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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, ISSN 2475-0379, Vol. 2, no 4, p. 718-725Article in journal (Refereed) Published
Abstract [en]

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 a2A-receptors on platelets and potentially enhance platelet reactivity.

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:liu:diva-156017 (URN)10.1002/rth2.12149 (DOI)30349891 (PubMedID)
Available from: 2019-04-02 Created: 2019-04-02 Last updated: 2019-04-02
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
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:liu:diva-144025 (URN)10.1177/0267659117733891 (DOI)000429907500003 ()28950757 (PubMedID)2-s2.0-85041931025 (Scopus ID)
Available from: 2018-01-03 Created: 2018-01-03 Last updated: 2019-05-01
Boknäs, N., Ramström, S., Faxälv, L. & Lindahl, T. (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 INC, 2018
Keywords
Bleeding disorders; flow cytometry; platelet function defects; platelet function tests; primary hemostasis
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:liu:diva-149398 (URN)10.1080/09537104.2017.1349305 (DOI)000434685300012 ()28895772 (PubMedID)
Note

Funding Agencies|Vetenskapsradet [521-2014-2792, 521-2012-2729]; ALF grants, Region Ostergotland; Lions research fund; Linkoping University

Available from: 2018-07-02 Created: 2018-07-02 Last updated: 2019-05-01
Södergren, A. & 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, 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, 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 alpha(IIb)beta(3), alpha-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 alpha(IIb)beta(3) 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
NATURE PUBLISHING GROUP, 2018
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:liu:diva-145133 (URN)10.1038/s41598-017-19126-8 (DOI)000423045400014 ()29362366 (PubMedID)
Note

Funding Agencies|LiU Fund of U and Linkoping University

Available from: 2018-02-13 Created: 2018-02-13 Last updated: 2019-05-01
Lindahl, T., Ramström, S., Boknäs, N. & Faxälv, L. (2016). Caveats in studies of the physiological role of polyphosphates in coagulation. Biochemical Society Transactions, 44, 35-39
Open this publication in new window or tab >>Caveats in studies of the physiological role of polyphosphates in coagulation
2016 (English)In: Biochemical Society Transactions, ISSN 0300-5127, E-ISSN 1470-8752, Vol. 44, p. 35-39Article, review/survey (Refereed) Published
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.

Place, publisher, year, edition, pages
Portland Press Ltd, 2016
Keywords
Blood; Coagulation; Contact activation; Phosphatase; Platelets; Polyphosphate
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-126155 (URN)10.1042/BST20150220 (DOI)26862185 (PubMedID)2-s2.0-84957871941 (Scopus ID)
Note

Funding Agencies|20140410, Hjärt-Lungfonden; K2013-65X-15060-10-3, Hjärt-Lungfonden

Available from: 2016-03-15 Created: 2016-03-15 Last updated: 2019-02-01
Ramström, S., Södergren, A., Tynngård, N. & Lindahl, T. (2016). Platelet Function Determined by Flow Cytometry: New Perspectives?. Seminars in Thrombosis and Hemostasis, 42(3), 268-281
Open this publication in new window or tab >>Platelet Function Determined by Flow Cytometry: New Perspectives?
2016 (English)In: Seminars in Thrombosis and Hemostasis, ISSN 0094-6176, E-ISSN 1098-9064, Vol. 42, no 3, p. 268-281Article in journal (Refereed) Published
Abstract [en]

Flow cytometry enables studies of several different aspects of platelet function in response to a variety of platelet agonists. This can be done using only a small volume of whole blood, and also in blood with low platelet counts. These properties, together with the increasing number of flow cytometers available in hospitals worldwide, make flow cytometry an interesting option for laboratories interested in studies of platelet function in different clinical settings. This review focuses on practical issues regarding the use of flow cytometry for platelet function testing. It provides an overview of available activation markers, platelet agonists, and experimental setup issues. The review summarizes previous experience and factors important to consider to perform high-quality platelet function testing by flow cytometry. It also discusses its current use and possibilities and challenges for future use of flow cytometry in clinical settings

