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  • 1.
    Aldred, Nick
    et al.
    1School of Marine Science and Technology, Newcastle University, Newcastle upon Tyne, NE1 7RU, UK..
    Ekblad, Tobias
    Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics . Linköping University, The Institute of Technology.
    Andersson, Olof
    Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics . Linköping University, The Institute of Technology.
    Liedberg, Bo
    Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics . Linköping University, The Institute of Technology.
    Clare, Anthony C.
    1School of Marine Science and Technology, Newcastle University, Newcastle upon Tyne, NE1 7RU, UK..
    In situ study of surface exploration by barnacle cyprids (Semibalanus balanoides) using imaging surface plasmon resonanceManuscript (preprint) (Other academic)
    Abstract [en]

    Imaging surface plasmon resonance (iSPR) was employed to investigate the interfacial adhesion phenomena that occur during the exploration of immersed surfaces by barnacle cyprids (Semibalanus balanoides). It was hypothesised that since the footprint material used by cyprids for temporary adhesion has previously been related to a large cuticular glycoprotein (SIPC), the passive deposition of cyprid footprints and the binding of SIPC to surfaces might correlate. Increased surface exploration (and footprint deposition) has also been related to increased likelihood of settlement in barnacle cyprids. If a correlation between footprint deposition and SIPC binding were to exist, therefore, there would be potential for the development of a high‐throughput assay to determine the efficacy of putative antifouling chemistries against cyprids prior to, or instead of, lengthy bio‐assays. Footprints were deposited in large numbers on carboxyl‐terminated self‐assembled monolayers (SAMs) and in very small numbers on ethylene glycol‐containing SAMs and hydrogel coatings. SIPC binding also followed the same trend. An exception to the correlation was an amineterminated SAM that accumulated few cyprid footprints, but bound SIPC strongly. It is concluded that there is great potential for the iSPR technique to be used in the evaluation of putatively non‐fouling surfaces as well as improving our understanding of the nature of the cyprid footprint material and its interactions with surfaces of different chemistry. However, the use of SIPC binding as a predictor of footprint accumulation/likelihood of settlement of cyprids to surfaces would be premature at this stage without first understanding the exceptions highlighted in this study.

  • 2.
    Bjorses, Katarina
    et al.
    Lund University.
    Faxälv, Lars
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Chemistry.
    Montan, Carl
    Lund University.
    Wildt-Persson, Katarina
    Magle Life Science.
    Fyhr, Peter
    Magle Life Science.
    Holst, Jan
    Lund University.
    Lindahl, Tomas
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Chemistry.
    In vitro and in vivo evaluation of chemically modified degradable starch microspheres for topical haemostasis2011In: ACTA BIOMATERIALIA, ISSN 1742-7061, Vol. 7, no 6, p. 2558-2565Article in journal (Refereed)
    Abstract [en]

    Degradable starch microspheres (DSMs) are starch chains cross-linked with epichlorhydrin, forming glycerol-ether links. DSMs have been used for many years for temporary vascular occlusion and drug delivery in treatment of malignancies. They are also approved and used for topical haemostasis by absorbing excess fluid from the blood and concentrating endogenous coagulation factors, thereby facilitating haemostasis. This mechanism of action is not sufficient for larger bleedings in current chemical formulations of DSMs, and modification of DSMs to trigger activation of platelets or coagulation would be required for use in such applications. Chemical modifications of DSMs with N-octenyl succinic anhydride, chloroacetic acid, acetic anhydride, diethylaminoethyl chloride and ellagic acid were performed and evaluated in vitro with thrombin generation and platelet adhesion tests, and in vivo using an experimental renal bleeding model in rat. DSMs modified to activate platelets in vitro were superior in haemostatic capacity in vivo. Further studies with non-toxic substances are warranted to confirm these results and develop the DSM as a more effective topical haemostatic agent.

  • 3.
    Boknäs, Niklas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Faxälv, Lars
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Lindahl, Tomas L
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Ramström, Sofia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Contact activation: important to consider when measuring the contribution of tissue factor-bearing microparticles to thrombin generation using phospholipid-containing reagents2014In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 12, no 4, p. 515-518Article in journal (Refereed)
    Abstract [en]

    Background A commercial MP reagent containing phospholipids is used for thrombin generation (TG) measurements to estimate the procoagulant activity of microparticles (MPs). Previous reports have shown that contact activation affects TG when TF levels are low, and that addition of phospholipids might augment this effect. Objectives To quantify the impact of contact activation on TG in the presence of phospholipids and low/no TF, as is the case using a commercially available MP-reagent. Methods Thrombin generation was analyzed using MP- or platelet-rich plasma (PRP)-reagent in the presence and absence of corn trypsin inhibitor and anti-TF antibodies, respectively. To quantify the impact of different experimental parameters on contact activation, microparticle-depleted plasma was analyzed in the presence of different concentrations of phospholipids, TF and/or contact activating agents (kaolin). Results Even with low contact activating blood collection tubes, substantial thrombin generation was observed with the MP-reagent, but this was completely inhibited by addition of corn trypsin inhibitor. Control experiments illustrate that the phospholipids in the reagent play a major role in enhancing TG initiated by FXIIa. Even with the PRP-reagent, which is recommended for determining the content of phospholipids from MPs, TG was partly dependent on contact activation. Conclusions Contact activation plays a major role in TG when using reagents/samples containing phospholipids but little or no tissue factor. This needs to be considered and accounted for in future clinical studies using TG to assess the procoagulant activity of MPs.

  • 4.
    Boknäs, Niklas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Faxälv, Lars
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Sanchez Centellas, Daniel
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Wallstedt, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Ramström, Sofia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Grenegård, Magnus
    University of Örebro, Sweden.
    Lindahl, Tomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Thrombin-induced platelet activation via PAR4: pivotal role for exosite II2014In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 112, no 3, p. 558-565Article in journal (Refereed)
    Abstract [en]

    Thrombin-induced platelet activation via PAR1 and PAR4 is an important event in haemostasis. Although the underlying mechanisms responsible for ensuring efficient PAR1 activation by thrombin have been extensively studied, the potential involvement of recognitions sites outside the active site of the protease in thrombin-induced PAR4 activation is largely unknown. In this study, we developed a new assay to assess the importance of exosite I and II for PAR4 activation with alpha- and gamma-thrombin. Surprisingly, we found that exosite II is critical for activation of PAR4. We also show that this dependency on exosite II likely represents a new mechanism, as it is unaffected by blockage of the previously known interaction between thrombin and glycoprotein Ib alpha.

