Semin Thromb Hemost 2024; 50(04): 527-536
DOI: 10.1055/s-0043-1774795
Review Article

What Role Does Microthrombosis Play in Long COVID?

1   Department of Emergency and Disaster Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
,
2   Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
,
3   Department of Anesthesiology, Critical Care, and Surgery, Duke University School of Medicine, Durham, North Carolina
› Author Affiliations
Funding This work was supported in part by a Grant-in-Aid for Special Research in Subsidies for ordinary expenses of private schools from The Promotion and Mutual Aid Corporation for Private Schools of Japan.

Abstract

Soon after the outbreak of coronavirus disease 2019 (COVID-19), unexplained sustained fatigue, cognitive disturbance, and muscle ache/weakness were reported in patients who had recovered from acute COVID-19 infection. This abnormal condition has been recognized as “long COVID (postacute sequelae of COVID-19 [PASC])” with a prevalence estimated to be from 10 to 20% of convalescent patients. Although the pathophysiology of PASC has been studied, the exact mechanism remains obscure. Microclots in circulation can represent one of the possible causes of PASC. Although hypercoagulability and thrombosis are critical mechanisms of acute COVID-19, recent studies have reported that thromboinflammation continues in some patients, even after the virus has cleared. Viral spike proteins and RNA can be detected months after patients have recovered, findings that may be responsible for persistent thromboinflammation and the development of microclots. Despite this theory, long-term results of anticoagulation, antiplatelet therapy, and vascular endothelial protection are inconsistent, and could not always show beneficial treatment effects. In summary, PASC reflects a heterogeneous condition, and microclots cannot explain all the presenting symptoms. After clarification of the pathomechanisms of each symptom, a symptom- or biomarker-based stratified approach should be considered for future studies.

Authors' Contributions

All authors met authorship criteria and participated significantly in the study. T.I. wrote the draft. J.M.C. and J.H.L. reviewed and revised the manuscript. All authors read and approved the final manuscript.




Publication History

Article published online:
25 September 2023

© 2023. Thieme. All rights reserved.

