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Singh, S., Damén, T., Nygren, A., Shams Hakimi, C., Ramström, S., Dellborg, M., . . . Jeppsson, A. (2019). Adrenaline Improves Platelet Reactivity in Ticagrelor-Treated Healthy Volunteers. Thrombosis and Haemostasis, 119(5), 735-743
Open this publication in new window or tab >>Adrenaline Improves Platelet Reactivity in Ticagrelor-Treated Healthy Volunteers
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2019 (English)In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 119, no 5, p. 735-743Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Administration of agents that enhance platelet reactivity may reduce the perioperative bleeding risk in patients treated with the adenosine diphosphate (ADP)-receptor antagonist ticagrelor. Adrenaline potentiates ADP-induced aggregation and activation in blood samples from ticagrelor-treated patients, but it has not previously been evaluated in vivo.

METHODS: Ten healthy male subjects were included in an interventional study. A loading dose of ticagrelor (180 mg) was administered, followed 2 hours later by a gradually increased intravenous adrenaline infusion (0.01, 0.05, 0.10 and 0.15 µg/kg/min; 15 minutes at each step). Blood pressure, heart rate, platelet aggregation (impedance aggregometry), platelet activation (flow cytometry), clot formation (rotational thromboelastometry) and adrenaline plasma concentration were determined before and after ticagrelor administration and at the end of each adrenaline step.

RESULTS:  = 0.007).

CONCLUSION: Infusion of adrenaline at clinically relevant doses improves in vivo platelet reactivity and clot formation in ticagrelor-treated subjects. Adrenaline could thus potentially be used to prevent perioperative bleeding complications in ticagrelor-treated patients. Studies in patients are necessary to determine the clinical importance of our observations.

TRIAL REGISTRY NUMBER: ClinicalTrials.gov NCT03441412.

Place, publisher, year, edition, pages
Georg Thieme Verlag KG, 2019
Keywords
adrenaline, ticagrelor, platelet function, flow cytometry, impedance aggregometry
National Category
Anesthesiology and Intensive Care Hematology Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:oru:diva-72786 (URN)10.1055/s-0039-1683461 (DOI)000467408100008 ()30780166 (PubMedID)2-s2.0-85065206111 (Scopus ID)
Funder
Swedish Heart Lung Foundation, 20150587Region Västra Götaland, ALFGBG-725131
Available from: 2019-02-26 Created: 2019-02-26 Last updated: 2019-06-19Bibliographically approved
Macwan, A. S., Boknäs, N., Ntzouni, M. P., Ramström, S., Gibbins, J. M., Faxälv, L. & Lindahl, T. L. (2019). Gradient-dependent inhibition of stimulatory signaling from platelet G protein-coupled receptors. Haematologica, 104(7)
Open this publication in new window or tab >>Gradient-dependent inhibition of stimulatory signaling from platelet G protein-coupled receptors
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2019 (English)In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 104, no 7Article in journal (Refereed) Published
Abstract [en]

As platelet activation is an irreversible and potentially harmful event, platelet stimulatory signaling must be tightly regulated to ensure the filtering-out of inconsequential fluctuations of agonist concentrations in the vascular milieu. Herein, we show that platelet activation via G protein-coupled receptors is gradient-dependent that is determined not only by agonist concentrations per se but also by how rapidly concentrations change over time. We demonstrate that gradient-dependent inhibition is a common feature of all major platelet stimulatory G protein-coupled receptors, while platelet activation via the non- G protein-coupled receptor glycoprotein VI is strictly concentration-dependent. By systematically characterizing the effects of variations in temporal agonist concentration gradients on different aspects of platelet activation, we demonstrate that gradient-dependent inhibition of protease-activated receptors exhibit different kinetics, with platelet activation occurring at lower agonist gradients for protease-activated receptor 4 than for protease-activated receptor 1, but share a characteristic bimodal effect distribution, as gradient-dependent inhibition increases over a narrow range of gradients, below which aggregation and granule secretion is effectively shut off. In contrast, the effects of gradient-dependent inhibition on platelet activation via adenosine diphosphate and thromboxane receptors increase incrementally over a large range of gradients. Further, depending on the affected activation pathway, gradient-dependent inhibition results in different degrees of refractoriness to subsequent autologous agonist stimulation. Mechanistically, our study identifies an important role for the cyclic adenosine monophosphate-dependent pathway in gradient-dependent inhibition. Together, our findings suggest that gradient-dependent inhibition may represent a new general mechanism for hemostatic regulation in platelets.

