Platelet activation and platelet-monocyte aggregate formation trigger tissue factor expression in patients with severe COVID-19
Eugenio D Hottz, Isaclaudia G Azevedo-Quintanilha, Lohanna Palhinha, Lívia Teixeira, Ester A Barreto, Camila R R Pão, Cassia Righy, Sérgio Franco, Thiago M L Souza, Pedro Kurtz, Fernando A Bozza, Patrícia T Bozza, Eugenio D Hottz, Isaclaudia G Azevedo-Quintanilha, Lohanna Palhinha, Lívia Teixeira, Ester A Barreto, Camila R R Pão, Cassia Righy, Sérgio Franco, Thiago M L Souza, Pedro Kurtz, Fernando A Bozza, Patrícia T Bozza
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an emergent pathogen responsible for the coronavirus disease 2019 (COVID-19). Since its emergence, the novel coronavirus has rapidly achieved pandemic proportions causing remarkably increased morbidity and mortality around the world. A hypercoagulability state has been reported as a major pathologic event in COVID-19, and thromboembolic complications listed among life-threatening complications of the disease. Platelets are chief effector cells of hemostasis and pathological thrombosis. However, the participation of platelets in the pathogenesis of COVID-19 remains elusive. This report demonstrates that increased platelet activation and platelet-monocyte aggregate formation are observed in severe COVID-19 patients, but not in patients presenting mild COVID-19 syndrome. In addition, exposure to plasma from severe COVID-19 patients increased the activation of control platelets ex vivo. In our cohort of COVID-19 patients admitted to the intensive care unit, platelet-monocyte interaction was strongly associated with tissue factor (TF) expression by the monocytes. Platelet activation and monocyte TF expression were associated with markers of coagulation exacerbation as fibrinogen and D-dimers, and were increased in patients requiring invasive mechanical ventilation or patients who evolved with in-hospital mortality. Finally, platelets from severe COVID-19 patients were able to induce TF expression ex vivo in monocytes from healthy volunteers, a phenomenon that was inhibited by platelet P-selectin neutralization or integrin αIIb/β3 blocking with the aggregation inhibitor abciximab. Altogether, these data shed light on new pathological mechanisms involving platelet activation and platelet-dependent monocyte TF expression, which were associated with COVID-19 severity and mortality.
© 2020 by The American Society of Hematology.
Figures
References
- Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579(7798):270–273.
- World Health Organization,. Coronavirus Disease (COVID-19) Situation Report-122. . Accessed 22 May 2020.
- Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020;18(4):844–847.
- 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.
- Middeldorp S, Coppens M, van Haaps TF, et al. Incidence of venous thromboembolism in hospitalized patients with COVID‐19. J Thromb Haemost. 2020;18(8):1995-2002.
- Giamarellos-Bourboulis EJ, Netea MG, Rovina N, et al. Complex immune dysregulation in COVID-19 patients with severe respiratory failure. Cell Host Microbe. 2020;27(6):992–1000.e3.
- 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.
- Yang X, Yang Q, Wang Y, et al. Thrombocytopenia and its association with mortality in patients with COVID‐19. J Thromb Haemost. 2020;18(6):1469–1472.
- Jiang S-Q, Huang Q-F, Xie W-M, Lv C, Quan X-Q. The association between severe COVID‐19 and low platelet count: evidence from 31 observational studies involving 7613 participants. Br J Haematol. 2020;190(1):e29–e33.
- Zhang L, Yan X, Fan Q, et al. D‐dimer levels on admission to predict in‐hospital mortality in patients with Covid‐19. J Thromb Haemost. 2020;18(6):1324–1329.
- 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.
- Stevens H, McFadyen JD. Platelets as central actors in thrombosis-reprising an old role and defining a new character. Semin Thromb Hemost. 2019;45(8):802–809.
- Koupenova M, Clancy L, Corkrey HA, Freedman JE. Circulating platelets as mediators of immunity, inflammation, and thrombosis. Circ Res. 2018;122(2):337–351.
- Middleton EA, Rondina MT, Schwertz H, Zimmerman GA. Amicus or adversary revisited: platelets in acute lung injury and acute respiratory distress syndrome. Am J Respir Cell Mol Biol. 2018;59(1):18–35.
- Kapur R, Zufferey A, Boilard E, Semple JW. Nouvelle cuisine: platelets served with inflammation. J Immunol. 2015;194(12):5579–5587.
- Semple JW, Italiano JE, Jr., Freedman J. Platelets and the immune continuum. Nat Rev Immunol. 2011;11(4):264–274.
