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Review
. 2020 Jun 16;75(23):2950-2973.
doi: 10.1016/j.jacc.2020.04.031. Epub 2020 Apr 17.

COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-Up: JACC State-of-the-Art Review

Behnood Bikdeli  1 , Mahesh V Madhavan  2 , David Jimenez  3 , Taylor Chuich  4 , Isaac Dreyfus  4 , Elissa Driggin  4 , Caroline Der Nigoghossian  4 , Walter Ageno  5 , Mohammad Madjid  6 , Yutao Guo  7 , Liang V Tang  8 , Yu Hu  8 , Jay Giri  9 , Mary Cushman  10 , Isabelle Quéré  11 , Evangelos P Dimakakos  12 , C Michael Gibson  13 , Giuseppe Lippi  14 , Emmanuel J Favaloro  15 , Jawed Fareed  16 , Joseph A Caprini  17 , Alfonso J Tafur  18 , John R Burton  4 , Dominic P Francese  19 , Elizabeth Y Wang  4 , Anna Falanga  20 , Claire McLintock  21 , Beverley J Hunt  22 , Alex C Spyropoulos  23 , Geoffrey D Barnes  24 , John W Eikelboom  25 , Ido Weinberg  26 , Sam Schulman  27 , Marc Carrier  28 , Gregory Piazza  29 , Joshua A Beckman  30 , P Gabriel Steg  31 , Gregg W Stone  32 , Stephan Rosenkranz  33 , Samuel Z Goldhaber  29 , Sahil A Parikh  34 , Manuel Monreal  35 , Harlan M Krumholz  36 , Stavros V Konstantinides  37 , Jeffrey I Weitz  38 , Gregory Y H Lip  39 ; 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
Affiliations
Review

COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-Up: JACC State-of-the-Art Review

Behnood Bikdeli et al. J Am Coll Cardiol. .

Abstract

Coronavirus disease-2019 (COVID-19), a viral respiratory illness caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), may predispose patients to thrombotic disease, both in the venous and arterial circulations, because of excessive inflammation, platelet activation, endothelial dysfunction, and stasis. In addition, many patients receiving antithrombotic therapy for thrombotic disease may develop COVID-19, which can have implications for choice, dosing, and laboratory monitoring of antithrombotic therapy. Moreover, during a time with much focus on COVID-19, it is critical to consider how to optimize the available technology to care for patients without COVID-19 who have thrombotic disease. Herein, the authors review the current understanding of the pathogenesis, epidemiology, management, and outcomes of patients with COVID-19 who develop venous or arterial thrombosis, of those with pre-existing thrombotic disease who develop COVID-19, or those who need prevention or care for their thrombotic disease during the COVID-19 pandemic.

Keywords: COVID-19; SARS-CoV-2; anticoagulant; antiplatelet; antithrombotic therapy; thrombosis.

