Pharmacologic Thromboprophylaxis and Thrombosis in Hospitalized Patients with COVID-19: A Pooled AnalysisFunding The authors received no specific funding for this work.
Background Coronavirus disease 2019 (COVID-19) increases thrombosis in hospitalized patients prompting adoption of different thromboprophylaxis strategies. Safety and efficacy of escalated-dose pharmacologic thromboprophylaxis are not established.
Objectives To determine the pooled incidence of thrombosis/bleeding in hospitalized patients with COVID-19 for standard-dose, intermediate-dose, therapeutic anticoagulation, and no pharmacologic thromboprophylaxis.
Methods MEDLINE, EMBASE, and Cochrane CENTRAL were searched up to August 29, 2020 for studies reporting pharmacologic thromboprophylaxis and thrombosis or bleeding. Pooled event rates were calculated using a random-effects model.
Results Thirty-five observational studies were included. The pooled incidence rates of total venous thromboembolism (N = 4,685) were: no prophylaxis 41.9% (95% confidence interval [CI]: 28.1–57.2, I 2 = 76%), standard-dose prophylaxis 19.8% (95% CI: 13.2–28.6, I 2 = 95%), intermediate-dose prophylaxis 11.9% (95% CI: 4.3–28.6, I 2 = 91%), and therapeutic-dose anticoagulants 10.5% (95% CI: 4.2–23.8, I 2 = 82%, p = 0.003). The pooled incidence rates of arterial thrombosis (N = 1,464) were: no prophylaxis 11.3% (95% CI: 5.2–23.0, I 2 = 0%), standard-dose prophylaxis 2.5% (95% CI: 1.4–4.3, I 2 = 45%), intermediate-dose prophylaxis 2.1% (95% CI: 0.5–7.7, I 2 = 45%), and therapeutic-dose anticoagulants 1.3% (95% CI: 0.2–8.8, I 2 = 0, p = 0.009). The pooled bleeding event rates (N = 6,393) were nonsignificantly higher in therapeutic-dose anticoagulants compared with standard-dose prophylaxis, (6.3 vs. 1.7%, p = 0.083).
Conclusion Thrombosis rates were lower in hospitalized COVID-19 patients who received pharmacologic thromboprophylaxis. Thrombosis and bleeding rates for patients receiving intermediate-dose thromboprophylaxis or therapeutic anticoagulation were similar to those who received standard-dose pharmacologic thromboprophylaxis.
* These two authors contributed equally to this work.
Received: 22 September 2020
Accepted: 08 November 2020
30 December 2020 (online)
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- 1 Medicine JHUa, Coronavirus Resource Center. Accessed May 16, 2020 at: https://coronavirus.jhu.edu/map.html
- 2 Connors JM, Levy JH. COVID-19 and its implications for thrombosis and anticoagulation. Blood 2020; 135 (23) 2033-2040
- 3 Varga Z, Flammer AJ, Steiger P. et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet 2020; 395 (10234): 1417-1418
- 4 Iba T, Levy JH, Levi M, Thachil J. Coagulopathy in COVID-19. J Thromb Haemost 2020; DOI: 10.1111/jth.14975.
