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Distinctive contact activation in systemic lupus erythematosus: The basis for new potential biomarkers to evaluate the risk of thrombotic events?
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. (Bo Nilsson)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. (Bo Nilsson)
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(English)Manuscript (preprint) (Other academic)
National Category
Basic Medicine
Identifiers
URN: urn:nbn:se:uu:diva-160342OAI: oai:DiVA.org:uu-160342DiVA: diva2:450639
Available from: 2011-10-21 Created: 2011-10-21 Last updated: 2011-11-23
In thesis
1. The Plasma Contact System: New Functional Insights from a Hemostatic and Thrombotic Perspective
Open this publication in new window or tab >>The Plasma Contact System: New Functional Insights from a Hemostatic and Thrombotic Perspective
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The physiological role of the plasma contact system still remains a partial enigma. The aim of the presented work was to expand our understanding of the plasma contact system, focusing on its physiological activation and function, principally from a hemostatic perspective. It also explored contact system activation under pathological conditions.

We found that when human platelets become activated in blood, plasma proteins of the contact system bind to platelets and initiate contact activation. The platelet-triggered contact activation contributed to clot formation by shortening the clotting time and enhancing clot stability.

We demonstrated that the regulation of contact activation elicited by activated platelets differed from the previously described contact activation elicited by negatively charged material surfaces. Platelet-triggered contact activation and activation propelled by clotting blood were found to be regulated by antithrombin, whereas material-induced activation was regulated by C1 inhibitor.

We also showed that the fibrin fibers that are formed during the clot process further enhance and propagate the contact activation initially induced by activated platelets. Fibrin not only activated factor XII but also seemed to increase the affinity of antithrombin for the proteases of the contact system, leading to the generation of contact enzyme-antithrombin complexes during clot formation.

To determine whether the contact system might be involved in the inflammation and vascular disease associated with systemic lupus erythematosus (SLE), we analyzed plasma samples from SLE patients. These patients were found to have altered levels of contact enzyme-serpin complexes, supporting the concept that the contact system may be involved in the pathophysiology of SLE. The contact enzyme-antithrombin complexes were clearly linked to platelet activation in vivo. Altered levels of both FXIIa-antithrombin and FXIIa-C1 inhibitor were found to be correlated with previous vascular disease and may therefore be potential biomarkers for assessing the risk of thrombotic events in SLE patients.

These findings add to our knowledge of how the plasma contact system is activated and functions in vivo and will help us to understand the role of the contact system, not only in hemostasis but also in vascular disease and thrombotic conditions.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2011. 65 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 718
Keyword
Contact activation, factor XII, platelets, coagulation, antithrombin, C1 inhibitor, hemostasis, biomarkers, vascular disease.
National Category
Basic Medicine
Research subject
Clinical Immunology
Identifiers
urn:nbn:se:uu:diva-160343 (URN)978-91-554-8200-8 (ISBN)
Public defence
2011-12-01, Rudbecksalen, Rudbeckslaboratoriet, Dag Hammarskjöldsväg 20, Uppsala, 09:15 (Swedish)
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Supervisors
Available from: 2011-11-10 Created: 2011-10-21 Last updated: 2011-11-23Bibliographically approved

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