Comprehensive platelet phenotyping supports the role of platelets in the pathogenesis of acute venous thromboembolism - results from clinical observation studies

Marina Panova-Noeva; Bianca Wagner; Markus Nagler; Thomas Koeck; Vincent ten Cate; Juergen H. Prochaska; Stefan Heitmeier; Imke Meyer; Christoph Gerdes; Volker Laux; Stavros Konstantinides; Henri M. Spronk; Thomas Muenzel; Karl J. Lackner; Kirsten Leineweber; Hugo ten Cate; Philipp S. Wild

doi:10.1016/j.ebiom.2020.102978

Comprehensive platelet phenotyping supports the role of platelets in the pathogenesis of acute venous thromboembolism - results from clinical observation studies

Marina Panova-Noeva^*, Bianca Wagner, Markus Nagler, Thomas Koeck, Vincent ten Cate, Juergen H. Prochaska, Stefan Heitmeier, Imke Meyer, Christoph Gerdes, Volker Laux, Stavros Konstantinides, Henri M. Spronk, Thomas Muenzel, Karl J. Lackner, Kirsten Leineweber, Hugo ten Cate, Philipp S. Wild

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

7 Citations (Web of Science)

Abstract

Background: The pathogenesis of arterial and venous thrombosis is in large part interlaced. How much platelet phenotype relates to acute venous thromboembolism (VTE) independent of the underlying cardiovascular profile is presently poorly investigated.

Methods: Platelet count and mean platelet volume (MPV), platelet aggregation in whole blood and platelet rich plasma (PRP), platelet-dependent thrombin generation (TG) and platelet surface activation markers were measured under standardized conditions. Machine learning was applied to identify the most relevant characteristics associated with VTE from a large array (N = 58) of clinical and plateletrelated variables.

Findings: VTE cases (N = 159) presented with lower platelet count and MPV vs controls (N = 140). Whole blood aggregation showed shorter collagen/Epinephrine closure times in cases, particularly within acetylsalicylic acid (ASA) users. Within ASA users, higher PRP aggregation after adenosine diphosphate (ADP), epinephrine, collagen and arachidonic acid was observed in cases vs controls. Within non-ASA and/or subjects on anticoagulants, cases presented with lower aggregation after ADP and collagen vs controls. Lower platelet-dependent TG, higher CD63 on resting and lower PAC-1 expression after collagen/ADP in-vitro stimulated platelets further characterized VTE cases vs controls, independent of therapy. Lasso regression analysis identified 26 variables associated with VTE of which 69% were platelet-related.

Interpretation: Comprehensive phenotyping of platelet function identified a large proportion of low responders to ASA in VTE cases. Lower platelet-dependent TG and lower platelet reactivity after ex-vivo stimulation characterized the "platelet exhausted syndrome" in cases. Finally, from a large array of covariates including clinical risk factors, platelet biomarkers comprised 69% of all selected variables differentiating VTE cases vs controls.

Original language	English
Article number	102978
Number of pages	10
Journal	EBioMedicine
Volume	60
DOIs	https://doi.org/10.1016/j.ebiom.2020.102978
Publication status	Published - Oct 2020

Keywords

ACUTE PULMONARY-EMBOLISM
RISK-FACTOR
ASPIRIN
VOLUME
ACTIVATION
PREVENTION
THROMBOSIS
DETERMINANTS
METAANALYSIS
OUTCOMES

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Panova-Noeva, M., Wagner, B., Nagler, M., Koeck, T., ten Cate, V., Prochaska, J. H., Heitmeier, S., Meyer, I., Gerdes, C., Laux, V., Konstantinides, S., Spronk, H. M., Muenzel, T., Lackner, K. J., Leineweber, K., ten Cate, H., & Wild, P. S. (2020). Comprehensive platelet phenotyping supports the role of platelets in the pathogenesis of acute venous thromboembolism - results from clinical observation studies. EBioMedicine, 60, [102978]. https://doi.org/10.1016/j.ebiom.2020.102978

