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Thulin, Åsa
Publications (10 of 11) Show all publications
Thulin, Å., Yan, J., Åberg, M., Christersson, C., Kamali-Moghaddam, M. & Siegbahn, A. (2018). Sensitive and Specific Detection of Platelet-Derived and Tissue Factor-Positive Extracellular Vesicles in Plasma using Solid-Phase Proximity Ligation Assay. Thrombosis and Haemostasis open
Open this publication in new window or tab >>Sensitive and Specific Detection of Platelet-Derived and Tissue Factor-Positive Extracellular Vesicles in Plasma using Solid-Phase Proximity Ligation Assay
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2018 (English)In: Thrombosis and Haemostasis open, ISSN 2512-9465Article in journal (Refereed) Published
Abstract [en]

Extracellular vesicles (EVs) derived from blood cells are promising biomarkers for various diseases. However, they are difficult to measure accurately in plasma due to their small size. Here, we demonstrate that platelet-derived EVs in plasma can be measured using solid-phase proximity ligation assay with high sensitivity and specificity using very small sample volume of biological materials. The results correlate well with high-sensitivity flow cytometry with the difference that the smallest EVs are detected. Briefly, the EVs are first captured on a solid phase, using lactadherin binding, and detection requires recognition with two antibodies followed by qPCR. The assay, using cholera toxin subunit-B or lactadherin as capture agents, also allowed detection of the more rare population of tissue factor (TF)-positive EVs at a concentration similar to sensitive TF activity assays. Thus, this assay can detect different types of EVs with high specificity and sensitivity, and has the potential to be an attractive alternative to flow cytometric analysis of preclinical and clinical samples. Improved techniques for measuring EVs in plasma will hopefully contribute to the understanding of their role in several diseases.

Place, publisher, year, edition, pages
Stuttgart: Georg Thieme Verlag KG, 2018
Keywords
microvesicles, myocardial infarction, cardiovascular diseases, vascular homeostasis
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-367344 (URN)10.1055/s-0038-1667204 (DOI)
Available from: 2018-11-30 Created: 2018-11-30 Last updated: 2019-02-14Bibliographically approved
Thulin, Å., Yan, J., Åberg, M., Christersson, C., Kamali-Moghaddam, M. & Siegbahn, A. (2018). Sensitive detection of platelet-derived and tissue factor positive extracellular vesicles in plasma using solid-phase proximity ligation assay. Paper presented at 5th Congress of the ESC-Council-on-Basic-Cardiovascular-Science on Frontiers in Cardio Vascular Biology, APR 20-22, 2018, Vienna, AUSTRIA. Cardiovascular Research, 114, S132-S132
Open this publication in new window or tab >>Sensitive detection of platelet-derived and tissue factor positive extracellular vesicles in plasma using solid-phase proximity ligation assay
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2018 (English)In: Cardiovascular Research, ISSN 0008-6363, E-ISSN 1755-3245, Vol. 114, p. S132-S132Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
OXFORD UNIV PRESS, 2018
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-357493 (URN)000430678500388 ()
Conference
5th Congress of the ESC-Council-on-Basic-Cardiovascular-Science on Frontiers in Cardio Vascular Biology, APR 20-22, 2018, Vienna, AUSTRIA
Available from: 2018-08-17 Created: 2018-08-17 Last updated: 2018-08-17Bibliographically approved
Stojkovic, S., Thulin, Å., Hell, L., Thaler, B., Rauscher, S., Baumgartner, J., . . . Åberg, M. (2017). IL-33 stimulates the release of procoagulant microvesicles from human monocytes and differentially increases tissue factor in human monocyte subsets. Thrombosis and Haemostasis, 117(7), 1379-1390
Open this publication in new window or tab >>IL-33 stimulates the release of procoagulant microvesicles from human monocytes and differentially increases tissue factor in human monocyte subsets
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2017 (English)In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 117, no 7, p. 1379-1390Article in journal (Refereed) Published
Abstract [en]

