COVID-19 and Thromboembolism: FAQs

Full update February 2022

Patients with COVID-19 appear to have a higher thrombosis risk than otherwise similar hospitalized or intensive care patients.3,5 The FAQ below provides information on thromboembolism pertinent to COVID-19 patients with an emphasis on thrombosis prevention and treatment. There are some special considerations that may affect treatment decisions, including risk of hospital staff exposure to infected patients.


Answer/Pertinent Information

What is the proposed pathophysiology of venous thromboembolism as a complication of COVID-19?

COVID-19 triggers all three arms of Virchow’s triad: endothelial injury, hypercoagulability, and blood flow stasis.3

  • COVID-19 may increase levels of von Willebrand factor and Factor VIII via endothelial injury.3
  • Release of inflammatory cytokines (cytokine storm) could activate the coagulation cascade.2 Antiphospholipid antibodies may play a role.2 On autopsy, megakaryocytes have been found in unusually high numbers outside the bone marrow (e.g., in the lungs and heart).4
  • Immobility, and treatments used for seriously ill COVID-19 patients such as fluid restriction and high PEEP, may cause blood flow stasis and microthrombi.3

COVID-19-induced hypoxia facilitates thrombus formation.1

Some drugs being used as treatments for COVID-19 may increase thrombosis risk directly (e.g., baricitinib), or indirectly by reducing efficacy of antithrombotics (e.g., tocilizumab could potentially speed metabolism of oral anticoagulants).2,13,14

Severely ill COVID-19 patients may have non-COVID-19-specific contributors to VTE risk, such as central lines.2

DIC has been reported, but it is unclear if this is related to a specific effect of COVID-19, or a nonspecific complication of critical illness.Contrary to what is usually seen in DIC, COVID-19 coagulopathy is characterized by normal or even increased fibrinogen.10 Moreover, overt bleeding seems not to be common in COVID-19 patients.10

How does COVID-19-associated thromboembolism present clinically?

In a German cohort of 12 autopsied patients (52 to 87 years of age) who died with a confirmed case of COVID-19, microthrombi were common in the lungs. Seven patients had DVT that had not been suspected before death. For four patients, PE was the cause of death.1

  • These findings suggest that clinicians should maintain a high index of suspicion for VTE in COVID-19 patients.1

Patients with severe COVID-19 may have myocardial injury (e.g., elevated troponin, electrocardiogram signs), which may be thrombotic ACS or myocarditis.2

Hemostasis lab abnormalities seen in COVID-19 patients include elevated D-dimer, low platelets, prolonged PT, and shortened aPTT.2

Which COVID-19 inpatients should receive VTE prophylaxis?

All hospitalized COVID-19 patients should receive VTE prophylaxis.6,19

Use LMWH (or fondaparinux for patients with HIT) for most patients.6

  • IPC is an alternative if an anticoagulant cannot be used, but combining mechanical and pharmacologic prophylaxis is generally not recommended.3,6

Should higher-than-usual anticoagulant doses be used for VTE prophylaxis in critically ill COVID-19 patients?

Current data support starting with standard-dose VTE prophylaxis in critically ill COVID-19 patients.19

  • In critically ill COVID-19 patients, a full-dose heparin (mostly enoxaparin) or intermediate-dose LMWH (enoxaparin 1 mg/kg/day) does not improve outcomes (e.g., thrombosis, mortality, need for organ support) vs usual-dose prophylaxis (e.g., enoxaparin 40 mg once daily) [Evidence level B-1].5,9,12

If, despite prophylactic anticoagulation, COVID-19 patients develop clots in vascular access devices or extracorporeal circuits, consider trying a different anticoagulant, or increasing the dose (i.e., full or intermediate dose) if bleeding risk allows.6

Should higher than usual anticoagulant doses be used for VTE prophylaxis in moderately ill hospitalizedCOVID-19 patients?

