Abstract
Since the beginning of the current coronavirus 2019 (COVID-19) outbreak,
an intense number of studies have been done in an attempt to discover
effective therapies, not only from the point of view of discovering new
drugs, but also from its repurposing. Recent studies have proposed
tranexamic acid (TXA), a hemostatic drug widely used in clinical
practice, as a potential therapeutic option for COVID-19 as it reduces
plasmin levels. Thus, this letter to the editor aims to provide a
critical overview on the use of TXA in the treatment of the severe acute
respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection.
Dear Editor,
Since the beginning of the current coronavirus disease 2019 (COVID-19)
outbreak, an intense number of studies have been done in an attempt to
discover effective therapies, not only looking from a point of view of
new drugs discovery but also drug repurposing. Recently, Chan et al.
[1] reported that tranexamic acid (TXA) is a potential therapeutic
option for COVID-19 as it reduces the plasmin levels, important in
cleaving the surface protein (SP) of severe acute respiratory
syndrome-coronavirus 2 (SARS-CoV-2). Their idea that the plasmin
inhibition might attenuate the disease progression is striking and
attractive since anti-plasmin drugs may reduce the SARS-CoV-2-associated
complications [2]. In the same manner, Baeker et al. [3] also
reported that high plasmin activity increases the SARS-CoV-2 virulence
while facilitate its entry and replication, thus anti-plasmin drugs may
prevent COVID-19 progression.
Briefly, TXA is a hemostatic drug in clinical practice and available as
both oral and intravenous forms and prescribed even for outpatients. It
is of concern and alarm that some non-professional and non-medical
readers of article published by Chan et al. [1] might be apt to and
tend to take TXA alone against COVID-19 in anticipation of its
anti-plasmin effect. But, as all drugs, TXA also has adverse effects,
with venous and arterial thrombosis being stated as major effects by
different studies [4, 5]. Chan et al. [1] also illustrated that
TXA has anti-inflammatory effects via inhibition of plasmin-mediated
activation of neutrophils, monocytes, complement system and tumor
necrosis factor alpha (TNF-α). Besides, TXA modulates coagulopathy via
suppression of fibrinolysis, and thus may prevent COVID-19 induced
disseminated intravascular coagulopathy (DIC) [6]. Therefore,
anti-coagulants should be co-administrated with TXA when used as an
anti-inflammatory agent to prevent DIC, as it may be fatal since
administration of TXA alone may exacerbates both organ and tissue damage
in DIC mice models [7]. Moreover, and worth of note is that, venous
thromboembolism and DIC have been linked to COVID-19 in about 20-30%
and 70% of cases, respectively [8]. Furthermore, it has been shown
that SARS-CoV-2 trigger inflammatory and endothelial cells for
inflammatory cytokines and pro-coagulants production and release, such
as Von Willebr and tissue factors, leading to fibrin clots’ formation.
These changes activate platelets and fibrinolysis with subsequent DIC
onset [9].
Tang et al. [9] also showed that DIC is linked to a poor prognosis
and high mortality in COVID-19 patients, since plasma fibrinogen levels
and anti-thrombin activity are reduced while D-dimer level is increased.
By itself, low fibrinogen and high D-dimer plasma levels are associated
with a high risk of acute respiratory distress syndrome (ARDS) [9].
Venous thromboembolism (VTE) and pulmonary embolism have also been
reported in COVID-19 patients (in around 25%) [10]. Besides,
arterial thrombosis has been reported and manifested as myocardial
infarction, ischemic stroke and limb ischemia [11].
The pathophysiology of thrombus formation in COVID-19 is mainly linked
to cytokine storm and endothelial dysfunction that together led to DIC,
hypercoagulation and ARDS [12]. Bester et al. [13] confirmed
that high levels of interleukin (IL)-6 and other pro-inflammatory
cytokines are associated with noteworthy disorders in
coagulation/fibrinolysis axis. So, COVID-19-induced cytokine storm and
associated DIC is more prevalent and directly correlated with ARDS.
Thus, the administration of TXA for its weak anti-inflammatory and
anti-plasmin effects in COVID-19 management may worsen preexistence DIC
and should be weighed against its benefit.
Previously, Tucker et al [14], even before the COVID-19, underlined
that fibrinolytic system is inhibited during acute lung injury (ALI) and
ARDS due to an increase in plasminogen activator inhibitor-1 (PAI-1)
levels in the bronchoalveolar fluid and plasma. Thus, pulmonary
fibrinolysis’ restoration by intravenous plasmin or urokinase
administration trigger a reduction in both ALI and ARDS severity
[15]. Herein, TXA administration may aggravate ALI and ARDS in
COVID-19 patients as it suppresses the plasmin effect, which has a great
role in removing necrotic proteins and improving lung oxygenation
[15]. Taken together, data presented here underline that TXA therapy
in COVID-19 patients depend on its antiviral merit, with its
administration might be balanced against the risk of DIC and PE, despite
a meta-analysis of previous trials indicated that TXA therapy has no
thrombotic risk [16].