Place, publisher, year, edition, pages
Ferrata Storti Foundation, 2019
Keywords
Arterial Thrombosis, G protein coupled receptors, Platelets, Protease activated receptors
National Category
Pharmacology and Toxicology Hematology
Identifiers
urn:nbn:se:oru:diva-71453 (URN)10.3324/haematol.2018.205815 (DOI)000473230500037 ()30630981 (PubMedID)
Funder
Swedish Heart Lung Foundation, 207-0440Swedish Research Council, 2017-01177
Note

Funding Agency:

British Heart Foundation  RG/15/2/31224

Available from: 2019-01-17 Created: 2019-01-17 Last updated: 2019-08-08Bibliographically approved
Boknäs, N., Macwan, A. S., Södergren, A. L. & Ramström, S. (2019). Platelet function testing at low platelet counts: When can you trust your analysis?. Research and Practice in Thrombosis and Haemostasis, 3(2), 285-290
Open this publication in new window or tab >>Platelet function testing at low platelet counts: When can you trust your analysis?
2019 (English)In: Research and Practice in Thrombosis and Haemostasis, E-ISSN 2475-0379, Vol. 3, no 2, p. 285-290Article in journal (Refereed) Published
Abstract [en]

Background: Although flow cytometry is often brought forward as a preferable method in the setting of thrombocytopenia, the relative effects of low sample counts on results from flow cytometry-based platelet function testing (FC-PFT) in comparison with light transmission aggregometry (LTA) and multiple electrode aggregometry (MEA) has not been reported.

Objectives: To compare the effects of different sample platelet counts (10, 50, 100, and 200x10(9)L(-1)) on platelet activation measured with FC-PFT, LTA, and MEA using the same anticoagulant and agonist concentrations as for the commercial MEA test.

Methods: Platelets were stimulated with two commonly used platelet agonists (ADP [6.5 mu molL(-1)] and PAR1-AP [TRAP, 32 mu molL(-1)]). The specified sample platelet counts were obtained by combining platelet-rich and platelet poor hirudinized plasma in different proportions with or without red blood cells.

Results: For FC, P-selectin exposure and PAC-1 binding was reduced at 10x10(9)L(-1) after stimulation with PAR1-AP (by approximately 20% and 50%, respectively), but remained relatively unchanged when ADP was used as agonist (n=9). The platelet count-dependent effects observed with PAR1-AP were eliminated when samples were pre-incubated with apyrase, implying that reduced purinergic signaling was the main underlying factor (n=5). Both aggregometry-based PFTs showed a 50% reduction at 50x10(9)L(-1) and more than 80% reduction at 10x10(9)L(-1), irrespective of agonist used (n=7).

Conclusions: Although FC-PFT is generally preferable to aggregometry-based PFTs in situations with low sample platelet counts, a careful optimization of experimental parameters is still required in order to eliminate platelet count-related effects.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2019
Keywords
platelet activation, platelet aggregation, platelet count, platelet function tests, thrombocytopenia
National Category
Hematology
Identifiers
urn:nbn:se:oru:diva-73960 (URN)10.1002/rth2.12193 (DOI)000464657400021 ()31011713 (PubMedID)
Funder
Swedish Heart Lung Foundation, 2017-0318Swedish Society of Medicine, SLS-787211
Note

Funding Agencies:

