Evaluation of Covid-19-Associated Hypercoagulability with Functional Coagulation Assays and Extracellular Vesicles

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Luca Spiezia


Most patients affected by the novel coronavirus SARS-CoV-2 — responsible for the Coronavirus disease, COVID-19 — remain asymptomatic or develop mild symptoms. Only a small percentage of cases develop a severe disease that may lead to a fatal outcome. Since the early reports published in the literature by Wuhan colleagues, we have learned that patients hospitalized for acute COVID-19 infection have different clinical and laboratory pictures of coagulopathy. In particular, a marked increase in blood clotting capacity has been reported in most hospitalized patients – COVID-19-associated coagulopathy, CAC – which in turn increases the risk of developing thrombotic complications. The main pathophysiological mechanisms underlying this hypercoagulable state are inflammation, endothelial damage, hypofibrinolysis and hypoxemia. Traditional coagulation tests fail to fully characterize the nature and severity of COVID-19-associated hypercoagulability (CAH). Hence the need for functional coagulation assays (i.e. tromboelastometry/graphy, thrombin generation, platelet function test) and circulating extracellular vesicles to better understand these peculiar conditions. Moreover, it would be very helpful to use these tests to identify patients at increased risk of developing thrombotic complications or with a worse prognosis as well as to ascertain the effectiveness of the anticoagulant treatment. The aim of our narrative review was to describe the main pathophysiologic mechanisms of CAH and to summarize the current knowledge on functional coagulation assays and extracellular vesicles tests in CAH.

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SPIEZIA, Luca. Evaluation of Covid-19-Associated Hypercoagulability with Functional Coagulation Assays and Extracellular Vesicles. Medical Research Archives, [S.l.], v. 10, n. 5, june 2022. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/2810>. Date accessed: 25 june 2022. doi: https://doi.org/10.18103/mra.v10i5.2810.
Research Articles


1. Gandhi RT, Lynch JB, Del Rio C. Mild or Moderate Covid-19. N Engl J Med. 2020;383(18):1757- 1766. doi: 10.1056/NEJMcp2009249.
2. Berlin DA, Gulick RM, Martinez FJ. Severe Covid-19. N Engl J Med. 2020;383(25):2451-2460. doi: 10.1056/NEJMcp2009575.
3. Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020;181(2):271-280.e8. doi: 10.1016/j.cell.2020.02.052.
4. Iba T, Levy JH, Levi M, Thachil J. Coagulopathy in COVID-19. J Thromb Haemost. 2020;18(9):2103-2109. doi: 10.1111/jth.14975.
5. Teimury A, Khameneh MT, Khaledi EM. Major coagulation disorders and parameters in COVID-19 patients. Eur J Med Res. 2022;27(1):25. doi: 10.1186/s40001-022-00655-6.
6. Colling ME, Kanthi Y. COVID-19-associated coagulopathy: An exploration of mechanisms. Vasc Med. 2020;25(5):471-478. doi: 10.1177/1358863X20932640.
7. Levi M, Iba T. COVID-19 coagulopathy: is it disseminated intravascular coagulation? Intern Emerg Med. 2021;16(2):309-312. doi: 10.1007/s11739-020-02601-y.
8. Kunutsor SK, Laukkanen JA. Incidence of venous and arterial thromboembolic complications in COVID-19: A systematic review and meta-analysis. Thromb Res. 2020;196:27-30. doi: 10.1016/j.thromres.2020.08.022.
9. Tan BK, Mainbourg S, Friggeri A, et al. Arterial and venous thromboembolism in COVID-19: a study-level meta-analysis. Thorax. 2021;76:970-979. doi: 10.1136/thoraxjnl-2020-215383.
10. Lodigiani C, Iapichino G, Carenzo L, et al. Humanitas COVID-19 Task Force. Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy. Thromb Res. 2020;191:9-14. doi: 10.1016/j.thromres.2020.04.024.
11. Llitjos JF, Leclerc M, Chochois C, et al. High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients. J Thromb Haemost. 2020;18:1743-1746. doi: 10.1111/jth.14869.
12. Middeldorp S, Coppens M, van Haaps TF, yet al. Incidence of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost. 2020;18:1995-2002. doi: 10.1111/jth.14888.
