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High-throughput elucidation of thrombus formation reveals sources of platelet function variability
- Source :
- Haematologica 104(6), 1256-1267 (2019). doi:10.3324/haematol.2018.198853, Haematologica, Haematologica-the Hematology Journal, 104(6), 1256-1267. Ferrata Storti Foundation
- Publication Year :
- 2019
-
Abstract
- 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 alpha(IIb)beta(3) activation and secretion. Common sequence variation of GP6 and FCER1G, associated with GPVI-induced alpha(IIb)beta(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.
- Subjects :
- Blood Platelets
Platelet Aggregation
Platelet Function Tests
DISORDERS
Integrin
Platelet Membrane Glycoproteins
ADHESION
Platelet membrane glycoprotein
Article
Immunophenotyping
Flow cytometry
03 medical and health sciences
0302 clinical medicine
Platelet Biology & Its Disorders
medicine
Humans
Platelet
Platelet activation
Thrombus
chemistry.chemical_classification
medicine.diagnostic_test
biology
Platelet Count
Thrombosis
Hematology
Flow Cytometry
Platelet Activation
medicine.disease
DIFFERENCE
High-Throughput Screening Assays
Cell biology
chemistry
biology.protein
GPVI
Glycoprotein
Biomarkers
030215 immunology
RESPONSES
Subjects
Details
- Language :
- English
- ISSN :
- 03906078
- Volume :
- 104
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- Haematologica-the Hematology Journal
- Accession number :
- edsair.doi.dedup.....46d3d8e77a0f55bc6a799fa2baf26289