Linköpings Universitet

Region Östergötland

LiU Fund of U; LiU Research Fellows Programme

Available from: 2019-04-29 Created: 2019-04-29 Last updated: 2019-04-29Bibliographically approved
Singh, S., Malm, C. J., Ramström, S., Hesse, C. & Jeppsson, A. (2018). Adrenaline enhances in vitro platelet activation and aggregation in blood samples from ticagrelor-treated patients. Research and Practice in Thrombosis and Haemostasis, 2(4), 718-725
Open this publication in new window or tab >>Adrenaline enhances in vitro platelet activation and aggregation in blood samples from ticagrelor-treated patients
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2018 (English)In: Research and Practice in Thrombosis and Haemostasis, E-ISSN 2475-0379, Vol. 2, no 4, p. 718-725Article in journal (Refereed) Published
Abstract [en]

Background: Temporarily improved platelet reactivity may reduce the bleeding in patients on antiplatelet therapy who have ongoing bleeding or who are in need of acute surgery. Adrenaline can bind to adrenergic alpha(2A)-receptors on platelets and potentially enhance platelet reactivity.

Objective: To assess if adrenaline can improve adenosine diphosphate (ADP)-induced platelet aggregation and activation in blood samples from patients on dual antiplatelet therapy with acetylsalicylic acid (ASA) and the ADP-receptor antagonist ticagrelor.

Methods: Blood samples were collected from a total of forty acute coronary syndrome patients on dual antiplatelet therapy with ASA and ticagrelor. ADP-induced platelet aggregation (by impedance aggregometry) and activation (by flow cytometry) were assessed before and after supplementation with adrenaline and/or platelet concentrate.

Results: Adrenaline supplementation (770 nmol L-1) increased median ADP-induced aggregation from 15 (25-75th percentiles: 10-20) to 26 (18-38) aggregation units. The effect was independent of concomitant platelet supplementation. Adrenaline also increased ADP-induced platelet activation: from 40% (36-54%) to 83% (74-88%) platelets with active fibrinogen receptor (binding PAC-1) and from 13% (7-21%) to 35% (18-50%) P-selectin-expressing platelets.

Conclusions: Adrenaline potentiated ADP-induced platelet aggregation and activation in blood samples from ticagrelor-treated patients. Adrenaline infusion may be a new method to enhance platelet function in ticagrelor-treated patients who are in need of acute surgery or have ongoing bleeding. In vivo studies are needed to confirm the present results.

Place, publisher, year, edition, pages
John Wiley & Sons, 2018
Keywords
adrenaline, flow cytometry, platelet aggregation, platelet aggregation inhibitors, platelet function tests
National Category
Hematology
Identifiers
urn:nbn:se:oru:diva-70871 (URN)10.1002/rth2.12149 (DOI)000452490400014 ()30349891 (PubMedID)
Funder
Swedish Heart Lung Foundation, 20150587
Note

Funding Agency:

Västra Götaland Region ALFGBG-146281  ALFGBG-725131

Available from: 2019-01-07 Created: 2019-01-07 Last updated: 2019-01-07Bibliographically approved
Ramström, S. (2018). Arachidonic acid causes lysis of blood cells and ADP-dependent platelet activation responses in platelet function tests. Platelets
Open this publication in new window or tab >>Arachidonic acid causes lysis of blood cells and ADP-dependent platelet activation responses in platelet function tests
2018 (English)In: Platelets, ISSN 0953-7104, E-ISSN 1369-1635Article in journal (Refereed) Epub ahead of print
Abstract [en]

The use of arachidonic acid (AA) to stimulate platelets is considered as a specific approach to study aspirin treatment efficacy. However, very high concentrations of AA are used, and it has been previously reported that AA can induce cell lysis in other settings. Several clinical studies have reported decreased responses to AA in whole blood tests in the presence of clopidogrel. Our aim was to investigate whether unspecific effects contribute to AA-induced aggregation and platelet activation in light transmission aggregometry (LTA) in platelet-rich plasma (PRP), and in assays using whole blood, multiple electrode aggregometry (MEA, Multiplate®), and flow cytometry. We report that cell lysis, especially of red blood cells, does occur at concentrations of AA used in the clinical tests and that ADP is very important for the AA-induced platelet activation responses. In flow cytometry, very limited platelet activation was detected before reaching AA concentrations in the millimolar range, where cell lysis also occurred, making it problematic to develop a reliable flow cytometry assay using AA as reagent. We conclude that cell lysis and ADP release contribute to AA-induced platelet responses, most markedly in whole blood assays. This finding could potentially explain some differences between studies comparing methods using whole blood and PRP and also how clopidogrel treatment could influence AA-induced aggregation results in previously published studies. Our findings highlight some issues with AA as reagent for platelet activation, which also have an impact on how platelet activation assays using AA should be interpreted.