  • 5.
    Boknäs, Niklas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Faxälv, Lars
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Ström, Jakob O
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Tengvall, Pentti
    Sahlgrenska Academy, University of Gothenburg, Sweden.
    Theodorsson, Elvar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Ramström, Sofia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Lindahl, Tomas L
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Response: platelets do not generate activated factor XII--how inappropriate experimental models have led to misleading conclusions2014In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, no 10, p. 1692-1694Article in journal (Other academic)
  • 6.
    Claesson, Kjersti
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Lindahl, Tomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Faxälv, Lars
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Counting the platelets: a robust and sensitive quantification method for thrombus formation2016In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 115, no 6, p. 1178-1190Article in journal (Refereed)
    Abstract [en]

    Flow chambers are common tools used for studying thrombus formation in vitro. However, the use of such devices is not standardised and there is a large diversity among the flow chamber systems currently used, and also in the methods used for quantifying the thrombus development. It was the study objective to evaluate a new method for analysis and quantification of platelet thrombus formation that can facilitate comparison of results between research groups. Whole blood was drawn over a collagen patch in commercial Ibid or in-house constructed PDMS flow chambers. Five percent of the platelets were fluorescently labelled and z-stack time-lapse images were captured during thrombus formation. Images were processed in a Python script in which the number of platelets and their respective x-, y- and z-positions were obtained. For comparison with existing methods the platelets were also labelled and quantified using fluorescence intensity and thrombus volume estimations by confocal microscopy. The presented method was found less sensitive to microscope and image adjustments and provides more details on thrombus development dynamics than the methods for measuring fluorescence intensity and thrombus volume estimation. The platelet count method produced comparable results with commercial and PDMS flow chambers, and could also obtain information regarding the stability of each detected platelet in the thrombus. In conclusion, quantification of thrombus formation by platelet count is a sensitive and robust method that enables measurement of platelet accumulation and platelet stability in an absolute scale that could be used for comparisons between research groups.

  • 7.
    Ekblad, Tobias
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics. Linköping University, The Institute of Technology.
    Faxälv, Lars
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Andersson, Olof
    Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics. Linköping University, The Institute of Technology.
    Wallmark, Nanny
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Larsson (Kaiser), Andréas
    Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics. Linköping University, The Institute of Technology.
    Lindahl, Tomas L.
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Liedberg, Bo
    Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics. Linköping University, The Institute of Technology.
    Patterned Hydrogels for Controlled Platelet Adhesion from Whole Blood and Plasma2010In: Advanced Functional Materials, ISSN 1616-301X, E-ISSN 1616-3028, Vol. 20, no 15, p. 2396-2403Article in journal (Refereed)
    Abstract [en]

    This work describes the preparation and properties of hydrogel surface chemistries enabling controlled and well-defined cell adhesion. The hydrogels may be prepared directly on plastic substrates, such as polystyrene slides or dishes, using a quick and experimentally simple photopolymerization process, compatible with photolithographic and microfluidic patterning methods. The intended application for these materials is as substrates for diagnostic cell adhesion assays, particularly for the analysis of human platelet function. The adsorption of fibrinogen and other platelet promoting molecules is shown to be completely inhibited by the hydrogel, provided that the film thickness is sufficient (>5 nm). This allows the hydrogel to be used as a matrix for presenting selected bioactive ligands without risking interference from nonspecifically adsorbed platelet adhesion factors, even in undiluted whole blood and blood plasma. This concept is demonstrated by preparing patterns of proteins on hydrogel surfaces, resulting in highly controlled platelet adhesion. Further insights into the protein immobilization and platelet adhesion processes are provided by studies using imaging surface plasmon resonance. The hydrogel surfaces used in this work appear to provide an ideal platform for cell adhesion studies of platelets, and potentially also for other cell types.

  • 8.
    Ericsson, Emma
    et al.
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Faxälv, Lars
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Weissenrieder, Anna
    St Paul, USA.
    Askendal, Agneta
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Lindahl, Tomas
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Tengvall, Pentti
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Glycerol monooleate-blood interactions2009In: Colloids and Surfaces B: Biointerfaces, ISSN 0927-7765, E-ISSN 1873-4367, Vol. 68, no 1, p. 20-26Article in journal (Refereed)
    Abstract [en]

    In the present study the initial blood compatibility of glycerol monooleate (GMO)-coated surfaces was evaluated after deposition to surfaces and in bulk. The model surface was silica onto which multiple layers of fibrinogen or human serum albumin (HSA) was immobilized. The protein-coated surfaces were subsequently dip-coated in GMO in ethanol and used for blood plasma and whole blood experiments. The characterization methods included null ellipsometry, scanning electron microscopy, imaging of coagulation, hemolysis test and whole blood coagulation time by free oscillation rheometry.

    The results showed a GMO film thickness of approximately 350 angstrom (similar to 4 mu g/cm(2)) upon dip-coating in ethanolic solution. A major part of the deposited layer detached in aqueous solutions, especially during shear conditions. The coagulation time on GMO was significantly prolonged compared to that on HSA coated silica. Whole blood tests showed that GMO is a very weak hemolytic agent. Deposited GMO detached easily from surfaces upon rinsing or shearing, although a stable layer with undefined phase structure and a thickness of 50-70 angstrom remained on HSA and fibrinogen precoated surfaces. This indicates that GMO has stronger adhesive forces to its substrate compared to the cohesive forces acting within the bulk GMO. The ability of GMO to detach from itself and tentatively form micelles or lipid bilayers when subjected to flowing blood may be of use in extravascular applications. It is concluded that GMO results in weak blood activation, and the material may in spite of this be suitable in selected biomaterial applications, especially as a biosealant and in colloidal dispersions.

  • 9.
    Faxälv, Lars
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Imaging methods for haemostasis research2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Blood is a vital part of the human physiology; a transport system that brings nutrients and oxygen to sustain living cells and simultaneously facilitates the removal of carbon dioxide and other waste products from the body. To assure the continuity of these functions, it is of uttermost importance to keep the flowing blood inside the vascular system at any cost. The principal components of the haemostatic system are the blood platelets and the plasma coagulation system, both working in concert to create a blood stopping haemostatic plug when a vessel is ruptured. In modern health care, methods for treatment and diagnostics often implicate the contact between blood and artificial materials (biomaterials). Biomaterial surfaces may activate platelets and the coagulation cascade by exposing a surface that during blood contact shares certain characteristics with surfaces found at the site of vascular injury. Therefore it is of great importance that the mechanisms behind the interactions between foreign surfaces and blood are studied in order to minimize, and if possible, prevent unnecessary reactions that may lead to thrombosis.