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

 
  • References

  • 1 Davis HE, McCorkell L, Vogel JM, Topol EJ. Long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol 2023; 21 (06) 408
  • 2 Ballering AV, van Zon SKR, Olde Hartman TC, Rosmalen JGM. Lifelines Corona Research Initiative. Persistence of somatic symptoms after COVID-19 in the Netherlands: an observational cohort study. Lancet 2022; 400 (10350): 452-461
  • 3 Soriano JB, Murthy S, Marshall JC, Relan P, Diaz JV. WHO Clinical Case Definition Working Group on Post-COVID-19 Condition. A clinical case definition of post-COVID-19 condition by a Delphi consensus. Lancet Infect Dis 2022; 22 (04) e102-e107
  • 4 Nalbandian A, Sehgal K, Gupta A. et al. Post-acute COVID-19 syndrome. Nat Med 2021; 27 (04) 601-615
  • 5 Apple AC, Oddi A, Peluso MJ. et al. Risk factors and abnormal cerebrospinal fluid associate with cognitive symptoms after mild COVID-19. Ann Clin Transl Neurol 2022; 9 (02) 221-226
  • 6 Suran M. Long COVID linked with unemployment in new analysis. JAMA 2023; 329 (09) 701-702
  • 7 Hastie CE, Lowe DJ, McAuley A. et al. Outcomes among confirmed cases and a matched comparison group in the Long-COVID in Scotland study. Nat Commun 2022; 13 (01) 5663
  • 8 Roessler M, Tesch F, Batram M. et al. Post-COVID-19-associated morbidity in children, adolescents, and adults: a matched cohort study including more than 157,000 individuals with COVID-19 in Germany. PLoS Med 2022; 19 (11) e1004122
  • 9 Mehandru S, Merad M. Pathological sequelae of long-haul COVID. Nat Immunol 2022; 23 (02) 194-202
  • 10 Iwasaki A, Putrino D. Why we need a deeper understanding of the pathophysiology of long COVID. Lancet Infect Dis 2023; 23 (04) 393-395
  • 11 Pretorius E, Venter C, Laubscher GJ. et al. Combined triple treatment of fibrin amyloid microclots and platelet pathology in individuals with long COVID/ post-acute sequelae of COVID-19 (PASC) can resolve their persistent symptoms. Accessed August 14, 2023 at: https://doi.org/10.21203/rs.3.rs-1205453/v1
  • 12 Laubscher GJ, Khan MA, Venter C, Pretorius JH, Kell DB, Pretorius E. Treatment of long COVID symptoms with triple anticoagulant therapy. Accessed August 14, 2023 at: https://doi.org/10.21203/rs.3.rs-2697680/v1
  • 13 Schulman S, Sholzberg M, Spyropoulos AC. et al; International Society on Thrombosis and Haemostasis. ISTH guidelines for antithrombotic treatment in COVID-19. J Thromb Haemost 2022; 20 (10) 2214-2225
  • 14 Iba T, Levy JH, Connors JM, Warkentin TE, Thachil J, Levi M. The unique characteristics of COVID-19 coagulopathy. Crit Care 2020; 24 (01) 360
  • 15 Iba T, Wada H, Levy JH. Platelet activation and thrombosis in COVID-19. Semin Thromb Hemost 2023; 49 (01) 55-61
  • 16 Connors JM, Iba T, Gandhi RT. Thrombosis and coronavirus disease 2019: controversies and (tentative) conclusions. Clin Infect Dis 2021; 73 (12) 2294-2297
  • 17 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
  • 18 Levy JH, Iba T, Olson LB, Corey KM, Ghadimi K, Connors JM. COVID-19: thrombosis, thromboinflammation, and anticoagulation considerations. Int J Lab Hematol 2021; 43 (Suppl 1): 29-35
  • 19 Nyström S, Hammarström P. Amyloidogenesis of SARS-CoV-2 Spike Protein. J Am Chem Soc 2022; 144 (20) 8945-8950
  • 20 von Meijenfeldt FA, Havervall S, Adelmeijer J. et al. Sustained prothrombotic changes in COVID-19 patients 4 months after hospital discharge. Blood Adv 2021; 5 (03) 756-759
  • 21 Townsend L, Fogarty H, Dyer A. et al. Prolonged elevation of D-dimer levels in convalescent COVID-19 patients is independent of the acute phase response. J Thromb Haemost 2021; 19 (04) 1064-1070