Current data suggest that VTE prophylaxis using full-dose anticoagulation (preferably LWWH) can benefit moderately ill, select patients (e.g., elevated D-dimer, requiring only low-flow oxygen, non-pregnant), without increased bleeding risk (e.g., platelets <50 x 109/L, hemoglobin <8 g/dL, DAPT, hospital visit for bleeding within the past 30 days, bleeding disorder) [Evidence level B-1].5,15,16,19

  • In a multiplatform adaptive-design trial (MPT) hospitalized patients not needing high-flow oxygen, noninvasive or invasive mechanical ventilation, or vasopressors, full-dose anticoagulation with a heparin (mostly enoxaparin) started within 72 hours of admission or positive in-hospital COVID-19 test increased days free of cardiovascular or respiratory support vs usual-dose VTE prophylaxis.15 Major bleeding occurred in 1.9% of the full-dose anticoagulation patients vs 0.9% of the usual-dose prophylaxis patients (not a statistically significant difference).
  • In the RAPID trial, non-ICU patients with elevated D-dimer (n=465) were randomized to a full-dose or prophylactic-dose heparin (mostly enoxaparin).16 Although there were fewer VTEs among patients who received full-dose anticoagulation (0.9% vs 2.5%; OR 0.34, 95% CI 0.07 to 1.71, p=0.19), there was no significant difference in occurrence of the primary composite outcome (need for non-invasive or invasive mechanical ventilation, ICU admission, or death). Major bleeding occurred in 1.7% of the full-dose anticoagulation patients vs 0.9% of the usual-dose prophylaxis patients (not a statistically significant difference). Mortality at 28 days was lower in the full-dose arm (OR 0.22 [95% CI 0.07 to 0.65, p=0.006).
  • In the HEP-COVID study (n=257), patients with D-dimer >4 times ULN or sepsis-induced coagulopathy score ≥4 were randomized to full-dose enoxaparin or a prophylactic/intermediate-dose heparin (mostly enoxaparin).5 The primary composite outcome was VTE, arterial thromboembolism, or death. Almost all patients were enrolled based on their D-dimer level. About 2/3 of the study patients were non-ICU patients. Only non-ICU patients benefited from full-dose enoxaparin, driven by reduced thrombosis (NNT = 5 to prevent one thrombotic event). Major bleeding occurred in 2.4% of the non-ICU patients treated with full-dose enoxaparin, vs 2.3% in the prophylactic/intermediate-dose group.

Patients in MPT and RAPID were relatively young (mean age ~60 years15,16). Patients with high bleeding risk or dual antiplatelet therapy were excluded from all three studies.5,15,16 In MPT and RAPID, few included patients were taking a single antiplatelet (~12%), and only about 7% had chronic kidney disease.15,16 In HEP-COVID, <4% of patients had chronic kidney disease.5

Should VTE prophylaxis be considered for outpatients?

It is generally recommended that VTE prophylaxis be discontinued at discharge.6,19

  • Post-discharge, VTE risk is low and comparable to the risk of other medical conditions.6 However, COVID-19 patients discharged early to free up hospital beds may need an assessment of their VTE risk.6
  • In a large, placebo controlled study in non-COVID-19 discharged medical patients (MARINER), extended duration VTE prophylaxis with rivaroxaban did not provide net benefit [Evidence level A-1].18 NNT to prevent one symptomatic VTE was 430. Major or clinically important bleeding (e.g., requiring discontinuation or medical contact) occurred in 1.7% of rivaroxaban patients vs 0.7% of placebo patients (NNH = 143).
  • In COVID-19 patients, one study (MICHELLE) suggests benefit of post-discharge VTE prophylaxis.7 However, findings are limited by open-label design, small sample size (n=320), and inclusion of patients with low bleeding risk (e.g., mean age 57.1 years, 95% not taking an antiplatelet, no severe renal disease).7 In MICHELLE, rivaroxaban 10 mg/day for 35 days post-discharge prevented a symptomatic or fatal VTE in 1 in 23 COVID-19 patients with high thrombosis risk (IMPROVE score ≥4, or 2-3 with D-dimer >500 ng/mL).7 Major bleeding did not occur.7

At discharge, educate COVID-19 patients to seek help for symptoms of VTE.6

For patients with mild COVID-19 who are isolating at home, advise keeping active.2

How is thromboembolism in COVID-19 patients treated?

Anticoagulation, for at least three months, is the mainstay of treatment.2,3 Initiate treatment with a parenteral agent in critically ill patients.3

Consider using anti-factor Xa levels to monitor UFH due to aPTT abnormalities in these patients.11

For patients with recurrent VTE despite appropriate anticoagulation, consider switching from oral therapy to LMWH, or increasing the LMWH dose by 25% to 30% in patients failing standard-dose LMWH, based on low-quality evidence in other populations.3

Catheter-directed therapy or systemic thrombolysis should be reserved for the most serious cases.2,3 See our chart, Pulmonary Embolism: Focus on Thrombolytics, for more information.