- 5 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
- 6 Violi F, Pastori D, Cangemi R, Pignatelli P, Loffredo L. Hypercoagulation and antithrombotic treatment in coronavirus 2019: a new challenge. Thromb Haemost 2020; 120 (06) 949-956
- 7 Klok FA, Kruip MJHA, van der Meer NJM. et al. Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis. Thromb Res 2020; 191: 148-150
- 8 Oxley TJ, Mocco J, Majidi S. et al. Large-vessel stroke as a presenting feature of Covid-19 in the young. N Engl J Med 2020; 382 (20) e60
- 9 Demelo-Rodríguez P, Cervilla-Muñoz E, Ordieres-Ortega L. et al. Incidence of asymptomatic deep vein thrombosis in patients with COVID-19 pneumonia and elevated D-dimer levels. Thromb Res 2020; 192: 23-26
- 10 Al-Samkari H, Karp Leaf RS, Dzik WH. et al. COVID and coagulation: bleeding and thrombotic manifestations of SARS-CoV2 infection. Blood 2020; 136 (04) 489-500
- 11 Zhang L, Feng X, Zhang D. et al. Deep vein thrombosis in hospitalized patients with coronavirus disease 2019 (COVID-19) in Wuhan, China: prevalence, risk factors, and outcome. Circulation 2020; 142 (02) 114-128
- 12 Vivas D, Roldan V, Esteve-Pastor MA. et al. Recommendations on antithrombotic treatment during the COVID-19 pandemic. Position statement of the Working Group on Cardiovascular Thrombosis of the Spanish Society of Cardiology [in Spanish]. Rev Esp Cardiol 2020; 73 (09) 749-757
- 13 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
- 14 American Society of Hematology. COVID-19 and VTE/anticoagulation: frequently asked questions. Accessed May 19, 2020 at: http://www.hematology.org/covid-19/covid-19-and-coagulopathy
- 15 Thachil J, Tang N, Gando S. et al. ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb Haemost 2020; 18 (05) 1023-1026
- 16 World Health Organization. Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected: interim guidance. Accessed October 14, 2020 at: https://www.who.int/docs/default-source/coronaviruse/clinical-management-of-novel-cov.pdf
- 17 Cattaneo M, Bertinato EM, Birocchi S. et al. Pulmonary embolism or pulmonary thrombosis in COVID-19? Is the recommendation to use high-dose heparin for thromboprophylaxis justified?. Thromb Haemost 2020; 120 (08) 1230-1232
- 18 Zhai Z, Li C, Chen Y. et al; Prevention Treatment of VTE Associated with COVID-19 Infection Consensus Statement Group. Prevention and treatment of venous thromboembolism associated with coronavirus disease 2019 infection: a consensus statement before guidelines. Thromb Haemost 2020; 120 (06) 937-948
- 19 Taskforce NC-CE. Australian guidelines for the clinical care of people with COVID-19. Accessed October 13, 2020 at: http://www.clinicalguidelines.gov.au/register/australian-guidelines-clinical-care-people-covid-19
- 20 Health NIo. COVID-19 Treatment Guidelines Panel. Coronavirus disease 2019 (COVID-19) treatment guidelines. Accessed October 13, 2020 at: http://www.covid19treatmentguidelines.nih.gov/
- 21 Kosior DA, Undas A, Kopeć G. et al. Guidance for anticoagulation management in venous thromboembolism during the coronavirus disease 2019 pandemic in Poland: an expert opinion of the Section on Pulmonary Circulation of the Polish Cardiac Society. Kardiol Pol 2020; 78 (06) 642-646
- 22 Llau JV, Ferrandis R, Sierra P. et al. SEDAR-SEMICYUC consensus recommendations on the management of haemostasis disorders in severely ill patients with COVID-19 infection. Rev Esp Anestesiol Reanim 2020; 67 (07) 391-399
- 23 Falavigna M, Colpani V, Stein C. et al. Guidelines for the pharmacological treatment of COVID-19. The task-force/consensus guideline of the Brazilian Association of Intensive Care Medicine, the Brazilian Society of Infectious Diseases and the Brazilian Society of Pulmonology and Tisiology. Rev Bras Ter Intensiva 2020; 32 (02) 166-196
- 24 Gerotziafas GT, Catalano M, Colgan MP. et al; Scientific Reviewer Committee. Guidance for the management of patients with vascular disease or cardiovascular risk factors and COVID-19: position paper from VAS-European Independent Foundation in Angiology/Vascular Medicine. Thromb Haemost 2020; DOI: 10.1055/s-0040-1715798.
- 25 American Society of Hematology. COVID-19 and coagulopathy: frequently asked questions. Accessed May 19, 2020 at: http://www.hematology.org/covid-19/covid-19-and-coagulopathy
- 26 Cohoon KP, Mahé G, Tafur AJ, Spyropoulos AC. Emergence of institutional antithrombotic protocols for coronavirus 2019. Res Pract Thromb Haemost 2020; 4 (04) 510-517
- 27 Patell R, Midha S, Kimani S. et al. Variability in institutional guidance for COVID-19-associated coagulopathy in the United States. Thromb Haemost 2020; DOI: 10.1055/s-0040-1715837.
