Download PDF
Semin Thromb Hemost 2023; 49(01): 027-033
DOI: 10.1055/s-0041-1742091
Review Article

What We Know (and Do not Know) Regarding the Pathogenesis of Pulmonary Thrombosis in COVID-19

Giuseppe Lippi
1   Section of Clinical Biochemistry, University of Verona, Verona, Italy
,
Emmanuel J. Favaloro
2   Department of Haematology, Institute of Clinical Pathology and Medical Research (ICPMR), NSW Health Pathology, Westmead Hospital, Westmead, NSW, Australia
3   Sydney Centres for Thrombosis and Haemostasis, Westmead, NSW, Australia
4   Faculty of Science and Health, Charles Sturt University, Wagga Wagga, NSW, Australia
› Author Affiliations
› Further Information
   Permissions and Reprints

Abstract

The clinical course of coronavirus disease 2019 (COVID-19) is often complicated by the onset of venous thrombosis and thromboembolism (VTE), encompassing also pulmonary thrombosis. Recent statistics attests that the cumulative frequency of VTE can be as high as 30% in COVID-19 hospitalized patients, increasing to nearly 40 to 70% (depending on systematic screening) in those with severe illness, mechanical ventilation, or intensive care unit admission. The risk of venous thrombosis seems mostly limited to the active phase of disease, and is directly associated with some genetic (i.e., inherited prothrombotic predisposition) and demographical factors (male sex, overweight/obesity), disease severity (risk increasing progressively from hospitalization to development of severe illness, being the highest in patients needing mechanical ventilation and/or intensive care), presence and extent of pulmonary disease, coexistence of multiple risk factors (immobilization, mechanical ventilation, co- or superinfections), along with increased values of inflammatory and thrombotic biomarkers. At least three different phenotypes of pulmonary thrombosis may develop in COVID-19 patients, one caused by typical embolization from peripheral venous thrombosis (e.g., deep vein thrombosis), a second type triggered by local inflammation of nearby pulmonary tissue, and a third one mostly attributable to the prothrombotic state consequent to the pronounced systemic inflammatory response (i.e., the so-called cytokine storm) that is frequently observed in COVID-19. Although the pathogenesis of these three conditions has different features, their discrimination is essential for diagnostic and therapeutic purposes. The prognosis of COVID-19 patients who develop pulmonary thrombosis is also considerably worse than those who do not, thus probably needing frequent monitoring and more aggressive therapeutic management.

