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Thromb Haemost 2022; 122(12): 2001-2010
DOI: 10.1055/s-0042-1757163
Cellular Haemostasis and Platelets

Hyperresponsive Platelets and a Reduced Platelet Granule Release Capacity Are Associated with Severity and Mortality in COVID-19 Patients

Fadel Muhammad Garishah 
1   Department of Internal Medicine and the Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
2   Center for Tropical and Infectious Diseases (CENTRID), Faculty of Medicine, Diponegoro University, Dr. Kariadi Hospital, Semarang, Indonesia
,
Dana Huskens 
3   Department of Platelet Pathophysiology, Synapse Research Institute, Maastricht, The Netherlands
4   Department of Functional Coagulation, Synapse Research Institute, Maastricht, The Netherlands
,
Setyo Gundi Pramudo
5   Department of Internal Medicine, Diponegoro National University Hospital, Faculty of Medicine, Diponegoro University, Semarang, Indonesia
,
Dessy Andriani
6   Department of Internal Medicine, KRMT Wongsonegoro General Hospital, Semarang, Indonesia
,
Mila Astrilia
6   Department of Internal Medicine, KRMT Wongsonegoro General Hospital, Semarang, Indonesia
,
Rizky Akbar Sentosa
5   Department of Internal Medicine, Diponegoro National University Hospital, Faculty of Medicine, Diponegoro University, Semarang, Indonesia
,
André J. A. M. van der Ven
1   Department of Internal Medicine and the Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
,
Bas de Laat
3   Department of Platelet Pathophysiology, Synapse Research Institute, Maastricht, The Netherlands
4   Department of Functional Coagulation, Synapse Research Institute, Maastricht, The Netherlands
,
Muhammad Hussein Gasem
2   Center for Tropical and Infectious Diseases (CENTRID), Faculty of Medicine, Diponegoro University, Dr. Kariadi Hospital, Semarang, Indonesia
5   Department of Internal Medicine, Diponegoro National University Hospital, Faculty of Medicine, Diponegoro University, Semarang, Indonesia
,
Quirijn de Mast   *
1   Department of Internal Medicine and the Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
,
Mark Roest   *
3   Department of Platelet Pathophysiology, Synapse Research Institute, Maastricht, The Netherlands
› Author Affiliations Funding F.M.G. was financially supported by the Indonesian Endowment Fund for Education (LPDP) Scholarship from the Ministry of Finance, Republic of Indonesia.
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Abstract

Background Coronavirus disease 2019 (COVID-19) is often associated with mild thrombocytopenia and increased platelet reactivity.

Objective The aim of the current study was to investigate the adenosine triphosphate (ATP) release kinetics of platelets in hospitalized SARS-CoV-2-infected patients.

Methods We studied time-dependent platelet activation in whole blood by monitoring the ATP release kinetics upon stimulation with a PAR1 receptor agonist in 41 hospitalized critically ill COVID-19 patients, 47 hospitalized noncritically ill COVID-19 patients, and 30 healthy controls.

Results Our study demonstrated that platelets of critically ill COVID-19 patients were hyper-responsive with a shorter platelet response time (PRT) and a reduced platelet granule release capacity (GRC), probably due to chronic activation. The median PRT of COVID-19 patients admitted to the critical care unit was 10 and 7 seconds shorter than the median PRT in healthy controls and noncritical COVID-19 patients, respectively. Both PRT and GRC were also associated with D-dimer (Spearman r [r s] = −0.51, p < 0.0001 and r s = −0.23, p < 0.05), C-reactive protein (CRP) (r s = −0.59, p < 0.0001 and r s = −0.41, p < 0.01), and neutrophil-to-lymphocyte ratio (NLR) (r s = −0.42, p < 0.0001 and r s = −0.26, p < 0.05). Moreover, an increased PRT and a reduced GRC were associated with an increased mortality (odds ratio [OR]: 18.8, 95% confidence interval [CI]: 6.5–62.8, p < 0.0001 and OR: 4.0; 95% CI: 1.6–10.4, p < 0.01). These relationships remained significant after adjustment for age, sex, D-dimer, CRP, and NLR.

Conclusion Using an accessible agonist-induced platelet granule ATP release assay, we show that platelet hyper-responsiveness and reduced platelet GRC in COVID-19 patients were associated with critical illness and mortality.

Keywords

ATP - COVID-19 - granule release capacity - platelets - platelet function

Ethical Approval

The study protocol was approved by the Medical Research Ethics Committee, Faculty of Medicine, Diponegoro University, Semarang, Indonesia (No:69/EC/KEPK/FKUNDIP/V/2020). Written informed consent was obtained from all participants, or from legal representatives of those unable to provide consent. All study procedures were performed in accordance with the Declaration of Helsinki.


Author Contributions

F.M.G., Q.d.M., M.R., S.G.P., M.H.G., and A.v.d.V. conceptualized the study. F.M.G., D.H., M.R., and Q.d.M. designed the measurement work flow. F.M.G., S.G.P., M.H.G., D.A., M.A., and R.A.S. provided the patient samples and clinical data. F.M.G. and R.A.S. performed the platelet function measurements. F.M.G., D.H., M.R., and Q.d.M. analyzed the data and wrote the original draft of the manuscript. Q.d.M., S.G.P., M.H.G,. and A.v.d.V. supervised the clinical study. All authors critically reviewed and edited the manuscript.


Note

The graphical abstract figure was created using Biorender (https://biorender.com).


* These authors share senior authorship.


Supplementary Material



Publication History

Received: 11 March 2022

Accepted: 07 August 2022

Article published online:
11 October 2022

© 2022. Thieme. All rights reserved.

Georg Thieme Verlag KG
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