Venous Thromboembolism in COVID-19
The coronavirus disease 2019 (COVID-19) is our latest pandemic, preceded by the H1N1 swine flu in 2009, which lasted approximately 19 months. One of the special characteristics of COVID-19 is the propensity to cause venous thromboembolism (VTE). Thromboinflammation seems to play a prominent role in the pathogenesis. We will here review some mechanisms in the pathogenesis and discuss some hematological biomarkers, and also whether they serve as useful risk factors for VTE. The role of general risk assessment models for medically ill patients specifically in COVID-19 is appraised. The type of prophylaxis and particularly whether standard or augmented doses of chemoprophylaxis should be used is reviewed based on available evidence. We are also comparing recommendations from 10 different guidance or position/consensus statements. Treatment recommendations for patients with COVID-19 and pulmonary embolism are discussed with current general treatment guidelines as reference. Specifics for patients with COVID-19 are pointed out and the potential role of thrombolytic treatment is explored.
KeywordsCOVID-19 - D-dimer - risk assessment models - venous thromboembolism - prophylaxis - treatment
Received: 05 August 2020
Accepted: 04 September 2020
24 October 2020 (online)
© 2020. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).
Georg Thieme Verlag KG
Stuttgart · New York
- 1 Al-Ani F, Chehade S, Lazo-Langner A. Thrombosis risk associated with COVID-19 infection. A scoping review. Thromb Res 2020; 192: 152-160
- 2 Huang C, Wang Y, Li X. et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395 (10223): 497-506
- 3 Chen N, Zhou M, Dong X. et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020; 395 (10223): 507-513
- 4 Danzi GB, Loffi M, Galeazzi G, Gherbesi E. Acute pulmonary embolism and COVID-19 pneumonia: a random association?. Eur Heart J 2020; 41 (19) 1858
- 5 Minet C, Potton L, Bonadona A. et al. Venous thromboembolism in the ICU: main characteristics, diagnosis and thromboprophylaxis. Crit Care 2015; 19: 287
- 6 Malato A, Dentali F, Siragusa S. et al. The impact of deep vein thrombosis in critically ill patients: a meta-analysis of major clinical outcomes. Blood Transfus 2015; 13 (04) 559-568
- 7 Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. HLH Across Speciality Collaboration, UK. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 2020; 395 (10229): 1033-1034
- 8 Qin C, Zhou L, Hu Z. et al. Dysregulation of immune response in patients with COVID-19 in Wuhan, China. Clin Infect Dis 2020; 71 (15) 762-768
- 9 Abou-Ismail MY, Diamond A, Kapoor S, Arafah Y, Nayak L. The hypercoagulable state in COVID-19: Incidence, pathophysiology, and management. Thromb Res 2020; 194: 101-115
- 10 Levi M, van der Poll T, Büller HR. Bidirectional relation between inflammation and coagulation. Circulation 2004; 109 (22) 2698-2704
- 11 Ranucci M, Ballotta A, Di Dedda U. et al. The procoagulant pattern of patients with COVID-19 acute respiratory distress syndrome. J Thromb Haemost 2020; 18 (07) 1747-1751
- 12 Magro C, Mulvey JJ, Berlin D. et al. Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: A report of five cases. Transl Res 2020; 220: 1-13
- 13 Gao T, Hu M, Zhang X. et al. Highly pathogenic coronavirus N protein aggravates lung injury by MASP-2-mediated complement over-activation. MedRxiv 2020; DOI: 10.1101/2020.03.29.20041962.
- 14 Leisman DE, Deutschman CS, Legrand M. Facing COVID-19 in the ICU: vascular dysfunction, thrombosis, and dysregulated inflammation. Intensive Care Med 2020; 46 (06) 1105-1108
- 15 Zhang Y, Xiao M, Zhang S. et al. Coagulopathy and antiphospholipid antibodies in patients with Covid-19. N Engl J Med 2020; 382 (17) e38
- 16 Xu XW, Wu XX, Jiang XG. et al. Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series. BMJ 2020; 368: m606
- 17 Duan Q, Gong Z, Song H. et al. Symptomatic venous thromboembolism is a disease related to infection and immune dysfunction. Int J Med Sci 2012; 9 (06) 453-461
- 18 Miesbach W, Makris M. COVID-19: coagulopathy, risk of thrombosis, and the rationale for anticoagulation. Clin Appl Thromb Hemost 2020; 26: 1076029620938149
- 19 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
- 20 Frydman GH, Boyer EW, Nazarian RM, Van Cott EM, Piazza G. Coagulation status and venous thromboembolism risk in African Americans: a potential risk factor in COVID-19. Clin Appl Thromb Hemost 2020; 26: 1076029620943671
- 21 Chen H, Guo J, Wang C. et al. Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records. Lancet 2020; 395 (10226): 809-815
- 22 Poggiali E, Bastoni D, Ioannilli E, Vercelli A, Magnacavallo A. Deep vein thrombosis and pulmonary embolism: two complications of COVID-19 pneumonia?. Eur J Case Rep Intern Med 2020; 7 (05) 001646
- 23 Vaughan CJ, Cronin H, Ryan PM, Caplice NM. Obesity and COVID-19: a Virchow's triad for the 21st century. Thromb Haemost 2020; DOI: 10.1055/s-0040-1714216.