Keywords

COVID-19 - SARS-CoV-2 - thrombosis - venous thromboembolism


Publication History

Article published online:
12 January 2022

© 2022. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Lippi G, Sanchis-Gomar F, Henry BM. Coronavirus disease 2019 (COVID-19): the portrait of a perfect storm. Ann Transl Med 2020; 8 (07) 497
    CrossrefPubMedGoogle Scholar
  • 2 John Hopkins University & Medicine. John Hopkins Coronavirus Resource Center. Accessed November 23, 2021 at: https://coronavirus.jhu.edu/map.html
    PubMedGoogle Scholar
  • 3 Liu Y, Rocklöv J. The reproductive number of the Delta variant of SARS-CoV-2 is far higher compared to the ancestral SARS-CoV-2 virus. J Travel Med 2021; 28 (07) 124
    CrossrefPubMedGoogle Scholar
  • 4 Qiu X, Nergiz AI, Maraolo AE, Bogoch II, Low N, Cevik M. The role of asymptomatic and pre-symptomatic infection in SARS-CoV-2 transmission-a living systematic review. Clin Microbiol Infect 2021; 27 (04) 511-519
    CrossrefPubMedGoogle Scholar
  • 5 Lippi G, Sanchis-Gomar F, Henry BM. COVID-19: unravelling the clinical progression of nature's virtually perfect biological weapon. Ann Transl Med 2020; 8 (11) 693
    CrossrefPubMedGoogle Scholar
  • 6 Lippi G, Plebani M. Cytokine “storm”, cytokine “breeze”, or both in COVID-19?. Clin Chem Lab Med 2020; 59 (04) 637-639
    CrossrefPubMedGoogle Scholar
  • 7 Jayarangaiah A, Kariyanna PT, Chen X, Jayarangaiah A, Kumar A. COVID-19-associated coagulopathy: an exacerbated immunothrombosis response. Clin Appl Thromb Hemost 2020; 26: 1076029620943293
    CrossrefPubMedGoogle Scholar
  • 8 Lippi G, Sanchis-Gomar F, Favaloro EJ, Lavie CJ, Henry BM. Coronavirus disease 2019-associated coagulopathy. Mayo Clin Proc 2021; 96 (01) 203-217
    CrossrefPubMedGoogle Scholar
  • 9 Favaloro EJ, Lippi G. Maintaining hemostasis and preventing thrombosis in coronavirus disease 2019 (COVID-19): part II. Semin Thromb Hemost 2021; 47 (04) 333-337
    Article in Thieme ConnectPubMedGoogle Scholar
  • 10 Poredos P, Poredos P. Involvement of inflammation in venous thromboembolic disease: an update in the age of COVID-19. Semin Thromb Hemost 2022; 48 (01) 93-99
    Article in Thieme ConnectPubMedGoogle Scholar
  • 11 Antoniak S. The coagulation system in host defense. Res Pract Thromb Haemost 2018; 2 (03) 549-557
    CrossrefPubMedGoogle Scholar
  • 12 Levi M, Thachil J. Coronavirus disease 2019 coagulopathy: disseminated intravascular coagulation and thrombotic microangiopathy-either, neither, or both. Semin Thromb Hemost 2020; 46 (07) 781-784
    Article in Thieme ConnectPubMedGoogle Scholar
  • 13 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
  • 14 Liu Y, Cai J, Wang C, Jin J, Qu L. A systematic review and meta-analysis of incidence, prognosis, and laboratory indicators of venous thromboembolism in hospitalized patients with coronavirus disease 2019. J Vasc Surg Venous Lymphat Disord 2021; 9 (05) 1099-1111.e6
    CrossrefPubMedGoogle Scholar
  • 15 Jenner WJ, Kanji R, Mirsadraee S. et al. Thrombotic complications in 2928 patients with COVID-19 treated in intensive care: a systematic review. J Thromb Thrombolysis 2021; 51 (03) 595-607
    CrossrefPubMedGoogle Scholar
  • 16 Ho FK, Man KKC, Toshner M. et al. Thromboembolic risk in hospitalized and nonhospitalized COVID-19 patients: a self-controlled case series analysis of a nationwide cohort. Mayo Clin Proc 2021; 96 (10) 2587-2597
    CrossrefPubMedGoogle Scholar
  • 17 Kollias A, Kyriakoulis KG, Lagou S, Kontopantelis E, Stergiou GS, Syrigos K. Venous thromboembolism in COVID-19: a systematic review and meta-analysis. Vasc Med 2021; 26 (04) 415-425
    CrossrefPubMedGoogle Scholar
  • 18 Miró Ò, Jiménez S, Mebazaa A. et al; Spanish Investigators on Emergency Situations TeAm (SIESTA) network. Pulmonary embolism in patients with COVID-19: incidence, risk factors, clinical characteristics, and outcome. Eur Heart J 2021; 42 (33) 3127-3142
    CrossrefPubMedGoogle Scholar