Monocytes and monocyte-derived microvesicles (MVs) are the main source of circulating tissue factor (TF). Increased monocyte TF expression and increased circulating levels of procoagulant MVs contribute to the formation of a prothrombotic state in patients with cardiovascular disease. Interleukin (IL)-33 is a pro-inflammatory cytokine involved in atherosclerosis and other inflammatory diseases, but its role in regulating thrombosis is still unclear. The aim of the present study was to investigate the effects of IL-33 on the procoagulant properties of human monocytes and monocyte-derived MVs. IL-33 induced a time- and concentration-dependent increase of monocyte TF mRNA and protein levels via binding to the ST2-receptor and activation of the NF-kappa B-pathway. The IL-33 treated monocytes also released CD14+TF+ MVs and IL-33 was found to increase the TF activity of both the isolated monocytes and monocyte-derived MVs. The monocytes were classified into subsets according to their CD14 and CD16 expression. Intermediate monocytes (IM) showed the highest ST2 receptor expression, followed by non-classical monocytes (NCM), and classical monocytes (CM). IL-33 induced a significant increase of TF only in the IM (p<0.01), with a tendency in NCM (p=0.06), but no increase was observed in CM. Finally, plasma levels of IL-33 were positively correlated with CD14+TF+ MVs in patients undergoing carotid endarterectomy (r=0.480; p=0.032; n=20). We hereby provide novel evidence that the proinflammatory cytokine IL-33 induces differential TF expression and activity in monocyte subsets, as well as the release of procoagulant MVs. In this manner, IL-33 may contribute to the formation of a prothrombotic state characteristic for cardiovascular disease.

Place, publisher, year, edition, pages
SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN, 2017
Keywords
Interleukin-33, tissue factor, monocyte subsets, microvesicles, thrombosis
National Category
Hematology Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-330042 (URN)10.1160/TH16-10-0784 (DOI)000404671700018 ()28492698 (PubMedID)
Funder
Swedish Research Council, 2012-2579
Available from: 2017-09-28 Created: 2017-09-28 Last updated: 2017-09-28
Christersson, C., Thulin, Å. & Siegbahn, A. (2017). Microparticles during long-term follow-up after acute myocardial infarction: Association to atherosclerotic burden and risk of cardiovascular events. Thrombosis and Haemostasis, 117(8), 1571-1581
Open this publication in new window or tab >>Microparticles during long-term follow-up after acute myocardial infarction: Association to atherosclerotic burden and risk of cardiovascular events
2017 (English)In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 117, no 8, p. 1571-1581Article in journal (Refereed) Published
Abstract [en]

Microparticles (MPs) are formed from platelets (PMPs), endothelial cells (EMPs) and monocytes (MMPs), and in acute myocardial infarction (MI), there is an increase of MPs in the culprit artery. In this study MPs were evaluated in whole blood in 105 patients with MI at five time-points during a two-year follow-up (FU). Patients with non-ST elevated MI had higher concentrations of CD41+MPs compared to ST elevated MI patients (p=0.024). The concentrations of PMPs in whole blood increased during the time period (p<0.001), but no significant change over time was found for EMPs and MMPs. CD62P+MP counts were higher in MI patients with diabetes (p=0.020), and patients with hypertension had increased levels of CD14+MPs (p=0.004). The amount of CD62P+TF+MPs increased significantly during FU (p<0.001). Patients with atherosclerosis in three arterial beds, i.e. coronary, carotid and peripheral arteries, had lower concentrations of CD62P+TF+MPs (p=0.035) and CD144+TF+MPs (p=0.004) compared to patients with atherosclerosis in one or two arterial beds. Higher concentrations of CD62P+MPs early after MI were associated with an increased risk of cardiovascular events during FU, hazard ratio 3.32 (95 %C11.20-9.31). Only small variations in PMP, EMP and MMP concentrations were found during long-term FU after MI and their levels seem to reflect the underlying cardiovascular disease rather than the acute MI. PMPs expressing P-selectin might be a promising biomarker for predicting future cardiovascular events, but further studies are needed to confirm these results.

Place, publisher, year, edition, pages
SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN, 2017
Keywords
P-selectin, tissue factor, atherosclerosis, platelets, endothelial cells
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-333722 (URN)10.1160/TH16-11-0837 (DOI)000407093200013 ()28424820 (PubMedID)
Funder
Swedish Research CouncilSwedish Heart Lung FoundationSwedish Foundation for Strategic Research
Available from: 2017-11-16 Created: 2017-11-16 Last updated: 2017-11-16Bibliographically approved
Eriksson, O., Thulin, Å., Asplund, A., Hegde, G., Navani, S. & Siegbahn, A. (2016). Cross-talk between the Tissue Factor/coagulation factor VIIa complex and the tyrosine kinase receptor EphA2 in cancer. BMC Cancer, 16, Article ID 341.
Open this publication in new window or tab >>Cross-talk between the Tissue Factor/coagulation factor VIIa complex and the tyrosine kinase receptor EphA2 in cancer
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2016 (English)In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 16, article id 341Article in journal (Refereed) Published
Abstract [en]

