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Semin Thromb Hemost 2023; 49(01): 055-061
DOI: 10.1055/s-0042-1749441
Review Article

Platelet Activation and Thrombosis in COVID-19

Toshiaki Iba
1   Department of Emergency and Disaster Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
,
Hideo Wada
2   Department of General Medicine, Mie Prefectural General Medical Center, Mie, Japan
,
Jerrold H. Levy
3   Department of Anesthesiology, Critical Care, and Surgery, Duke University School of Medicine, Durham, North Carolina
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Abstract

Although thrombosis frequently occurs in infectious diseases, the coagulopathy associated with COVID-19 has unique characteristics. Compared with bacterial sepsis, COVID-19-associated coagulopathy presents with minimal changes in platelet counts, normal prothrombin times, and increased D-dimer and fibrinogen levels. These differences can be explained by the distinct pathophysiology of the thromboinflammatory responses. In sepsis-induced coagulopathy, leukocytes are primarily responsible for the coagulopathy by expressing tissue factor, releasing neutrophil extracellular traps, multiple procoagulant substances, and systemic endothelial injury that is often associated with vasoplegia and shock. In COVID-19-associated coagulopathy, platelet activation is a major driver of inflammation/thrombogenesis and von Willebrand factor and platelet factor 4 are deeply involved in the pathogenesis. Although the initial responses are localized to the lung, they can spread systemically if the disease is severe. Since the platelets play major roles, arterial thrombosis is not uncommon in COVID-19. Despite platelet activation, platelet count is usually normal at presentation, but sensitive biomarkers including von Willebrand factor activity, soluble P-selectin, and soluble C-type lectin-like receptor-2 are elevated, and they increase as the disease progresses. Although the role of antiplatelet therapy is still unproven, current studies are ongoing to determine its potential effects.

Keywords

COVID-19 - platelet - thrombosis - von Willebrand factor - platelet factor 4 - P-selectin - C-type lectin-like receptor 2 - antiplatelet


