Consideration of Tranexamic Acid Administration to COVID-19 Patients

To the Editor: Ji et al. (7) reported that SARS-CoV-2, the causative virus of coronavirus disease 2019 (COVID-19), becomes more virulent when the S protein of this virus is cleaved by plasmin. Therefore, their idea that suppression of plasmin might prevent disease progression of COVID-19 is attractive (5, 7). We also support this idea and, in fact, have proposed nafamostat, which is a protease inhibitor that is used as an antithrombin drug and is also characterized by strong antiplasmin action, as one of the drugs in the arsenal being trialed against COVID-19 (1).

Nafamostat has been used for over 30 yr against disseminated intravascular coagulation (DIC), especially for enhanced-fibrinolytic-type DIC (4), in Japan. However, because of the weak antithrombin activity of nafamostat, combination therapy with heparin is recommended in the use of nafamostat against DIC with COVID-19 (1).

Since tranexamic acid, a representative antifibrinolytic drug, reduces plasmin production, it is mainly used as a hemostatic agent in clinical practice. As the oral form of this drug is available in addition to the intravenous form, it can be easily prescribed even for outpatients. If the drug is actually able to suppress the disease progression of COVID-19 as is supposed by Ji et al. (7), it would be good news for many patients suffering from this disease. However, it should be noted that tranexamic acid has the adverse side effect of thrombosis.

As was mentioned by Barker and Wagener (5), it is true that thrombotic complications are unlikely to occur when the drug is used for melasma; however, for 50 yr, there have been several reports that sole administration of tranexamic acid or other antifibrinolytic agents without simultaneously using anticoagulants for the purpose of stopping bleeding events that result from DIC (the most serious setting of thrombosis) caused systemic thrombosis that was sometimes fatal (6, 8–10). In addition, in our research using the rat DIC model, tranexamic acid exacerbated organ damage and thrombus formation that was initiated by the DIC state (2, 3).

In patients admitted with COVID-19, even under preventative administration of anticoagulant therapy with low-molecular-weight heparin or unfractionated heparin, it has been reported that thrombosis, especially venous thromboembolism, is detected at the rate of 20–30%. In addition, it has also been reported that DIC occurs in 70% of fatal cases (11).

As described above, due to the extraordinary degree of hypercoagulability in DIC with COVID-19, the sole administration of tranexamic acid to COVID-19 patients is considered to be hazardous and might cause lethal thrombosis. It is of concern that some readers of manuscripts by Barker and Wagener (5) or Ji et al. (7) might tend to administer tranexamic acid alone against COVID-19 in anticipation of its antiplasmin effect.

As mentioned by Barker and Wagener (5), if tranexamic acid is prescribed to COVID-19 patients, concomitant use of anticoagulant therapy, such as direct oral anticoagulants, would be necessary even in patients on mild outpatient treatment.

Early administration of tranexamic acid would prevent or decrease the onset of severe symptoms including the need for admission to the intensive care unit, and clinical trials of tranexamic acid for COVID-19 (NCT04338074, NCT04338126) are currently underway. However, to maximize the benefits and minimize the adverse side effects of tranexamic acid, both strict patient selection (mild cases and normal range of D-dimer) and concomitant anticoagulant therapy are recommended.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.