    This thesis describes two important methods to study blood – surface interactions in terms of surface induced plasma coagulation and platelet adhesion/aggregation. The method ‘Imaging of coagulation’, a coagulation assay based on time-lapse image capture of the coagulation process was developed during the course of this work. The use of images enables the method to answer questions regarding where coagulation was initiated and how fast coagulation propagates. Such questions are highly relevant in the study of blood-biomaterial interactions but also in general haemostasis research. In vivo, platelet adhesion and aggregation are events that always proceed under flow conditions. Therefore we also developed a cone-and-plate flow model to study these mechanisms under similar conditions in vitro. The cone-and-plate setup was found to be a flexible platform and was used for both blood compatibility testing of potential biomaterials as well as for general haemostasis research.

    With the above mentioned methods we tested the haemocompatibility of glycerol monooleate (GMO), a proposed substance for use in biomaterial applications. It was found that GMO did not activate coagulation to any great extent either in plasma or in whole blood.

    Surface induced coagulation and platelet adhesion was also studied on PEG-containing hydrogels and compared with hydrogels constructed from three different non-PEG-containing monomers. It was concluded that all the grafted hydrogels, in particular those produced from the monomers 2-hydroxyethyl methacrylate (HEMA) and/or PEG- methacrylate (PEGMA), demonstrated good haemocompatibility.

    Supported phospholipid bilayers were used to investigate the relationship between surface charge and procoagulant activity. The coagulation process was studied in a straightforward manner using the imaging of coagulation setup. We concluded that the content of negatively charged 1-palmitoyl-2-oleoyl-sn-glycero-3-[phospho-L-serine] (POPS) in the bilayer must exceed ~ 6% for the bilayer to exert procoagulant activity.

    The physiological role of factor XII in human haemostasis and thrombosis was investigated in the imaging of coagulation setup and the cone and plate setup by the use of surfaces with thrombogenic coatings. We found that tissue factor initiated coagulation could be greatly accelerated by the presence of contact activating agents in a platelet dependent manner.

    In conclusion, the method ‘Imaging of coagulation’ and platelet adhesion/aggregation in the cone-and-plate flow model are both versatile methods with many possible applications. The combination of the two methods provides a solid foundation for biomaterial and haemostasis research.

    List of papers
    1. Imaging of blood plasma coagulation and its propagation at surfaces
    Open this publication in new window or tab >>Imaging of blood plasma coagulation and its propagation at surfaces
    2008 (English)In: Journal of biomedical materials research. Part A, ISSN 1552-4965, Vol. 85, no 4, p. 1129-1134Article in journal (Refereed) Published
    Abstract [en]

    A new method utilizing image capture and processing was developed for the analysis of blood plasma coagulation at surfaces. The coagulation was detected in a cuvette by time-lapse image capture of light scattering from the developing fibrin network. By image processing and computer analysis of the captured image data, both early detection of coagulation at the surface and the propagation phase of coagulation could be measured in the same experiment. It is possible to use both platelet-rich plasma (PRP) and platelet-free plasma (PFP) with the method, and thereby study the platelet contribution to both surface coagulation and propagation of coagulation. Two well-known model surfaces, hydrophilic and hydrophobic glass, were used in combination with PRP and PFP to illustrate the method. Hydrophilic glass activated coagulation significantly faster (PRP: 7.0 +/- 1.7 min, PFP: 5.9 +/- 1.2 min, n= 16) than hydrophobic glass (PRP: 50 +/- 14 min, PFP: 65 +/- 32 min, n = 16) in both PRP and PFP. Hydrophilic surfaces showed a faster initial propagation of coagulation adjacent to the surface (mean velocity: 0.14 +/- 0.05 mm/ minute) compared with the propagation observed further out from the surface (mean velocity: 0.05 +/- 0.01 mm/min). The method is very flexible and can be suitable for screening hemocompatibility of biomaterials.

    Keywords
    Glycerol monooleate, Blood compatibility, Shear, Ellipsometry
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-19173 (URN)10.1002/jbm.a.31529 (DOI)17907239 (PubMedID)
    Available from: 2009-06-12 Created: 2009-06-12 Last updated: 2009-08-18Bibliographically approved
    2. Glycerol monooleate-blood interactions
    Open this publication in new window or tab >>Glycerol monooleate-blood interactions
    Show others...
    2009 (English)In: Colloids and Surfaces B: Biointerfaces, ISSN 0927-7765, E-ISSN 1873-4367, Vol. 68, no 1, p. 20-26Article in journal (Refereed) Published
    Abstract [en]

    In the present study the initial blood compatibility of glycerol monooleate (GMO)-coated surfaces was evaluated after deposition to surfaces and in bulk. The model surface was silica onto which multiple layers of fibrinogen or human serum albumin (HSA) was immobilized. The protein-coated surfaces were subsequently dip-coated in GMO in ethanol and used for blood plasma and whole blood experiments. The characterization methods included null ellipsometry, scanning electron microscopy, imaging of coagulation, hemolysis test and whole blood coagulation time by free oscillation rheometry.

    The results showed a GMO film thickness of approximately 350 angstrom (similar to 4 mu g/cm(2)) upon dip-coating in ethanolic solution. A major part of the deposited layer detached in aqueous solutions, especially during shear conditions. The coagulation time on GMO was significantly prolonged compared to that on HSA coated silica. Whole blood tests showed that GMO is a very weak hemolytic agent. Deposited GMO detached easily from surfaces upon rinsing or shearing, although a stable layer with undefined phase structure and a thickness of 50-70 angstrom remained on HSA and fibrinogen precoated surfaces. This indicates that GMO has stronger adhesive forces to its substrate compared to the cohesive forces acting within the bulk GMO. The ability of GMO to detach from itself and tentatively form micelles or lipid bilayers when subjected to flowing blood may be of use in extravascular applications. It is concluded that GMO results in weak blood activation, and the material may in spite of this be suitable in selected biomaterial applications, especially as a biosealant and in colloidal dispersions.