Reserve IVC filters for recurrent PE despite appropriate anticoagulation, or clinically important VTE with absolute contraindications to anticoagulation.2

What are some general considerations for antithrombotic use of special relevance to COVID-19?

Extrapolating from other populations, antiplatelets (e.g., aspirin) are likely inferior to anticoagulants for VTE prophylaxis in COVID-19 patients needing hospitalization.3

For patients who might need procedures, consider parenteral antithrombotics over oral antithrombotics due to shorter duration of action.2

DOACs may be difficult to manage in hospitalized COVID-19 patients due to clinical instability resulting in impaired oral drug absorption or deterioration of renal function, and drug interactions with COVID-19 treatments.3

In the hospital, consider fondaparinux (not for intensive care patients) or LMWH over UFH to reduce caregiver viral exposure and to reduce the risk of missed doses; fondaparinux and LMWH require less frequent blood draws for monitoring and fewer daily doses.2,3 However, UFH might be preferred for patients with hemodynamic instability or renal insufficiency due to quicker offset.3

In patients with ACS and elevated bleeding risk (e.g., due to DIC), consider clopidogrel over other antiplatelets.2

In patients taking antithrombotics chronically who develop known or suspected DIC without overt bleeding, consider risk/benefit of reducing the intensity of therapy or discontinuation. For example, in patients taking DAPT, consider risk/benefit of continuing DAPT if platelets ≥50,000/mm3, switching to a single antiplatelet if platelets are ≥25,000 to <50,000/mm3, or discontinuing if platelets <25,000/mm3.2

In outpatients, consider a DOAC or LMWH over warfarin if home or drive-in INR monitoring is not available, assuming use is feasible given cost, indication (e.g., prosthetic heart valve), comorbidities (e.g., pregnancy), etc.2,8

Outpatients with COVID-19 and previously diagnosed thrombotic or CV disease should generally continue their usual antithrombotic regimen (e.g., aspirin, anticoagulant).

Educate outpatients taking antithrombotics to discern clinically important bleeding from nuisance bleeding to reduce unnecessary emergency room visits.2

Be alert for drug interactions between antithrombotics and drugs used to treat COVID-19. Select drug interactions are covered in the next section.

What are some select drug interactions between anticoagulants and drugs used treat COVID-19?

Dexamethasone (high dose): increased warfarin effect.14 Dexamethasone is a CYP3A4 inducer, but whether it significantly reduces DOAC efficacy is unknown.6

Methylprednisolone (high dose): increased warfarin effect.14

Paxlovid (nirmatrelvir/ritonavir): increased rivaroxaban effect; avoid.17 Monitor INR closely in patients taking warfarin (may increase or decrease).17

Sarilumab: may increase CYP450 activity, potentially decreasing efficacy of warfarin, apixaban, and rivaroxaban.14

Tocilizumab: may increase CYP450 activity, potentially decreasing efficacy of warfarin, apixaban, and rivaroxaban.14

See the Liverpool COVID-19 Drug Interaction website: to screen for more drug interactions.

Abbreviations: ACS = acute coronary syndrome; aPTT = activated partial thromboplastin time; CV = cardiovascular; DAPT = dual antiplatelet therapy; DIC = disseminated intravascular coagulation; DOAC = direct oral anticoagulant; DVT = deep venous thrombosis; ECMO = extracorporeal membrane oxygenation; HIT = heparin-induced thrombocytopenia; ICU = intensive care unit; IMPROVE = International Medical Prevention Registry on Venous Thromboembolism; IPC = intermittent pneumatic compression; IVC = inferior vena cava; PCI = percutaneous coronary intervention; PEEP = positive end-expiratory pressure; PT = prothrombin time; VTE = venous thromboembolism; LMWH = low molecular-weight heparin; PE = pulmonary embolism; UFH = unfractionated heparin; ULN = upper limit of normal

Levels of Evidence

In accordance with our goal of providing Evidence-Based information, we are citing the LEVEL OF EVIDENCE for the clinical recommendations we publish.