Place, publisher, year, edition, pages
Taylor & Francis, 2018
Keywords
Arachidonic acid, aspirin, flow cytometry, platelet aggregation, platelet function tests
National Category
Immunology Pharmacology and Toxicology
Identifiers
urn:nbn:se:oru:diva-71191 (URN)10.1080/09537104.2018.1557614 (DOI)30580677 (PubMedID)
Available from: 2019-01-08 Created: 2019-01-08 Last updated: 2019-01-08Bibliographically approved
Olsson, A., Alfredsson, J., Ramström, S., Svedjeholm, R., Kenny, D., Håkansson, E., . . . Berg, S. (2018). Better platelet function, less fibrinolysis and less hemolysis in re-transfused residual pump blood with the Ringer’s chase technique: a randomized pilot study. Perfusion, 33(3), 185-193
Open this publication in new window or tab >>Better platelet function, less fibrinolysis and less hemolysis in re-transfused residual pump blood with the Ringer’s chase technique: a randomized pilot study
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2018 (English)In: Perfusion, ISSN 0267-6591, E-ISSN 1477-111X, Vol. 33, no 3, p. 185-193Article in journal (Refereed) Published
Abstract [en]

Introduction: Residual pump blood from the cardiopulmonary bypass (CPB) circuit is often collected into an infusion bag (IB) and re-transfused. An alternative is to chase the residual blood into the circulation through the arterial cannula with Ringer’s acetate. Our aim was to assess possible differences in hemostatic blood quality between these two techniques.

Methods: Forty adult patients undergoing elective coronary artery bypass graft surgery with CPB were randomized to receive the residual pump blood by either an IB or through the Ringer’s chase (RC) technique. Platelet activation and function (impedance aggregometry), coagulation and hemolysis variables were assessed in the re-transfused blood and in the patients before, during and after surgery. Results are presented as median (25-75 quartiles).

Results: Total hemoglobin and platelet levels in the re-transfused blood were comparable with the two methods, as were soluble platelet activation markers P-selectin and soluble glycoprotein VI (GPVI). Platelet aggregation (U) in the IB blood was significantly lower compared to the RC blood, with the agonists adenosine diphosphate (ADP) 24 (10-32) vs 46 (33-65), p<0.01, thrombin receptor activating peptide (TRAP) 50 (29-73) vs 69 (51-92), p=0.04 and collagen 24 (17-28) vs 34 (26-59), p<0.01. The IB blood had higher amounts of free hemoglobin (mg/L) (1086 (891-1717) vs 591(517-646), p<0.01) and D-dimer 0.60 (0.33-0.98) vs 0.3 (0.3-0.48), p<0.01. Other coagulation variables showed no difference between the groups. Conclusions: The handling of blood after CPB increases hemolysis, impairs platelet function and activates coagulation and fibrinolysis. The RC technique preserved the blood better than the commonly used IB technique.

Place, publisher, year, edition, pages
Sage Publications, 2018
Keywords
cardiopulmonary bypass, hemostasis, methods, platelet function tests
National Category
Cell Biology Hematology
Identifiers
urn:nbn:se:oru:diva-66024 (URN)10.1177/0267659117733891 (DOI)000429907500003 ()28950757 (PubMedID)2-s2.0-85041931025 (Scopus ID)
Note

Export Date: 22 March 2018; Article in Press; CODEN: PERFE; Correspondence Address: Olsson, A.email: sarah.larkin@sagepub.co.uk

Available from: 2018-03-22 Created: 2018-03-22 Last updated: 2018-09-18Bibliographically approved
Boknäs, N., Ramström, S., Faxälv, L. & Lindahl, T. L. (2018). Flow cytometry-based platelet function testing is predictive of symptom burden in a cohort of bleeders. Platelets, 29(5), 512-519
Open this publication in new window or tab >>Flow cytometry-based platelet function testing is predictive of symptom burden in a cohort of bleeders
2018 (English)In: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 29, no 5, p. 512-519Article in journal (Refereed) Published
Abstract [en]