13. Avruscio G, Camporese G, Campello E, et al. COVID-VTE Study Group. COVID-19 and Venous Thromboembolism in Intensive Care or Medical Ward. Clin Transl Sci. 2020;13:1108-1114. doi: 10.1111/cts.12907.
14. Angelini DE, Kaatz S, Rosovsky RP, et al. COVID-19 and venous thromboembolism: A narrative review. Res Pract Thromb Haemost. 2022;6(2):e12666. doi: 10.1002/rth2.12666.
15. Flumignan RL, Civile VT, Tinôco JDS, et al. Anticoagulants for people hospitalised with COVID-19. Cochrane Database Syst Rev. 2022;3(3):CD013739. doi: 10.1002/14651858.CD013739.pub2.
16. Kaivola J, Nyman TA, Matikainen S. Inflammasomes and SARS-CoV-2 Infection. Viruses. 2021;13(12):2513. doi: 10.3390/v13122513.
17. Gao YM, Xu G, Wang B, Liu BC. Cytokine storm syndrome in coronavirus disease 2019: A narrative review. J Intern Med. 2021;289(2):147-161. doi: 10.1111/joim.13144.
18. Ekşioğlu-Demiralp E, Alan S, Sili U, et al. Peripheral innate and adaptive immune cells during COVID-19: Functional neutrophils, pro-inflammatory monocytes, and half-dead lymphocytes. Cytometry B Clin Cytom. 2022;102(2):153-167. doi: 10.1002/cyto.b.22042.
19. Suri A, Singh NK, Perumal V. Association of inflammatory biomarker abnormalities with mortality in COVID-19: a meta-analysis. Bull Natl Res Cent. 2022;46(1):54. doi: 10.1186/s42269-022-00733-z.
20. Sinkovits G, Réti M, Müller V, et al. Associations between the von Willebrand Factor-ADAMTS13 Axis, Complement Activation, and COVID-19 Severity and Mortality. Thromb Haemost. 2022;122(2):240-256. doi: 10.1055/s-0041-1740182.
21. Bumiller-Bini V, de Freitas Oliveira-Toré C, Carvalho TM, et al. MASPs at the crossroad between the complement and the coagulation cascades - the case for COVID-19. Genet Mol Biol. 2021;44(1 Suppl 1):e20200199. doi: 10.1590/1678-4685-GMB-2020-0199.
22. Tomar B, Anders HJ, Desai J, Mulay SR. Neutrophils and Neutrophil Extracellular Traps Drive Necroinflammation in COVID-19. Cells. 2020;9(6):1383. doi: 10.3390/cells9061383.
23. Ma Z, Yang KY, Huang Y, Lui KO. Endothelial contribution to COVID-19: an update on mechanisms and therapeutic implications. J Mol Cell Cardiol. 2022;164:69-82. doi: 10.1016/j.yjmcc.2021.11.010.
24. Won T, Wood MK, Hughes DM, et al. Endothelial thrombomodulin downregulation caused by hypoxia contributes to severe infiltration and coagulopathy in COVID-19 patient lungs. EBioMedicine. 2022;75:103812. doi: 10.1016/j.ebiom.2022.103812.
25. Schmaier AA, Pajares Hurtado GM, Manickas-Hill ZJ, et al. Tie2 activation protects against prothrombotic endothelial dysfunction in COVID-19. JCI Insight. 2021;6(20):e151527. doi: 10.1172/jci.insight.151527.
26. Wadowski PP, Jilma B, Kopp CW, Ertl S, Gremmel T, Koppensteiner R. Glycocalyx as Possible Limiting Factor in COVID-19. Front Immunol. 2021;12:607306. doi: 10.3389/fimmu.2021.607306.
27. Bachler M, Bösch J, Stürzel DP, et al. Impaired fibrinolysis in critically ill COVID-19 patients. Br J Anaesth. 2021;126(3):590-598. doi: 10.1016/j.bja.2020.12.010.
28. Wright FL, Vogler TO, Moore EE, et al. Fibrinolysis shutdown correlation with thromboembolic events in severe COVID-19 infection. J Am Coll Surg. 2020;231:193-203. doi: 10.1016/j.jamcollsurg.2020.05.007.
29. Devreese KMJ. COVID-19-related laboratory coagulation findings. Int J Lab Hematol. 2021;43(Suppl 1):36-42. doi: 10.1111/ijlh.13547.
