COVID-19 and Thromboembolism: FAQs

Patients with COVID-19, the disease caused by the SARS-CoV-2 virus, appear to have a higher thrombosis risk than other hospitalized or intensive care patients.3 The chart below provides information or resources on thromboembolism pertinent to COVID-19 patients. The information is presented in an FAQ format, with an emphasis on thrombosis prevention and treatment. Keep in mind that although there is little information specific to COVID-19 thrombosis management, there are some special considerations that may affect treatment decisions, including risk of hospital staff exposure to infected patients.


Clinical Question

Pertinent Information and Resources

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 facilities thrombus formation.1
  • Some drugs being investigated 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.2 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.2,10

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

For which COVID-19 patients should thromboembolism prophylaxis be considered, and how should it be provided?

  • Experts advocate prophylaxis for all COVID-19 patients.3,5,6 For patients with contraindications to anticoagulants such as active bleeding or platelets <25,000/mm3, use IPC.2,3,5,6 The benefit of combining anticoagulants with IPC in critically ill patients has not been demonstrated and is generally not recommended for COVID-19 patients.3,6,11
  • In general, use the same VTE prophylaxis regimens as for non-COVID patients.8 Consider LMWH for most patients, even those with DIC but without overt bleeding; it may decrease thrombin.2 Fondaparinux is a choice for patients with heparin-induced thrombocytopenia.6 As for other acutely ill hospitalized patients, avoid prophylaxis with DOACs due to higher bleeding risk.3
  • See our charts, Venous Thromboembolism Prophylaxis, Cancer-Associated Thrombosis FAQs, and LMWH Dosing in Special Populations (e.g., obesity) for prophylaxis options and dosing used in non-COVID patients.
  • Although seriously ill COVID-19 patients are prothrombotic, whether they have a higher risk of VTE than other critically ill patients is unclear.6  Reported rates vary due to differences in VTE screening, confounders such as comorbidities, and treatments.6  There has been interest in using anticoagulant doses higher than those normally used for prophylaxis, such as enoxaparin 40 mg twice daily or 60 mg once daily, or dosing as for VTE treatment.8,11  However:
    • in critically ill COVID-19 patients, 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 prophylaxis (e.g., enoxaparin 40 mg once daily) [Evidence level B-1].9,12
    • in more moderately ill COVID-19 patients (e.g., hospitalized but not needing high-flow oxygen, noninvasive or invasive mechanical ventilation, or vasopressors), full-dose anticoagulation with heparin (mostly enoxaparin) started within 72 hours of admission or positive in-hospital COVID-19 test increases days free of cardiovascular or respiratory support vs usual-dose VTE prophylaxis [Evidence level B-1].15  Patients in this study were relatively young (mean age ~59 +/- 14 years).  Patients with high bleeding risk or dual antiplatelet therapy were excluded, and few included patients were taking a single antiplatelet (12%). Less than 7% of patients had chronic kidney disease. 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).  Heparin may have benefited these moderately ill patients via an anti-inflammatory effect that is lost in more serious disease.
  • If feasible, reserve higher than usual anticoagulant doses for clinical trials6 (see www.clinicaltrials.gov).
  • 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 if bleeding risk allows.6
  • Extrapolating from other populations, antiplatelets (e.g., aspirin) are likely inferior to anticoagulants for VTE prophylaxis in COVID-19 patients needing hospitalization.3
  • At discharge , educate COVID-19 patients to seek help for symptoms of VTE.6  Studies of extended-duration VTE prophylaxis in COVID-19 and non-COVID medical patients don’t clearly show that VTE reduction outweighs bleeding.6,7,15
  • For patients with mild COVID-19 who are isolating at home, advise keeping active.2 Pharmacologic prophylaxis may be considered for very high-risk patients (e.g., immobility, history of VTE, active cancer) without high bleeding risk.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?

  • 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 this patient population 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).2 But for patients taking warfarin, consider transitioning to a DOAC or LMWH.2
  • 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. Consider using injectable antithrombotics when drug interactions are a concern.2

What are some select drug interactions between antithrombotics and drugs being investigated to 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
  • 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 www.covid19-druginteractions.org for more 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; 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.

Level

Definition

Study Quality

A

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

B

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

C

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. http://www.aafp.org/afp/2004/0201/p548.pdf.]

Project Leader in preparation of this clinical resource (360817): Melanie Cupp, Pharm.D., BCPS; Last modified September 2021

References

  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 May 6. doi: 10.7326/M20-2003.
  2. Bikdeli B, Madhaven 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. Thachil J, Tang N, Gando S, et al. ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb Haemost 2020;18:1023-6.
  6. American Society of Hematology. COVID-19 and VTE/anticoagulation: frequently asked questions. July 15, 2021. https://www.hematology.org/covid-19/covid-19-and-vte-anticoagulation. (Accessed September 18, 2021).
  7. Clinical Resource, Comparison of Oral Anticoagulants. Pharmacist’s Letter/Prescriber’s Letter. December 2019.
  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. https://www.acc.org/latest-in-cardiology/articles/2020/04/17/14/42/thrombosis-and-coronavirus-disease-2019-covid-19-faqs-for-current-practice. (Accessed July 25, 2020).
  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.  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. http://www.clinicalkey.com. (Accessed September 18, 2021).
  15. ATTACC Investigators; ACTIV-4a Investigators; REMAP-CAP Investigators; et al.  Therapeutic anticoagulation with heparin in noncritically ill patients with COVID-19N Engl J Med 2021;305:790-002.

Cite this document as follows: Clinical Resource, COVID-19 and Thromboembolism: FAQs. Hospital Pharmacist’s Letter/Prescriber’s Letter. August 2020.