- Popa M, Tahir S, Elrod J, et al. Role of CD40 and ADAMTS13 in von Willebrand factor-mediated endothelial cell-platelet-monocyte interaction. Proc Natl Acad Sci USA. 2018;115(24):E5556–E5565.
- Pan D, Amison RT, Riffo-Vasquez Y, et al. P-Rex and Vav Rac-GEFs in platelets control leukocyte recruitment to sites of inflammation. Blood. 2015;125(7):1146–1158.
- Weyrich AS, Elstad MR, McEver RP, et al. Activated platelets signal chemokine synthesis by human monocytes. J Clin Invest. 1996;97(6):1525–1534.
- Hottz ED, Medeiros-de-Moraes IM, Vieira-de-Abreu A, et al. Platelet activation and apoptosis modulate monocyte inflammatory responses in dengue. J Immunol. 2014;193(4):1864–1872.
- Clark SR, Ma AC, Tavener SA, et al. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat Med. 2007;13(4):463–469.
- Swystun LL, Liaw PC. The role of leukocytes in thrombosis. Blood. 2016;128(6):753–762.
- Celi A, Pellegrini G, Lorenzet R, et al. P-selectin induces the expression of tissue factor on monocytes. Proc Natl Acad Sci USA. 1994;91(19):8767–8771.
- Ivanov II, Apta BHR, Bonna AM, Harper MT. Platelet P-selectin triggers rapid surface exposure of tissue factor in monocytes. Sci Rep. 2019;9(1):13397.
- Lindmark E, Tenno T, Siegbahn A. Role of platelet P-selectin and CD40 ligand in the induction of monocytic tissue factor expression. Arterioscler Thromb Vasc Biol. 2000;20(10):2322–2328.
- Grover SP, Mackman N. Tissue factor: an essential mediator of hemostasis and trigger of thrombosis. Arterioscler Thromb Vasc Biol. 2018;38(4):709–725.
- Martinod K, Wagner DD. Thrombosis: tangled up in NETs. Blood. 2014;123(18):2768–2776.
- Franks ZG, Campbell RA, Weyrich AS, Rondina MT. Platelet-leukocyte interactions link inflammatory and thromboembolic events in ischemic stroke. Ann N Y Acad Sci. 2010;1207:11–17.
- Hottz ED, Bozza FA, Bozza PT. Platelets in immune response to virus and immunopathology of viral infections. Front Med (Lausanne) 2018;5:121.
- Sung PS, Huang TF, Hsieh SL. Extracellular vesicles from CLEC2-activated platelets enhance dengue virus-induced lethality via CLEC5A/TLR2. Nat Commun. 2019;10(1):2402.
- Hottz ED, Quirino-Teixeira AC, Valls-de-Souza R, Zimmerman GA, Bozza FA, Bozza PT. Platelet function in HIV plus dengue coinfection associates with reduced inflammation and milder dengue illness. Sci Rep. 2019;9(1):7096.
- Mesquita EC, Hottz ED, Amancio RT, et al. Persistent platelet activation and apoptosis in virologically suppressed HIV-infected individuals. Sci Rep. 2018;8(1):14999.
- Koupenova M, Corkrey HA, Vitseva O, et al. The role of platelets in mediating a response to human influenza infection. Nat Commun. 2019;10(1):1780.
- Hottz ED, Lopes JF, Freitas C, et al. Platelets mediate increased endothelium permeability in dengue through NLRP3-inflammasome activation. Blood. 2013;122(20):3405–3414.
- Quirino-Teixeira AC, Rozini SV, Barbosa-Lima G, et al. Inflammatory signaling in dengue-infected platelets requires translation and secretion of nonstructural protein 1. Blood Adv. 2020;4(9):2018–2031.
- Guo T, Fan Y, Chen M, et al. Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19) JAMA Cardiol. 2020;5(7):1–8.
- Wu C, Chen X, Cai Y, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med. 2020;180(7):1–11.
- Shi S, Qin M, Shen B, et al. Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China. JAMA Cardiol. 2020;5(7):802.
- Akhvlediani T, Ali SM, Angus DC, et al. ISARIC Clinical Characterisation Group Global outbreak research: harmony not hegemony. Lancet Infect Dis. 2020;20(7):770–772.
- Vabret N, Britton GJ, Gruber C, et al. Sinai Immunology Review Project Immunology of COVID-19: current state of the science. Immunity. 2020;52(6):910–941.
- Chen G, Wu D, Guo W, et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest. 2020;130(5):2620–2629.
- Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ, HLH Across Speciality Collaboration, UK COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395(10229):1033–1034.
- Jose RJ, Manuel A. COVID-19 cytokine storm: the interplay between inflammation and coagulation. Lancet Respir Med. 2020;8(6):e46–e47.
- Larsen E, Celi A, Gilbert GE, et al. PADGEM protein: a receptor that mediates the interaction of activated platelets with neutrophils and monocytes. Cell. 1989;59(2):305–312.
- Guo L, Rondina MT. The era of thromboinflammation: platelets are dynamic sensors and effector cells during infectious diseases. Front Immunol. 2019;10:2204.
- Durrant TN, van den Bosch MT, Hers I. Integrin αIIbβ3 outside-in signaling. Blood. 2017;130(14):1607–1619.
- Vardakas KZ, Matthaiou DK, Falagas ME. Incidence, characteristics and outcomes of patients with severe community acquired-MRSA pneumonia. Eur Respir J. 2009;34(5):1148–1158.
- Boussekey N, Leroy O, Georges H, Devos P, d'Escrivan T, Guery B. Diagnostic and prognostic values of admission procalcitonin levels in community-acquired pneumonia in an intensive care unit. Infection. 2005;33(4):257–263.
- Wong RSM, Wu A, To KF, et al. Haematological manifestations in patients with severe acute respiratory syndrome: retrospective analysis. BMJ. 2003;326(7403):1358–1362.
- Nguyen T, Kyle UG, Jaimon N, et al. Coinfection with Staphylococcus aureus increases risk of severe coagulopathy in critically ill children with influenza A (H1N1) virus infection. Crit Care Med. 2012;40(12):3246–3250.
- Ackermann M, Verleden SE, Kuehnel M, et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N Engl J Med. 2020;383(2):120–128.
- Dolhnikoff M, Duarte-Neto AN, de Almeida Monteiro RA, et al. Pathological evidence of pulmonary thrombotic phenomena in severe COVID-19. J Thromb Haemost. 2020;18(6):1517–1519.
- Connors JM, Levy JH. COVID-19 and its implications for thrombosis and anticoagulation. Blood. 2020;135(23):2033–2040.
- Schwertz H, Tolley ND, Foulks JM, et al. Signal-dependent splicing of tissue factor pre-mRNA modulates the thrombogenicity of human platelets. J Exp Med. 2006;203(11):2433–2440.
- Müller I, Klocke A, Alex M, et al. Intravascular tissue factor initiates coagulation via circulating microvesicles and platelets. FASEB J. 2003;17(3):476–478.
- Rondina MT, Schwertz H, Harris ES, et al. The septic milieu triggers expression of spliced tissue factor mRNA in human platelets. J Thromb Haemost. 2011;9(4):748–758.
- Franks Z, Campbell RA, Vieira de Abreu A, et al. Methicillin-resistant Staphylococcus aureus-induced thrombo-inflammatory response is reduced with timely antibiotic administration. Thromb Haemost. 2013;109(4):684–695.
- Mayne E, Funderburg NT, Sieg SF, et al. Increased platelet and microparticle activation in HIV infection: upregulation of P-selectin and tissue factor expression. J Acquir Immune Defic Syndr. 2012;59(4):340–346.
- Li H, Liu L, Zhang D, et al. SARS-CoV-2 and viral sepsis: observations and hypotheses. Lancet. 2020;395(10235):1517–1520.
- Schechter ME, Andrade BB, He T, et al. Inflammatory monocytes expressing tissue factor drive SIV and HIV coagulopathy. Sci Transl Med. 2017;9(405):eaam5441.
- Christersson C, Johnell M, Siegbahn A. Tissue factor and IL8 production by P-selectin-dependent platelet-monocyte aggregates in whole blood involves phosphorylation of Lyn and is inhibited by IL10. J Thromb Haemost. 2008;6(6):986–994.
- Christersson C, Johnell M, Siegbahn A. The influence of direct thrombin inhibitors on the formation of platelet-leukocyte aggregates and tissue factor expression. Thromb Res. 2010;126(4):e327–e333.
- Dann R, Hadi T, Montenont E, et al. Platelet-derived MRP-14 induces monocyte activation in patients with symptomatic peripheral artery disease. J Am Coll Cardiol. 2018;71(1):53–65.
- Campbell RA, Franks Z, Bhatnagar A, et al. Granzyme A in human platelets regulates the synthesis of proinflammatory cytokines by monocytes in aging. J Immunol. 2018;200(1):295–304.
Source: PubMed