By: Veeraya White, PharmD Candidate 2022 – University of Health Sciences and Pharmacy in St. Louis

Mentor: Brooke E. Gengler, PharmD, BCCP; Pharmacy Clinical Specialist, Cardiology, SSM Health Saint Louis University Hospital

Introduction
Coronavirus disease 2019 (COVID-19) is a viral respiratory infection caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) which has become a significant threat worldwide. The infection triggers host defense systems resulting in activation of coagulation and thrombin generation, called thromboinflammation.¹ As a result, some patients with COVID-19 encounter complications associated with cytokine overproduction, hypercoagulability, and thrombosis. Thromboinflammation may lead to a life-threatening condition, disseminated intravascular coagulopathy (DIC), a condition in which blood clots throughout the body use up available clotting factors thereby increasing the risk of bleeding.^2,3 Anticoagulants (ACs), such as low molecular weight heparin (LMWH), and unfractionated heparin (UFH), are used to prevent thrombosis.² This article will discuss the appropriate criteria for anticoagulant venous thromboembolism (VTE) prophylaxis in patients with COVID-19. 

Literature Review
Early in the pandemic, clinicians identified that DIC was commonly associated with severe cases of COVID-19 that resulted in death.⁴ Upon closer examination, many of these patients experienced microvascular thrombosis or venous thromboembolism.⁵ As a result, several studies attempted to find an association between various biomarkers such as D-dimer and risk of thrombosis. One retrospective study from Wuhan, China found that patients with sepsis-induced coagulopathy scores (SIC) ≥4 or elevated D-dimers who were given prophylactic doses of LMWH had reduced mortality compared to those without.⁶

Larger, prospective, randomized controlled trials have explored whether prophylactic anticoagulation is enough to prevent thrombosis or if intermediate intensity, doses between prophylactic and therapeutic anticoagulation, should be used instead. The ACTION study evaluated extended duration therapeutic anticoagulation with rivaroxaban or enoxaparin during admission followed by rivaroxaban for 30 days after discharge in acutely ill COVID-19 patients. Compared to standard VTE prophylaxis, therapeutic anticoagulation increased the risk of bleeding without improving clinical outcomes.⁷ In critically ill patients, receipt of early therapeutic anticoagulation within two days of admission was not associated with reduced mortality.⁸ Preliminary data from the multi-platform randomized controlled trial (mpRCT) also indicate that therapeutic anticoagulation did not improve survival or days free from organ support compared to standard pharmacologic prophylaxis. This trial was stopped early due to futility.⁹ Based on currently available evidence, most COVID-19 patients admitted to the hospital should be initiated on standard VTE prophylaxis rather than an intensified regimen.

Application in Practice

Thrombosis prophylaxis in hospitalized COVID-19 patients

• Routine thromboprophylaxis should be used in all hospitalized non-pregnant patients with a standard dose of LMWH or UFH after careful assessment of bleeding risk. LMWH is the preferred agent due to lower frequency of administration.^11,16,17
• VTE prophylaxis regimens should be modified based on body weight, severe thrombocytopenia (i.e. platelet counts <25,000/µL in non-bleeding patients or 50,000/µL in bleeding patients), or declining renal function.^10,13
• In patients with a contraindication to pharmacologic prophylaxis, consistent application of intermittent pneumatic compression devices should be used with regular assessment.¹⁷
• In critically ill patients, thromboprophylaxis should be initiated at standard doses. An intermediate dose may be considered in patients at high risk of thrombosis.¹⁷

Recommended standard prophylaxis doses of anticoagulants (dose adjustments for renal function and obesity not included)^10,12,13

• Enoxaparin 40 mg subcutaneously (SUBQ) daily
• Heparin 5000 units SUBQ every 8 hours (preferred in patients with creatinine clearance (CrCl) <15 mL/min or dialysis)

Recommended intermediate doses of anticoagulants¹⁷

• Enoxaparin 0.5 mg/kg SUBQ twice daily
• Heparin 7500 units SUBQ every 8 hours

Duration of VTE prophylaxis after hospital discharge¹⁰

• Post-hospital VTE prophylaxis may be considered on a case-by-case basis for patients with COVID-19 who are low bleeding risk (e.g. IMPROVE bleed score <7.0) and:
• • Were admitted to the ICU, intubated, sedated, and possibly paralyzed for multiple days
  • Have ongoing VTE risk factors at the discharge (e.g. limited mobility, profound weakness, or not at baseline physical status)

References

1. Connors JM, Levy JH. COVID-19 and its implications for thrombosis and anticoagulation. Blood. 2020;135(23):2033-2040.
2. Moonla C, Sosothikul D, Chiasakul T, Rojnuckarin P, Uaprasert N. Anticoagulation and in-hospital mortality from coronavirus disease 2019: a systematic review and meta-analysis. Clin Appl Thromb Hemost. 2021; 27:10760296211008999.
3. National Heart Lung and Blood Institute. Disseminated intravascular coagulation. Published October 2019. Accessed June 21, 2021.
4. 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;18:844-847.
5. McFadyen JD, Stevens H, Peter K. The emerging threat of (micro)thrombosis in COVID-19 and its therapeutic implications. Circulation Research. 2020;127:571-587.
6. 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(5):1094-1099.
7. Lopes RD, de Barros E Silva PGM, Furtado RHM, et al. Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19 and elevated D-dimer concentration (ACTION): an open-label, multicentre, randomised, controlled trial. Lancet. 2021;397(10291):2253-2263.
8. Al-Samkari H, Gupta S, Leaf RK, et al. Thrombosis, bleeding, and the observational effect of early therapeutic anticoagulation on survival in critically ill patients with COVID-19 [published correction appears in Ann Intern Med. 2021 Jun;174(6):888]. Ann Intern Med. 2021;174(5):622-632.
9. Zarychanski R. The REMAP-CAP, ACTIV-4a, ATTACC investigators. Therapeutic anticoagulation in critically ill patients with COVID-19 – preliminary report.
10. Benge C, DeWitt K. Anticoagulation Forum. Anticoagulation in COVID-19: summary of societal guidance. Updated December 2020. Accessed June 21, 2021.
11. National Institutes of Health. Antithrombotic therapy in patients with COVID-19. Published February 2021. Accessed June 21, 2021.
12. 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(23):2950-2973.
13. 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(5):1023-1026.
14. 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(3):1143-1163.
15. Cuker A, Tseng EK, Nieuwlaat R, et al. American Society of Hematology 2021 guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19. Blood Adv. 2021;5(3):872-888.
16. 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(8):1859-1865.
17. 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(1):72-81.