  • 22 Bull-Otterson L, Baca S, Saydah S. et al. Post–COVID conditions among adult COVID-19 survivors aged 18–64 and ≥65 years—United States, March 2020–November 2021. MMWR Morb Mortal Wkly Rep 2022; 71: 713-717
  • 23 Xie Y, Xu E, Bowe B, Al-Aly Z. Long-term cardiovascular outcomes of COVID-19. Nat Med 2022; 28 (03) 583-590
  • 24 Fan BE, Wong SW, Sum CLL. et al; COVID-19 Clotting and Bleeding Investigators. Hypercoagulability, endotheliopathy, and inflammation approximating 1 year after recovery: assessing the long-term outcomes in COVID-19 patients. Am J Hematol 2022; 97 (07) 915-923
  • 25 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
  • 26 Giannis D, Allen SL, Tsang J. et al. Postdischarge thromboembolic outcomes and mortality of hospitalized patients with COVID-19: the CORE-19 registry. Blood 2021; 137 (20) 2838-2847
  • 27 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
  • 28 Vaughn VM, Yost M, Abshire C. et al. Trends in venous thromboembolism anticoagulation in patients hospitalized with COVID-19. JAMA Netw Open 2021; 4 (06) e2111788
  • 29 Kalaivani MK, Dinakar S. Association between D-dimer levels and post-acute sequelae of SARS-CoV-2 in patients from a tertiary care center. Biomarkers Med 2022; 16 (11) 833-838
  • 30 Pasini E, Corsetti G, Romano C. et al. Serum metabolic profile in patients with long-Covid (PASC) syndrome: clinical implications. Front Med (Lausanne) 2021; 8: 714426
  • 31 Bornstein SR, Voit-Bak K, Donate T. et al. Chronic post-COVID-19 syndrome and chronic fatigue syndrome: is there a role for extracorporeal apheresis?. Mol Psychiatry 2022; 27 (01) 34-37
  • 32 García-Abellán J, Padilla S, Fernández-González M. et al. Antibody response to SARS-CoV-2 is associated with long-term clinical outcome in patients with COVID-19: a longitudinal study. J Clin Immunol 2021; 41 (07) 1490-1501
  • 33 Bansal AS, Bradley AS, Bishop KN, Kiani-Alikhan S, Ford B. Chronic fatigue syndrome, the immune system and viral infection. Brain Behav Immun 2012; 26 (01) 24-31
  • 34 Maes M, Twisk FN, Kubera M, Ringel K. Evidence for inflammation and activation of cell-mediated immunity in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): increased interleukin-1, tumor necrosis factor-α, PMN-elastase, lysozyme and neopterin. J Affect Disord 2012; 136 (03) 933-939
  • 35 Glassford JA. The neuroinflammatory etiopathology of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Front Physiol 2017; 8: 88
  • 36 Masiá M, Fernández-González M, Telenti G. et al. Durable antibody response one year after hospitalization for COVID-19: a longitudinal cohort study. J Autoimmun 2021; 123: 102703
  • 37 Phetsouphanh C, Darley DR, Wilson DB. et al. Immunological dysfunction persists for 8 months following initial mild-to-moderate SARS-CoV-2 infection. Nat Immunol 2022; 23 (02) 210-216
  • 38 Wang C, Yu C, Jing H. et al. Long COVID: the nature of thrombotic sequelae determines the necessity of early anticoagulation. Front Cell Infect Microbiol 2022; 12: 861703
  • 39 Gentile LF, Cuenca AG, Efron PA. et al. Persistent inflammation and immunosuppression: a common syndrome and new horizon for surgical intensive care. J Trauma Acute Care Surg 2012; 72 (06) 1491-1501
  • 40 Muscedere J, Waters B, Varambally A. et al. The impact of frailty on intensive care unit outcomes: a systematic review and meta-analysis. Intensive Care Med 2017; 43 (08) 1105-1122
  • 41 Willems LH, Nagy M, Ten Cate H. et al. Sustained inflammation, coagulation activation and elevated endothelin-1 levels without macrovascular dysfunction at 3 months after COVID-19. Thromb Res 2022; 209: 106-114
