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Monocytes, Tissue Factor and Heparin-coated Surfaces: Clinical and Experimental Studies
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cardiopulmonary bypass (CPB) is associated with inflammatory response and activation of coagulation. Heparin coating of the CPB circuit is shown to improve the biocompatibility of the surface. The biological effects of a new heparin surface, the Corline Heparin Surface (CHS), prepared according to a new principle, have been studied.

The CHS used during coronary artery bypass grafting with CPB in sixty patients prevented adhesion of cells to the extracorporeal device. The activation of inflammation, coagulation, and fibrinolysis was significantly reduced by the use of CHS. Both a reduced and an increased dose of systemic heparin in combination with the heparin-coated surface resulted in more activation of inflammation and coagulation.

Photoelectron spectroscopy studies of the molecular structure of the CHS demonstrated that a single layer of the heparin surface, equivalent to what was used in the in vivo studies, did not completely cover the substrate surface. Additional layer of immobilized heparin has resulted in a complete coverage. We examined the biological effects, i.e. activation of inflammation and coagulation, by CHS in one and two layers in an in vitro-study. The data from this study clearly demonstrated that a uniform surface coating of the CHS results in only minor activation of coagulation, inflammation and cell activation.

Monocytes do not normally express tissue factor (TF), initiator of the coagulation in vivo, but can be induced upon adhesion to artificial surfaces. TF is receptor for coagulation factor VIIa (FVIIa) and binding subsequently leads to formation of thrombin. Other biological effects beyond coagulation, as inflammation and angiogenesis, has recently been associated with the formation of TF·FVIIa. The TF∙FVIIa signal transduction induced an increased sensitivity to PDGF-BB-stimulated migration and an increased production of IL-8 and TNF-α in monocytes. These could be important mechanisms for continued recruitment of cells to sites of inflammation.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2003. , p. 65
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1299
Keyword [en]
Medicine, monocytes, tissue factor, heparin-coated surfaces, coagulation, inflammation, thrombin, cytokines, cardiopulmonary bypass, biocompatibility, migration, chemotaxis
Keyword [sv]
Medicin
National Category
Dermatology and Venereal Diseases
Identifiers
URN: urn:nbn:se:uu:diva-3740ISBN: 91-554-5779-7 (print)OAI: oai:DiVA.org:uu-3740DiVA, id: diva2:163569
Public defence
2003-11-21, Robergsalen, ingång 40, Akademiska sjukhuset, Uppsala, 13:15
Opponent
Supervisors
Available from: 2003-10-30 Created: 2003-10-30Bibliographically approved
List of papers
1. Coagulation, fibrinolysis and cell activation in patients and shed mediastinal blood during coronary artery bypass grafting using a new heparin-coated surface
Open this publication in new window or tab >>Coagulation, fibrinolysis and cell activation in patients and shed mediastinal blood during coronary artery bypass grafting using a new heparin-coated surface
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2002 (English)In: Journal of Thoracic and Cardiovascular Surgery, ISSN 0022-5223, E-ISSN 1097-685X, Vol. 124, no 2, p. 321-332Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES: Heparin coating of the cardiopulmonary bypass circuit is shown to improve the biocompatibility of the surface. We have studied a new heparin surface, the Corline Heparin Surface, applied to a complete set of an extracorporeal device used during coronary artery bypass grafting in terms of activation of inflammation, coagulation, and fibrinolysis in patients and in shed mediastinal blood.

METHODS: Sixty patients scheduled for coronary artery bypass grafting were randomized to one of 3 groups with heparin-coated devices receiving either a standard, high, or low dose of systemic heparin or to an uncoated but otherwise identical circuit receiving a standard dose of systemic heparin. Samples were drawn before, during, and after the operation from the pericardial cavity and in shed mediastinal blood. No autotransfusion of shed mediastinal blood was performed.

RESULTS: The Corline Heparin Surface significantly reduced the activation of coagulation, fibrinolysis, platelets, and inflammation compared with that seen with the uncoated surface in combination with a standard dose of systemic heparin during cardiac surgery with cardiopulmonary bypass. Both a decrease and an increase of systemic heparin in combination with the coated heparin surface resulted in higher activation of these processes. A significantly higher expression of all studied parameters was found in the shed mediastinal blood compared with in systemic blood at the same time.

