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The Plasma Contact System: New Functional Insights from a Hemostatic and Thrombotic Perspective
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. (Bo Nilsson)
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 [en]
Contact activation, factor XII, platelets, coagulation, antithrombin, C1 inhibitor, hemostasis, biomarkers, vascular disease.
National Category
Basic Medicine
Research subject
Clinical Immunology
Identifiers
URN: urn:nbn:se:uu:diva-160343ISBN: 978-91-554-8200-8 (print)OAI: oai:DiVA.org:uu-160343DiVA: diva2:450654
Public defence
2011-12-01, Rudbecksalen, Rudbeckslaboratoriet, Dag Hammarskjöldsväg 20, Uppsala, 09:15 (Swedish)
Opponent
Supervisors
Available from: 2011-11-10 Created: 2011-10-21 Last updated: 2011-11-23Bibliographically approved
List of papers
1. Activated human platelets induce factor XIIa-mediated contact activation
Open this publication in new window or tab >>Activated human platelets induce factor XIIa-mediated contact activation
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2010 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 391, no 1, 11-17 p.Article in journal (Refereed) Published
Abstract [en]

Earlier studies have shown that isolated platelets in buffer systems can promote activation of FXII or amplify contact activation, in the presence of a negatively charge substance or material. Still proof is lacking that FXII is activated by platelets in a more physiological environment. In this study we investigate if activated platelets can induce FXII-mediated contact activation and whether this activation affects clot formation in human blood. Human platelets were activated with a thrombin receptor-activating peptide, SFLLRN-amide, in platelet-rich plasma or in whole blood. FXIIa and FXIa in complex with preferentially antithrombin (AT) and to some extent C1-inhibitor (C1INH) were generated in response to TRAP stimulation. This contact activation was independent of surface-mediated contact activation, tissue factor pathway or thrombin. In clotting whole blood FXIIa-AT and FXIa-AT complexes were specifically formed, demonstrating that AT is a potent inhibitor of FXIIa and FXIa generated by platelet activation. Contact activation proteins were analyzed by flow cytometry and FXII, FXI, high-molecular weight kininogen, and prekallikrein were detected on activated platelets. Using chromogenic assays, enzymatic activity of platelet-associated FXIIa, FXIa, and kallikrein were demonstrated. Inhibition of FXIIa in non-anticoagulated blood also prolonged the clotting time. We conclude that platelet activation triggers FXII-mediated contact activation on the surface and in the vicinity of activated platelets. This leads specifically to generation of FXIIa-AT and FXIa-AT complexes, and contributes to clot formation. Activated platelets may thereby constitute an intravascular locus for contact activation, which may explain the recently reported importance of FXII in thrombus formation.

Keyword
Antithrombin, Clot formation, Contact activation, Factor XII, Platelets
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-124283 (URN)10.1016/j.bbrc.2009.10.123 (DOI)000273624500003 ()19878657 (PubMedID)
Available from: 2010-05-04 Created: 2010-05-03 Last updated: 2017-12-12Bibliographically approved
2. Distinctive regulation of contact activation by antithrombin and C1-inhibitor on activated platelets and material surfaces
Open this publication in new window or tab >>Distinctive regulation of contact activation by antithrombin and C1-inhibitor on activated platelets and material surfaces
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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.

Keyword
Antithrombin, Blood clotting, C1-inhibitor, Contact activation, Factor XII, Platelet
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-124284 (URN)10.1016/j.biomaterials.2009.07.052 (DOI)000271347900002 ()19783299 (PubMedID)
Available from: 2010-05-03 Created: 2010-05-03 Last updated: 2017-12-12Bibliographically approved
3. Formation of the fibrin network during clotting triggers factor XII-mediated contact activation and subsequent regulation by antithrombin
Open this publication in new window or tab >>Formation of the fibrin network during clotting triggers factor XII-mediated contact activation and subsequent regulation by antithrombin
(English)Manuscript (preprint) (Other academic)
National Category
Basic Medicine
Identifiers
urn:nbn:se:uu:diva-160341 (URN)
Available from: 2011-10-21 Created: 2011-10-21 Last updated: 2011-11-23
4. Distinctive contact activation in systemic lupus erythematosus: The basis for new potential biomarkers to evaluate the risk of thrombotic events?
Open this publication in new window or tab >>Distinctive contact activation in systemic lupus erythematosus: The basis for new potential biomarkers to evaluate the risk of thrombotic events?
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Basic Medicine
Identifiers
urn:nbn:se:uu:diva-160342 (URN)
Available from: 2011-10-21 Created: 2011-10-21 Last updated: 2011-11-23

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