Publication History

Article published online:
23 June 2022

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  • References

  • 1 de Roquetaillade C, Chousterman BG, Tomasoni D. et al. Unusual arterial thrombotic events in COVID-19 patients. Int J Cardiol 2021; 323: 281-284
    CrossrefPubMedGoogle Scholar
  • 2 Goudot G, Amrane M, El Ayoubi R. et al. Thrombus of the aorta and SARS-CoV-2 infection: cause or trigger?. Front Cardiovasc Med 2021; 8: 700292
    CrossrefPubMedGoogle Scholar
  • 3 Burley NB, Dy PS, Kalantri S, Razzaq K. Aortic thrombosis and acute limb ischemia secondary to COVID hypercoagulability. Cureus 2021; 13 (07) e16171
    PubMedGoogle Scholar
  • 4 Azouz E, Yang S, Monnier-Cholley L, Arrivé L. Systemic arterial thrombosis and acute mesenteric ischemia in a patient with COVID-19. Intensive Care Med 2020; 46 (07) 1464-1465
    CrossrefPubMedGoogle Scholar
  • 5 Lau K, White-Gittens I, Schor J, Guerges M. COVID-19-associated ischaemic stroke due to underlying carotid artery thrombosis in a healthy young woman. BMJ Case Rep 2021; 14 (08) e244396
    CrossrefPubMedGoogle Scholar
  • 6 Elbadry MI, Tawfeek A, Abdellatif MG. et al. Unusual pattern of thrombotic events in young adult non-critically ill patients with COVID-19 may result from an undiagnosed inherited and acquired form of thrombophilia. Br J Haematol 2022; 196 (04) 902-922
    CrossrefPubMedGoogle Scholar
  • 7 Iba T, Levy JH, Levi M, Thachil J. Coagulopathy in COVID-19. J Thromb Haemost 2020; 18 (09) 2103-2109
    CrossrefPubMedGoogle Scholar
  • 8 Di Minno A, Ambrosino P, Calcaterra I, Di Minno MND. COVID-19 and venous thromboembolism: a meta-analysis of literature studies. Semin Thromb Hemost 2020; 46 (07) 763-771
    Article in Thieme ConnectPubMedGoogle Scholar
  • 9 Schmidt M, Horvath-Puho E, Thomsen RW, Smeeth L, Sørensen HT. Acute infections and venous thromboembolism. J Intern Med 2012; 271 (06) 608-618
    CrossrefPubMedGoogle Scholar
  • 10 Gerber GF, Chaturvedi S. How to recognize and manage COVID-19-associated coagulopathy. Hematology (Am Soc Hematol Educ Program) 2021; 2021 (01) 614-620
    CrossrefPubMedGoogle Scholar
  • 11 Iba T, Connors JM, Nagaoka I, Levy JH. Recent advances in the research and management of sepsis-associated DIC. Int J Hematol 2021; 113 (01) 24-33
    CrossrefPubMedGoogle Scholar
  • 12 Nicolai L, Leunig A, Brambs S. et al. Immunothrombotic dysregulation in COVID-19 pneumonia is associated with respiratory failure and coagulopathy. Circulation 2020; 142 (12) 1176-1189
    CrossrefPubMedGoogle Scholar
  • 13 Iba T, Levy JH. The roles of platelets in COVID-19-associated coagulopathy and vaccine-induced immune thrombotic thrombocytopenia. Trends Cardiovasc Med 2022; 32 (01) 1-9
    CrossrefPubMedGoogle Scholar
  • 14 Bautista-Vargas M, Bonilla-Abadía F, Cañas CA. Potential role for tissue factor in the pathogenesis of hypercoagulability associated with in COVID-19. J Thromb Thrombolysis 2020; 50 (03) 479-483
    CrossrefPubMedGoogle Scholar
  • 15 Iba T, Levy JH, Connors JM, Warkentin TE, Thachil J, Levi M. Managing thrombosis and cardiovascular complications of COVID-19: answering the questions in COVID-19-associated coagulopathy. Expert Rev Respir Med 2021; 15 (08) 1003-1011
    CrossrefPubMedGoogle Scholar
  • 16 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
    CrossrefPubMedGoogle Scholar
  • 17 Hernández-Huerta MT, Pérez-Santiago AD, Pérez-Campos Mayoral L. et al. Mechanisms of immunothrombosis by SARS-CoV-2. Biomolecules 2021; 11 (11) 1550
    CrossrefPubMedGoogle Scholar
  • 18 Zhang S, Liu Y, Wang X. et al. SARS-CoV-2 binds platelet ACE2 to enhance thrombosis in COVID-19. J Hematol Oncol 2020; 13 (01) 120
    CrossrefPubMedGoogle Scholar
  • 19 Datta PK, Liu F, Fischer T, Rappaport J, Qin X. SARS-CoV-2 pandemic and research gaps: understanding SARS-CoV-2 interaction with the ACE2 receptor and implications for therapy. Theranostics 2020; 10 (16) 7448-7464
    CrossrefPubMedGoogle Scholar
  • 20 Verdecchia P, Cavallini C, Spanevello A, Angeli F. COVID-19: ACE2centric infective disease?. Hypertension 2020; 76 (02) 294-299
    CrossrefPubMedGoogle Scholar
  • 21 Barrett TJ, Bilaloglu S, Cornwell M. et al. Platelets contribute to disease severity in COVID-19. J Thromb Haemost 2021; 19 (12) 3139-3153
    CrossrefPubMedGoogle Scholar