Background: Tissue Factor (TF) forms a proteolytically active complex together with coagulation factor VIIa (FVIIa) and functions as the trigger of blood coagulation or alternatively activates cell signaling. We recently described that EphA2 of the Eph tyrosine kinase receptor family is cleaved directly by the TF/FVIIa complex. The aim of the present study was to further characterize the cross-talk between TF/FVIIa and EphA2 using in vitro model systems and human cancer specimens. Methods: Cleavage and phosphorylation of EphA2 was studied by Western blot. Subcellular localization of TF and EphA2 was investigated by a proximity ligation assay and confocal microscopy. Phalloidin staining of the actin cytoskeleton was used to study cell rounding and retraction fiber formation. Expression of TF and EphA2 in human colorectal cancer specimens was examined by immunohistochemistry. Results: TF and EphA2 co-localized constitutively in MDA-MB-231 cells, and addition of FVIIa resulted in cleavage of EphA2 by a PAR2-independent mechanism. Overexpression of TF in U251 glioblastoma cells lead to co-localization with EphA2 at the leading edge and FVIIa-dependent cleavage of EphA2. FVIIa potentiated ephrin-A1-induced cell rounding and retraction fiber formation in MDA-MB-231 cells through a RhoA/ROCK-dependent pathway that did not require PAR2-activation. TF and EphA2 were expressed in colorectal cancer specimens, and were significantly correlated. Conclusions: These results suggest that TF/FVIIa-EphA2 cross-talk might potentiate ligand-dependent EphA2 signaling in human cancers, and provide initial evidence that it is possible for this interaction to occur in vivo.

Keywords
Tissue Factor, Coagulation factor, EphA2, Colorectal cancer, Cell signaling
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-298867 (URN)10.1186/s12885-016-2375-1 (DOI)000376963600001 ()27246245 (PubMedID)
Funder
Swedish Research Council
Available from: 2016-07-11 Created: 2016-07-11 Last updated: 2017-11-28Bibliographically approved
Eriksson, O., Thulin, Å., Asplund, A., Hedge, G., Navani, S. & Siegbahn, A. (2015). Cross-talk between tissue factor and EPHA2 in cancer: potentiation of ligand-dependent EPHA2-signaling in vitro and co-expression in human colorectal cancer specimens. Paper presented at XXV Congress of the International Society on Thrombosis and Haemostasis, June 20–25, 2015, Toronto, Canada. Journal of Thrombosis and Haemostasis, 13(S2), 111-111, Article ID OR046.
Open this publication in new window or tab >>Cross-talk between tissue factor and EPHA2 in cancer: potentiation of ligand-dependent EPHA2-signaling in vitro and co-expression in human colorectal cancer specimens
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2015 (English)In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 13, no S2, p. 111-111, article id OR046Article in journal, Meeting abstract (Other academic) Published
National Category
Cardiac and Cardiovascular Systems Hematology
Identifiers
urn:nbn:se:uu:diva-259203 (URN)000356426901296 ()
Conference
XXV Congress of the International Society on Thrombosis and Haemostasis, June 20–25, 2015, Toronto, Canada
Available from: 2015-07-30 Created: 2015-07-29 Last updated: 2017-12-04Bibliographically approved
Thulin, Å., Yan, J., Kamali-Moghaddam, M. & Siegbahn, A. (2015). New technique to study cell-derived microparticles. Paper presented at XXV Congress of the International Society on Thrombosis and Haemostasis, June 20–25, 2015, Toronto, Canada. Journal of Thrombosis and Haemostasis, 13(S2), 627-627, Article ID PO330-TUE.
Open this publication in new window or tab >>New technique to study cell-derived microparticles
2015 (English)In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 13, no S2, p. 627-627, article id PO330-TUEArticle in journal, Meeting abstract (Other academic) Published
National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-259208 (URN)000356426904047 ()
Conference
XXV Congress of the International Society on Thrombosis and Haemostasis, June 20–25, 2015, Toronto, Canada
Available from: 2015-07-30 Created: 2015-07-29 Last updated: 2017-12-04Bibliographically approved
Christersson, C., Jönelid, B., Thulin, Å. & Siegbahn, A. (2015). The change of the amount of circulating microparticles and their association to the general atherosclerotic burden after acute coronary syndrome. Paper presented at XXV Congress of the International Society on Thrombosis and Haemostasis, June 20–25, 2015, Toronto, Canada. Journal of Thrombosis and Haemostasis, 13(S2), 214-214, Article ID OR312.
Open this publication in new window or tab >>The change of the amount of circulating microparticles and their association to the general atherosclerotic burden after acute coronary syndrome
2015 (English)In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 13, no S2, p. 214-214, article id OR312Article in journal, Meeting abstract (Other academic) Published
National Category
Hematology Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-259204 (URN)000356426902031 ()
Conference
XXV Congress of the International Society on Thrombosis and Haemostasis, June 20–25, 2015, Toronto, Canada
Available from: 2015-07-30 Created: 2015-07-29 Last updated: 2017-12-04Bibliographically approved
Cedervall, J., Zhang, Y., Ringvall, M., Thulin, Å., Moustakas, A., Jahnen-Dechent, W., . . . Olsson, A.-K. (2013). HRG regulates tumor progression, epithelial to mesenchymal transition and metastasis via platelet-induced signaling in the pre-tumorigenic microenvironment. Angiogenesis, 16(4), 889-902
Open this publication in new window or tab >>HRG regulates tumor progression, epithelial to mesenchymal transition and metastasis via platelet-induced signaling in the pre-tumorigenic microenvironment
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2013 (English)In: Angiogenesis, ISSN 0969-6970, E-ISSN 1573-7209, Vol. 16, no 4, p. 889-902Article in journal (Refereed) Published
Abstract [en]