Place, publisher, year, edition, pages
Elsevier, 2016
Keywords
blood platelets; flow cytometry; platelet activation; platelet function testing
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-126156 (URN)10.1055/s-0035-1570082 (DOI)000373139300011 ()26886398 (PubMedID)
Available from: 2016-03-15 Created: 2016-03-15 Last updated: 2017-11-30Bibliographically approved
Södergren, A., Tynngård, N., Berlin, G. & Ramström, S. (2016). Responsiveness of platelets during storage studied with flow cytometry - formation of platelet subpopulations and LAMP-1 as new markers for the platelet storage lesion. Vox Sanguinis, 110(2), 116-125
Open this publication in new window or tab >>Responsiveness of platelets during storage studied with flow cytometry - formation of platelet subpopulations and LAMP-1 as new markers for the platelet storage lesion
2016 (English)In: Vox Sanguinis, ISSN 0042-9007, E-ISSN 1423-0410, Vol. 110, no 2, p. 116-125Article in journal (Refereed) Published
Abstract [en]

Background and ObjectivesStorage lesions may prevent transfused platelets to respond to agonists and arrest bleeding. The aim of this study was to evaluate and quantify the capacity of platelet activation during storage using flow cytometry and new markers of platelet activation. Materials and MethodsActivation responses of platelets prepared by apheresis were measured on days 1, 5, 7 and 12. In addition, comparisons were made for platelet concentrates stored until swirling was affected. Lysosome-associated membrane protein-1 (LAMP-1), P-selectin and phosphatidylserine (PS) exposure were assessed by flow cytometry on platelets in different subpopulations in resting state or following stimulation with platelet agonists (cross-linked collagen-related peptide (CRP-XL), PAR1- and PAR4-activating peptides). ResultsThe ability to form subpopulations upon activation was significantly decreased already at day 5 for some agonist combinations. The agonist-induced exposure of PS and LAMP-1 also gradually decreased with time. Spontaneous exposure of P-selectin and PS increased with time, while spontaneous LAMP-1 exposure was unchanged. In addition, agonist-induced LAMP-1 expression clearly discriminated platelet concentrates with reduced swirling from those with retained swirling. This suggests that LAMP-1 could be a good marker to capture changes in activation capacity in stored platelets. ConclusionThe platelet activation potential seen as LAMP-1 exposure and fragmentation into platelet subpopulations is potential sensitive markers for the platelet storage lesion.

Place, publisher, year, edition, pages
WILEY-BLACKWELL, 2016
Keywords
apheresis; haemostasis; platelet concentrates; platelet function; platelet transfusion
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-126141 (URN)10.1111/vox.12324 (DOI)000370657500002 ()26389538 (PubMedID)
Note

Funding Agencies|Region Ostergotland; Linkoping University through the LiU Research Fellows program

Available from: 2016-03-15 Created: 2016-03-15 Last updated: 2018-10-25
Södergren, A., Svensson Holm, A.-C., Ramström, S., Lindström, E., Grenegård, M. & Öllinger, K. (2016). Thrombin-induced lysosomal exocytosis in human platelets is dependent on secondary activation by ADP and regulated by endothelial-derived substances. Platelets, 27(1), 86-92
Open this publication in new window or tab >>Thrombin-induced lysosomal exocytosis in human platelets is dependent on secondary activation by ADP and regulated by endothelial-derived substances
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2016 (English)In: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 27, no 1, p. 86-92Article in journal (Refereed) Published
Abstract [en]

Exocytosis of lysosomal contents from platelets has been speculated to participate in clearance of thrombi and vessel wall remodelling. The mechanisms that regulate lysosomal exocytosis in platelets are, however, still unclear. The aim of this study was to identify the pathways underlying platelet lysosomal secretion and elucidate how this process is controlled by platelet inhibitors. We found that high concentrations of thrombin induced partial lysosomal exocytosis as assessed by analysis of the activity of released N-acetyl--glucosaminidase (NAG) and by identifying the fraction of platelets exposing the lysosomal-associated membrane protein (LAMP)-1 on the cell surface by flow cytometry. Stimulation of thrombin receptors PAR1 or PAR4 with specific peptides was equally effective in inducing LAMP-1 surface expression. Notably, lysosomal exocytosis in response to thrombin was significantly reduced if the secondary activation by ADP was inhibited by the P2Y(12) antagonist cangrelor, while inhibition of thromboxane A(2) formation by treatment with acetylsalicylic acid was of minor importance in this regard. Moreover, the NO-releasing drug S-nitroso-N-acetyl penicillamine (SNAP) or the cyclic AMP-elevating eicosanoid prostaglandin I-2 (PGI(2)) significantly suppressed lysosomal exocytosis. We conclude that platelet inhibitors that mimic functional endothelium such as PGI(2) or NO efficiently counteract lysosomal exocytosis. Furthermore, we suggest that secondary release of ADP and concomitant signaling via PAR1/4- and P2Y(12) receptors is important for efficient platelet lysosomal exocytosis by thrombin.