  • 42 Tserel L, Jõgi P, Naaber P. et al. Long-term elevated inflammatory protein levels in asymptomatic SARS-CoV-2 infected individuals. Front Immunol 2021; 12: 709759
  • 43 Wang SSY, Chee K, Wong SW. et al; COVID-19 Clotting and Bleeding Investigators. Increased platelet activation demonstrated by elevated CD36 and P-selectin expression in 1-year post-recovered COVID-19 patients. Semin Thromb Hemost 2023; 49 (05) 561-564
  • 44 Martins-Gonçalves R, Campos MM, Palhinha L. et al. Persisting platelet activation and hyperactivity in COVID-19 survivors. Circ Res 2022; 131 (11) 944-947
  • 45 Hottz ED, Bozza PT. Platelet-leukocyte interactions in COVID-19: contributions to hypercoagulability, inflammation, and disease severity. Res Pract Thromb Haemost 2022; 6 (03) e12709
  • 46 Fogarty H, Townsend L, Morrin H. et al; Irish COVID-19 Vasculopathy Study (iCVS) investigators. Persistent endotheliopathy in the pathogenesis of long COVID syndrome. J Thromb Haemost 2021; 19 (10) 2546-2553
  • 47 Fogarty H, Ward SE, Townsend L. et al; Irish COVID-19 Vasculopathy Study (iCVS) Investigators. Sustained VWF-ADAMTS-13 axis imbalance and endotheliopathy in long COVID syndrome is related to immune dysfunction. J Thromb Haemost 2022; 20 (10) 2429-2438
  • 48 Conway EM, Mackman N, Warren RQ. et al. Understanding COVID-19-associated coagulopathy. Nat Rev Immunol 2022; 22 (10) 639-649
  • 49 Pretorius E, Vlok M, Venter C. et al. Persistent clotting protein pathology in long COVID/post-acute sequelae of COVID-19 (PASC) is accompanied by increased levels of antiplasmin. Cardiovasc Diabetol 2021; 20 (01) 172
  • 50 Kell DB, Laubscher GJ, Pretorius E. A central role for amyloid fibrin microclots in long COVID/PASC: origins and therapeutic implications. Biochem J 2022; 479 (04) 537-559
  • 51 Merlini M, Rafalski VA, Rios Coronado PE. et al. Fibrinogen induces microglia-mediated spine elimination and cognitive impairment in an Alzheimer's disease model. Neuron 2019; 101 (06) 1099-1108.e6
  • 52 Piazza F, Greenberg SM, Savoiardo M. et al. Anti-amyloid β autoantibodies in cerebral amyloid angiopathy-related inflammation: implications for amyloid-modifying therapies. Ann Neurol 2013; 73 (04) 449-458
  • 53 Kruger A, Vlok M, Turner S. et al. Proteomics of fibrin amyloid microclots in long COVID/post-acute sequelae of COVID-19 (PASC) shows many entrapped pro-inflammatory molecules that may also contribute to a failed fibrinolytic system. Cardiovasc Diabetol 2022; 21 (01) 190
  • 54 Willyard C. Could tiny blood clots cause long COVID's puzzling symptoms?. Nature 2022; 608 (7924) 662-664
  • 55 Tiny blood clots may be to blame for long COVID symptoms, some researchers say. Accessed August 14, 2023 at: https://time.com/6238147/microclots-long-covid/
  • 56 Constantinescu-Bercu A, Kessler A, de Groot R. et al. Analysis of thrombogenicity under flow reveals new insights into the prothrombotic state of patients with post-COVID syndrome. J Thromb Haemost 2023; 21 (01) 94-100
  • 57 Parotto M, Gyöngyösi M, Howe K. et al. Post-acute sequelae of COVID-19: understanding and addressing the burden of multisystem manifestations. Lancet Respir Med 2023; 11 (08) 739-754
  • 58 Moreno-Pérez O, Merino E, Leon-Ramirez J-M. et al; COVID19-ALC research group. Post-acute COVID-19 syndrome. Incidence and risk factors: a Mediterranean cohort study. J Infect 2021; 82 (03) 378-383
  • 59 Kamal M, Abo Omirah M, Hussein A, Saeed H. Assessment and characterisation of post-COVID-19 manifestations. Int J Clin Pract 2021; 75 (03) e13746
  • 60 Sudre CH, Murray B, Varsavsky T. et al. Attributes and predictors of long COVID. Nat Med 2021; 27 (04) 626-631