- 24 Helms J, Tacquard C, Severac F. et al. CRICS TRIGGERSEP Group (Clinical Research in Intensive Care and Sepsis Trial Group for Global Evaluation and Research in Sepsis). High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med 2020; 46 (06) 1089-1098
- 25 Terpos E, Ntanasis-Stathopoulos I, Elalamy I. et al. Hematological findings and complications of COVID-19. Am J Hematol 2020; 95 (07) 834-847
- 26 Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost 2020; 18 (04) 844-847
- 27 Zhang L, Feng X, Zhang D. et al. Deep vein thrombosis in hospitalized patients with COVID-19 in Wuhan, China: prevalence, risk factors, and outcome. Circulation 2020; 142 (02) 114-128
- 28 Zerwes S, Hernandez Cancino F, Liebetrau D. et al. Increased risk of deep vein thrombosis in intensive care unit patients with CoViD-19 infections?-Preliminary data [in German]. Chirurg 2020; 91 (07) 588-594
- 29 Koch V, Biener M, Müller-Hennessen M. et al. Diagnostic performance of D-dimer in predicting venous thromboembolism and acute aortic dissection. Eur Heart J Acute Cardiovasc Care 2020; DOI: 10.1177/2048872620907322.
- 30 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
- 31 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
- 32 Jin S, Jin Y, Xu B, Hong J, Yang X. Prevalence and impact of coagulation dysfunction in COVID-19 in China: a meta-analysis. Thromb Haemost 2020; DOI: 10.1055/s-0040-1714369.
- 33 Lagunas-Rangel FA. Neutrophil-to-lymphocyte ratio and lymphocyte-to-C-reactive protein ratio in patients with severe coronavirus disease 2019 (COVID-19): A meta-analysis. J Med Virol 2020; DOI: 10.1002/jmv.25819.
- 34 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
- 35 Guan WJ, Ni ZY, Hu Y. et al. China Medical Treatment Expert Group for Covid-19. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020; 382 (18) 1708-1720
- 36 Taylor Jr FB, Toh CH, Hoots WK, Wada H, Levi M. Scientific Subcommittee on Disseminated Intravascular Coagulation (DIC) of the International Society on Thrombosis and Haemostasis (ISTH). Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb Haemost 2001; 86 (05) 1327-1330
- 37 Wang D, Hu B, Hu C. et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020; 323 (11) 1061-1069
- 38 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
- 39 Chaudhary R, Kreutz RP, Bliden KP, Tantry US, Gurbel PA. Personalizing antithrombotic therapy in COVID-19: role of thromboelastography and thromboelastometry. Thromb Haemost 2020; DOI: 10.1055/s-0040-1714217.
- 40 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 (06) 998-1000
- 41 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; DOI: 10.1055/s-0040-1714350.
- 42 Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost 2020; 18 (05) 1094-1099
- 43 Klok FA, Kruip MJHA, van der Meer NJM. et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res 2020; 191: 145-147
- 44 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 (07) 1743-1746
- 45 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
- 46 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; DOI: 10.1055/s-0040-1715456.