  • 19 Roubinian NH, Dusendang JR, Mark DG. et al. Incidence of 30-day venous thromboembolism in adults tested for SARS-CoV-2 infection in an integrated health care system in Northern California. JAMA Intern Med 2021; 181 (07) 997-1000
    CrossrefPubMedGoogle Scholar
  • 20 Stals M, Grootenboers M, van Guldener C. et al; Dutch COVID, Thrombosis Coalition (DCTC). Risk of thrombotic complications in influenza versus COVID-19 hospitalized patients. Res Pract Thromb Haemost 2021; 5 (03) 412-420
    CrossrefPubMedGoogle Scholar
  • 21 Engelen MM, Vandenbriele C, Balthazar T. et al. Venous thromboembolism in patients discharged after COVID-19 hospitalization. Semin Thromb Hemost 2021; 47 (04) 362-371
    Article in Thieme ConnectPubMedGoogle Scholar
  • 22 Ramos-Martínez A, Parra-Ramírez LM, Morrás I. et al. Frequency, risk factors, and outcomes of hospital readmissions of COVID-19 patients. Sci Rep 2021; 11 (01) 13733
    CrossrefPubMedGoogle Scholar
  • 23 Li P, Zhao W, Kaatz S, Latack K, Schultz L, Poisson L. Factors associated with risk of postdischarge thrombosis in patients with COVID-19. JAMA Netw Open 2021; 4 (11) e2135397
    CrossrefPubMedGoogle Scholar
  • 24 Whitworth H, Sartain SE, Kumar R. et al. Rate of thrombosis in children and adolescents hospitalized with COVID-19 or MIS-C. Blood 2021; 138 (02) 190-198
    CrossrefPubMedGoogle Scholar
  • 25 Carsana L, Sonzogni A, Nasr A. et al. Pulmonary post-mortem findings in a series of COVID-19 cases from northern Italy: a two-centre descriptive study. Lancet Infect Dis 2020; 20 (10) 1135-1140
    CrossrefPubMedGoogle Scholar
  • 26 Wichmann D, Sperhake JP, Lütgehetmann M. et al. Autopsy findings and venous thromboembolism in patients with COVID-19: a prospective cohort study. Ann Intern Med 2020; 173 (04) 268-277
    Google Scholar
  • 27 Bussani R, Schneider E, Zentilin L. et al. Persistence of viral RNA, pneumocyte syncytia and thrombosis are hallmarks of advanced COVID-19 pathology. EBioMedicine 2020; 61: 103104
    CrossrefPubMedGoogle Scholar
  • 28 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
    Google Scholar
  • 29 Anderson JJ, Ho FK, Niedzwiedz CL. et al. Remote history of VTE is associated with severe COVID-19 in middle and older age: UK Biobank cohort study. J Thromb Haemost 2021; 19 (10) 2533-2538
    CrossrefPubMedGoogle Scholar
  • 30 Pathak GA, Singh K, Miller-Fleming TW. et al. Integrative genomic analyses identify susceptibility genes underlying COVID-19 hospitalization. Nat Commun 2021; 12 (01) 4569
    CrossrefPubMedGoogle Scholar
  • 31 Gómez CA, Sun CK, Tsai IT. et al. Mortality and risk factors associated with pulmonary embolism in coronavirus disease 2019 patients: a systematic review and meta-analysis. Sci Rep 2021; 11 (01) 16025
    CrossrefPubMedGoogle Scholar
  • 32 Cui LY, Cheng WW, Mou ZW. et al. Risk factors for pulmonary embolism in patients with COVID-19: a systemic review and meta-analysis. Int J Infect Dis 2021; 111: 154-163
    CrossrefPubMedGoogle Scholar
  • 33 Elmokadem AH, Bayoumi D, El-Morsy A, Ehab A, Abo-Hedibah SA. Relationship of the pulmonary disease severity scoring with thromboembolic complications in COVID-19. Emerg Radiol 2022; 29 (01) 9-21
    CrossrefPubMedGoogle Scholar
  • 34 Morris MF, Pershad Y, Kang P. et al. Altered pulmonary blood volume distribution as a biomarker for predicting outcomes in COVID-19 disease. Eur Respir J 2021; 58 (03) 2004133
    CrossrefPubMedGoogle Scholar
  • 35 Lippi G, Franchini M. Pathogenesis of venous thromboembolism: when the cup runneth over. Semin Thromb Hemost 2008; 34 (08) 747-761
    Article in Thieme ConnectPubMedGoogle Scholar
  • 36 Cao Y, Geng C, Li Y, Zhang Y. In situ pulmonary artery thrombosis: a previously overlooked disease. Front Pharmacol 2021; 12: 671589
    CrossrefPubMedGoogle Scholar
  • 37 Thachil J, Srivastava A. SARS-2 coronavirus-associated hemostatic lung abnormality in COVID-19: is it pulmonary thrombosis or pulmonary embolism?. Semin Thromb Hemost 2020; 46 (07) 777-780
