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Putting polyphosphates to the test: evidence against platelet-induced activation of factor XII
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.
Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
University of Gothenburg, Gothenburg, Sweden .
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2013 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 122, no 23, 3818-3824 p.Article in journal (Refereed) Published
Abstract [en]

The recent claim that stimulated platelets activate the intrinsic pathway of coagulation by the release of polyphosphates has been considered a breakthrough in hemostasis research. In little more than 3 years, the original publication by Muller et al has been cited greater than100 times. However, none of the citing articles has sought to independently validate this potentially paradigm-shifting concept. To this end, we performed extensive experimentation in vitro and in vivo in an attempt to verify the claim that factor XII (FXII) is primarily activated by stimulated platelets. In contrast to the original assertion, platelet-derived polyphosphates were found to be weak activators of FXII, with a FXIIa-generating activity of less than10% compared with equivalent concentrations of kaolin. Using different coagulation assays, it was shown that platelet contribution to whole blood coagulation was unrelated to the generation of activated FXII in vitro. Additionally, key results used to verify the hypothesis in the original study in vivo were found to be irreproducible. We conclude that platelet-derived polyphosphates are not physiologically relevant activators of FXII.

Place, publisher, year, edition, pages
American Society of Hematology , 2013. Vol. 122, no 23, 3818-3824 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-104301DOI: 10.1182/blood-2013-05-499384ISI: 000329735000021OAI: oai:DiVA.org:liu-104301DiVA: diva2:697161
Available from: 2014-02-17 Created: 2014-02-14 Last updated: 2017-12-06
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)
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Supervisors
Available from: 2016-11-09 Created: 2016-11-09 Last updated: 2016-11-09Bibliographically approved

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Faxälv, LarsBoknäs, NiklasStröm, JakobTheodorsson, ElvarRamström, SofiaLindahl, Tomas

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