Anti-thrombotic therapy in patients with COVID-19

In patients with severe or critical Coronavirus disease 2019 (COVID-19) manifestations, a thromboinflammatory syndrome, with diffuse microvascular thrombosis, is increasingly evident as the final step of pro-inflammatory cytokines storm. Actually, no proven effective therapies for novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection exist. Preliminary observations on anticoagulant therapy appear to be associated with better outcomes in moderate and severe COVID-19 patients with signs of coagulopathy and in those requiring mechanical ventilation.

At the moment, there is no solid scientific evidence on antithrombotic treatment for COVID-19 and further prospective investigations are warranted.

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Is COVID-19 associated with an increased risk for venous thromboembolism (VTE)?

The incidence of VTE in COVID-19 patients varies depending on the patient population. Reports have ranged from 1.1% in non-ICU hospital wards to 69% in ICU patients screened with lower extremity ultrasound. Like other medical patients, those with more severe disease, especially if they have additional risk factors (e.g., older, male, obesity, cancer, history of VTE, comorbid diseases, ICU care), have a higher risk of VTE than those with mild or asymptomatic disease. The risk of VTE following hospital discharge appears low and similar to other patients following a medical admission. VTE rate in those who do not require hospitalization has not been reported.

What is the recommended VTE prophylaxis in patients with COVID-19?

All hospitalized adults with COVID-19 should receive pharmacologic thromboprophylaxis with LMWH over unfractionated heparin to reduce contact, unless the risk of bleeding outweighs the risk of thrombosis. In the setting of heparin-induced thrombocytopenia, fondaparinux is recommended.

Despite the lack of quality published evidence, many institutional protocols have adopted an intermediate-intensity (i.e., administering the usual daily LMWH dose twice daily) or even a therapeutic-intensity dose strategy for thromboprophylaxis based on local experience.

Should seriously ill COVID-19 patients receive therapeutic-intensity anticoagulation empirically?

Microvascular thrombosis is hypothesized to be involved in hypoxemic respiratory failure in some patients with COVID-19. Autopsy studies show large vessel and microvascular thrombosis, pulmonary hemorrhage and high prevalence of VTE. Whether critically ill COVID-19 patients should receive therapeutic-intensity anticoagulation in the absence of confirmed or suspected VTE is currently unknown. Multiple randomized controlled trials are investigating the effects of different doses of heparin on patient outcomes. We encourage participation in clinical trials rather than empiric use of therapeutic-dose heparin in COVID-19 patients with no other indication for therapeutic dose anticoagulation.

Should COVID-19 patients receive post-discharge thromboprophylaxis?

Patients hospitalized for acute medical illness are at increased risk for VTE for up to 90 days after discharge. A symptomatic VTE incidence between 0-0.6% at 30-42 days post discharge has been reported in patients with COVID-19. Whether post-discharge thromboprophylaxis is warranted is being investigated in clinical trials and enrollment is encouraged. Any decision to use post-discharge thromboprophylaxis should consider the individual patient’s VTE risk factors at the time of discharge, including reduced mobility and bleeding risk, as well as feasibility. For example, COVID-19 patients who are discharged early to free up inpatient beds (“home hospital” approach) might still have significantly reduced mobility.

Aspirin has been studied for VTE prophylaxis in low-risk patients after hip or knee arthroplasty and is currently being investigated for COVID-19 post-discharge thromboprophylaxis. Patients should be educated on the signs and symptoms of VTE at hospital discharge and advised to seek urgent medical attention should these develop.

If a patient with COVID-19 requires therapeutic anticoagulation for VTE or AFIB stroke prevention, are there any special considerations?

Multiple medications are being used for COVID-19 treatment. Dexamethasone is an inducer of CYP3A4 and the extent of the drug interaction with direct oral anticoagulants is unknown. Sarilumab and tocilizumab can increase cytochrome P450 enzyme activity and so they should not be used together with apixaban or rivaroxaban and may also increase the doses of warfarin required.

Atazanavir and lopinavir/ritonavir will increase drug concentrations of apixaban and rivaroxaban and decrease the active metabolite of clopidogrel and prasugrel.

LMWH or UFH in hospitalized critically ill patients is preferred because of the shorter half-life and fewer drug-drug interactions compared with direct oral anticoagulants. Regular warfarin users who are unable to get INR monitoring during isolation may be candidates for direct oral anticoagulant therapy, but patients with mechanical heart valves, ventricular assist devices, valvular atrial fibrillation, antiphospholipid antibody syndrome, or lactation should generally continue treatment with warfarin therapy. LMWH or UFH remain the anticoagulants of choice in pregnancy.

Antithrombotic Therapy during pregnancy, labor and delivery with COVID-19

The following recommendations have been added to this section:

For pregnant patients hospitalized for severe COVID-19, prophylactic dose anticoagulation is recommended if there are no contraindications to its use (BIII).
As for nonpregnant patients, VTE prophylaxis after hospital discharge is not recommended for pregnant patients (AIII). Decisions to continue VTE prophylaxis in the pregnant or postpartum patient after discharge should be individualized, considering concomitant VTE risk factors.
Anticoagulation therapy use during labor and delivery requires specialized care and planning. It should be managed in pregnant patients with COVID-19 in a similar way as in pregnant patients with other conditions that require anticoagulation in pregnancy (AIII).