Study Quality


Good-quality patient-oriented evidence.*

  1. High-quality randomized controlled trial (RCT)
  2. Systematic review (SR)/Meta-analysis of RCTs with consistent findings
  3. All-or-none study


Inconsistent or limited-quality patient-oriented evidence.*

  1. Lower-quality RCT
  2. SR/Meta-analysis with low-quality clinical trials or of studies with inconsistent findings
  3. Cohort study
  4. Case control study


Consensus; usual practice; expert opinion; disease-oriented evidence (e.g., physiologic or surrogate endpoints); case series for studies of diagnosis, treatment, prevention, or screening.

*Outcomes that matter to patients (e.g., morbidity, mortality, symptom improvement, quality of life).

[Adapted from Ebell MH, Siwek J, Weiss BD, et al. Strength of Recommendation Taxonomy (SORT): a patient-centered approach to grading evidence in the medical literature. Am Fam Physician 2004;69:548-56.]


  1. Wichmann D, Sperhake JP, Lutgehetmann M, et al. Autopsy findings and venous thromboembolism in patients with COVID-19: a prospective cohort study. Ann Intern Med 2020;173:268-277.
  2. Bikdeli B, Madhavan MV, Jimenez D, et al. 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;75:2950-73.
  3. Moores LK, Tritschler T, Brosnahan S, et al. Prevention, diagnosis, and treatment of VTE in patients with coronavirus disease 2019: Chest guideline and expert panel report. Chest 2020;158:1143-63.
  4. Rapkiewicz AV, Mai X, Carsons SE. Megakaryocytes and platelet-fibrin thrombi characterize multi-organ thrombosis at autopsy in COVID-19: a case series. EClinicalMedicine 2020;24:100434.
  5. Spyropoulos AC, Goldin M, Glannis D, et al. Efficacy and safety of therapeutic-dose heparin vs 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 2021;181:1612-20.
  6. American Society of Hematology. COVID-19 and VTE/anticoagulation: frequently asked questions. Version 13.0; last updated January 24, 2022. (Accessed February 2, 2022).
  7. Ramacciotti E, Agati LB, Calderaro D, et al. Rivaroxaban versus no anticoagulation for post-discharge thromboprophylaxis after hospitalisation for COVID-19 (MICHELLE): an open-label, multicentre, randomised, controlled trial. Lancet 2022;399:50-9.
  8. Spyropoulos AC, Levy JH, Ageno W, et al. 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;18:1859-65.
  9. INSPIRATION Investigators, Sadeghipour P, Talasaz AH, et al. Effect of intermediate-dose vs 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 2021;325:1620-30.
  10. American College of Cardiology. Thrombosis and COVID-19: FAQs for current practice. April 22, 2020. (Accessed January 17, 2022).
  11. 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;50:72-81.
  12. REMAP-CAP Investigators, ACTIV-4a Investigators, ATTACC Investigators, et al. Therapeutic anticoagulation with heparin in critically ill patients with COVID-19. N Engl J Med 2021;385:777-89.
  13. Kalil AC, Patterson TF, Mehta AK, et al. Baricitinib plus remdesivir for hospitalized adults with Covid-19. N Engl J Med 2021;384:795-807.
  14. Clinical Pharmacology powered by ClinicalKey. Tampa (FL): Elsevier. 2022. (Accessed January 17, 2022).
  15. ATTACC Investigators; ACTIV-4a Investigators; REMAP-CAP Investigators; et al. Therapeutic anticoagulation with heparin in noncritically ill patients with COVID-19. N Engl J Med 2021;385:790-802.
  16. Scholzberg M, Tang GH, Rahhal H, et al. 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 2021;375:n2400.
  17. FDA. Fact sheet for healthcare providers: emergency use authorization for Paxlovid. December 22, 2021. (Accessed January 18, 2022).
  18. Spyropoulos AC, Ageno W, Albers GW, et al. Rivaroxaban for thromboprophylaxis after hospitalization for medical illness. N Eng J Med 2018;379:1118-27.
  19. NIH. Coronavirus disease 2019 (COVID-19). Treatment guidelines. Last updated February 1, 2022. (Accessed February 2, 2022).

Cite this document as follows: Clinical Resource, COVID-19 and Thromboembolism. Pharmacist’s Letter/Prescriber’s Letter. February 2022. [380218]