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Figures

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Graphical abstract
Figure 1
Figure 1
Variability in Resources and Testing Strategies, and in Contracting COVID-19 After Exposure to SARS-CoV-2 Such variability explains the dissimilar population rates of the infection, and the distinct case fatality rates, across various regions and countries. Inflammatory response, increased age, and bedridden status—which are more frequently observed in severe coronavirus disease-2019 (COVID-19)—may contribute to thrombosis and adverse outcomes. DIC = disseminated intravascular coagulation; SARS-CoV-2 = severe acute respiratory syndrome-coronavirus-2; VTE = venous thromboembolism.
Central Illustration
Central Illustration
Postulated Mechanisms of Coagulopathy and Pathogenesis of Thrombosis in COVID-19 (A) Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection activates an inflammatory response, leading to release of inflammatory mediators. Endothelial and hemostatic activation ensues, with increase in von Willebrand factor and increased tissue factor. The inflammatory response to severe infection is marked by lymphopenia and thrombocytopenia. Liver injury may lead to decreased coagulation and antithrombin formation. (B) Coronavirus disease-2019 (COVID-19) may be associated with hemostatic derangement and elevated troponin levels. (C) Increased prothrombotic state results in venous thromboembolism, myocardial infarction, or in case of further hemostatic derangement, disseminated intravascular coagulation. CKD = chronic kidney disease; COPD = chronic obstructive pulmonary disease; CRP = C-reactive protein; FDP = fibrin degradation product; HF = heart failure; IL = interleukin; LDH = lactate dehydrogenase; PT = prothrombin time.
Figure 2
Figure 2
Risk Stratification of ACS and Venous Thromboembolism With COVID-19 Proposed algorithm to risk stratify patients based on severity of acute coronary syndromes (ACS), VTE, and COVID-19 presentations. ∗High-risk ACS refers to patients with hemodynamic instability, left ventricular dysfunction or focal wall motion abnormality, or worsening or refractory symptoms. High-risk VTE refers to patients with pulmonary embolism who are hemodynamically unstable, evidence of right ventricular dysfunction or dilatation, or worsening of refractory symptoms. †High-risk COVID-19 refers to patients with high suspicion for or confirmed COVID-19, including individuals with high viral load, symptomatic with coughing or sneezing or other respiratory symptoms, and at risk for requiring intubation and aerosolizing viral particles. ‡Hemodynamic support includes intra-aortic balloon pump, percutaneous ventricular assist device, and extracorporeal membrane oxygenation. Hemodynamic monitoring refers to Swan-Ganz catheter for invasive hemodynamic assessment. For potential drug-drug interactions, please refer to Tables 3 and 4. GDMT = guideline-directed medical therapy; TTE = transthoracic echocardiogram; other abbreviations as in Figure 1.
Figure 3
Figure 3
Considerations for Switching VKAs Because of Limitations With Access to Care or Health Care Resources During the COVID-19 Pandemic If switching the anticoagulant agent is planned, care should be taken to be sure that the patient is able to afford and receive the alternative therapy. Contraindications to direct oral anticoagulant (DOACs) include mechanical heart valves, valvular atrial fibrillation (AF), pregnancy or breastfeeding, antiphospholipid syndrome (APLS), and coadministration of medications including strong CYP3A and P-glycoprotein inhibitors (-azole medications), HIV protease inhibitors (dependent on DOAC, may just require dose reduction), CYP3A4 inducers (antiepileptics), St. John’s wort, rifampin, etc. Patient education about stable dietary habits while receiving VKAs is also important. If DOACs are not available or approved by insurance, low-molecular-weight heparin (LMWHs) could be used in select cases. COVID-19 = coronavirus disease-2019; INR = international normalized ratio; VKA= vitamin K antagonist.
Figure 4
Figure 4
Considerations for Thrombotic Disease for Patients, Health Care Providers, and Health Systems and Professional Societies During the COVID-19 Pandemic The approach to safe evaluation and management of thrombotic disease in patients with COVID-19 has several levels of involvement. Hospitalized patients with existing VTE should continue on anticoagulation with consideration of drug-drug interactions, especially with antiviral medications (Table 4). Hospitalized patients with reduced mobility should be started on VTE prophylaxis. Patients who are discharged or not hospitalized should continue recommended anticoagulation therapy. Telemedicine and drive-through or home INR checks can reduce the risk of exposure of both patients and health care providers to COVID-19 while assuring proper management of anticoagulation. In appropriate cases, consider switching VKAs to DOACs to diminish the need for frequent INR checks. Health care workers should continue existing precautions including use of personal protective equipment (PPE) and minimizing individual contact with COVID-19 patients. If emergent procedures for thrombotic disease (e.g., cardiac catheterization, pulmonary thrombectomy) are needed, procedure rooms should be disinfected, and the use of negative pressure operating rooms should be implemented as available. Expedited funding for observational and randomized control trials in management of thrombotic disease is encouraged. APTT = activated partial thromboplastin time; PT = prothrombin time; other abbreviations as in Figures 1 and 3.
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