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Interactions between platelets and complement with implications for the regulation at surfaces
Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Disturbances of host integrity have the potential to evoke activation of innate immunologic and hemostatic protection mechanisms in blood. Irrespective of whether the activating stimulus is typically immunogenic or thrombotic, it will generally affect both the complement system and platelets to a certain degree. The theme of this thesis is complement and platelet activity, which is intersected in all five included papers. The initial aim was to study the responses and mechanisms of the complement cascade in relation to platelet activation. The secondary aim was to use an applied approach to regulate platelets and complement on model biomaterial and cell surfaces.   

Complement activation was found in the fluid phase in response to platelet activation in whole blood. The mechanism was traced to platelet release of stored chondroitin sulfate-A (CS-A) and classical pathway activation via C1q. C3 was detected at the platelet surface, though its binding was independent of complement activation. The inhibitors factor H and C4-binding protein (C4BP) were detected on activated platelets, and their binding was partly dependent on surface-exposed CS-A. Collectively, these results showed that platelet activation induces inflammatory complement activation in the fluid phase. CS-A was shown to be a central molecule in the complement-modulatory functions of platelets by its interaction with C1q, C4BP, and factor H.

Platelet activation and surface adherence were successfully attenuated by conjugating an ADP-degrading apyrase on a model biomaterial. Only minor complement regulation was seen, and was therefore targeted specifically on surfaces and cells by co-immobilizing a factor H-binding peptide together with the apyrase. This combined approach led to a synchronized inhibition of both platelet and complement activation at the interface of biomaterials/xenogeneic cells and blood.

In conclusion, here presents a novel crosstalk-mechanism for activation of complement when triggering platelets, which highlights the importance of regulating both complement and platelets to lower inflammatory events. In addition, a strategy to enhance the biocompatibility of biomaterials and cells by simultaneously targeting ADP-dependent platelet activation and the alternative complement C3-convertase is proposed.

Place, publisher, year, edition, pages
Växjö, Kalmar: Linnaeus University Press, 2012. , 87 p.
, Linnaeus University Dissertations, 83/2012
Keyword [en]
complement system (activation, regulation), platelets (activation, regulation), biomaterials, biocompatibility, chondroitin sulfate-A, apyrase, C1q, C3, factor H, C4BP, ADP
National Category
Immunology Biomaterials Science Biochemistry and Molecular Biology Cell and Molecular Biology
Research subject
Natural Science, Biomedical Sciences
URN: urn:nbn:se:lnu:diva-18321ISBN: 978-91-86983-46-8OAI: diva2:515586
Public defence
2012-05-11, N2007, Smålandsgatan 26, Kalmar, 09:30 (English)
Available from: 2012-04-16 Created: 2012-04-13 Last updated: 2016-03-01Bibliographically approved
List of papers
1. Complement activation triggered by chondroitin sulfate reelased by thrombin receptor-activated platelets
Open this publication in new window or tab >>Complement activation triggered by chondroitin sulfate reelased by thrombin receptor-activated platelets
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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
National Category
Natural Sciences
Research subject
Biomedical Sciences, Immunology
urn:nbn:se:lnu:diva-1857 (URN)
Available from: 2010-04-06 Created: 2010-04-06 Last updated: 2012-04-16Bibliographically approved
2. Contribution of Chondroitin Sulfate A to the Binding of Complement Proteins to Activated Platelets
Open this publication in new window or tab >>Contribution of Chondroitin Sulfate A to the Binding of Complement Proteins to Activated Platelets
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2010 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 5, no 9, e12889Article in journal (Refereed) Published
Abstract [en]

Background: Exposure of chondroitin sulfate A (CS-A) on the surface of activated platelets is well established. The aim of the present study was to investigate to what extent CS-A contributes to the binding of the complement recognition molecule C1q and the complement regulators C1 inhibitor (C1INH), C4b-binding protein (C4BP), and factor H to platelets.Principal Findings: Human blood serum was passed over Sepharose conjugated with CS-A, and CS-A-specific binding proteins were identified by Western blotting and mass spectrometric analysis. C1q was shown to be the main protein that specifically bound to CS-A, but C4BP and factor H were also shown to interact. Binding of C1INH was dependent of the presence of C1q and then not bound to CS-A from C1q-depleted serum. The specific interactions observed of these proteins with CS-A were subsequently confirmed by surface plasmon resonance analysis using purified proteins. Importantly, C1q, C4BP, and factor H were also shown to bind to activated platelets and this interaction was inhibited by a CS-A-specific monoclonal antibody, thereby linking the binding of C1q, C4BP, and factor H to exposure of CS-A on activated platelets. CS-A-bound C1q was also shown to amplify the binding of model immune complexes to both microtiter plate-bound CS-A and to activated platelets.

Conclusions: This study supports the concept that CS-A contributes to the binding of C1q, C4BP, and factor H to platelets, thereby adding CS-A to the previously reported binding sites for these proteins on the platelet surface. CS-A-bound C1q also seems to amplify the binding of immune complexes to activated platelets, suggesting a role for this molecule in immune complex diseases. 

National Category
Biomedical Laboratory Science/Technology
Research subject
Natural Science, Biomedical Sciences
urn:nbn:se:lnu:diva-7683 (URN)10.1371/journal.pone.0012889 (DOI)
Available from: 2010-08-23 Created: 2010-08-23 Last updated: 2016-07-19Bibliographically approved
3. The creation of an antithrombotic surface by apyrase immobilization
Open this publication in new window or tab >>The creation of an antithrombotic surface by apyrase immobilization
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2010 (English)In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 31, no 16, 4484-4491 p.Article in journal (Refereed) Published
Abstract [en]

Blood incompatibility reactions caused by surfaces often involve platelet activation and subsequent platelet-initiated activation of the coagulation and complement cascades. The goal of this study was to immobilize apyrase on a biomaterial surface in order to develop an enzymatically active surface that would have the capacity to inhibit platelet activation by degrading ADP. We were able to immobilize apyrase on a polystyrene surface with preservation of the enzymatic activity. We then analyzed the hemocompatibility of the apyrase surface and of control surfaces by incubation with platelet-rich plasma (PRP) or whole blood. Monitoring of markers of platelet, coagulation, and complement activation and staining of the surfaces revealed decreased levels of platelet and coagulation activation parameters on the apyrase surface. The formation of antithrombin-thrombin and antithrombin-factor XIa complexes and the extent of platelet consumption were significantly lower on the apyrase surface than on any of the control surfaces. No significant differences were seen in complement activation (C3a levels). Staining of the apyrase surface revealed low platelet adherence and no formation of granulocyte platelet complexes. These results demonstrate that it is possible to create an antithrombotic surface targeting the ADP amplification of platelet activation by immobilizing apyrase.

Blood compatibiliy; Apyrase; Platelet; Platelet regulation; Adenosine diphosphate
National Category
Immunology in the medical area
Research subject
Biomedical Sciences, Immunology; Natural Science, Biomedical Sciences
urn:nbn:se:lnu:diva-2176 (URN)10.1016/j.biomaterials.2010.02.036 (DOI)
Available from: 2010-04-06 Created: 2010-04-06 Last updated: 2014-02-25Bibliographically approved

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