    Keywords
    Glycerol monooleate, Blood compatibility, Shear, Ellipsometry
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-16356 (URN)10.1016/j.colsurfb.2008.09.016 (DOI)
    Available from: 2009-01-16 Created: 2009-01-16 Last updated: 2017-12-14Bibliographically approved
    3. Blood compatibility of photografted hydrogel coatings
    Open this publication in new window or tab >>Blood compatibility of photografted hydrogel coatings
    2010 (English)In: ACTA BIOMATERIALIA, ISSN 1742-7061, Vol. 6, no 7, p. 2599-2608Article in journal (Other academic) Published
    Abstract [en]

    In this work we have evaluated the haemocompatibility of different surface modifications, intended for biomaterials and biosensor applications. Polystyrene slides were coated with thin hydrogel films by self-initiated photografting of four different monomers. The hydrogel surface modifications were thoroughly characterized and tested for their protein resistance and ability to facilitate platelet adhesion and activation of the coagulation system. There was very little protein adsorption from human plasma on the hydrogels formed from poly(ethylene glycol) methacrylate (PEGMA) and 2-hydroxyethyl methacrylate (HEMA). Platelet adhesion tests performed under both static and flow conditions showed that these coatings also demonstrated very high resistance towards platelet adhesion. A small amount of platelets were found to adhere to hydrogels formed from ethylene glycol methyl ether methacrylate (EGMEMA) and 2-carboxyethyl methacrylate (CEA). The polystyrene substrates themselves facilitated large amounts of platelet adhesion under both static and flow conditions. Utilizing a novel setup for imaging of coagulation, it was shown that none of the hydrogel surfaces activated the coagulation system to any great extent. We suggest that this simple fabrication method can be used to produce hydrogel coatings with unusually high blood compatibility, suitable for demanding biomaterials applications.

    Place, publisher, year, edition, pages
    Elsevier Science B.V. Amsterdam, 2010
    Keywords
    Hydrogel; Biomaterial; Protein adsorption; Coagulation; Platelet
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-19175 (URN)10.1016/j.actbio.2009.12.046 (DOI)000278868000027 ()
    Available from: 2009-06-12 Created: 2009-06-12 Last updated: 2011-03-23Bibliographically approved
    4. Activation of blood coagulation at charged supported lipid membranes
    Open this publication in new window or tab >>Activation of blood coagulation at charged supported lipid membranes
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    The purpose of this work was to investigate the relationship between surface charge of phospholipid membranes and coagulation. Also, we wanted to demonstrate that coagulation at phospholipid membranes could successfully be studied in the method for imaging of coagulation.

    Analytical procedure: Supported phospholipid membranes were formed from palmitoyl-oleoyl-glycero-3-ethylphosphocholine (POEPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), and 1- palmitoyl-2-oleoyl-sn-glycero-3-[phospho-L-serine] (POPS) on silicon substrates. The surface charge of the phospholipid membranes was controlled by using different compositions of POPS (negative net charge), POPC (weak negative net charge) and POEPC (positive net charge). Imaging of coagulation experiments were performed on all phospholipid membrane coated surfaces as well as the clean silicon substrate. The experiments were performed in platelet-free plasma (PFP) diluted 50:50 with phosphate-buffered saline (PBS).

    Results: Comparing the negatively charged SiO2 surface with the negatively charged POPS (30%)/POPC(70%) we found an interesting difference. Although both surfaces activated coagulation rapidly, the POPS surface facilitated a faster propagation of coagulation from the surface than the SiO2 surface. It was also found that in order for the phospholipid membranes to exert procoagulant properties, the POPS content in the membrane had to exceed ~6 %. It was also found that positively charged phospholipid membranes did not induce activation of coagulation.

    Conclusions: The work in this paper demonstrated that the coagulation process at phospholipid membranes can be studied in a straightforward manner using the imaging of coagulation setup. Furthermore, we speculate that the negatively charged phospholipid membranes but not the SiO2 surface can support the binding of coagulation factor complexes, thus facilitating a faster propagation of coagulation. The fact that the POPS content must exceed ~ 6% to fully exert procoagulant properties was also a very interesting result, especially since platelets, when activated, become procoagulant by increasing their negatively charged phosphatidylserine exposure from ~0 % to maximally ~10 %.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-19176 (URN)
    Available from: 2009-06-12 Created: 2009-06-12 Last updated: 2015-09-18Bibliographically approved
    5. The role of coagulation factor XII in propagation of coagulation
    Open this publication in new window or tab >>The role of coagulation factor XII in propagation of coagulation
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    The physiological relevance and function of coagulation factor XII (FXII), the first zymogen in the intrinsic pathway, has for a long time been a matter of debate. The aim of this study was to shed some light on the role of factor XII in thrombus formation with a focus on its effect during the propagation phase of coagulation. In order to study propagation of coagulation we utilized a new imaging method to measure propagation rates from an activating surface in both platelet-free plasma and platelet-rich plasma. The most essential results revealed that both FXII and its substrate FXI are located on the surface of activated platelets. The surface of preexisting clots does not support coagulation in a FXII dependent manner. However, we found strong evidence for an accelerated propagation of tissue factor initiated coagulation when contact activation of FXII simultaneously occurred in the proximity. In vivo sources for contact activation may be exposed subendothelial collagen as well as soluble and cell derived poly-anions. If such in vivo contact activation of FXII occurs, even though moderate, it could contribute to in vivo thrombus growth rate and thus be of pathophysiological importance.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-19177 (URN)
    Available from: 2009-06-12 Created: 2009-06-12 Last updated: 2015-03-13Bibliographically approved
  • 10.
    Faxälv, Lars
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Boknäs, Niklas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Lindahl, Tomas
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    PAR1, PAR4 and GPIB form functional interdependent units in a receptor complex mediating platelet activation by thrombin in JOURNAL OF THROMBOSIS AND HAEMOSTASIS, vol 9, issue SI, pp 11-112011In: JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Wiley-Blackwell , 2011, Vol. 9, no SI, p. 11-11Conference paper (Refereed)
    Abstract [en]

    n/a

  • 11.
    Faxälv, Lars
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Boknäs, Niklas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Ström, Jakob
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Tengvall, Pentti
    University of Gothenburg, Gothenburg, Sweden .
    Theodorsson, Elvar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Ramström, Sofia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Lindahl, Tomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Putting polyphosphates to the test: evidence against platelet-induced activation of factor XII2013In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 122, no 23, p. 3818-3824Article in journal (Refereed)
    Abstract [en]

    The recent claim that stimulated platelets activate the intrinsic pathway of coagulation by the release of polyphosphates has been considered a breakthrough in hemostasis research. In little more than 3 years, the original publication by Muller et al has been cited greater than100 times. However, none of the citing articles has sought to independently validate this potentially paradigm-shifting concept. To this end, we performed extensive experimentation in vitro and in vivo in an attempt to verify the claim that factor XII (FXII) is primarily activated by stimulated platelets. In contrast to the original assertion, platelet-derived polyphosphates were found to be weak activators of FXII, with a FXIIa-generating activity of less than10% compared with equivalent concentrations of kaolin. Using different coagulation assays, it was shown that platelet contribution to whole blood coagulation was unrelated to the generation of activated FXII in vitro. Additionally, key results used to verify the hypothesis in the original study in vivo were found to be irreproducible. We conclude that platelet-derived polyphosphates are not physiologically relevant activators of FXII.