30. Nielsen ND, Rollins-Raval MA, Raval JS, Thachil J. Is it hyperfibrinolysis or fibrinolytic shutdown in severe COVID-19? Thromb Res. 2022;210:1-3. doi: 10.1016/j.thromres.2021.12.012.
31. Maier CL, Truong AD, Auld SC, Polly DM, Tanksley CL, Duncan A. COVID-19-associated hyperviscosity: a link between inflammation and thrombophilia? Lancet. 2020;395(10239):1758-1759. doi: 10.1016/S0140-6736(20)31209-5.
32. Nader E, Nougier C, Boisson C, et al. Increased blood viscosity and red blood cell aggregation in patients with COVID-19. Am J Hematol. 2022;97(3):283-292. doi: 10.1002/ajh.26440.
33. Taniguchi-Ponciano K, Vadillo E, Mayani H, et al. Increased expression of hypoxia-induced factor 1a mRNA and its related genes in myeloid blood cells from critically ill COVID-19 patients. Ann Med. 2021;53(1):197-207. doi: 10.1080/07853890.2020.1858234.
34. Carll T, Wool GD. Basic principles of viscoelastic testing. Transfusion. 2020;60(S6):S1-S9. doi: 10.1111/trf.16071.
35. Bareille M, Hardy M, Douxfils J, et al. Viscoelastometric Testing to Assess Hemostasis of COVID-19: A Systematic Review. J Clin Med. 2021;10(8):1740. doi: 10.3390/jcm10081740.
36. Hartmann J, Ergang A, Mason D, Dias JD. The Role of TEG Analysis in Patients with COVID-19-Associated Coagulopathy: A Systematic Review. Diagnostics (Basel). 2021;11(2):172. doi: 10.3390/diagnostics11020172.
37. Pavoni V, Gianesello L, Pazzi M, Dattolo P, Prisco D. Questions about COVID-19 associated coagulopathy: possible answers from the viscoelastic tests. J Clin Monit Comput. 2022;36(1):55-69. doi: 10.1007/s10877-021-00744-7.
38. Boss K, Kribben A, Tyczynski B. Pathological findings in rotation thromboelastometry associated with thromboembolic events in COVID-19 patients. Thromb J. 2021;19(1):10. doi: 10.1186/s12959-021-00263-0.
39. Panigada M, Bottino N, Tagliabue P, et al. Hypercoagulability of COVID-19 patients in intensive care unit: a report of thromboelastography findings and other parameters of hemostasis. J Thromb Haemost. 2020;18(7):1738–1742. doi: 10.1111/jth.14850.
40. Pavoni V, Gianesello L, Pazzi M, Horton A, Suardi LR. Derangement of the coagulation process using subclinical markers and viscoelastic measurements in critically ill patients with coronavirus disease 2019 pneumonia and non-coronavirus disease 2019 pneumonia. Blood Coagul Fibrinolysis. 2021;32(2):80–6. doi: 10.1097/MBC.0000000000000971.
41. Sadd C, Rowe T, Nazeef M, Kory P, Sultan S, Faust H. Thromboelastography to detect hypercoagulability and reduced fibrinolysis in coronavirus disease 2019 acute distress respiratory syndrome patients. Crit Care Explor. 2020;2(9):e0192. doi: 10.1097/CCE.0000000000000192.
42. Spiezia L, Boscolo A, Poletto F, et al. COVID-19-related severe hypercoagulability in patients admitted to intensive care unit for acute respiratory failure. Thromb Haemost. 2020;120(6):998-1000. doi: 10.1055/s-0040-1710018.
43. Boscolo A, Spiezia L, Correale C, et al. Different hypercoagulable profiles in patients with COVID-19 admitted to the internal medicine ward and the intensive care unit. Thromb Haemost. 2020;120(10):1474-1477. doi: 10.1055/s-0040-1714350.
44. Spiezia L, Campello E, Cola M, et al. More severe hypercoagulable state in acute COVID-19 pneumonia as compared with other pneumonia. Mayo Clin Proc Innov Qual Outcomes. 2020;4(6):696-702. doi: 10.1016/j.mayocpiqo.2020.09.002.
45. Poletto F, Spiezia L, Simion C, et al. Risk factors of venous thromboembolism in noncritically ill patients hospitalized for acute COVID-19 pneumonia receiving prophylactic-dose anticoagulation. Viruses. 2022;14:737 [In press].
