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Complement activation triggered by chondroitin sulfate released by thrombin receptor-activated platelets
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology. (Complement and Biomatherial)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
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2008 (English)In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 6, no 8, 1413-1421 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Chondroitin sulfate (CS) is a glycosaminoglycan released by activated platelets. OBJECTIVE: Here we test the hypothesis that CS released by activated platelets can trigger complement activation in the fluid phase. METHODS AND RESULTS: Thrombin receptor-activating peptide (TRAP)-6 was used to activate platelets in platelet-rich plasma and blood, anticoagulated with the thrombin inhibitor lepirudin. TRAP activation induced fluid-phase complement activation, as reflected by the generation of C3a and sC5b-9, which could be attenuated by the C3 inhibitor compstatin. Chondroitinase ABC treatment of supernatants from activated platelets totally inhibited the activation, indicating that platelet-derived CS had initiated the complement activation. Furthermore, addition of purified CS to plasma strongly triggered complement activation. C1q was identified as the recognition molecule, as it bound directly to CS, and CS-triggered complement activation could be restored in C1q-depleted serum by adding purified C1q. TRAP activation of whole blood increased the expression of CD11b on leukocytes and generation of leukocyte-platelet complexes. It was demonstrated that these leukocyte functions were dependent on C3 activation and signaling via C5a, as this expression could be inhibited by compstatin and by a C5aR antagonist. CONCLUSIONS: We conclude that platelets trigger complement activation in the fluid phase by releasing CS, which leads to inflammatory signals mediated by C5a.

Place, publisher, year, edition, pages
2008. Vol. 6, no 8, 1413-1421 p.
Keyword [en]
chondroitin sulfate, coagulation, complement, platelets, thrombin receptor-activating peptide (TRAP)
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-16841DOI: 10.1111/j.1538-7836.2008.03034.xISI: 000257757000024PubMedID: 18503629OAI: oai:DiVA.org:uu-16841DiVA: diva2:44612
Platelet mediated complement activation
Available from: 2008-06-05 Created: 2008-06-05 Last updated: 2010-05-18Bibliographically approved
In thesis
1. Crosstalk Between Activated Platelets and the Complement System
Open this publication in new window or tab >>Crosstalk Between Activated Platelets and the Complement System
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Several studies have shown that complement and thrombotic events co-exist. Platelets have been suspected to act as the bridge between the two cascade systems.

To study the platelet-induced complement activation we developed a system in which platelets were activated by thrombin receptor activating peptide (TRAP) in platelet rich plasma (PRP) or whole blood anti-coagulated using the specific thrombin inhibitor, lepirudin.

TRAP-activated platelets induced a fluid-phase complement activation measured as generation of C3a and sC5b-9, triggered by released chondroitin sulphate-A (CS-A) which interacted with C1q and activated the complement system through the classical pathway.

Complement components C1q, C3, C4 and C9 were also shown to bind to TRAP-activated platelets but this binding did not seem to be due to a complement activation since blocking of complement activation at the C1q or C3 levels did not affect the binding of the complement proteins. The C3 which bound to activated platelets consisted of C3(H2O), indicating that bound C3 was not proteolytically activated. Binding of C1q was partially dependent on CS-A exposure on activated platelets. The abolished complement activation on the surface of activated platelets was suggested to be dependent on the involvement of several complement inhibitors. We confirmed the binding of C1INH and factor H to activated platelets. To this list we have added another potent complement inhibitor, C4BP. The binding of factor H and C4BP was shown to be dependent on exposure of CS-A on activated platelets.

The physiological relevance of these reactions was reflected in an elevated expression of CD11b on leukocytes, and increased generation of platelet-leukocyte complexes. The platelets were involved in these events by at least two different mechanisms; generation of C5a which activated leukocytes and binding of C3(H2O)/iC3(H2O), a ligand to the intergrin CD11b/CD18 on their surface.

These mechanisms add further to the understanding of how platelets interact with the complement system and will help us to understand the role of the complement system in cardiovascular disease and thrombotic conditions.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2010. 82 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 567
platelets, activated platelets, TRAP, chondroitin sulfate, C1q, factor H, C4BP, C3, Compstatin, complement, platelet-leukocyte complexes, platelet microparticles
National Category
Immunology in the medical area
Research subject
Clinical Immunology
urn:nbn:se:uu:diva-123681 (URN)978-91-554-7822-3 (ISBN)
Public defence
2010-06-01, Rudbecksalen, Rudbeck Laboratory, Dag Hammarskjölds väg 20, Uppsala, 09:15 (Swedish)
Platelet Mediated Complement Activation
Available from: 2010-05-11 Created: 2010-04-28 Last updated: 2010-05-24Bibliographically approved

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Hamad, Osama A.Ekdahl, Kristina NilssonAndersson, J.Nilsson, Bo
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