  • 12.
    Faxälv, Lars
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Bolin, Maria
    Linköping University, Department of Science and Technology. Linköping University, The Institute of Technology.
    Jager, Edwin
    Linköping University, Department of Physics, Chemistry and Biology, Biosensors and Bioelectronics. Linköping University, The Institute of Technology. Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, Faculty of Science & Engineering.
    Lindahl, Tomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Berggren, Magnus
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, The Institute of Technology.
    Electronic control of platelet adhesion using conducting polymer microarrays2014In: Lab on a Chip, ISSN 1473-0197, E-ISSN 1473-0189, Vol. 14, no 16, p. 3043-3049Article in journal (Refereed)
    Abstract [en]

    We hereby report a method to fabricate addressable micropatterns of e-surfaces based on the conducting polymer poly(3,4-ethylenedioxythiophene) doped with the anion tosylate (PEDOT:Tos) to gain dynamic control over the spatial distribution of platelets in vitro. With thin film processing and microfabrication techniques, patterns down to 10 mu m were produced to enable active regulation of platelet adhesion at high spatial resolution. Upon electronic addressing, both reduced and oxidized surfaces were created within the same device. This surface modulation dictates the conformation and/or orientation, rather than the concentration, of surface proteins, thus indirectly regulating the adhesion of platelets. The reduced electrode supported platelet adhesion, whereas the oxidized counterpart inhibited adhesion. PEDOT:Tos electrode fabrication is compatible with most of the classical patterning techniques used in printing as well as in the electronics industry. The first types of tools promise ultra-low-cost production of low-resolution (greater than30 mu m) electrode patterns that may combine with traditional substrates and dishes used in a classical analysis setup. Platelets play a pronounced role in cardiovascular diseases and have become an important drug target in order to prevent thrombosis. This clinical path has in turn generated a need for platelet function tests to monitor and assess platelet drug efficacy. The spatial control of platelet adherence presented here could prove valuable for blood cell separation or biosensor microarrays, e.g. in diagnostic applications where platelet function is evaluated.

  • 13.
    Faxälv, Lars
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Ekblad, Tobias
    Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics . Linköping University, The Institute of Technology.
    Liedberg, Bo
    Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics . Linköping University, The Institute of Technology.
    Lindahl, Tomas L.
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Blood compatibility of photografted hydrogel coatings2010In: ACTA BIOMATERIALIA, ISSN 1742-7061, Vol. 6, no 7, p. 2599-2608Article in journal (Other academic)
    Abstract [en]

    In this work we have evaluated the haemocompatibility of different surface modifications, intended for biomaterials and biosensor applications. Polystyrene slides were coated with thin hydrogel films by self-initiated photografting of four different monomers. The hydrogel surface modifications were thoroughly characterized and tested for their protein resistance and ability to facilitate platelet adhesion and activation of the coagulation system. There was very little protein adsorption from human plasma on the hydrogels formed from poly(ethylene glycol) methacrylate (PEGMA) and 2-hydroxyethyl methacrylate (HEMA). Platelet adhesion tests performed under both static and flow conditions showed that these coatings also demonstrated very high resistance towards platelet adhesion. A small amount of platelets were found to adhere to hydrogels formed from ethylene glycol methyl ether methacrylate (EGMEMA) and 2-carboxyethyl methacrylate (CEA). The polystyrene substrates themselves facilitated large amounts of platelet adhesion under both static and flow conditions. Utilizing a novel setup for imaging of coagulation, it was shown that none of the hydrogel surfaces activated the coagulation system to any great extent. We suggest that this simple fabrication method can be used to produce hydrogel coatings with unusually high blood compatibility, suitable for demanding biomaterials applications.

  • 14.
    Faxälv, Lars
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Hume, Jasmin
    Chalmers.
    Kasemo, Bengt
    Chalmers.
    Svedhem, Sofia
    Chalmers.
    Imaging of blood plasma coagulation at supported lipid membranes2011In: Journal of Colloid and Interface Science, ISSN 0021-9797, E-ISSN 1095-7103, Vol. 364, no 2, p. 582-587Article in journal (Refereed)
    Abstract [en]

    The blood coagulation system relies on lipid membrane constituents to act as regulators of the coagulation process upon vascular trauma, and in particular the 2D configuration of the lipid membranes is known to efficiently catalyze enzymatic activity of blood coagulation factors. This work demonstrates a new application of a recently developed methodology to study blood coagulation at lipid membrane interfaces with the use of imaging technology. Lipid membranes with varied net charges were formed on silica supports by systematically using different combinations of lipids where neutral phosphocholine (PC) lipids were mixed with phospholipids having either positively charged ethylphosphocholine (EPC), or negatively charged phosphatidylserine (PS) headgroups. Coagulation imaging demonstrated that negatively charged SiO(2) and membrane surfaces exposing PS (obtained from liposomes containing 30% of PS) had coagulation times which were significantly shorter than those for plain PC membranes and EPC exposing membrane surfaces (obtained from liposomes containing 30% of EPC). Coagulation times decreased non-linearly with increasing negative surface charge for lipid membranes. A threshold value for shorter coagulation times was observed below a PS content of similar to 6%. We conclude that the lipid membranes on solid support studied with the imaging setup as presented in this study offers a flexible and non-expensive solution for coagulation studies at biological membranes. It will be interesting to extend the present study towards examining coagulation on more complex lipid-based model systems. (C) 2011 Elsevier Inc. All rights reserved.

