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

Fadel Muhammad Garishah; Dana Huskens; Setyo Gundi Pramudo; Dessy Andriani; Mila Astrilia; Rizky Akbar Sentosa; André J. A. M. van der Ven; Bas de Laat; Muhammad Hussein Gasem; Quirijn de Mast; Mark Roest

doi:10.1055/s-0042-1757163

Thrombosis and Haemostasis, Inhaltsverzeichnis

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

¹Department of Internal Medicine and the Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands

²Center for Tropical and Infectious Diseases (CENTRID), Faculty of Medicine, Diponegoro University, Dr. Kariadi Hospital, Semarang, Indonesia

,

Dana Huskens

³Department of Platelet Pathophysiology, Synapse Research Institute, Maastricht, The Netherlands

⁴Department of Functional Coagulation, Synapse Research Institute, Maastricht, The Netherlands

,

Setyo Gundi Pramudo

⁵Department of Internal Medicine, Diponegoro National University Hospital, Faculty of Medicine, Diponegoro University, Semarang, Indonesia

,

Dessy Andriani

⁶Department of Internal Medicine, KRMT Wongsonegoro General Hospital, Semarang, Indonesia

,

Mila Astrilia

⁶Department of Internal Medicine, KRMT Wongsonegoro General Hospital, Semarang, Indonesia

,

Rizky Akbar Sentosa

⁵Department of Internal Medicine, Diponegoro National University Hospital, Faculty of Medicine, Diponegoro University, Semarang, Indonesia

,

André J. A. M. van der Ven

¹Department of Internal Medicine and the Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands

,

Bas de Laat

³Department of Platelet Pathophysiology, Synapse Research Institute, Maastricht, The Netherlands

⁴Department of Functional Coagulation, Synapse Research Institute, Maastricht, The Netherlands

,

Muhammad Hussein Gasem

²Center for Tropical and Infectious Diseases (CENTRID), Faculty of Medicine, Diponegoro University, Dr. Kariadi Hospital, Semarang, Indonesia

⁵Department of Internal Medicine, Diponegoro National University Hospital, Faculty of Medicine, Diponegoro University, Semarang, Indonesia

,

Quirijn de Mast^*

¹Department of Internal Medicine and the Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands

,

Mark Roest^*

³Department of Platelet Pathophysiology, Synapse Research Institute, Maastricht, The Netherlands