    Article in Thieme ConnectPubMedGoogle Scholar
  • 38 Thachil J, Lisman T. Pulmonary megakaryocytes in coronavirus disease 2019 (COVID-19): roles in thrombi and fibrosis. Semin Thromb Hemost 2020; 46 (07) 831-834
    Article in Thieme ConnectPubMedGoogle Scholar
  • 39 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
  • 40 Grillet F, Busse-Coté A, Calame P, Behr J, Delabrousse E, Aubry S. COVID-19 pneumonia: microvascular disease revealed on pulmonary dual-energy computed tomography angiography. Quant Imaging Med Surg 2020; 10 (09) 1852-1862
    CrossrefPubMedGoogle Scholar
  • 41 Wang L, Chen F, Bai L, Yi Q, Peng Y. In situ pulmonary thrombosis in patients with COVID-19 pneumonia: different phenotypes may exist. Thromb Res 2020; 196: 541-542
    CrossrefPubMedGoogle Scholar
  • 42 Satturwar S, Fowkes M, Farver C. et al. Postmortem findings associated with SARS-CoV-2: systematic review and meta-analysis. Am J Surg Pathol 2021; 45 (05) 587-603
    CrossrefPubMedGoogle Scholar
  • 43 Tsolaki V, Zakynthinos GE, Mantzarlis K. Right ventricular dilation: the additive effect of mechanical ventilation on pulmonary embolism in Covid-19 patients. Thromb Res 2020; 196: 25-26
    CrossrefPubMedGoogle Scholar
  • 44 Belletti A, Todaro G, Valsecchi G. et al. Barotrauma in coronavirus disease 2019 patients undergoing invasive mechanical ventilation: a systematic literature review. Crit Care Med 2022; 50 (03) 491-500
    PubMedGoogle Scholar
  • 45 Haitsma JJ, Schultz MJ, Hofstra JJ. et al. Ventilator-induced coagulopathy in experimental Streptococcus pneumoniae pneumonia. Eur Respir J 2008; 32 (06) 1599-1606
    CrossrefPubMedGoogle Scholar
  • 46 Rajdev K, Spanel AJ, McMillan S. et al. Pulmonary barotrauma in COVID-19 patients with ARDS on invasive and non-invasive positive pressure ventilation. J Intensive Care Med 2021; 36 (09) 1013-1017
    CrossrefPubMedGoogle Scholar
  • 47 de la Morena-Barrio ME, Bravo-Pérez C, de la Morena-Barrio B. et al. A pilot study on the impact of congenital thrombophilia in COVID-19. Eur J Clin Invest 2021; 51 (05) e13546
    CrossrefPubMedGoogle Scholar
  • 48 El Hasbani G, Taher AT. Should we screen Eastern Mediterranean COVID-19 patients for inherited thrombophilia?. Med Hypotheses 2021; 152: 110621
    CrossrefPubMedGoogle Scholar
  • 49 Lippi G, Szergyuk I, de Oliveira MHS. et al. The role of lipoprotein(a) in coronavirus disease 2019 (COVID-19) with relation to development of severe acute kidney injury. J Thromb Thrombolysis 2021;1–5
    PubMedGoogle Scholar
  • 50 Favaloro EJ, Henry BM, Lippi G. Is lupus anticoagulant a significant feature of COVID-19? A critical appraisal of the literature. Semin Thromb Hemost 2022; 48 (01) 55-71
    Article in Thieme ConnectPubMedGoogle Scholar
  • 51 Favaloro EJ, Henry BM, Lippi G. COVID-19 and antiphospholipid antibodies: time for a reality check?. Semin Thromb Hemost 2022; 48 (01) 72-92
    Article in Thieme ConnectPubMedGoogle Scholar
  • 52 Bikdeli B, Madhavan MV, Jimenez D. et al; Global COVID-19 Thrombosis Collaborative Group, Endorsed by the ISTH, NATF, ESVM, and the IUA, Supported by the ESC Working Group on Pulmonary Circulation and Right Ventricular Function. COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up: JACC State-of-the-Art Review. J Am Coll Cardiol 2020; 75 (23) 2950-2973
    CrossrefPubMedGoogle Scholar
  • 53 Flaczyk A, Rosovsky RP, Reed CT, Bankhead-Kendall BK, Bittner EA, Chang MG. Comparison of published guidelines for management of coagulopathy and thrombosis in critically ill patients with COVID 19: implications for clinical practice and future investigations. Crit Care 2020; 24 (01) 559
    CrossrefPubMedGoogle Scholar
  • 54 Narasimhan B, Lorente-Ros M, Aguilar-Gallardo JS. et al. Anticoagulation in COVID-19: a review of current literature and guidelines. Hosp Pract (1995) 2021; 49 (05) 307-324
    CrossrefPubMedGoogle Scholar