  • 15.
    Faxälv, Lars
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Hume, Jasmin
    Deptartment of Applied Physics, Chalmers University of Technology,.
    Lindahl, Tomas L.
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Kasemo, Bengt
    Department of Applied Physics, Chalmers University of Technology, SE-412 96 Göteborg, Sweden.
    Svedhem, Sofia
    Department of Applied Physics, Chalmers University of Technology, SE-412 96 Göteborg, Sweden.
    Activation of blood coagulation at charged supported lipid membranesManuscript (preprint) (Other academic)
    Abstract [en]

    The purpose of this work was to investigate the relationship between surface charge of phospholipid membranes and coagulation. Also, we wanted to demonstrate that coagulation at phospholipid membranes could successfully be studied in the method for imaging of coagulation.

    Analytical procedure: Supported phospholipid membranes were formed from palmitoyl-oleoyl-glycero-3-ethylphosphocholine (POEPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), and 1- palmitoyl-2-oleoyl-sn-glycero-3-[phospho-L-serine] (POPS) on silicon substrates. The surface charge of the phospholipid membranes was controlled by using different compositions of POPS (negative net charge), POPC (weak negative net charge) and POEPC (positive net charge). Imaging of coagulation experiments were performed on all phospholipid membrane coated surfaces as well as the clean silicon substrate. The experiments were performed in platelet-free plasma (PFP) diluted 50:50 with phosphate-buffered saline (PBS).

    Results: Comparing the negatively charged SiO2 surface with the negatively charged POPS (30%)/POPC(70%) we found an interesting difference. Although both surfaces activated coagulation rapidly, the POPS surface facilitated a faster propagation of coagulation from the surface than the SiO2 surface. It was also found that in order for the phospholipid membranes to exert procoagulant properties, the POPS content in the membrane had to exceed ~6 %. It was also found that positively charged phospholipid membranes did not induce activation of coagulation.

    Conclusions: The work in this paper demonstrated that the coagulation process at phospholipid membranes can be studied in a straightforward manner using the imaging of coagulation setup. Furthermore, we speculate that the negatively charged phospholipid membranes but not the SiO2 surface can support the binding of coagulation factor complexes, thus facilitating a faster propagation of coagulation. The fact that the POPS content must exceed ~ 6% to fully exert procoagulant properties was also a very interesting result, especially since platelets, when activated, become procoagulant by increasing their negatively charged phosphatidylserine exposure from ~0 % to maximally ~10 %.

  • 16.
    Faxälv, Lars
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Ramström, Sofia
    Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland.
    Soutukorva, Kristina
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Tengvall, Pentti
    Linköping University, Department of Physics, Chemistry and Biology, Applied Physics. Linköping University, The Institute of Technology.
    Lindahl, Tomas L.
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    The role of coagulation factor XII in propagation of coagulationManuscript (preprint) (Other academic)
    Abstract [en]

    The physiological relevance and function of coagulation factor XII (FXII), the first zymogen in the intrinsic pathway, has for a long time been a matter of debate. The aim of this study was to shed some light on the role of factor XII in thrombus formation with a focus on its effect during the propagation phase of coagulation. In order to study propagation of coagulation we utilized a new imaging method to measure propagation rates from an activating surface in both platelet-free plasma and platelet-rich plasma. The most essential results revealed that both FXII and its substrate FXI are located on the surface of activated platelets. The surface of preexisting clots does not support coagulation in a FXII dependent manner. However, we found strong evidence for an accelerated propagation of tissue factor initiated coagulation when contact activation of FXII simultaneously occurred in the proximity. In vivo sources for contact activation may be exposed subendothelial collagen as well as soluble and cell derived poly-anions. If such in vivo contact activation of FXII occurs, even though moderate, it could contribute to in vivo thrombus growth rate and thus be of pathophysiological importance.

  • 17.
    Faxälv, Lars
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Tengvall, Pentti
    Linköping University, Department of Physics, Chemistry and Biology, Applied Physics . Linköping University, The Institute of Technology.
    Lindahl, Tomas L
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Imaging of blood plasma coagulation and its propagation at surfaces2008In: Journal of biomedical materials research. Part A, ISSN 1552-4965, Vol. 85, no 4, p. 1129-1134Article in journal (Refereed)
    Abstract [en]

    A new method utilizing image capture and processing was developed for the analysis of blood plasma coagulation at surfaces. The coagulation was detected in a cuvette by time-lapse image capture of light scattering from the developing fibrin network. By image processing and computer analysis of the captured image data, both early detection of coagulation at the surface and the propagation phase of coagulation could be measured in the same experiment. It is possible to use both platelet-rich plasma (PRP) and platelet-free plasma (PFP) with the method, and thereby study the platelet contribution to both surface coagulation and propagation of coagulation. Two well-known model surfaces, hydrophilic and hydrophobic glass, were used in combination with PRP and PFP to illustrate the method. Hydrophilic glass activated coagulation significantly faster (PRP: 7.0 +/- 1.7 min, PFP: 5.9 +/- 1.2 min, n= 16) than hydrophobic glass (PRP: 50 +/- 14 min, PFP: 65 +/- 32 min, n = 16) in both PRP and PFP. Hydrophilic surfaces showed a faster initial propagation of coagulation adjacent to the surface (mean velocity: 0.14 +/- 0.05 mm/ minute) compared with the propagation observed further out from the surface (mean velocity: 0.05 +/- 0.01 mm/min). The method is very flexible and can be suitable for screening hemocompatibility of biomaterials.

  • 18.
    Fink, Helen
    et al.
    University of Gothenburg.
    Faxälv, Lars
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Molnar, Gabor F
    Semmelweis University of Medicine.
    Drotz, Kristoffer
    Chalmers.
    Risberg, Bo
    University of Gothenburg.
    Lindahl, Tomas
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Sellborn, Anders
    University of Gothenburg.
    Real-time measurements of coagulation on bacterial cellulose and conventional vascular graft materials2010In: ACTA BIOMATERIALIA, ISSN 1742-7061, Vol. 6, no 3, p. 1125-1130Article in journal (Refereed)
    Abstract [en]

