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Responsiveness of platelets during storage studied with flow cytometry - formation of platelet subpopulations and LAMP-1 as new markers for the platelet storage lesion
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
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. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.ORCID iD: 0000-0002-1920-3962
2016 (English)In: Vox Sanguinis, ISSN 0042-9007, E-ISSN 1423-0410, Vol. 110, no 2, p. 116-125Article in journal (Refereed) Published
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Text
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. Vol. 110, no 2, p. 116-125
Keywords [en]
apheresis; haemostasis; platelet concentrates; platelet function; platelet transfusion
National Category
Clinical Medicine
Identifiers
URN: urn:nbn:se:liu:diva-126141DOI: 10.1111/vox.12324ISI: 000370657500002PubMedID: 26389538OAI: oai:DiVA.org:liu-126141DiVA, id: diva2:912023
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
In thesis
1. Formation and Relevance of Platelet Subpopulations
Open this publication in new window or tab >>Formation and Relevance of Platelet Subpopulations
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Platelets are important players in the hemostatic system, acting as guardians of vessel integrity. When they come across a breach in the vessel wall, they quickly adhere to the damaged surface, secrete activating and adhesive compounds from their secretory granules, recruit additional platelets into a growing platelet plug and support the action of the coagulation system. In the past decades, it has become clear that platelets form functionally different platelet subpopulations. The aggregatory platelets build the platelet plug, whereas the procoagulant subpopulation support and direct the actions of the coagulation system. The aim of this thesis was to examine the formation and features of the different platelet subpopulations, and elucidate their respective roles in hemostasis.

Platelet lysosomal secretion is not well characterized. In Paper I, we found that lysosomal secretion, detected as LAMP-1 surface exposure, occur upon potent platelet stimulation including secondary activation by ADP. This is regulated by the endothelial platelet inhibitors nitric oxide and prostacyclin. As observed in Paper II, lysosomal secretion might also be of clinical relevance as a quality indicator for platelet concentrates used for transfusion, an area were quality control may become increasingly important in the future. Among several evaluated platelet activation markers, platelet LAMP-1 exposure and the ability to form procoagulant platelets may be useful as novel indicators of platelet responsiveness. Moreover, the ability to form procoagulant platelets varies extensively between individuals, something we established in Paper III. Here we also present a novel flow cytometry protocol enabling the simultaneous investigation of 6 different platelet activation markers. Using this protocol we investigate the formation of procoagulant platelets and reveal that only a subpopulation of platelets may become procoagulant. Further we show that this is dependent on the agonist stimulation applied. Finally in Paper IV, we explore the influence of the procoagulant platelet subpopulation on different aspects of hemostasis. While platelet aggregation was not affected, the fraction of procoagulant platelets was found to strongly correlate to peak thrombin generation, and to be associated with plasma cholesterol levels.

In conclusion, this thesis presents evidence for the use of LAMP-1 surface exposure and the formation of a procoagulant platelet subpopulation as potential indicators of platelet activation potential. The formation of procoagulant platelets varies extensively between individuals, influence hemostasis and is associated with the known risk factor cholesterol. Thus, the formation of a procoagulant platelet subpopulation may be a candidate biomarker for cardiovascular disease, to be explored in the future.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2018. p. 61
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1642
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:liu:diva-152280 (URN)10.3384/diss.diva-152280 (DOI)9789176852156 (ISBN)
Public defence
2018-11-02, Berzeliussalen, Campus US, Linköping, 09:00 (English)
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Supervisors
Available from: 2018-10-25 Created: 2018-10-25 Last updated: 2018-10-25Bibliographically approved

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Södergren, AnnaTynngård, NahreenBerlin, GöstaRamström, Sofia

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