- 28 Slim K, Nini E, Forestier D, Kwiatkowski F, Panis Y, Chipponi J. Methodological index for non-randomized studies (minors): development and validation of a new instrument. ANZ J Surg 2003; 73 (09) 712-716
- 29 Longchamp A, Longchamp J, Manzocchi-Besson S. et al. Venous thromboembolism in critically Ill patients with COVID-19: results of a screening study for deep vein thrombosis. Res Pract Thromb Haemost 2020; 4 (05) 842-847
- 30 Nahum J, Morichau-Beauchant T, Daviaud F. et al. Venous thrombosis among critically ill patients with coronavirus disease 2019 (COVID-19). JAMA Netw Open 2020; 3 (05) e2010478
- 31 Alonso-Fernández A, Toledo-Pons N, Cosío BG. et al. Prevalence of pulmonary embolism in patients with COVID-19 pneumonia and high D-dimer values: a prospective study. PLoS One 2020; 15 (08) e0238216
- 32 Al-Samkari H, Karp Leaf RS, Dzik WH. et al. COVID-19 and coagulation: bleeding and thrombotic manifestations of SARS-CoV-2 infection. Blood 2020; 136 (04) 489-500
- 33 Artifoni M, Danic G, Gautier G. et al. Systematic assessment of venous thromboembolism in COVID-19 patients receiving thromboprophylaxis: incidence and role of D-dimer as predictive factors. J Thromb Thrombolysis 2020; 50 (01) 211-216
- 34 Bompard F, Monnier H, Saab I. et al. Pulmonary embolism in patients with COVID-19 pneumonia. Eur Respir J 2020; 56 (01) 2001365
- 35 Chen S, Zhang D, Zheng T, Yu Y, Jiang J. DVT incidence and risk factors in critically ill patients with COVID-19. J Thromb Thrombolysis 2020; DOI: 10.1007/s11239-020-02181-w.
- 36 Cho ES, McClelland PH, Cheng O. et al. Utility of D-dimer for diagnosis of deep vein thrombosis in coronavirus disease–19 infection. J Vasc Surg Venous Lymphat Disord 2020; DOI: 10.1016/j.jvsv.2020.07.009.
- 37 Criel M, Falter M, Jaeken J. et al. Venous thromboembolism in SARS-CoV-2 patients: only a problem in ventilated ICU patients, or is there more to it?. Eur Respir J 2020; 56 (01) 2001201
- 38 Cui S, Chen S, Li X, Liu S, Wang F. Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia. J Thromb Haemost 2020; 18 (06) 1421-1424
- 39 Fauvel C, Weizman O, Trimaille A. et al; Critical Covid-19 France Investigators. Pulmonary embolism in COVID-19 patients: a French multicentre cohort study. Eur Heart J 2020; 41 (32) 3058-3068
- 40 Grandmaison G, Andrey A, Périard D. et al. Systematic screening for venous thromboembolic events in COVID-19 pneumonia. TH Open 2020; 4 (02) e113-e115
- 41 Koleilat I, Galen B, Choinski K. et al. Clinical characteristics of acute lower extremity deep venous thrombosis diagnosed by duplex in patients hospitalized for coronavirus disease 2019. J Vasc Surg Venous Lymphat Disord 2020; DOI: 10.1016/j.jvsv.2020.06.012.
- 42 Llitjos J-F, Leclerc M, Chochois C. et al. High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients. J Thromb Haemost 2020; 18 (07) 1743-1746
- 43 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
- 44 Mei F, Fan J, Yuan J. et al. Comparison of venous thromboembolism risks between COVID-19 pneumonia and community-acquired pneumonia patients. Arterioscler Thromb Vasc Biol 2020; 40 (09) 2332-2337
- 45 Middeldorp S, Coppens M, van Haaps TF. et al. Incidence of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost 2020; 18 (08) 1995-2002
- 46 Moll M, Zon RL, Sylvester KW. et al. VTE in ICU patients with COVID-19. Chest 2020; 158 (05) P2130-P2135
- 47 Pesavento R, Ceccato D, Pasquetto G. et al. The hazard of (sub)therapeutic doses of anticoagulants in non-critically ill patients with Covid-19: the Padua province experience. J Thromb Haemost 2020; DOI: 10.1111/jth.15022.