  • 61 Rosa RG, Cavalcanti AB, Azevedo LCP. et al. Association between acute disease severity and one-year quality of life among post-hospitalisation COVID-19 patients: coalition VII prospective cohort study. Intensive Care Med 2023; 49 (02) 166-177
  • 62 Blanco JR, Cobos-Ceballos MJ, Navarro F. et al. Pulmonary long-term consequences of COVID-19 infections after hospital discharge. Clin Microbiol Infect 2021; 27 (06) 892-896
  • 63 Douaud G, Lee S, Alfaro-Almagro F. et al. SARS-CoV-2 is associated with changes in brain structure in UK Biobank. Nature 2022; 604 (7907) 697-707
  • 64 Kremer S, Jäger HR. Brain changes after COVID-19 - how concerned should we be?. Nat Rev Neurol 2022; 18 (06) 321-322
  • 65 Yang AC, Kern F, Losada PM. et al. Publisher correction: dysregulation of brain and choroid plexus cell types in severe COVID-19. Nature 2021; 598 (7882) E4
  • 66 Etter MM, Martins TA, Kulsvehagen L. et al. Severe neuro-COVID is associated with peripheral immune signatures, autoimmunity and neurodegeneration: a prospective cross-sectional study. Nat Commun 2022; 13 (01) 6777
  • 67 Spudich S, Nath A. Nervous system consequences of COVID-19. Science 2022; 375 (6578) 267-269
  • 68 Elizalde-Díaz JP, Miranda-Narváez CL, Martínez-Lazcano JC, Martínez-Martínez E. The relationship between chronic immune response and neurodegenerative damage in long COVID-19. Front Immunol 2022; 13: 1039427
  • 69 Theoharides TC. Could SARS-CoV-2 spike protein be responsible for long-COVID syndrome?. Mol Neurobiol 2022; 59 (03) 1850-1861
  • 70 Barda N, Dagan N, Ben-Shlomo Y. et al. Safety of the BNT162b2 mRNA Covid-19 vaccine in a nationwide setting. N Engl J Med 2021; 385 (12) 1078-1090
  • 71 Joukar F, Yaghubi Kalurazi T, Khoshsorour M. et al. Persistence of SARS-CoV-2 RNA in the nasopharyngeal, blood, urine, and stool samples of patients with COVID-19: a hospital-based longitudinal study. Virol J 2021; 18 (01) 134
  • 72 Zollner A, Koch R, Jukic A. et al. Postacute COVID-19 is characterized by gut viral antigen persistence in inflammatory bowel diseases. Gastroenterology 2022; 163 (02) 495.e8-506.e8
  • 73 Goh D, Lim JCT, Fernaíndez SB. et al. Case report: persistence of residual antigen and RNA of the SARS-CoV-2 virus in tissues of two patients with long COVID. Front Immunol 2022; 13: 939989
  • 74 Patterson BK, Francisco EB, Yogendra R. et al. Persistence of SARS CoV-2 S1 protein in CD16+ monocytes in post-acute sequelae of COVID-19 (PASC) up to 15 months post-infection. Front Immunol 2022; 12: 746021
  • 75 Schultheiß C, Willscher E, Paschold L. et al. Liquid biomarkers of macrophage dysregulation and circulating spike protein illustrate the biological heterogeneity in patients with post-acute sequelae of COVID-19. J Med Virol 2023; 95 (01) e28364
  • 76 Son K, Jamil R, Chowdhury A. et al. Circulating anti-nuclear autoantibodies in COVID-19 survivors predict long COVID symptoms. Eur Respir J 2023; 61 (01) 2200970
  • 77 Apostolou E, Rizwan M, Moustardas P. et al. Saliva antibody-fingerprint of reactivated latent viruses after mild/asymptomatic COVID-19 is unique in patients with myalgic-encephalomyelitis/chronic fatigue syndrome. Front Immunol 2022; 13: 949787
  • 78 Finlay JB, Brann DH, Abi Hachem R. et al. Persistent post-COVID-19 smell loss is associated with immune cell infiltration and altered gene expression in olfactory epithelium. Sci Transl Med 2022; 14 (676) eadd0484
  • 79 Dennis A, Cuthbertson DJ, Wootton D. et al. Multi-organ impairment and long COVID: a 1-year prospective, longitudinal cohort study. J R Soc Med 2023; 116 (03) 97-112
