High-throughput elucidation of thrombus formation reveals sources of platelet function variability.

Autor: van Geffen JP; Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, the Netherlands., Brouns SLN; Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, the Netherlands., Batista J; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, UK.; National Health Service Blood and Transplant (NHSBT), Cambridge Biomedical Campus, UK., McKinney H; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, UK.; National Health Service Blood and Transplant (NHSBT), Cambridge Biomedical Campus, UK., Kempster C; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, UK.; National Health Service Blood and Transplant (NHSBT), Cambridge Biomedical Campus, UK., Nagy M; Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, the Netherlands., Sivapalaratnam S; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, UK.; The Royal London Haemophilia Centre, London, UK., Baaten CCFMJ; Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, the Netherlands., Bourry N; Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, the Netherlands., Frontini M; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, UK.; National Health Service Blood and Transplant (NHSBT), Cambridge Biomedical Campus, UK.; BHF Centre of Excellence, Division of Cardiovascular Medicine, Cambridge University Hospitals, Cambridge Biomedical Campus, UK., Jurk K; Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg University Mainz, Germany., Krause M; DKD Helios Klinik Wiesbaden, Germany., Pillitteri D; DKD Helios Klinik Wiesbaden, Germany., Swieringa F; Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, the Netherlands., Verdoold R; Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, the Netherlands., Cavill R; Department of Data Science & Knowledge Engineering, Faculty of Humanities and Sciences, Maastricht University, the Netherlands., Kuijpers MJE; Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, the Netherlands., Ouwehand WH; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, UK.; National Health Service Blood and Transplant (NHSBT), Cambridge Biomedical Campus, UK.; BHF Centre of Excellence, Division of Cardiovascular Medicine, Cambridge University Hospitals, Cambridge Biomedical Campus, UK.; NIHR BioResource, University of Cambridge, Cambridge Biomedical Campus, UK.; Department of Human Genetics, The Wellcome Sanger Institute, Hinxton, Cambridge, UK., Downes K; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, UK jwm.heemskerk@maastrichtuniversity.nl kd286@cam.ac.uk.; National Health Service Blood and Transplant (NHSBT), Cambridge Biomedical Campus, UK.; NIHR BioResource, University of Cambridge, Cambridge Biomedical Campus, UK., Heemskerk JWM; Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, the Netherlands jwm.heemskerk@maastrichtuniversity.nl kd286@cam.ac.uk.
Jazyk: angličtina
Zdroj: Haematologica [Haematologica] 2019 Jun; Vol. 104 (6), pp. 1256-1267. Date of Electronic Publication: 2018 Dec 13.
DOI: 10.3324/haematol.2018.198853
Abstrakt: In combination with microspotting, whole-blood microfluidics can provide high-throughput information on multiple platelet functions in thrombus formation. Based on assessment of the inter- and intra-subject variability in parameters of microspot-based thrombus formation, we aimed to determine the platelet factors contributing to this variation. Blood samples from 94 genotyped healthy subjects were analyzed for conventional platelet phenotyping: i.e. hematologic parameters, platelet glycoprotein (GP) expression levels and activation markers (24 parameters). Furthermore, platelets were activated by ADP, CRP-XL or TRAP. Parallel samples were investigated for whole-blood thrombus formation (6 microspots, providing 48 parameters of adhesion, aggregation and activation). Microspots triggered platelet activation through GP Ib-V-IX, GPVI, CLEC-2 and integrins. For most thrombus parameters, inter-subject variation was 2-4 times higher than the intra-subject variation. Principal component analyses indicated coherence between the majority of parameters for the GPVI-dependent microspots, partly linked to hematologic parameters, and glycoprotein expression levels. Prediction models identified parameters per microspot that were linked to variation in agonist-induced α IIb β 3 activation and secretion. Common sequence variation of GP6 and FCER1G , associated with GPVI-induced α IIb β 3 activation and secretion, affected parameters of GPVI-and CLEC-2-dependent thrombus formation. Subsequent analysis of blood samples from patients with Glanzmann thrombasthenia or storage pool disease revealed thrombus signatures of aggregation-dependent parameters that were subject-dependent, but not linked to GPVI activity. Taken together, this high-throughput elucidation of thrombus formation revealed patterns of inter-subject differences in platelet function, which were partly related to GPVI-induced activation and common genetic variance linked to GPVI, but also included a distinct platelet aggregation component.
(Copyright© 2019 Ferrata Storti Foundation.)
Databáze: MEDLINE
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