- 47 Lax SF, Skok K, Zechner P. et al. Pulmonary arterial thrombosis in COVID-19 with fatal outcome: results from a prospective, single-center, clinicopathologic case series. Ann Intern Med 2020; 173 (05) 350-361
- 48 Wichmann D, Sperhake JP, Lütgehetmann M. et al. Autopsy findings and venous thromboembolism in patients with COVID-19. Ann Intern Med 2020; 173 (04) 268-277
- 49 Stals MAM, Grootenboers MJ, van Guldener C. et al. Higher incidence of thrombotic complications in hospitalized patients with SARS-COV-2 virus versus influenza virus infections [abstract]. Res Pract Thromb Haemost. 2020 4. (Suppl 1. Available at: https://abstracts.isth.org/abstract/higher-incidence-of-thrombotic-complications-in-hospitalized-patients-with-sars-cov-2-virus-versus-influenza-virus-infections/. Accessed September 22, 2020
- 50 Chopard P, Spirk D, Bounameaux H. Identifying acutely ill medical patients requiring thromboprophylaxis. J Thromb Haemost 2006; 4 (04) 915-916
- 51 Barbar S, Noventa F, Rossetto V. et al. A risk assessment model for the identification of hospitalized medical patients at risk for venous thromboembolism: the Padua Prediction Score. J Thromb Haemost 2010; 8 (11) 2450-2457
- 52 Gibson CM, Spyropoulos AC, Cohen AT. et al. The IMPROVEDD VTE risk score: incorporation of D-dimer into the IMPROVE score to improve venous thromboembolism risk stratification. TH Open 2017; 1 (01) e56-e65
- 53 Rosenberg D, Eichorn A, Alarcon M, McCullagh L, McGinn T, Spyropoulos AC. External validation of the risk assessment model of the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) for medical patients in a tertiary health system. J Am Heart Assoc 2014; 3 (06) e001152
- 54 Blondon M, Spirk D, Kucher N. et al. Comparative performance of clinical risk assessment models for hospital-acquired venous thromboembolism in medical patients. Thromb Haemost 2018; 118 (01) 82-89
- 55 Testa S, Prandoni P, Paoletti O. et al. Direct oral anticoagulant plasma levels' striking increase in severe COVID-19 respiratory syndrome patients treated with antiviral agents: the Cremona experience. J Thromb Haemost 2020; 18 (06) 1320-1323
- 56 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
- 57 Yin S, Huang M, Li D, Tang N. Difference of coagulation features between severe pneumonia induced by SARS-CoV2 and non-SARS-CoV2. J Thromb Thrombolysis 2020; DOI: 10.1007/s11239-020-02105-8.
- 58 Paranjpe I, Fuster V, Lala A. et al. Association of treatment dose anticoagulation with in-hospital survival among hospitalized patients with COVID-19. J Am Coll Cardiol 2020; 76 (01) 122-124
- 59 Tremblay D, van Gerwen M, Alsen M. et al. Impact of anticoagulation prior to COVID-19 infection: a propensity score-matched cohort study. Blood 2020; 136 (01) 144-147
- 60 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
- 61 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.
- 62 Al-Samkari H, Gupta S, Karp Leaf R. et al. Thrombosis, bleeding, and the effect of anticoagulation on survival in critically ill patients with COVID-19 in the United States [abstract]. Res Pract Thromb Haemost. 2020 4. (Suppl 1. Available at: https://abstracts.isth.org/abstract/thrombosis-bleeding-and-the-effect-of-anticoagulation-on-survival-in-critically-ill-patients-with-covid-19-in-the-united-states/. Accessed September 22, 2020
- 63 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
- 64 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
- 65 Spyropoulos AC, Levy JH, Ageno W. et al. Subcommittee on Perioperative, Critical Care Thrombosis, Haemostasis of the Scientific, Standardization Committee of the International Society on Thrombosis and Haemostasis. Scientific and Standardization Committee communication: clinical guidance on the diagnosis, prevention, and treatment of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost 2020; 18 (08) 1859-1865
- 66 Khider L, Soudet S, Laneelle D. et al. French Society of Vascular Medicine (SFMV). Proposal of the French Society of Vascular Medicine for the prevention, diagnosis and treatment of venous thromboembolic disease in outpatients with COVID-19. J Med Vasc 2020; 45 (04) 210-213
- 67 Marietta M, Ageno W, Artoni A. et al. COVID-19 and haemostasis: a position paper from Italian Society on Thrombosis and Haemostasis (SISET). Blood Transfus 2020; 18 (03) 167-169