@article{63678695c593426c9e4461c40da6cb30,

title = "Comprehensive platelet phenotyping supports the role of platelets in the pathogenesis of acute venous thromboembolism - results from clinical observation studies",

abstract = "Background: The pathogenesis of arterial and venous thrombosis is in large part interlaced. How much platelet phenotype relates to acute venous thromboembolism (VTE) independent of the underlying cardiovascular profile is presently poorly investigated.Methods: Platelet count and mean platelet volume (MPV), platelet aggregation in whole blood and platelet rich plasma (PRP), platelet-dependent thrombin generation (TG) and platelet surface activation markers were measured under standardized conditions. Machine learning was applied to identify the most relevant characteristics associated with VTE from a large array (N = 58) of clinical and plateletrelated variables.Findings: VTE cases (N = 159) presented with lower platelet count and MPV vs controls (N = 140). Whole blood aggregation showed shorter collagen/Epinephrine closure times in cases, particularly within acetylsalicylic acid (ASA) users. Within ASA users, higher PRP aggregation after adenosine diphosphate (ADP), epinephrine, collagen and arachidonic acid was observed in cases vs controls. Within non-ASA and/or subjects on anticoagulants, cases presented with lower aggregation after ADP and collagen vs controls. Lower platelet-dependent TG, higher CD63 on resting and lower PAC-1 expression after collagen/ADP in-vitro stimulated platelets further characterized VTE cases vs controls, independent of therapy. Lasso regression analysis identified 26 variables associated with VTE of which 69% were platelet-related.Interpretation: Comprehensive phenotyping of platelet function identified a large proportion of low responders to ASA in VTE cases. Lower platelet-dependent TG and lower platelet reactivity after ex-vivo stimulation characterized the {"}platelet exhausted syndrome{"} in cases. Finally, from a large array of covariates including clinical risk factors, platelet biomarkers comprised 69% of all selected variables differentiating VTE cases vs controls.Funding: German Federal Ministry of Education and Research, CTH-Mainz and Bayer AG. (c) 2020 The Authors. Published by Elsevier B.V.",

keywords = "ACUTE PULMONARY-EMBOLISM, RISK-FACTOR, ASPIRIN, VOLUME, ACTIVATION, PREVENTION, THROMBOSIS, DETERMINANTS, METAANALYSIS, OUTCOMES",

author = "Marina Panova-Noeva and Bianca Wagner and Markus Nagler and Thomas Koeck and {ten Cate}, Vincent and Prochaska, {Juergen H.} and Stefan Heitmeier and Imke Meyer and Christoph Gerdes and Volker Laux and Stavros Konstantinides and Spronk, {Henri M.} and Thomas Muenzel and Lackner, {Karl J.} and Kirsten Leineweber and {ten Cate}, Hugo and Wild, {Philipp S.}",

year = "2020",

month = oct,

doi = "10.1016/j.ebiom.2020.102978",

language = "English",

volume = "60",

journal = "EBioMedicine",

issn = "2352-3964",

publisher = "Elsevier",

}

Panova-Noeva, M, Wagner, B, Nagler, M, Koeck, T, ten Cate, V, Prochaska, JH, Heitmeier, S, Meyer, I, Gerdes, C, Laux, V, Konstantinides, S, Spronk, HM, Muenzel, T, Lackner, KJ, Leineweber, K, ten Cate, H & Wild, PS 2020, 'Comprehensive platelet phenotyping supports the role of platelets in the pathogenesis of acute venous thromboembolism - results from clinical observation studies', EBioMedicine, vol. 60, 102978. https://doi.org/10.1016/j.ebiom.2020.102978

TY - JOUR

T1 - Comprehensive platelet phenotyping supports the role of platelets in the pathogenesis of acute venous thromboembolism - results from clinical observation studies

AU - Panova-Noeva, Marina

AU - Wagner, Bianca

AU - Nagler, Markus

AU - Koeck, Thomas

AU - ten Cate, Vincent

AU - Prochaska, Juergen H.

AU - Heitmeier, Stefan

AU - Meyer, Imke

AU - Gerdes, Christoph

AU - Laux, Volker

AU - Konstantinides, Stavros

AU - Spronk, Henri M.

AU - Muenzel, Thomas

AU - Lackner, Karl J.

AU - Leineweber, Kirsten

AU - ten Cate, Hugo

AU - Wild, Philipp S.