  • 22 Althaus K, Möller P, Uzun G. et al. Antibody-mediated procoagulant platelets in SARS-CoV-2-vaccination associated immune thrombotic thrombocytopenia. Haematologica 2021; 106 (08) 2170-2179
    CrossrefPubMedGoogle Scholar
  • 23 Argañaraz GA, Palmeira JDF, Argañaraz ER. Phosphatidylserine inside out: a possible underlying mechanism in the inflammation and coagulation abnormalities of COVID-19. Cell Commun Signal 2020; 18 (01) 190
    CrossrefPubMedGoogle Scholar
  • 24 Katsoularis I, Fonseca-Rodríguez O, Farrington P, Lindmark K, Fors Connolly AM. Risk of acute myocardial infarction and ischaemic stroke following COVID-19 in Sweden: a self-controlled case series and matched cohort study. Lancet 2021; 398 (10300): 599-607
    CrossrefPubMedGoogle Scholar
  • 25 Klok FA, Kruip MJHA, van der Meer NJM. et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res 2020; 191: 145-147
    CrossrefPubMedGoogle Scholar
  • 26 Cheruiyot I, Kipkorir V, Ngure B, Misiani M, Munguti J, Ogeng'o J. Arterial thrombosis in coronavirus disease 2019 patients: a rapid systematic review. Ann Vasc Surg 2021; 70: 273-281
    CrossrefPubMedGoogle Scholar
  • 27 Glober N, Stewart L, Seo J. et al. Incidence and characteristics of arterial thromboemboli in patients with COVID-19. Thromb J 2021; 19 (01) 104
    CrossrefPubMedGoogle Scholar
  • 28 Bekelis K, Missios S, Ahmad J. et al. Ischemic stroke occurs less frequently in patients with COVID-19: a multicenter cross-sectional study. Stroke 2020; 51 (12) 3570-3576
    CrossrefPubMedGoogle Scholar
  • 29 Lippi G, Plebani M, Henry BM. Thrombocytopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: a meta-analysis. Clin Chim Acta 2020; 506: 145-148
    CrossrefPubMedGoogle Scholar
  • 30 Zhou F, Yu T, Du R. et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020; 395 (10229): 1054-1062
    Google Scholar
  • 31 Shah B, Valdes V, Nardi MA, Hu L, Schrem E, Berger JS. Mean platelet volume reproducibility and association with platelet activity and anti-platelet therapy. Platelets 2014; 25 (03) 188-192
    CrossrefPubMedGoogle Scholar
  • 32 Lippi G, Henry BM, Favaloro EJ. Mean platelet volume predicts severe COVID-19 illness. Semin Thromb Hemost 2021; 47 (04) 456-459
    Article in Thieme ConnectPubMedGoogle Scholar
  • 33 Sugimoto M, Miyata S. Functional property of von Willebrand factor under flowing blood. Int J Hematol 2002; 75 (01) 19-24
    CrossrefPubMedGoogle Scholar
  • 34 Mancini I, Baronciani L, Artoni A. et al. The ADAMTS13-von Willebrand factor axis in COVID-19 patients. J Thromb Haemost 2021; 19 (02) 513-521
    CrossrefPubMedGoogle Scholar
  • 35 Rostami M, Mansouritorghabeh H, Parsa-Kondelaji M. High levels of Von Willebrand factor markers in COVID-19: a systematic review and meta-analysis. Clin Exp Med 2021; 6: 1-11
    PubMedGoogle Scholar
  • 36 Favaloro EJ, Henry BM, Lippi G. Increased VWF and decreased ADAMTS-13 in COVID-19: creating a milieu for (micro)thrombosis. Semin Thromb Hemost 2021; 47 (04) 400-418
    Article in Thieme ConnectPubMedGoogle Scholar
  • 37 Ward SE, Fogarty H, Karampini E. et al; Irish COVID-19 Vasculopathy Study (iCVS) investigators. ADAMTS13 regulation of VWF multimer distribution in severe COVID-19. J Thromb Haemost 2021; 19 (08) 1914-1921
    CrossrefPubMedGoogle Scholar
  • 38 Barale C, Melchionda E, Morotti A, Russo I. Prothrombotic phenotype in COVID-19: focus on platelets. Int J Mol Sci 2021; 22 (24) 13638
    CrossrefPubMedGoogle Scholar
  • 39 Rampotas A, Pavord S. Platelet aggregates, a marker of severe COVID-19 disease. J Clin Pathol 2021; 74 (11) 750-751
    CrossrefPubMedGoogle Scholar
  • 40 Middleton EA, He XY, Denorme F. et al. Neutrophil extracellular traps contribute to immunothrombosis in COVID-19 acute respiratory distress syndrome. Blood 2020; 136 (10) 1169-1179
    CrossrefPubMedGoogle Scholar
  • 41 Iba T, Levy JH, Warkentin TE. Recognizing vaccine-induced immune thrombotic thrombocytopenia. Crit Care Med 2022; 50 (01) e80-e86
    CrossrefPubMedGoogle Scholar
  • 42 Cacciola R, Gentilini Cacciola E, Vecchio V, Cacciola E. Cellular and molecular mechanisms in COVID-19 coagulopathy: role of inflammation and endotheliopathy. J Thromb Thrombolysis 2022; Feb; 53 (02) 282-290
    CrossrefPubMedGoogle Scholar
  • 43 Merten M, Thiagarajan P. P-selectin in arterial thrombosis. Z Kardiol 2004; 93 (11) 855-863
    CrossrefPubMedGoogle Scholar
  • 44 Ferroni P, Martini F, Riondino S. et al. Soluble P-selectin as a marker of in vivo platelet activation. Clin Chim Acta 2009; 399 (1-2): 88-91
