1932

Abstract

Shortly after the emergence of coronavirus disease 2019 (COVID-19) in late 2019, clinicians rapidly recognized an apparent association between the disease and both arterial and venous thrombotic complications, which was confirmed in epidemiologic studies. Based on these data, hospitals empirically developed and implemented protocols with different strategies for anticoagulation of hospitalized COVID-19 patients. Subsequent randomized controlled trials (RCTs) clarified the role of anticoagulation in patients hospitalized with COVID-19 and recently discharged from the hospital. In this review, we discuss the epidemiology and pathophysiology of thrombosis in patients with COVID-19, observational comparative effectiveness analyses that provided hints of a benefit from anticoagulation, and finally the RCTs that established which patients with COVID-19 benefit from treatment-dose anticoagulation. These RCTs have demonstrated that hospitalized, noncritically ill patients with COVID-19 benefit from treatment-dose anticoagulation, but patients who are hospitalized and critically ill, discharged from the hospital, or not hospitalized do not benefit.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-med-042921-110257
2023-01-27
2024-06-23
Loading full text...

Full text loading...

/deliver/fulltext/med/74/1/annurev-med-042921-110257.html?itemId=/content/journals/10.1146/annurev-med-042921-110257&mimeType=html&fmt=ahah

Literature Cited

  1. 1.
    Cui S, Chen S, Li X et al. 2020. Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia. J. Thromb. Haemost. 18:1421–24
    [Google Scholar]
  2. 2.
    Piazza G, Campia U, Hurwitz S et al. 2020. Registry of arterial and venous thromboembolic complications in patients with COVID-19. J. Am. Coll. Cardiol. 76:2060–72
    [Google Scholar]
  3. 3.
    Bilaloglu S, Aphinyanaphongs Y, Jones S et al. 2020. Thrombosis in hospitalized patients with COVID-19 in a New York City health system. JAMA 324:799–801
    [Google Scholar]
  4. 4.
    Lodigiani C, Iapichino G, Carenzo L et al. 2020. Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy. Thromb. Res. 191:9–14
    [Google Scholar]
  5. 5.
    Middeldorp S, Coppens M, van Haaps TF et al. 2020. Incidence of venous thromboembolism in hospitalized patients with COVID-19. J. Thromb. Haemost. 18:1995–2002
    [Google Scholar]
  6. 6.
    Helms J, Tacquard C, Severac F et al. 2020. High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med 46:1089–98
    [Google Scholar]
  7. 7.
    Klok FA, Kruip MJHA, van der Meer NJM et al. 2020. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb. Res. 191:145–47
    [Google Scholar]
  8. 8.
    Poissy J, Goutay J, Caplan M et al. 2020. Pulmonary embolism in patients with COVID-19: awareness of an increased prevalence. Circulation 142:184–86
    [Google Scholar]
  9. 9.
    Al-Samkari H, Karp Leaf RS, Dzik WH et al. 2020. COVID-19 and coagulation: bleeding and thrombotic manifestations of SARS-CoV-2 infection. Blood 136:489–500
    [Google Scholar]
  10. 10.
    Fraissé M, Logre E, Pajot O et al. 2020. Thrombotic and hemorrhagic events in critically ill COVID-19 patients: a French monocenter retrospective study. Crit. Care 24:275
    [Google Scholar]
  11. 11.
    Bellosta R, Luzzani L, Natalini G et al. 2020. Acute limb ischemia in patients with COVID-19 pneumonia. J. Vasc. Surg. 72:1864–72
    [Google Scholar]
  12. 12.
    Perini P, Nabulsi B, Massoni CB et al. 2020. Acute limb ischaemia in two young, non-atherosclerotic patients with COVID-19. Lancet 395:1546
    [Google Scholar]
  13. 13.
    Oxley TJ, Mocco J, Majidi S et al. 2020. Large-vessel stroke as a presenting feature of Covid-19 in the young. N. Engl. J. Med. 382:e60
    [Google Scholar]
  14. 14.
    Al-Samkari H, Gupta S, Karp Leaf R et al. 2021. Thrombosis, bleeding, and the observational effect of early therapeutic anticoagulation on survival in critically ill patients with COVID-19. Ann. Intern. Med. 174:622–32
    [Google Scholar]
  15. 15.
    Ackermann M, Verleden SE, Kuehnel M et al. 2020. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N. Engl. J. Med. 383:120–28
    [Google Scholar]
  16. 16.
    Jhaveri KD, Meir LR, Flores Chang BS et al. 2020. Thrombotic microangiopathy in a patient with COVID-19. Kidney Int 98:509–12