- 68 American Society of Hematology. COVID-19 and VTE/anticoagulation: frequently asked questions. 2020 [cited 2020 July 26]. Available at: https://www.hematology.org/covid-19/covid-19-and-vte-anticoagulation . Accessed September 22, 2020
- 69 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
- 70 Barnes GD, Burnett A, Allen A. et al. Thromboembolism and anticoagulant therapy during the COVID-19 pandemic: interim clinical guidance from the anticoagulation forum. J Thromb Thrombolysis 2020; 50 (01) 72-81
- 71 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. Rev Esp Cardiol 2020; 73 (09) 749-757
- 72 Casini A, Alberio L, Angelillo-Scherrer A. et al. Thromboprophylaxis and laboratory monitoring for in-hospital patients with COVID-19 - a Swiss consensus statement by the Working Party Hemostasis. Swiss Med Wkly 2020; 150: w20247
- 73 Roberts LN, Whyte MB, Georgiou L. et al. Postdischarge venous thromboembolism following hospital admission with COVID-19. Blood 2020; 136 (11) 1347-1350
- 74 Konstantinides SV, Meyer G, Becattini C. et al. ESC Scientific Document Group. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J 2020; 41 (04) 543-603
- 75 Mazzolai L, Aboyans V, Ageno W. et al. Diagnosis and management of acute deep vein thrombosis: a joint consensus document from the European Society of Cardiology working groups of aorta and peripheral vascular diseases and pulmonary circulation and right ventricular function. Eur Heart J 2018; 39 (47) 4208-4218
- 76 Kearon C, Akl EA, Ornelas J. et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest 2016; 149 (02) 315-352
- 77 Kirchhof P, Benussi S, Kotecha D. et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Europace 2016; 18 (11) 1609-1678
- 78 Steffel J, Verhamme P, Potpara TS. et al. ESC Scientific Document Group. The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J 2018; 39 (16) 1330-1393
- 79 Poissy J, Goutay J, Caplan M. et al. Lille ICU Haemostasis COVID-19 Group. Pulmonary embolism in patients with COVID-19: awareness of an increased prevalence. Circulation 2020; 142 (02) 184-186
- 80 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
- 81 Connors JM, Levy JH. COVID-19 and its implications for thrombosis and anticoagulation. Blood 2020; 135 (23) 2033-2040
- 82 Bikdeli B, Madhavan MV, Gupta A. et al. Global COVID-19 Thrombosis Collaborative Group. Pharmacological agents targeting thromboinflammation in COVID-19: review and implications for future research. Thromb Haemost 2020; 120 (07) 1004-1024
- 83 Xiao M, Zhang Y, Zhang S. et al. Brief report: anti-phospholipid antibodies in critically ill patients with coronavirus disease 2019 (COVID-19). Arthritis Rheumatol 2020; DOI: 10.1002/art.41425.
- 84 Pineton de Chambrun M, Frere C, Miyara M. et al. High frequency of antiphospholipid antibodies in critically-ill COVID-19 patients: a link with hypercoagulability?. J Intern Med 2020; DOI: 10.1111/joim.13126.
- 85 Abdel-Wahab N, Talathi S, Lopez-Olivo MA, Suarez-Almazor ME. Risk of developing antiphospholipid antibodies following viral infection: a systematic review and meta-analysis. Lupus 2018; 27 (04) 572-583
- 86 Pengo V, Denas G, Zoppellaro G. et al. Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome. Blood 2018; 132 (13) 1365-1371
- 87 Bauersachs R, Langer F, Kalka C. et al. Treatment of the antiphospholipid syndrome with direct oral anticoagulantsPosition statement of German societies. Vasa 2019; 48 (06) 483-486
- 88 Whyte CS, Morrow GB, Mitchell JL, Chowdary P, Mutch NJ. Fibrinolytic abnormalities in acute respiratory distress syndrome (ARDS) and versatility of thrombolytic drugs to treat COVID-19. J Thromb Haemost 2020; 18 (07) 1548-1555
- 89 Konstantinides SV, Vicaut E, Danays T. et al. Impact of thrombolytic therapy on the long-term outcome of intermediate-risk pulmonary embolism. J Am Coll Cardiol 2017; 69 (12) 1536-1544
- 90 ESC. ESC guidance for the diagnosis and management of CV disease during the COVID-19 pandemic. 2020 . Available at: https://www.escardio.org/Education/COVID-19-and-Cardiology/ESC-COVID-19-Guidance . Accessed September 22, 2020
- 91 Meyer G, Vicaut E, Danays T. et al. PEITHO Investigators. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med 2014; 370 (15) 1402-1411
- 92 Zondag W, Mos IC, Creemers-Schild D. et al. Hestia Study Investigators. Outpatient treatment in patients with acute pulmonary embolism: the Hestia Study. J Thromb Haemost 2011; 9 (08) 1500-1507