    CrossrefPubMedGoogle Scholar
  • 45 Karsli E, Sabirli R, Altintas E. et al. Soluble P-selectin as a potential diagnostic and prognostic biomarker for COVID-19 disease: a case-control study. Life Sci 2021; 277: 119634
    CrossrefPubMedGoogle Scholar
  • 46 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
    CrossrefPubMedGoogle Scholar
  • 47 Suzuki-Inoue K, Tsukiji N, Shirai T, Osada M, Inoue O, Ozaki Y. Platelet CLEC-2: roles beyond hemostasis. Semin Thromb Hemost 2018; 44 (02) 126-134
    Article in Thieme ConnectPubMedGoogle Scholar
  • 48 Rayes J, Watson SP, Nieswandt B. Functional significance of the platelet immune receptors GPVI and CLEC-2. J Clin Invest 2019; 129 (01) 12-23
    CrossrefPubMedGoogle Scholar
  • 49 Suzuki-Inoue K, Osada M, Ozaki Y. Physiologic and pathophysiologic roles of interaction between C-type lectin-like receptor 2 and podoplanin: partners from in utero to adulthood. J Thromb Haemost 2017; 15 (02) 219-229
    CrossrefPubMedGoogle Scholar
  • 50 Suzuki-Inoue K, Fuller GL, García A. et al. A novel Syk-dependent mechanism of platelet activation by the C-type lectin receptor CLEC-2. Blood 2006; 107 (02) 542-549
    CrossrefPubMedGoogle Scholar
  • 51 Yamashita Y, Suzuki K, Mastumoto T. et al. Elevated plasma levels of soluble C-type lectin-like receptor 2 (CLEC2) in patients with thrombotic microangiopathy. Thromb Res 2019; 178: 54-58
    CrossrefPubMedGoogle Scholar
  • 52 Yamamoto A, Wada H, Ichkawa Y. et al. Soluble C-type lectin-like receptor 2 is a biomarker for disseminated intravascular coagulation. J Clin Med 2021; 10 (13) 2860
    CrossrefPubMedGoogle Scholar
  • 53 Inoue O, Osada M, Nakamura J. et al. Soluble CLEC-2 is generated independently of ADAM10 and is increased in plasma in acute coronary syndrome: comparison with soluble GPVI. Int J Hematol 2019; 110 (03) 285-294
    CrossrefPubMedGoogle Scholar
  • 54 Nishigaki A, Ichikawa Y, Ezaki M. et al. Soluble C-type lectin-like receptor 2 elevation in patients with acute cerebral infarction. J Clin Med 2021; 10 (15) 3408
    CrossrefPubMedGoogle Scholar
  • 55 Wada H, Ichikawa Y, Ezaki M. et al. Plasma soluble C-type lectin-like receptor 2 is associated with the risk of coronavirus disease 2019. J Clin Med 2022; 11 (04) 985
    CrossrefPubMedGoogle Scholar
  • 56 Sayed Ahmed HA, Merrell E, Ismail M. et al. Rationales and uncertainties for aspirin use in COVID-19: a narrative review. Fam Med Community Health 2021; 9 (02) e000741
    CrossrefPubMedGoogle Scholar
  • 57 Chow JH, Khanna AK, Kethireddy S. et al. Aspirin use is associated with decreased mechanical ventilation, intensive care unit admission, and in-hospital mortality in hospitalized patients with Coronavirus disease 2019. Anesth Analg 2021; 132 (04) 930-941
    CrossrefPubMedGoogle Scholar
  • 58 Salah HM, Mehta JL. Meta-analysis of the effect of aspirin on mortality in COVID-19. Am J Cardiol 2021; 142: 158-159
    CrossrefPubMedGoogle Scholar
  • 59 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
    CrossrefPubMedGoogle Scholar
  • 60 RECOVERY Collaborative Group. Aspirin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet 2022; 399 (10320): 143-151
    CrossrefPubMedGoogle Scholar
  • 61 Connors JM, Brooks MM, Sciurba FC. et al; ACTIV-4B Investigators. Effect of antithrombotic therapy on clinical outcomes in outpatients with clinically stable symptomatic COVID-19: the ACTIV-4B randomized clinical trial. JAMA 2021; 326 (17) 1703-1712
    CrossrefPubMedGoogle Scholar
  • 62 Osborne TF, Veigulis ZP, Arreola DM, Mahajan SM, Röösli E, Curtin CM. Association of mortality and aspirin prescription for COVID-19 patients at the Veterans Health Administration. PLoS One 2021; 16 (02) e0246825
    CrossrefPubMedGoogle Scholar
  • 63 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
    CrossrefPubMedGoogle Scholar
  • 64 Fröhlich GM, Jeschke E, Eichler U. et al. Impact of oral anticoagulation on clinical outcomes of COVID-19: a nationwide cohort study of hospitalized patients in Germany. Clin Res Cardiol 2021; 110 (07) 1041-1050
    CrossrefPubMedGoogle Scholar
  • 65 Ho G, Dusendang JR, Schmittdiel J, Kavecansky J, Tavakoli J, Pai A. Association of chronic anticoagulant and antiplatelet use on disease severity in SARS-COV-2 infected patients. J Thromb Thrombolysis 2021; 52 (02) 476-481
    CrossrefPubMedGoogle Scholar