    The search for a functional, small diameter (andlt;5 mm) vascular graft has been ongoing for over 30 years, but yet there is no consistently reliable synthetic graft The primary mechanisms of graft failure are intimal hyperplasia. poor blood flow and surface thrombogenicity Bacterial cellulose (BC) became therefore a proposed new biosynthetic vascular graft material Since conventional methods are not suited for coagulation measurements on BC, we have adapted the automated calibrated thrombin generation method for measurements of biomaterial-induced coagulation of BC as compared with clinically used graft materials ie, expanded poly(tetrafluoroethylene) (ePTFE) and poly(ethyleneterephtalat) (PET) We have also visualized the coagulation propagation at the material surfaces Thrombin generation experiments revealed dramatic differences between the materials tested. Both ePTFE and BC were found to generate longer lag times and ttpeak values than PET Most importantly. BC was found to generate the lowest.. peak", indicating a slower coagulation process at the surface These results are also Supported by the measurements of factor XIIa generation and analysis of surface coagulation times, which were detected in the following increasing order (mean +/- SD) PET (27 +/- 8 min) andlt; BC (46 +/- 9 min) andlt; ePTFE (61 +/- 21 min) Real-time measurement of coagulation seems to have the potential for becoming a powerful too] for evaluation of biomaterials for blood-contacting devices

  • 19.
    H Nilsson, Per
    et al.
    Linnaeus University.
    Engberg, Anna E
    Linnaeus University.
    Back, Jennie
    University Uppsala Hospital.
    Faxälv, Lars
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Lindahl, Tomas
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Nilsson, Bo
    University Uppsala Hospital.
    Ekdahl, Kristina N
    Linnaeus University.
    The creation of an antithrombotic surface by apyrase immobilization2010In: BIOMATERIALS, ISSN 0142-9612, Vol. 31, no 16, p. 4484-4491Article in journal (Refereed)
    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.

  • 20.
    Hillarp, A.
    et al.
    University and Regional Laboratories Region Skåne, Malmö, Sweden.
    Gustafsson, Kerstin
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Faxälv, Lars
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Strandberg, K.
    University and Regional Laboratories Region Skåne, Malmö, Sweden.
    Baghaei, F.
    Sahlgrenska University Hospital, Sweden; University of Gothenburg, Sweden.
    Fagerberg Blixter, I.
    Sahlgrenska University Hospital, Sweden; University of Gothenburg, Sweden.
    Berndtsson, M.
    Karolinska University Hospital, Stockholm, Sweden.
    Lindahl, Tomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Effects of the oral, direct factor Xa inhibitor apixaban on routine coagulation assays and anti-FXa assays2014In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 12, no 9, p. 1545-1553Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION:

    Apixaban is an oral direct factor Xa inhibitor developed for the prophylaxis and treatment of thromboembolic disorders. Laboratory monitoring is not necessary, but the effects on common coagulation reagents and assays constitute clinically valuable information.

    OBJECTIVES:

    To investigate the effects of apixaban on commonly used coagulation methods, and to evaluate anti-FXa assays for specific determination of the drug concentration.

    MATERIALS AND METHODS:

    Apixaban was added to plasma from healthy subjects in the concentration range 0-1000 μg L(-1) , and analyses were performed with different reagents for activated partial thromboplastin time (APTT), prothrombin time (PT), antithrombin, protein C, and protein S. A lupus anticoagulant assay and an APTT assay with varying phospholipid concentrations were used to study the phospholipid dependence.

    RESULTS:

    In general, apixaban showed fewer effects in vitro than have been shown for rivaroxaban, another direct FXa inhibitor. The concentration needed to double the APTT varied between 2200 and 4700 μg L(-1) , and the concentration needed to double the PT varied between 700 and 3900 μg L(-1) . The effects on antithrombin, protein C and protein S assays were dependent on the type of reagent. Apixaban did not cause false-positive lupus anticoagulant results. Chromogenic anti-FXa assays showed linear dose-response curves with apixaban.

    CONCLUSIONS:

    Therapeutic concentrations of apixaban variably affect different assay groups, and even different reagents within an assay group. The effects were much smaller than with rivaroxaban. The use of APTT and/or PT assays to screen the anticoagulant activity of apixaban cannot be recommended. A chromogenic anti-FXa assay can be used for reliable measurements of apixaban concentration.

  • 21.
    Hulander, M
    et al.
    University of Gothenburg, Sweden .
    Lundgren, A
    Chalmers, Sweden .
    Faxälv, Lars
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Lindahl, Tomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Palmquist, A
    University of Gothenburg, Sweden .
    Berglin, M
    University of Gothenburg, Sweden .
    Elwing, H
    University of Gothenburg, Sweden .
    Gradients in surface nanotopography used to study platelet adhesion and activation2013In: Colloids and Surfaces B: Biointerfaces, ISSN 0927-7765, E-ISSN 1873-4367, Vol. 110, p. 261-269Article in journal (Refereed)
    Abstract [en]

    Gradients in surface nanotopography were prepared by adsorbing gold nanoparticles on smooth gold substrates using diffusion technique. Following a sintering procedure the particle binding chemistry was removed, and integration of the particles into the underlying gold substrate was achieved, leaving a nanostructured surface with uniform surface chemistry. After pre-adsorption of human fibrinogen, the effect of surface nanotopography on platelets was studied. The use of a gradient in nanotopography allowed for platelet adhesion and activation to be studied as a function of nanoparticle coverage on one single substrate. A peak in platelet adhesion was found at 23% nanoparticle surface coverage. The highest number of activated platelets was found on the smooth control part of the surface, and did not coincide with the number of adhered platelets. Activation correlated inversely with particle coverage, hence the lowest fraction of activated platelets was found at high particle coverage. Hydrophobization of the gradient surface lowered the total number of adhering cells, but not the ratio of activated cells. Little or no effect was seen on gradients with 36 nm particles, suggesting the existence of a lower limit for sensing of surface nano-roughness in platelets. These results demonstrate that parameters such as ratio between size and inter-particle distance can be more relevant for cell response than wettability on nanostructured surfaces. The minor effect of hydrophobicity, the generally reduced activation on nanostructured surfaces and the presence of a cut-off in activation of human platelets as a function of nanoparticle size could have implications for the design of future blood-contacting biomaterials.