Platelet function disorders (PFDs) are common in patients with mild bleeding disorders (MBDs), yet the significance of laboratory findings suggestive of a PFD remain unclear due to the lack of evidence for a clinical correlation between the test results and the patient phenotype. Herein, we present the results from a study evaluating the potential utility of platelet function testing using whole-blood flow cytometry in a cohort of 105 patients undergoing investigation for MBD. Subjects were evaluated with a test panel comprising two different activation markers (fibrinogen binding and P-selectin exposure) and four physiologically relevant platelet agonists (ADP, PAR1-AP, PAR4-AP, and CRP-XL). Abnormal test results were identified by comparison with reference ranges constructed from 24 healthy controls or with the fifth percentile of the entire patient cohort. We found that the abnormal test results are predictive of bleeding symptom severity, and that the greatest predictive strength was achieved using a subset of the panel, comparing measurements of fibrinogen binding after activation with all four agonists with the fifth percentile of the patient cohort (p = 0.00008, hazard ratio 8.7; 95% CI 2.5-40). Our results suggest that whole-blood flow cytometry-based platelet function testing could become a feasible alternative for the investigation of MBDs. We also show that platelet function testing using whole-blood flow cytometry could provide a clinically relevant quantitative assessment of platelet-related hemostasis.

Place, publisher, year, edition, pages
Taylor & Francis, 2018
Keywords
Bleeding disorders, flow cytometry, platelet function defects, platelet function tests, primary hemostasis
National Category
Hematology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:oru:diva-64427 (URN)10.1080/09537104.2017.1349305 (DOI)000434685300012 ()28895772 (PubMedID)2-s2.0-85029424950 (Scopus ID)
Funder
Swedish Research Council, 521-2014-2792 521-2012-2729
Note

Funding Agencies:

ALF grants, Region Östergötland  

Lions research fund  

Linköping University 

Available from: 2018-01-19 Created: 2018-01-19 Last updated: 2019-03-26Bibliographically approved
Södergren, A. L. & Ramström, S. (2018). Platelet subpopulations remain despite strong dual agonist stimulation and can be characterised using a novel six-colour flow cytometry protocol. Scientific Reports, 8(1), Article ID 1441.
Open this publication in new window or tab >>Platelet subpopulations remain despite strong dual agonist stimulation and can be characterised using a novel six-colour flow cytometry protocol
2018 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, no 1, article id 1441Article in journal (Refereed) Published
Abstract [en]

It is recognised that platelets respond differently to activation, where a subpopulation of platelets adopt a procoagulant phenotype while others are aggregatory. However, it has not been thoroughly tested whether these subpopulations will remain in maximally activated samples, or if they are merely a result of different platelet sensitivities to agonist activation. Here platelets were activated with gradually increasing concentrations of thrombin and/or the GPVI agonist cross-linked collagen-related peptide (CRP-XL). Platelet activation was investigated using a novel six-colour flow cytometry protocol evaluating exposure of phosphatidylserine, active conformation of the fibrinogen receptor αIIbβ3, α-granule and lysosomal release (P-selectin and LAMP-1 exposure), mitochondrial membrane integrity and platelet fragmentation. Upon activation by CRP-XL or thrombin+CRP-XL, platelets formed three differently sized subpopulations. Normal-sized platelets showed high exposure of aggregatory active αIIbβ3 and intact mitochondria, while the smaller platelets and platelet fragments showed high exposure of procoagulant phosphatidylserine. The distribution of platelets between the differently sized subpopulations remained stable despite high agonist concentrations. All three were still present after 30 and 60 min of activation, showing that all platelets will not have the same characteristics even after maximal stimulation. This suggests that platelet subpopulations with distinct activation patterns exist within the total platelet population.