46. Yuriditsky E, Horowitz JM, Merchan C, et al. Thromboelastography profiles of critically ill patients with coronavirus disease 2019. Crit Care Med. 2020;48(9):1319-1326. doi: 10.1097/CCM.0000000000004471.
47. Shah A, Donovan K, McHugh A, et al. Thrombotic and haemorrhagic complications in critically ill patients with COVID-19: a multicentre observational study. Crit Care. 2020;24(1):561. doi: 10.1186/s13054-020-03260-3.
48. van Veenendaal N, Scheeren TWL, Meijer K, van der Voort PHJ. Rotational thromboelastometry to assess hypercoagulability in COVID-19 patients. Thromb Res. 2020;196:379-381. doi: 10.1016/j.thromres.2020.08.046
49. Kruse JM, Magomedov A, Kurreck A, et al. Thromboembolic complications in critically ill COVID-19 patients are associated with impaired fibrinolysis. Crit Care. 2020;24(1):676. doi: 10.1186/s13054-020-03401-8.
50. Nougier C, Benoit R, Simon M, et al. Hypofibrinolytic state and high thrombin generation may play a major role in SARS-COV2 associated thrombosis. J Thromb Haemost. 2020;18(9):2215-2219. doi: 10.1111/jth.15016.
51. Castoldi E, Rosing J. Thrombin generation tests. Thromb Res. 2011;127 Suppl 3:S21-S25. doi: 10.1016/S0049-3848(11)70007-X.
52. Campello E, Bulato C, Spiezia L, et al. Thrombin generation in patients with COVID-19 with and without thromboprophylaxis. Clin Chem Lab Med. 2021;59(7):1323-1330. doi: 10.1515/cclm-2021-0108.
53. de la Morena-Barrio ME, Bravo-Pérez C, Miñano A, et al. Prognostic value of thrombin generation parameters in hospitalized COVID-19 patients. Sci Rep. 2021;11(1):7792. doi: 10.1038/s41598-021-85906-y.
54. Rohlfing AK, Rath D, Geisler T, Gawaz M. Platelets and COVID-19. Hamostaseologie. 2021;41(5):379-385. doi: 10.1055/a-1581-4355.
55. 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(1):50. doi: 10.1038/s41419-020-03333-9.
56. Barale C, Melchionda E, Morotti A, Russo I. Prothrombotic Phenotype in COVID-19: Focus on Platelets. Int J Mol Sci. 2021;22(24):13638. doi: 10.3390/ijms222413638.
57. 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(1):48-53. doi: 10.1080/09537104.2021.1961718.
58. 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(1):17-31. doi: 10.1111/jth.15566.
59. Balbi C, Burrello J, Bolis S, et al. Circulating extracellular vesicles are endowed with enhanced procoagulant activity in SARS-CoV-2 infection. EBioMedicine. 2021;67,103369. doi: 10.1016/j.ebiom.2021.103369.
60. Campello E, Radu CM, Simion C, et al. Longitudinal Trend of Plasma Concentrations of Extracellular Vesicles in Patients Hospitalized for COVID-19. Front Cell Dev Biol. 2022;9:770463. doi: 10.3389/fcell.2021.770463.
61. Cappellano G, Raineri D, Rolla R, et al. Circulating Platelet-Derived Extracellular Vesicles Are a Hallmark of Sars-Cov-2 Infection. Cells. 2021;10(1):85. doi: 10.3390/cells10010085.
62. Guervilly C, Bonifay A, Burtey S, et al. Dissemination of extreme levels of extracellular vesicles: tissue factor activity in patients with severe COVID-19. Blood Adv. 2021;5(3):628-634. doi: 10.1182/bloodadvances.2020003308.
63. Kudryavtsev I, Kalinina O, Bezrukikh V, Melnik O, Golovkin A. The Significance of Phenotyping and Quantification of Plasma Extracellular Vesicles Levels Using High-Sensitivity Flow Cytometry during COVID-19 Treatment. Viruses. 2021;13(5):767. doi: 10.3390/v13050767.
64. Traby L, Kollars M, Kussmann M, et al. Extracellular vesicles and citrullinated histone H3 in coronavirus disease 2019 patients. Thromb Haemost. 2022;122(1):113-122. doi: 10.1055/a-1522-4131.