It has become clear in recent months that the severe acute respiratory syndrome 2 (SARS-CoV-2) virus, which causes coronavirus disease 2019 (COVID-19) affects the cardiovascular system, in addition to the lungs, prompting clinicians to reevaluate common standard care procedures for patients infected with the coronavirus. An expert panel released a set of 22 guidelines for the prevention, detection, and treatment of venous thromboembolism (VTE) and hypercoagulability in patients infected with COVID-19, which were published in Chest. 1

Patients with severe coronavirus infections can have a dramatic rise in cytokine levels causing a cytokine storm, which activates the body’s coagulation system, leading to a hypercoagulable state. Laboratory results from patients infected with the virus show highly abnormal D-dimer levels, indicating that fibrin degradation products are circulating in the blood stream.2

Anticoagulant therapy appears to be essential for patients admitted to the intensive care unit (ICU) with COVID-19. According to observational studies, even when treated with at least a standard dose of an anticoagulant, up to 54% of patients were diagnosed with VTE.3 A 24% reduction in absolute mortality was reported by clinicians in a hospital in Wuhan, China, for patients with severe COVID-19 and sepsis-induced coagulopathy who were treated with vs without heparin.4 These patients may have an elevated risk for VTE. It is recommended that patients hospitalized for COVID-19 be administered anticoagulant thromboprophylaxis, in the absence of contraindications for these drugs. The use of antiplatelet medications is not recommended. In patients without COVID-19, anticoagulants are favored over antiplatelets, as heparin has been shown to reduce the incidence of pulmonary embolisms (PEs) and proximal and distal VTEs.

Direct oral anticoagulants (DOACs) may not be recommended for patients with severe COVID-19 and acute VTE for 4 reasons: SARS-CoV-2 can cause gastrointestinal symptoms (ie, vomiting and diarrhea) which may reduce the effectiveness of oral medications; some patients with COVID-19 require inhibitors or inducers of P-glycoprotein or cytochrome P450, which may reduce the safety and/or efficacy of DOACs; viral infection increases the incidence of acute kidney injury, which is a contraindication for DOACs. In 12 patients with a severe SARS-CoV-2 infection that were being treated with DOACs, C-trough DOAC levels were 6 times higher than before hospitalization.5


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Due to SARS-CoV-2-related gastrointestinal symptoms, subcutaneous therapies (heparin or fondaparinux) are the preferred delivery method. Low molecular weight heparin (LMWH) or fondaparinux are both administered once daily without the need, in most cases, for monitoring. Unfractionated heparin (UFH), requires 2 doses per day, increasing the staff’s risk for exposure. In addition, treatment with high doses of UFH which may be required to increase the activated partial thromboplastin time, may lead to heparin resistance. It is therefore recommended that patients with severe COVID-19 and acute VTE be treated with LMWH or fondaparinux, and that patients in the ICU be given LMWH, as no study has examined the safety and efficacy of fondaparinux in this patient population.

Patients with COVID-19 should be treated with standard anticoagulant dosage (LMWH BID or weight-based dosing). In most cases, thromboprophylaxis therapy should be discontinued after hospital discharge.

For inpatients with COVID-19 and proximal deep vein thrombosis (DVT) or PE, an initial parenteral anticoagulant of weight-adjusted LMWH followed by dabigatran or edoxaban with a vitamin K antagonist overlap is recommended. For patients with COVID-10 and proximal DVT or PE who are being cared for at home, LMWH is not recommended; apixaban, dabigatran, rivaroxaban, or edoxaban are preferred with a vitamin K antagonist overlap. For patients with COVID-19 in the ICU with proximal DVT or PE, oral therapies should be avoided. In all patients with a proximal DVT or PE, it is recommended that thromboprophylaxis be continued for 3 months.

Diffuse alveolar damage6 and frank alveolar hemorrhage7 were observed in autopsies of patients who died from COVID-19, indicating an increased risk for bleeding, and suggesting that advanced therapies (ie, systemic thrombolysis, thrombectomy, or catheter-directed thrombolysis) should not be used for the treatment of most patients with COVID-19.

Three categories of patients with COVID-19 are candidates for thrombolytic therapy: Patients with acute PE, no hypotension, and a low risk for bleeding who exhibit cardiopulmonary deterioration (progressing increase in heart rate, blood pressure maintained at >90 mm Hg, increase in jugular venous pressure, worsening gas exchange, shock, progressing right heart dysfunction, or an increase in cardiac biomarkers) after anticoagulant therapy; Patients with objectively confirmed VTE or in whom cardiac arrest is anticipated; and Patients with acute, objectively confirmed PE, hypotension, and a low risk for bleeding. In these patients, systemic thrombolysis using a peripheral vein should be used over catheter-directed thrombolysis.

In patients with acute, objectively confirmed PE without hypotension (systolic blood pressure <90 mm Hg or at least a 15-minute drop in blood pressure below 40 mm Hg), systemic thrombolytic therapy should not be used.

Despite a lack of evidence regarding the use of mechanical prophylaxis in addition to pharmacologic thromboprophylaxis in patients with COVID-19, the guidance authors recommend the sole use of mechanical prophylaxis in patient with a contraindication for LMWH.

In cases of recurrent VTE despite anticoagulation treatment with weight-adjusted LMWH, the dosage should be increased by 25% to 30%. Patient treated with oral anticoagulants should be switched to LMWH.

Routine ultrasound screenings for the detection of asymptomatic DVT in severely ill patients should be avoided unless the patient exhibits unexplained right ventricular dysfunction or refractory hypoxemia.

Limitations of these guidelines include the fact that they were formulated based on studies examining these treatment in patients with and without COVID-19. In the latter case, recommendations were issued based on general standards of care, which may not be optimal for patients with COVID-19. In addition, well-designed, randomized trials will be needed to determine optimal anticoagulant dosing, and specific treatments for macro vs microthrombosis.

“As we consider this a living document that will be updated, we will incorporate additional questions to these updates as needed,” noted the guidelines authors.

Disclosures: Some authors declared receiving consulting or funding from the pharmaceutical industry. A complete list of disclosures can be found in the original study.

References

  1. Moores L K, Tritschler T, Bronsnahan S, et al. Prevention, diagnosis, and treatment of venous thromboembolism in patients with COVID-19: CHEST Guideline and Expert Panel Report. [available online June 2, 2020] Chest. doi:10.1016/j.chest.2020.05.559
  2. Cui S, Chen S, Li X, et al. Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia. J Thromb Haemost. 2020;18(6):1421-1424.
  3. Helms J T C, Severac F, Leonard-Lorant I, et al. High risk of thrombosis in patients in severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med. 2020;46(6):1089-1098.
  4. Tang N, Bai H, Chen X, et al. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020;18(5):1094-1099.
  5. 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(6):1320-1323.
  6. Wichmann D, Sperhake J P, Lutgehetmann M, et al. Autopsy Findings and Venous Thromboembolism in Patients With COVID-19: A Prospective Cohort Study. Ann Intern Med. 2020;M20-2003.
  7. Tian S, Xiong Y, Liu H, et al. Pathological study of the 2019 novel coronavirus disease (COVID-19) through postmortem core biopsies. Mod Pathol. 2020;33(6):1007-1014.