CONCLUSIONS: The Corline Heparin Surface used in cardiopulmonary bypass proved to be more biocompatible than an uncoated surface when using a standard systemic heparin dose. The low dose of systemic heparin might not be sufficient to maintain the antithrombotic activity, and the high dose resulted in direct cell activation rather than a further anti-inflammatory and anticoagulatory effect.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-91003 (URN)10.1067/mtc.2002.122551 (DOI)12167793 (PubMedID)
Available from: 2003-10-30 Created: 2003-10-30 Last updated: 2018-05-31Bibliographically approved
2. Cell adhesion and tissue factor upregulation in oxygenators used during coronary artery bypass grafting are modified by the Corline Heparin Surface
Open this publication in new window or tab >>Cell adhesion and tissue factor upregulation in oxygenators used during coronary artery bypass grafting are modified by the Corline Heparin Surface
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2002 (English)In: Scandinavian Cardiovascular Journal, ISSN 1401-7431, E-ISSN 1651-2006, Vol. 36, no 6, p. 351-357Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: Cardiopulmonary bypass (CPB) is associated with inflammatory response and activation of coagulation. We investigated the influence of a new heparin surface on the activation of cells retrieved from oxygenators used during coronary artery bypass grafting (CABG).

DESIGN: Sixty patients undergoing CABG with CPB were randomly assigned to either uncoated or completely Corline Heparin Surface (CHS)-coated circuits with one of three different levels of systemic heparin: standard, high or low. At end of surgery adhered cells were retrieved from the oxygenators and cell count, tissue factor (TF)- and CD11b-expression on monocytes and monocytic TFmRNA were analysed.

RESULTS: The heparin coating of the oxygenator prevented adhesion of granulocytes, monocytes and platelets. TF-expression on monocytes from the oxygenators was significantly higher than on circulating cells in all groups. Monocytes from the uncoated oxygenators showed low levels of TF-expression with high levels of TFmRNA. The coated group with high level of heparin showed higher surface-expression of TF with low levels of TFmRNA.

CONCLUSION: The CHS was most biocompatible with the standard level of heparin used during CABG whereas elevation of systemic heparin rather increased the activation and TF upregulation in monocytes from oxygenators.

Keyword
Tissue Factor, Cabg, Heparin, Leukocyte
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-91004 (URN)10.1080/140174302762659076 (DOI)12626202 (PubMedID)
Available from: 2003-10-30 Created: 2003-10-30 Last updated: 2018-05-31Bibliographically approved
3. The influence of different heparin surface concentrations and antithrombin-binding capacity on inflammation and coagulation
Open this publication in new window or tab >>The influence of different heparin surface concentrations and antithrombin-binding capacity on inflammation and coagulation
2005 (English)In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 26, no 14, p. 1731-1739Article in journal (Refereed) Published
Abstract [en]

The corline heparin surface (CHS) used in the extracorporeal circuit during coronary artery bypass grafting is shown to decrease the activation of inflammation and coagulation. Synchrotron radiation studies have shown that a single layer of the CHS may not completely cover the substrate surface. However, a double layer of CHS results in a uniform surface. We investigated the effect of surfaces with different surface concentrations of heparin on cell activation and coagulation compared to an uncoated surface.

The CHS is prepared by a conditioning layer of polymeric amine onto which a macromolecular heparin conjugate is attached. We used PVC tubing, uncoated or modified with a single or double layer of the CHS, and circulated fresh whole blood from healthy volunteers in a loop model system at 37°C up to 4 h. Blood was drawn from the loops at different times and activation of inflammation and coagulation was studied by real-time PCR, flow cytometry and ELISA. The activation of leukocytes and platelets and formation of leukocyte–platelet aggregates were reduced by use of the single-layered CHS compared to the uncoated surface. Use of double-layered CHS resulted in significantly reduced cell activation and thrombin generation. Development of the CHS obtained by the double layer of the coating has improved the biocompatibility of the surface.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-91005 (URN)10.1016/j.biomaterials.2004.05.029 (DOI)15576147 (PubMedID)
Available from: 2003-10-30 Created: 2003-10-30 Last updated: 2017-12-14Bibliographically approved
4. Formation of the proteolytically active tissue factorFVIIa complex leads to enhanced PDGF-BB-stimulated chemotaxis and IL-8 and TNF-α production in monocytes
Open this publication in new window or tab >>Formation of the proteolytically active tissue factorFVIIa complex leads to enhanced PDGF-BB-stimulated chemotaxis and IL-8 and TNF-α production in monocytes
Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-91006 (URN)
Available from: 2003-10-30 Created: 2003-10-30 Last updated: 2010-01-13Bibliographically approved

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