- 48 Ren B, Yan F, Deng Z. et al. Extremely high incidence of lower extremity deep venous thrombosis in 48 patients with severe COVID-19 in Wuhan. Circulation 2020; 142 (02) 181-183
- 49 Santoliquido A, Porfidia A, Nesci A. et al; GEMELLI AGAINST COVID-19 Group. Incidence of deep vein thrombosis among non-ICU patients hospitalized for COVID-19 despite pharmacological thromboprophylaxis. J Thromb Haemost 2020; DOI: 10.1111/jth.14992.
- 50 Tavazzi G, Civardi L, Caneva L, Mongodi S, Mojoli F. Thrombotic events in SARS-CoV-2 patients: an urgent call for ultrasound screening. Intensive Care Med 2020; 46 (06) 1121-1123
- 51 Thomas W, Varley J, Johnston A. et al. Thrombotic complications of patients admitted to intensive care with COVID-19 at a teaching hospital in the United Kingdom. Thromb Res 2020; 191: 76-77
- 52 Aleva FE, van Mourik L, Broeders MEAC, Paling AJ, de Jager CPC. COVID-19 in critically ill patients in North Brabant, the Netherlands: patient characteristics and outcomes. J Crit Care 2020; 60: 111-115
- 53 Dugar S, Duggal A, Bassel A, Soliman M, Moghekar A. Spontaneous echo contrast in venous ultrasound of severe COVID-19 patients. Intensive Care Med 2020; 46 (08) 1637-1639
- 54 Hanif A, Khan S, Mantri N. et al. Thrombotic complications and anticoagulation in COVID-19 pneumonia: a New York City hospital experience. Ann Hematol 2020; 99 (10) 2323-2328
- 55 Le Jeune S, Suhl J, Benainous R. et al. High prevalence of early asymptomatic venous thromboembolism in anticoagulated COVID-19 patients hospitalized in general wards. J Thromb Thrombolysis 2020; DOI: 10.1007/s11239-020-02246-w.
- 56 Mattioli M, Benfaremo D, Mancini M. et al. Safety of intermediate dose of low molecular weight heparin in COVID-19 patients. J Thromb Thrombolysis 2020; DOI: 10.1007/s11239-020-02243-z.
- 57 Paolisso P, Bergamaschi L, D'Angelo EC. et al. Preliminary experience with low molecular weight heparin strategy in COVID-19 patients. Front Pharmacol 2020; 11 (101548923): 1124
- 58 Pizzolo F, Rigoni AM, De Marchi S. et al. Deep vein thrombosis in SARS-CoV-2 pneumonia-affected patients within standard care units: exploring a submerged portion of the iceberg. Thromb Res 2020; 194: 216-219
- 59 Nadkarni GN, Lala A, Bagiella E. et al. Anticoagulation, bleeding, mortality, and pathology in hospitalized patients with COVID-19. J Am Coll Cardiol 2020; 76 (16) 1815-1826
- 60 Flumignan RLG, Tinôco JDdS, Pascoal PIF. et al. Prophylactic anticoagulants for people hospitalised with COVID-19. Cochrane Database Syst Rev 2020; DOI: 10.1002/14651858.CD013739.
- 61 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
- 62 Rosovsky RP, Sanfilippo KM, Wang TF. et al. Anticoagulation practice patterns in COVID-19: a global survey. Res Pract Thromb Haemost 2020; 4 (06) 969-983
- 63 Cohen AT, Spiro TE, Spyropoulos AC. MAGELLAN Steering Committee. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med 2013; 368 (20) 1945-1946
- 64 Leizorovicz A, Cohen AT, Turpie AG, Olsson CG, Vaitkus PT, Goldhaber SZ. PREVENT Medical Thromboprophylaxis Study Group. Randomized, placebo-controlled trial of dalteparin for the prevention of venous thromboembolism in acutely ill medical patients. Circulation 2004; 110 (07) 874-879
- 65 Samama MM, Cohen AT, Darmon JY. et al; Prophylaxis in Medical Patients with Enoxaparin Study Group. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. N Engl J Med 1999; 341 (11) 793-800
- 66 Cook D, Crowther M, Meade M. et al. Deep venous thrombosis in medical-surgical critically ill patients: prevalence, incidence, and risk factors. Crit Care Med 2005; 33 (07) 1565-1571
- 67 Chi G, Lee JJ, Jamil A. et al. Venous thromboembolism among hospitalized patients with COVID-19 undergoing thromboprophylaxis: a systematic review and meta-analysis. J Clin Med 2020; 9 (08) E2489