Mice lacking histidine-rich glycoprotein (HRG) display an accelerated angiogenic switch and larger tumors-a phenotype caused by enhanced platelet activation in the HRG-deficient mice. Here we show that platelets induce molecular changes in the pre-tumorigenic environment in HRG-deficient mice, promoting cell survival, angiogenesis and epithelial-to-mesenchymal transition (EMT) and that these effects involved signaling via TBK1, Akt2 and PDGFR beta. These early events subsequently translate into an enhanced rate of spontaneous metastasis to distant organs in mice lacking HRG. Later in tumor development characteristic features of pathological angiogenesis, such as decreased perfusion and pericyte coverage, are more pronounced in HRG-deficient mice. At this stage, platelets are essential to support the larger tumor volumes formed in mice lacking HRG by keeping their tumor vasculature sufficiently functional. We conclude that HRG-deficiency promotes tumor progression via enhanced platelet activity and that platelets play a dual role in this process. During early stages of transformation, activated platelets promote tumor cell survival, the angiogenic switch and invasiveness. In the more progressed tumor, platelets support the enhanced pathological angiogenesis and hence increased tumor growth seen in the absence of HRG. Altogether, our findings strengthen the notion of HRG as a potent tumor suppressor, with capacity to attenuate the angiogenic switch, tumor growth, EMT and subsequent metastatic spread, by regulating platelet activity.

Keywords
Platelets, Angiogenesis, HRG, Metastasis, EMT
National Category
Basic Medicine
Identifiers
urn:nbn:se:uu:diva-209153 (URN)10.1007/s10456-013-9363-8 (DOI)000324326900013 ()
Available from: 2013-10-15 Created: 2013-10-15 Last updated: 2018-01-11Bibliographically approved
Thulin, Å., Ringvall, M., Dimberg, A., Kårehed, K., Väisänen, T., Väisänen, M.-R., . . . Olsson, A.-K. (2009). Activated platelets provide a functional microenvironment for the antiangiogenic fragment of histidine-rich glycoprotein. Molecular Cancer Research, 7(11), 1792-1802
Open this publication in new window or tab >>Activated platelets provide a functional microenvironment for the antiangiogenic fragment of histidine-rich glycoprotein
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2009 (English)In: Molecular Cancer Research, ISSN 1541-7786, E-ISSN 1557-3125, Vol. 7, no 11, p. 1792-1802Article in journal (Refereed) Published
Abstract [en]

The angiogenesis inhibitor histidine-rich glycoprotein (HRG) constitutes one of several examples of molecules regulating both angiogenesis and hemostasis. The antiangiogenic properties of HRG are mediated via its proteolytically released histidine- and proline-rich (His/Pro-rich) domain.Using a combination of immunohistochemistry and massspectrometry, we here provide biochemical evidence for thepresence of a proteolytic peptide, corresponding to the antiangiogenic domain of HRG, in vivo in human tissue. This finding supports a role for HRG as an endogenous regulator of angiogenesis. Interestingly, the His/Pro-rich peptide bound to the vessel wall in tissue from cancer patients but not to the vasculature in tissue from healthy persons.Moreover, the His/Pro-rich peptide was found in close association with platelets. Relesate from in vitro–activated platelets promoted binding of the His/Pro-rich domain of HRG to endothelial cells, an effect mediated by Zn2+.Previous studies have shown that zinc-dependent bindingof the His/Pro-rich domain of HRG to heparan sulfate on endothelial cells is required for inhibition of angiogenesis.We describe a novel mechanism to increase the local concentration and activity of an angiogenesis inhibitor,which may reflect a host response to counteract angiogenesis during pathologic conditions. Our finding that tumor angiogenesis is elevated in HRG-deficient mice supports this conclusion.

Keywords
histidine-rich glycoprotein, angiogenesis, cancer, platelets
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-110827 (URN)10.1158/1541-7786.MCR-09-0094 (DOI)000272006300005 ()19903770 (PubMedID)
Available from: 2009-11-26 Created: 2009-11-26 Last updated: 2017-12-12Bibliographically approved
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