    [Google Scholar]
  17. 17.
    Pellegrini D, Kawakami R, Guagliumi G et al. 2021. Microthrombi as a major cause of cardiac injury in COVID-19: a pathologic study. Circulation 143:1031–42
    [Google Scholar]
  18. 18.
    Kerr R, Stirling D, Ludlam CA. 2001. Interleukin 6 and haemostasis. Br. J. Haematol. 115:3–12
    [Google Scholar]
  19. 19.
    Varga Z, Flammer AJ, Steiger P et al. 2020. Endothelial cell infection and endotheliitis in COVID-19. Lancet 395:1417–18
    [Google Scholar]
  20. 20.
    Smilowitz NR, Subashchandran V, Yuriditsky E et al. 2021. Thrombosis in hospitalized patients with viral respiratory infections versus COVID-19. Am. Heart J. 231:93–95
    [Google Scholar]
  21. 21.
    Tufano A, Rendina D, Abate V et al. 2021. Venous thromboembolism in COVID-19 compared to non-COVID-19 cohorts: a systematic review with meta-analysis. J. Clin. Med. 10:4925
    [Google Scholar]
  22. 22.
    Rashidi F, Barco S, Kamangar F et al. 2021. Incidence of symptomatic venous thromboembolism following hospitalization for coronavirus disease 2019: prospective results from a multi-center study. Thromb. Res. 198:135–38
    [Google Scholar]
  23. 23.
    Roberts LN, Whyte MB, Georgiou L et al. 2020. Postdischarge venous thromboembolism following hospital admission with COVID-19. Blood 136:1347–50
    [Google Scholar]
  24. 24.
    Patell R, Bogue T, Koshy A et al. 2020. Postdischarge thrombosis and hemorrhage in patients with COVID-19. Blood 136:1342–46
    [Google Scholar]
  25. 25.
    Engelen MM, Vandenbriele C, Balthazar T et al. 2021. Venous thromboembolism in patients discharged after COVID-19 hospitalization. Semin. Thromb. Hemost. 47:362–71
    [Google Scholar]
  26. 26.
    Paranjpe I, Fuster V, Lala A et al. 2020. Association of treatment dose anticoagulation with in-hospital survival among hospitalized patients with COVID-19. J. Am. Coll. Cardiol. 76:122–24
    [Google Scholar]
  27. 27.
    Nadkarni GN, Lala A, Bagiella E et al. 2020. Anticoagulation, mortality, bleeding and pathology among patients hospitalized with COVID-19: a single health system study. J. Am. Coll. Cardiol. 76:1815–26
    [Google Scholar]
  28. 28.
    Kollias A, Kyriakoulis KG, Trontzas IP et al. 2021. High versus standard intensity of thromboprophylaxis in hospitalized patients with COVID-19: a systematic review and meta-analysis. J. Clin. Med. 10:5549
    [Google Scholar]
  29. 29.
    Fanaroff AC, Califf RM, Harrington RA et al. 2020. Randomized trials versus common sense and clinical observation: JACC review topic of the week. J. Am. Coll. Cardiol. 76:580–89
    [Google Scholar]
  30. 30.
    Lopes RD, Fanaroff AC. 2020. Anticoagulation in COVID-19: It is time for high-quality evidence. J. Am. Coll. Cardiol. 76:1827–29
    [Google Scholar]
  31. 31.
    Connors JM, Brooks MM, Sciurba FC et al. 2021. Effect of antithrombotic therapy on clinical outcomes in outpatients with clinically stable symptomatic COVID-19: the ACTIV-4b randomized clinical trial. JAMA 326:1703–12
    [Google Scholar]
  32. 32.
    Sadeghipour P, Talasaz AH, Rashidi F et al. 2021. Effect of intermediate-dose versus standard-dose prophylactic anticoagulation on thrombotic events, extracorporeal membrane oxygenation treatment, or mortality among patients with COVID-19 admitted to the intensive care unit: the INSPIRATION randomized clinical trial. JAMA 325:1620–30
    [Google Scholar]
  33. 33.
    Perepu US, Chambers I, Wahab A et al. 2021. Standard prophylactic versus intermediate dose enoxaparin in adults with severe COVID-19: a multi-center, open-label, randomized controlled trial. J. Thromb. Haemost. 19:2225–34
    [Google Scholar]
  34. 34.
    Toh CH, Hoots WK, SSC on Disseminated Intravascular Coagulation of the ISTH 2007. The scoring system of the Scientific and Standardisation Committee on Disseminated Intravascular Coagulation of the International Society on Thrombosis and Haemostasis: a 5-year overview. J. Thromb. Haemost. 5:604–6
    [Google Scholar]
  35. 35.
    REMAP-CAP Investig., ACTIV-4a Investig., ATTACC Investig 2021. Therapeutic anticoagulation with heparin in critically ill patients with Covid-19. N. Engl. J. Med. 385:777–89
    [Google Scholar]