  • 22.
    Lindahl, Tomas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Faxälv, Lars
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Stable solution2015Patent (Other (popular science, discussion, etc.))
  • 23.
    Lindahl, Tomas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Ramström, Sofia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Boknäs, Niklas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Faxälv, Lars
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Caveats in studies of the physiological role of polyphosphates in coagulation2016In: Biochemical Society Transactions, ISSN 0300-5127, E-ISSN 1470-8752, Vol. 44, p. 35-39Article in journal (Refereed)
    Abstract [en]

    Platelet-derived polyphosphates (polyP), stored in dense granule and released upon platelet activation, have been claimed to enhance thrombin activation of coagulation factor XI (FXI) and to activate FXII directly. The latter claim is controversial and principal results leading to these conclusions are probably influenced by methodological problems. It is important to consider that low-grade contact activation is initiated by all surfaces and is greatly amplified by the presence of phospholipids simulating the procoagulant membranes of activated platelets. Thus, proper use of inhibitors of the contact pathway and a careful choice of materials for plates and tubes is important to avoid artefacts. The use of phosphatases used to degrade polyP has an important drawback as it also degrades the secondary activators ADP and ATP, which are released from activated platelets. In addition, the use of positively charged inhibitors, such as polymyxin B, to inhibit polyP in platelet-rich plasma and blood is problematic, as polymyxin B also slows coagulation in the absence of polyP. In conclusion we hope awareness of the above caveats may improve research on the physiological roles of polyP in coagulation. © 2016 Authors; published by Portland Press Limited.

  • 24.
    Saleiban, Amina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Faxälv, Lars
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Claesson, Kjersti
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Jönsson, Jan-Ingvar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Osman, Abdimajid
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    miR-20b regulates expression of proteinase-activated receptor-1 (PAR-1) thrombin receptor in melanoma cells2014In: Pigment Cell & Melanoma Research, ISSN 1755-1471, E-ISSN 1755-148X, Vol. 27, no 3, p. 431-441Article in journal (Refereed)
    Abstract [en]

    The proteinase-activated receptor 1 (PAR-1) plays a central role in melanoma progression and its expression level is believed to correlate with the degree of cancer invasiveness. Here, we show that PAR-1 is post-transcriptionally regulated by miR-20b microRNA in human melanoma cells. PAR-1 was found to be expressed in metastatic melanoma cells but was barely detectable in primary melanoma. By transducing primary melanoma cells with a lentivirus containing a 3-UTR construct of PAR-1 mRNA, we could show that endogenous melanoma microRNAs interacted with PAR-1 3-UTR and silenced a fused luciferase reporter. Transfection of an inhibitor against miR-20b into primary melanoma cells reversed this process. Finally, transfection of miR-20b mimic into metastatic melanoma cells caused downregulation of the luciferase reporter. We conclude that miR-20b regulates expression of melanoma PAR-1 receptor, which may explain the differential expression of PAR-1 observed in human melanoma.

  • 25.
    Sjoberg, Sara
    et al.
    University of Gothenburg.
    Faxälv, Lars
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemestry.
    Wikstrom, Johannes
    AstraZeneca R&D.
    Andersson, Marcus
    University Gothenburg.
    Bourghardt, Johan
    University Gothenburg.
    Tivesten, Asa
    University Gothenburg.
    Sellborn, Anders
    Sahlgrens University Hospital.
    Gan, Li-Ming
    AstraZeneca R&D.
    Lindahl, Tomas
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemestry. Linköping University, Faculty of Health Sciences.
    Krettek , Alexandra
    University of Gothenburg.
    CD44-Deficiency does not Influence Atherogenesis in Low Density Lipoprotein Receptor-Deficient Mice but Affects Blood Clotting by Reduced Antithrombin Activity2008In: CIRCULATION,ISSN 0009-7322: Volume 118 Issue 18, 2008, Vol. 118, no 18, p. S378-S378Conference paper (Refereed)
  • 26.
    Tunströmer, Kjersti
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Faxälv, Lars
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Boknäs, Niklas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Lindahl, Tomas L.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Quantification of Platelet Contractile Movements during Thrombus Formation2018In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 118, no 09, p. 1600-1611Article in journal (Refereed)
    Abstract [en]

    Imaging methods based on time-lapse microscopy are important tools for studying the dynamic events that shape thrombus formation upon vascular injury. However, there is a lack of methods to translate the vast amount of visual data generated in such experiments into quantitative variables describing platelet movements that can be subjected to systematic analysis. In this study, we developed experimental and computational protocols allowing for a detailed mathematical analysis of platelet movements within a developing thrombus. We used a flow chamber-based model of thrombosis wherein a collagen strip was used to initiate platelet adhesion and activation. Combining the use of a platelet staining protocol, designed to enable identification of individual platelets, and image processing, we tracked the movements of a large number of individual platelets during thrombus formation and consolidation. These data were then processed to generate aggregate measures describing the heterogeneous movements of platelets in different areas of the thrombus and at different time points. Applying this model and its potential, to a comparative analysis on a panel of platelet inhibitors, we found that total platelet intra-thrombus movements are only slightly reduced by blocking the interactions between glycoproteins IIb/IIIa and Ib and their ligands or by inhibiting thromboxane synthesis or P2Y12 signalling. In contrast, whereas 30 to 40% of the platelets movements (for the CD42a-labelled platelets) and 20% (for the pro-coagulant platelets), within a thrombus, are contractile, i.e., towards the centre of the thrombus, this contractile component is almost totally abolished in the presence of agents inhibiting these pathways.

  • 27.
    Tynngård, Nahreen
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Wallstedt, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Södergren, Anna L
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Faxälv, Lars
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Ramström, Sofia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Platelet adhesion changes during storage studied with a novel method using flow cytometry and protein-coated beads2015In: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 26, no 2, p. 177-185Article in journal (Refereed)
    Abstract [en]

    The aim of the present study was to set up and evaluate a novel method for studies of platelet adhesion and activation in blood and platelet suspensions such as platelet concentrate (PC) samples using protein-coated polystyrene beads and flow cytometry. To demonstrate its usefulness, we studied PCs during storage. PCs were prepared by aphaeresis technique (n = 7). Metabolic variables and platelet function was measured on day 1, 5, 7 and 12 of storage. Spontaneous and TRAP-6-induced adhesion to fibrinogen- and collagen-coated beads was analyzed by flow cytometry. P-selectin and phosphatidyl serine (PS) expression was assessed on platelets bound to beads as well as on non-adherent platelets. Platelet adhesion to fibrinogen beads had increased by day 12 and adhesion to collagen beads at day 7 of storage (p < 0.05). TRAP-6 stimulation significantly increased the platelet adhesion to fibrinogen beads (p < 0.05) as well as the P-selectin and PS exposure on platelets bound to beads (p < 0.01) during the first 7 days of storage, but by day 12, significant changes were no longer induced by TRAP-6 stimulation. We demonstrate that our adhesion assay using protein-coated polystyrene beads can be used to assess the adhesion properties of platelets during storage without the addition of red blood cells. Therefore it may offer a useful tool for future studies of platelet adhesive capacity in transfusion medicine and other settings.

1 - 27 of 27
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