› Institutsangaben

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

Volltext

Referenzen

References
1 Tafazoli A, Anil Kumar S, Othman M. Thrombocytopathy vs platelet hyper-reactivity in COVID-19: diverse pathologies, disease outcomes and therapeutic implications. Platelets 2022; 33 (01) 48-53
2 Semple JW, Italiano Jr JE, Freedman J. Platelets and the immune continuum. Nat Rev Immunol 2011; 11 (04) 264-274
3 Carestia A, Kaufman T, Schattner M. Platelets: new bricks in the building of neutrophil extracellular traps. Front Immunol 2016; 7 (271) 271
4 Ackermann M, Verleden SE, Kuehnel M. et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N Engl J Med 2020; 383 (02) 120-128
5 Rapkiewicz AV, Mai X, Carsons SE. et al. Megakaryocytes and platelet-fibrin thrombi characterize multi-organ thrombosis at autopsy in COVID-19: a case series. EClinicalMedicine 2020; 24: 100434
6 Gupta S, Konradt C, Corken A. et al. Hemostasis vs. homeostasis: platelets are essential for preserving vascular barrier function in the absence of injury or inflammation. Proc Natl Acad Sci U S A 2020; 117 (39) 24316-24325
7 Ho-Tin-Noé B, Demers M, Wagner DD. How platelets safeguard vascular integrity. J Thromb Haemost 2011; 9 (Suppl. 01) 56-65
8 Gu SX, Tyagi T, Jain K. et al. Thrombocytopathy and endotheliopathy: crucial contributors to COVID-19 thromboinflammation. Nat Rev Cardiol 2021; 18 (03) 194-209
9 Hottz ED, Azevedo-Quintanilha IG, Palhinha L. et al. Platelet activation and platelet-monocyte aggregate formation trigger tissue factor expression in patients with severe COVID-19. Blood 2020; 136 (11) 1330-1341
10 Manne BK, Denorme F, Middleton EA. et al. Platelet gene expression and function in patients with COVID-19. Blood 2020; 136 (11) 1317-1329
11 Zaid Y, Guessous F, Puhm F. et al. Platelet reactivity to thrombin differs between patients with COVID-19 and those with ARDS unrelated to COVID-19. Blood Adv 2021; 5 (03) 635-639
12 Huang Y, Lu Y, Huang YM. et al. Obesity in patients with COVID-19: a systematic review and meta-analysis. Metabolism 2020; 113: 154378
13 van der Meijden PEJ, Heemskerk JWM. Platelet biology and functions: new concepts and clinical perspectives. Nat Rev Cardiol 2019; 16 (03) 166-179
14 Comer SP, Cullivan S, Szklanna PB. et al; COCOON Study investigators. COVID-19 induces a hyperactive phenotype in circulating platelets. PLoS Biol 2021; 19 (02) e3001109
15 Zaid Y, Puhm F, Allaeys I. et al. Platelets can associate with SARS-Cov-2 RNA and are hyperactivated in COVID-19. Circ Res 2020; 127 (11) 1404-1418
16 Jonigk D, Märkl B, Helms J. COVID-19: what the clinician should know about post-mortem findings. Intensive Care Med 2021; 47 (01) 86-89
17 Elezkurtaj S, Greuel S, Ihlow J. et al. Causes of death and comorbidities in hospitalized patients with COVID-19. Sci Rep 2021; 11 (01) 4263
18 Giannis D, Ziogas IA, Gianni P. Coagulation disorders in coronavirus infected patients: COVID-19, SARS-CoV-1, MERS-CoV and lessons from the past. J Clin Virol 2020; 127: 104362
19 Caillon A, Trimaille A, Favre J, Jesel L, Morel O, Kauffenstein G. Role of neutrophils, platelets, and extracellular vesicles and their interactions in COVID-19-associated thrombopathy. J Thromb Haemost 2022; 20 (01) 17-31
20 Yuriditsky E, Horowitz JM, Merchan C. et al. Thromboelastography profiles of critically ill patients with coronavirus disease 2019. Crit Care Med 2020; 48 (09) 1319-1326
21 Michels M, Alisjahbana B, De Groot PG. et al. Platelet function alterations in dengue are associated with plasma leakage. Thromb Haemost 2014; 112 (02) 352-362
22 Rondina MT, Brewster B, Grissom CK. et al. In vivo platelet activation in critically ill patients with primary 2009 influenza A(H1N1). Chest 2012; 141 (06) 1490-1495
23 Bongiovanni D, Klug M, Lazareva O. et al. SARS-CoV-2 infection is associated with a pro-thrombotic platelet phenotype. Cell Death Dis 2021; 12 (01) 50
24 Hoxie JA, Ahuja M, Belmonte E, Pizarro S, Parton R, Brass LF. Internalization and recycling of activated thrombin receptors. J Biol Chem 1993; 268 (18) 13756-13763
25 Garcia C, Au Duong J, Poëtte M. et al. Platelet activation and partial desensitization are associated with viral xenophagy in patients with severe COVID-19. Blood Adv 2022; 6 (13) 3884-3898
26 Bonaventura A, Vecchié A, Dagna L. et al. Endothelial dysfunction and immunothrombosis as key pathogenic mechanisms in COVID-19. Nat Rev Immunol 2021; 21 (05) 319-329
27 Buijsers B, Yanginlar C, Maciej-Hulme ML, de Mast Q, van der Vlag J. Beneficial non-anticoagulant mechanisms underlying heparin treatment of COVID-19 patients. EBioMedicine 2020; 59: 102969
28 Weyrich AS, Zimmerman GA. Platelets in lung biology. Annu Rev Physiol 2013; 75: 569-591
29 Meizlish ML, Goshua G, Liu Y. et al. Intermediate-dose anticoagulation, aspirin, and in-hospital mortality in COVID-19: a propensity score-matched analysis. Am J Hematol 2021; 96 (04) 471-479
30 Wang Y, Ao G, Nasr B, Qi X. Effect of antiplatelet treatments on patients with COVID-19 infection: a systematic review and meta-analysis. Am J Emerg Med 2021; 43: 27-30
31 Sriram K, Insel PA. Inflammation and thrombosis in COVID-19 pathophysiology: proteinase-activated and purinergic receptors as drivers and candidate therapeutic targets. Physiol Rev 2021; 101 (02) 545-567

Zusatzmaterial

Supplementary Material