  36. 36.
    Lawler PR, Goligher EC, Berger JS et al. 2021. Therapeutic anticoagulation with heparin in noncritically ill patients with Covid-19. N. Engl. J. Med. 385:790–802
    [Google Scholar]
  37. 37.
    Sholzberg M, Tang GH, Rahhal H et al. 2021. Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or intensive care unit admission in moderately ill patients with covid-19 admitted to hospital: RAPID randomised clinical trial. BMJ 375:n2400
    [Google Scholar]
  38. 38.
    Spyropoulos AC, Goldin M, Giannis D et al. 2021. Efficacy and safety of therapeutic-dose heparin versus standard prophylactic or intermediate-dose heparins for thromboprophylaxis in high-risk hospitalized patients with COVID-19: the HEP-COVID randomized clinical trial. JAMA Intern. Med. 181:1612–20
    [Google Scholar]
  39. 39.
    Lopes RD, de Barros e Silva PGM, Furtado RHM et al. 2021. Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19 and elevated D-dimer concentration (ACTION): an open-label, multicentre, randomised, controlled trial.. Lancet 397:2253–63
    [Google Scholar]
  40. 40.
    Marcos-Jubilar M, Carmona-Torre F, Vidal R et al. 2022. Therapeutic versus prophylactic bemiparin in hospitalized patients with nonsevere COVID-19 pneumonia (BEMICOP study): an open-label, multicenter, randomized, controlled trial. Thromb. Haemost. 122:295–99
    [Google Scholar]
  41. 41.
    Page C. 2013. Heparin and related drugs: beyond anticoagulant activity. Int. Sch. Res. Not. Pharmacol. 2013:e910743
    [Google Scholar]
  42. 42.
    Mousavi S, Moradi M, Khorshidahmad T, Motamedi M. 2015. Anti-inflammatory effects of heparin and its derivatives: a systematic review. Adv. Pharmacol. Sci. 2015:507151
    [Google Scholar]
  43. 43.
    Ludwig RJ. 2009. Therapeutic use of heparin beyond anticoagulation. Curr. Drug Discov. Technol. 6:281–89
    [Google Scholar]
  44. 44.
    Berger JS, Kornblith LZ, Gong MN et al. 2022. Effect of P2Y12 inhibitors on survival free of organ support among non-critically ill hospitalized patients with COVID-19: a randomized clinical trial. JAMA 327:227–36
    [Google Scholar]
  45. 45.
    RECOVERY Collab. Group 2022. Aspirin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet 399:143–51
    [Google Scholar]
  46. 46.
    Ramacciotti E, Agati LB, Calderaro D et al. 2022. Rivaroxaban versus no anticoagulation for post-discharge thromboprophylaxis after hospitalisation for COVID-19 (MICHELLE): an open-label, multicentre, randomised, controlled trial. Lancet 399:50–59
    [Google Scholar]
  47. 47.
    Spyropoulos AC, Anderson FA, FitzGerald G et al. 2011. Predictive and associative models to identify hospitalized medical patients at risk for VTE. Chest 140:706–14
    [Google Scholar]
  48. 48.
    NIH COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines Natl. Inst. Health. https://www.covid19treatmentguidelines.nih.gov/. Accessed July 29, 2022
    [Google Scholar]
  49. 49.
    Bai C, Chotirmall SH, Rello J et al. 2020. Updated guidance on the management of COVID-19: from an American Thoracic Society/European Respiratory Society coordinated International Task Force (29 July 2020). Eur. Respirat. Rev. 29:200287
    [Google Scholar]
  50. 50.
    Dentali F, Douketis JD, Gianni M et al. 2007. Meta-analysis: anticoagulant prophylaxis to prevent symptomatic venous thromboembolism in hospitalized medical patients. Ann. Intern. Med. 146:278–88
    [Google Scholar]
  51. 51.
    Alhazzani W, Lim W, Jaeschke RZ et al. 2013. Heparin thromboprophylaxis in medical-surgical critically ill patients: a systematic review and meta-analysis of randomized trials. Crit. Care Med. 41:2088–98
    [Google Scholar]
  52. 52.
    Schünemann HJ, Cushman M, Burnett AE et al. 2018. American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients. Blood Adv 2:3198–225
    [Google Scholar]
  53. 53.
    Zayed Y, Kheiri B, Barbarawi M et al. 2020. Extended duration of thromboprophylaxis for medically ill patients: a systematic review and meta-analysis of randomised controlled trials. Intern. Med. J. 50:192–99
    [Google Scholar]
/content/journals/10.1146/annurev-med-042921-110257
Loading
/content/journals/10.1146/annurev-med-042921-110257
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error