Place, publisher, year, edition, pages
TAYLOR & FRANCIS INC, 2016
Keywords
ADP receptors; endothelium; exocytosis; lysosome; platelet physiology; protease activated receptors (PAR); thrombin
National Category
Clinical Medicine Biological Sciences
Identifiers
urn:nbn:se:liu:diva-125318 (URN)10.3109/09537104.2015.1042446 (DOI)000368717700011 ()25970449 (PubMedID)
Note

Funding Agencies|County Council of Ostergotland; Swedish Research Council

Available from: 2016-02-24 Created: 2016-02-19 Last updated: 2018-10-25
Connolly-Andersen, A.-M., Sundberg, E., Ahlm, C., Hultdin, J., Baudin, M., Larsson, J., . . . Nilsson, S. (2015). Increased Thrombopoiesis and Platelet Activation in Hantavirus-Infected Patients. Journal of Infectious Diseases, 212(7), 1061-1069
Open this publication in new window or tab >>Increased Thrombopoiesis and Platelet Activation in Hantavirus-Infected Patients
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2015 (English)In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 212, no 7, p. 1061-1069Article in journal (Refereed) Published
Abstract [en]

Background. Thrombocytopenia is a common finding during viral hemorrhagic fever, which includes hemorrhagic fever with renal syndrome (HFRS). The 2 main causes for thrombocytopenia are impaired thrombopoiesis and/or increased peripheral destruction of platelets. In addition, there is an increased intravascular coagulation risk during HFRS, which could be due to platelet activation. Methods. Thrombopoiesis was determined by quantification of platelet counts, thrombopoietin, immature platelet fraction, and mean platelet volume during HFRS. The in vivo platelet activation was determined by quantification of soluble P-selectin (sP-selectin) and glycoprotein VI (sGPVI). The function of circulating platelets was determined by ex vivo stimulation followed by flow cytometry analysis of platelet surface-bound fibrinogen and P-selectin exposure. Intravascular coagulation during disease was determined by scoring for disseminated intravascular coagulation (DIC) and recording thromboembolic complications. Results. The levels of thrombopoietin, immature platelet fraction, and mean platelet volume all indicate increased thrombopoiesis during HFRS. Circulating platelets had reduced ex vivo function during disease compared to follow-up. Most interestingly, we observed significantly increased in vivo platelet activation in HFRS patients with intravascular coagulation (DIC and thromboembolic complications) as shown by sP-selectin and sGPVI levels. Conclusions. HFRS patients have increased thrombopoiesis and platelet activation, which contributes to intravascular coagulation.

Place, publisher, year, edition, pages
OXFORD UNIV PRESS INC, 2015
Keywords
disseminated intravascular coagulation; hantavirus; hemorrhagic fever with renal syndrome; platelets; thrombosis; viral hemorrhagic fever
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-122665 (URN)10.1093/infdis/jiv161 (DOI)000363191300007 ()25762786 (PubMedID)
Note

Funding Agencies|Medical Faculty of Umea University; County Council of Vasterbotten [216851, 243061, 238461, 321411]; County Councils of Northern Sweden [296301]

Available from: 2015-11-16 Created: 2015-11-13 Last updated: 2017-12-01
Tynngård, N., Wallstedt, M., Södergren, A. L., Faxälv, L. & Ramström, S. (2015). Platelet adhesion changes during storage studied with a novel method using flow cytometry and protein-coated beads. Platelets, 26(2), 177-185
Open this publication in new window or tab >>Platelet adhesion changes during storage studied with a novel method using flow cytometry and protein-coated beads
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2015 (English)In: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 26, no 2, p. 177-185Article in journal (Refereed) Published
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.

National Category
Basic Medicine
Identifiers
urn:nbn:se:liu:diva-111533 (URN)10.3109/09537104.2014.891728 (DOI)000351740700012 ()24679340 (PubMedID)
Available from: 2014-10-22 Created: 2014-10-22 Last updated: 2018-01-11Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0002-1920-3962

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