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Distinctive regulation of contact activation by antithrombin and C1-inhibitor on activated platelets and material surfaces
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
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2009 (English)In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 30, no 34, 6573-6580 p.Article in journal (Refereed) Published
Abstract [en]

Activated human plate lets trigger FXII-mediated contact activation, which leads to the generation of FXIIa-antithrombin (AT) and FXIa-AT complexes. This suggests that contact activation takes place at different sites, on activated platelets and material surfaces, during therapeutic procedures involving biomaterials in contact with blood and is differentially regulated. Here we show that activation in platelet-poor plasma, platelet-rich plasma (PRP), and whole blood induced by glass, kaolin, and polyphosphate elicited high levels of FXIIa-C1-inhibitor (C1INH), low levels of FXIa-C1INH and KK-C1INH, and almost no AT complexes. Platelet activation, in both PRP and blood, led to the formation of FXIIa-AT, FXIa-AT, and kallikrein (KK)-AT but almost no C1INH complexes. In severe trauma patients, FXIIa-AT and FXIa-AT were correlated with the release of thrombospondin-1 (TSP-1) from activated platelets. In contrast, FXIIa-C1INH complexes were detected when the FXIIa-AT levels were low. No correlations were found between FXIIa-C1INH and FXIIa-AT or TSP-1. Inhibition of FXIIa on material surfaces was also shown to affect the function of aggregating platelets. In conclusion, formation of FXIIa-AT and FXIIa-C1INH complexes can help to distinguish between contact activation triggered by biomaterial surfaces and by activated platelets. Platelet aggregation studies also demonstrated that platelet function is influenced by material surface-mediated contact activation and that generation of FXIIa-AT complexes may serve as a new biomarker for thrombotic reactions during therapeutic procedures employing biomaterial devices.

Place, publisher, year, edition, pages
2009. Vol. 30, no 34, 6573-6580 p.
Keyword [en]
Antithrombin, Blood clotting, C1-inhibitor, Contact activation, Factor XII, Platelet
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-124284DOI: 10.1016/j.biomaterials.2009.07.052ISI: 000271347900002PubMedID: 19783299OAI: oai:DiVA.org:uu-124284DiVA: diva2:317292
Available from: 2010-05-03 Created: 2010-05-03 Last updated: 2012-05-10Bibliographically approved
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.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 718
Contact activation, factor XII, platelets, coagulation, antithrombin, C1 inhibitor, hemostasis, biomarkers, vascular disease.
National Category
Basic Medicine
Research subject
Clinical Immunology
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)
Available from: 2011-11-10 Created: 2011-10-21 Last updated: 2011-11-23Bibliographically approved

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