable for the study of plateletcoagulation interfaces.

My third project comprised an assessment of the methodological difficulties encountered when trying to measure the ability of platelets to initiate secondary hemostasis by the release of microparticles expressing tissue factor. Our study shows that the functional assays available for this purpose are highly susceptible to error caused by artificial contact activation. These results could help to improve the methodology of future research and thus pave the way for new insights into the roles of tissue factor-bearing microparticles in the pathophysiology of various thrombotic disorders.

From a personal perspective, my PhD project has been a fascinating scientific odyssey into the largely unexplored interfaces between primary and secondary hemostasis. Looking forward, my ambition is to continue our work exploring platelet-coagulation interactions and to translate these insights into clinically meaningful information, which may someday improve the treatment of patients with bleeding and/or thrombosis.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2016. 80 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1544
National Category
Biochemistry and Molecular Biology Pharmacology and Toxicology Medicinal Chemistry Basic Medicine
Identifiers
urn:nbn:se:liu:diva-132413 (URN)10.3384/diss.diva-132413 (DOI)9789176856635 (ISBN)
Public defence
2016-11-12, Berzeliussalen, Campus US, Linköping, 11:00 (Swedish)
Opponent
Supervisors
Available from: 2016-11-09 Created: 2016-11-09 Last updated: 2016-11-09Bibliographically approved

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Boknäs, NiklasFaxälv, LarsStröm, Jakob OTheodorsson, ElvarRamström, SofiaLindahl, Tomas L

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Boknäs, NiklasFaxälv, LarsStröm, Jakob OTheodorsson, ElvarRamström, SofiaLindahl, Tomas L
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Division of Microbiology and Molecular MedicineFaculty of Health SciencesDepartment of Clinical Chemistry
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