  • 80 Dennis A, Wamil M, Alberts J. et al; COVERSCAN study investigators. Multiorgan impairment in low-risk individuals with post-COVID-19 syndrome: a prospective, community-based study. BMJ Open 2021; 11 (03) e048391
  • 81 Castanares-Zapatero D, Chalon P, Kohn L. et al. Pathophysiology and mechanism of long COVID: a comprehensive review. Ann Med 2022; 54 (01) 1473-1487
  • 82 Antonelli M, Penfold RS, Merino J. et al. Risk factors and disease profile of post-vaccination SARS-CoV-2 infection in UK users of the COVID Symptom Study app: a prospective, community-based, nested, case-control study. Lancet Infect Dis 2022; 22 (01) 43-55
  • 83 Ayoubkhani D, Bermingham C, Pouwels KB. et al. Trajectory of long covid symptoms after covid-19 vaccination: community based cohort study. BMJ 2022; 377: e069676
  • 84 Azzolini E, Levi R, Sarti R. et al. Association between BNT162b2 vaccination and long COVID after infections not requiring hospitalization in health care workers. JAMA 2022; 328 (07) 676-678
  • 85 Al-Aly Z, Bowe B, Xie Y. Long COVID after breakthrough SARS-CoV-2 infection. Nat Med 2022; 28 (07) 1461-1467
  • 86 Couzin-Frankel J, Vogel G. Vaccines may cause rare, Long Covid-like symptoms. Science 2022; 375 (6579) 364-366
  • 87 Xie Y, Choi T, Al-Aly Z. Association of treatment with nirmatrelvir and the risk of post-COVID-19 condition. JAMA Intern Med 2023; 183 (06) 554-564
  • 88 Mandal S, Barnett J, Brill SE. et al; ARC Study Group. ‘Long-COVID’: a cross-sectional study of persisting symptoms, biomarker and imaging abnormalities following hospitalisation for COVID-19. Thorax 2021; 76 (04) 396-398
  • 89 Cuker A, Tseng EK, Nieuwlaat R. et al. American Society of Hematology living guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19: July 2021 update on postdischarge thromboprophylaxis. Blood Adv 2022; 6 (02) 664-671
  • 90 Knight R, Walker V, Ip S. et al; CVD-COVID-UK/COVID-IMPACT Consortium and the Longitudinal Health and Wellbeing COVID-19 National Core Study. Association of COVID-19 with major arterial and venous thrombotic diseases: a population-wide cohort study of 48 million adults in England and Wales. Circulation 2022; 146 (12) 892-906
  • 91 Piazza G, Spyropoulos AC, Hsia J. et al; PREVENT-HD Investigators. Rivaroxaban for prevention of thrombotic events, hospitalization, and death in outpatients with COVID-19: a randomized clinical trial. Circulation 2023; 147 (25) 1891-1901
  • 92 Helms J, Iba T, Connors JM. et al. How to manage coagulopathies in critically ill patients. Intensive Care Med 2023; 49 (03) 273-290
  • 93 Castro P, Palomo M, Moreno-Castaño AB. et al. Is the endothelium the missing link in the pathophysiology and treatment of COVID-19 complications?. Cardiovasc Drugs Ther 2022; 36 (03) 547-560
  • 94 Pretorius E, Venter C, Laubscher GJ. et al. Prevalence of symptoms, comorbidities, fibrin amyloid microclots and platelet pathology in individuals with Long COVID/Post-Acute Sequelae of COVID-19 (PASC). Cardiovasc Diabetol 2022; 21 (01) 148
  • 95 Long COVID. Could antiplatelet therapy help?. Accessed August 14, 2023 at: https://www.medicalnewstoday.com/articles/long-covid-could-antiplatelet-therapy-help
  • 96 Plasma exchange therapy for Post- COVID-19 condition. A pilot, randomized double-blind study. Accessed August 14, 2023 at: https://classic.clinicaltrials.gov/ct2/show/NCT05445674
  • 97 Jaeger BR, Arron HE, Kalka-Moll WM, Seidel D. The potential of heparin-induced extracorporeal LDL/fibrinogen precipitation (H.E.L.P.)-apheresis for patients with severe acute or chronic COVID-19. Front Cardiovasc Med 2022; 9: 1007636