Place, publisher, year, edition, pages
London, UK: Nature Publishing Group, 2018
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:oru:diva-64716 (URN)10.1038/s41598-017-19126-8 (DOI)000423045400014 ()29362366 (PubMedID)2-s2.0-85041015411 (Scopus ID)
Note

Funding Agency:

LiU Fund of U and Linköping University

Available from: 2018-02-01 Created: 2018-02-01 Last updated: 2018-02-06Bibliographically approved
Centellas, D. S., Gudlur, S., Vicente-Carrillo, A., Ramström, S. & Lindahl, T. L. (2017). A cluster of aspartic residues in the extracellular loop II of PAR 4 is important for thrombin interaction and activation of platelets. Thrombosis Research, 154, 84-92
Open this publication in new window or tab >>A cluster of aspartic residues in the extracellular loop II of PAR 4 is important for thrombin interaction and activation of platelets
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2017 (English)In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 154, p. 84-92Article in journal (Refereed) Published
Abstract [en]

Thrombin activates platelets via proteolytic cleavage of protease-activated receptors (PARs) 1 and 4. The two PARs have distinct but complementary roles. The mechanisms responsible for PAR1 activation by thrombin have been extensively studied. However, much less is known regarding thrombin activation of PAR4, especially the potential involvement of regions of PAR4 other than the N-terminal, which is bound to the catalytic site of thrombin. We have studied PAR4 in S. cerevisiae strainMMY12, an expression system in which the GPCR receptors are connected to a Lac Z reporter gene resulting in increased beta-galactosidase activity. This approach was used to assess PAR4 mutants to evaluate the contribution of different aspartic residues in facilitating PAR4 activation. Furthermore, peptides mimicking parts of the PAR4 N-terminal and the second extracellular loop (ECLII) were tested for their ability to inhibit platelet activation by thrombin. Binding of these peptides to gamma-thrombin was studied by monitoring the decrease in tryptophan fluorescence intensity of thrombin. We conclude that not only the N-terminal but also the electronegative aspartic residues D224, D230 and D235 (located in ECLII) are be important for PAR4 binding to thrombin. We further suggest that they play a role for the tethered ligand binding to the receptor, as mutations also affected activation in response to a PAR4-activating peptide mimicking the new N-terminal formed after cleavage. This agrees with previous results on PAR1 and thrombin binding. We suggest that the ECLII of PAR4 could be a potential target for antithrombotic drug development.

Place, publisher, year, edition, pages
Elsevier, 2017
National Category
Cell Biology
Identifiers
urn:nbn:se:oru:diva-66023 (URN)10.1016/j.thromres.2017.04.006 (DOI)000402491600016 ()28448853 (PubMedID)
Available from: 2018-03-22 Created: 2018-03-22 Last updated: 2018-04-10Bibliographically approved
Södergren, A. L. & Ramström, S. (2017). Detection of Lysosomal Exocytosis in Platelets by Flow Cytometry. Methods in Molecular Biology, 1594, 191-203
Open this publication in new window or tab >>Detection of Lysosomal Exocytosis in Platelets by Flow Cytometry
2017 (English)In: Methods in Molecular Biology, ISSN 1064-3745, E-ISSN 1940-6029, Vol. 1594, p. 191-203Article in journal (Refereed) Published
Abstract [en]

Flow cytometry is a method that allows high throughput analysis of individual cells in suspension. By inclusion of fluorescently labelled antibodies, it is possible to analyze the abundance of one or more surface antigens, such as LAMP-1, without prior lysis of cells. Here we describe the special considerations required for the investigation of lysosomal exocytosis from platelets analyzed with flow cytometry.

Place, publisher, year, edition, pages
Springer, 2017
Keywords
Flow cytometry, Granule, Lysosomal exocytosis, Lysosomal-associated membrane protein-1 (LAMP-1), Lysosome, Platelet, Platelet activation, Platelet secretion
National Category
Medical and Health Sciences Immunology
Identifiers
urn:nbn:se:oru:diva-64428 (URN)10.1007/978-1-4939-6934-0_12 (DOI)28456984 (PubMedID)2-s2.0-85018271844 (Scopus ID)
Available from: 2018-01-19 Created: 2018-01-19 Last updated: 2019-03-26Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-1920-3962

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