PY - 2020/10

Y1 - 2020/10

N2 - Background: The pathogenesis of arterial and venous thrombosis is in large part interlaced. How much platelet phenotype relates to acute venous thromboembolism (VTE) independent of the underlying cardiovascular profile is presently poorly investigated.Methods: Platelet count and mean platelet volume (MPV), platelet aggregation in whole blood and platelet rich plasma (PRP), platelet-dependent thrombin generation (TG) and platelet surface activation markers were measured under standardized conditions. Machine learning was applied to identify the most relevant characteristics associated with VTE from a large array (N = 58) of clinical and plateletrelated variables.Findings: VTE cases (N = 159) presented with lower platelet count and MPV vs controls (N = 140). Whole blood aggregation showed shorter collagen/Epinephrine closure times in cases, particularly within acetylsalicylic acid (ASA) users. Within ASA users, higher PRP aggregation after adenosine diphosphate (ADP), epinephrine, collagen and arachidonic acid was observed in cases vs controls. Within non-ASA and/or subjects on anticoagulants, cases presented with lower aggregation after ADP and collagen vs controls. Lower platelet-dependent TG, higher CD63 on resting and lower PAC-1 expression after collagen/ADP in-vitro stimulated platelets further characterized VTE cases vs controls, independent of therapy. Lasso regression analysis identified 26 variables associated with VTE of which 69% were platelet-related.Interpretation: Comprehensive phenotyping of platelet function identified a large proportion of low responders to ASA in VTE cases. Lower platelet-dependent TG and lower platelet reactivity after ex-vivo stimulation characterized the "platelet exhausted syndrome" in cases. Finally, from a large array of covariates including clinical risk factors, platelet biomarkers comprised 69% of all selected variables differentiating VTE cases vs controls.Funding: German Federal Ministry of Education and Research, CTH-Mainz and Bayer AG. (c) 2020 The Authors. Published by Elsevier B.V.

AB - Background: The pathogenesis of arterial and venous thrombosis is in large part interlaced. How much platelet phenotype relates to acute venous thromboembolism (VTE) independent of the underlying cardiovascular profile is presently poorly investigated.Methods: Platelet count and mean platelet volume (MPV), platelet aggregation in whole blood and platelet rich plasma (PRP), platelet-dependent thrombin generation (TG) and platelet surface activation markers were measured under standardized conditions. Machine learning was applied to identify the most relevant characteristics associated with VTE from a large array (N = 58) of clinical and plateletrelated variables.Findings: VTE cases (N = 159) presented with lower platelet count and MPV vs controls (N = 140). Whole blood aggregation showed shorter collagen/Epinephrine closure times in cases, particularly within acetylsalicylic acid (ASA) users. Within ASA users, higher PRP aggregation after adenosine diphosphate (ADP), epinephrine, collagen and arachidonic acid was observed in cases vs controls. Within non-ASA and/or subjects on anticoagulants, cases presented with lower aggregation after ADP and collagen vs controls. Lower platelet-dependent TG, higher CD63 on resting and lower PAC-1 expression after collagen/ADP in-vitro stimulated platelets further characterized VTE cases vs controls, independent of therapy. Lasso regression analysis identified 26 variables associated with VTE of which 69% were platelet-related.Interpretation: Comprehensive phenotyping of platelet function identified a large proportion of low responders to ASA in VTE cases. Lower platelet-dependent TG and lower platelet reactivity after ex-vivo stimulation characterized the "platelet exhausted syndrome" in cases. Finally, from a large array of covariates including clinical risk factors, platelet biomarkers comprised 69% of all selected variables differentiating VTE cases vs controls.Funding: German Federal Ministry of Education and Research, CTH-Mainz and Bayer AG. (c) 2020 The Authors. Published by Elsevier B.V.

KW - ACUTE PULMONARY-EMBOLISM

KW - RISK-FACTOR

KW - ASPIRIN

KW - VOLUME

KW - ACTIVATION

KW - PREVENTION

KW - THROMBOSIS

KW - DETERMINANTS

KW - METAANALYSIS

KW - OUTCOMES

U2 - 10.1016/j.ebiom.2020.102978

DO - 10.1016/j.ebiom.2020.102978

M3 - Article

C2 - 32920367

VL - 60

JO - EBioMedicine

JF - EBioMedicine

SN - 2352-3964

M1 - 102978

ER -