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injury is the recommended parenteral dose for massive hem- Fourth, current literature does not robustly address TXA use
orrhage. The half-life of IV TXA is ~2–3 hours, and in several in epistaxis from DOACs like rivaroxaban and apixiban. Both
prior in vivo and in vitro studies, 5–15mg/L appears to be the drugs have a rising share of the anticoagulant prescription
effective plasma concentration for the drug to work as an anti- drug market and do not have an affordable, accessible rever-
fibrinolytic agent. Wong et al recently studied topical TXA sal agent. None of our three cases tested ATXA with DOAC
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use during closure of total knee arthroplasty (TKA) cases. In epistaxis. In June 2018, the US Food and Drug Administra-
their prospective, double-blind, placebo-controlled trial, they tion provided accelerated approval for coagulation factor Xa
split TKA cases into three treatment groups: low-dose top- (recombinant) and andexanet alfa (Andexxa, Portola Pharma-
ical TXA (1.5 g in 100mL), high-dose topical TXA (3 g in ceuticals), with a clinical indication for use in life-threatening
100mL), and placebo. Their main conclusion from a data set bleeding from both DOACs. Andexanet alfa comes in a low-
of 99 patients was that topical TXA reduced postoperative and high-dose bolus followed by an infusion regimen with the
bleeding by 20% to 25%. Furthermore, they showed topical cost ranging from $25,000 to $50,000 per use. At this time,
TXA resulted in ~70% of the plasma concentration compared Andexxa has limited availability and a narrow scope of use.
17
with an equivalent IV dose of TXA. The low-dose group had Fifth, no data exist on the use of TXA (or ATXA) for posterior
a mean plasma level of 4.5mg/L; the high-dose group had a epistaxis cases, which make up ~10% of all epistaxis cases.
mean plasma level of 8.5mg/L. The high-dose group’s mean Posterior epistaxis cases are rare but very challenging and of-
plasma levels fell into the cited effective therapeutic plasma ten require urgent surgical intervention. Finally, there have
concentration for TXA. The study authors remarked that it been varying controversies over the prothrombotic risk with
was likely that some of the effect of topical TXA in their study TXA. 18,19 Specific to this case series, a 2018 meta-analysis of
was due to systemic absorption. 16 67 studies and more than 6,000 patients concluded that top-
ical TXA “reduced transfusion risk and blood loss compared
The data presented by Wong et al concerning plasma concen- to placebo without increasing thromboembolic risks.” The
20
tration hold promise for our belief that in difficult-to-treat ep- same study noted no difference between topical and IV TXA
istaxis and possibly in combat medicine, a concentrated form for safety and efficacy but that more investigation is needed
of ATXA with a single or multiple application delivery system about topical applications outside of orthopedics.
could be developed. In our three cases, we used a varying total
dose between 300 and 500mg for small vessel epistaxis. For Conclusion
massive hemorrhage, ATXA would likely need to be concen-
trated at doses higher than current TCCC recommended IV In this small case series, ATXA appears to be a safe, effective
doses yet still deliver small, inhaled volumes of 0.5–1mL. On a adjunct for patients not responding to standard epistaxis treat-
tactical level, the syringe for ATXA would need to be prefilled, ments. ATXA should be considered after conventional meth-
lightweight, shatter resistant, and weatherproof. US military ods have failed but before final packing or using a hemostatic
medical personnel are already familiar using an MAD with matrix agent. There may be potential uses for ATXA in tacti-
INK, so extending that training to ATXA should be straight- cal and prolonged field care. Further work needs to be done to
forward. Ultimately, a concentrated ATXA, if proved to be as elucidate the mechanism of action, specific formulation, dos-
effective as IV TXA, could improve on TXA use on the battle- age, use indications, and safety profile of ATXA.
field. If Vu et al are successful in testing IM TXA, depending
on the dosing, a prefilled syringe of TXA could be created for Take-home points are that:
IM or atomized use and thus give treating medical personnel
flexibility. • Difficult-to-treat epistaxis cases are often challenging to
manage and resource intensive.
• Preparation and stepwise use of multiple treatment mo-
There are several limits to our case series. First, this brief re-
port was done with only three cases, no control population, dalities are crucial for hemostasis in epistaxis.
and at a single center. Second, because there are no standard- • ATXA, if modified for potency and/or delivery system,
ized approaches to epistaxis management and our cases had may hold merit as an adjunctive therapy in difficult-to-
several common use therapies tried first, it is possible that treat epistaxis and other hemorrhage control settings.
ATXA use was superfluous and hemostasis would have been
achieved by repeating or slightly varying those therapies. Each Acknowledgments
of our three cases was packed after using ATXA, but it is our The authors wish to thank Dr Aimee Moulin and her re-
preliminary conclusion that using this adjunctive therapy search team at University of California-Davis, Department of
avoided ENT consultation, transfer to a higher level of medi- Emergency Medicine. Figure 1 photographs of ENS Benjamin
cal care, hospitalization, and repeat ED visits. Third, TXA is Jacobs and Aubrey Masino, RN, are used with their permis-
a lysine analog that binds to plasminogen and prevents fibri- sion and consent.
nolysis to promote clot stability. It is unclear how this mecha-
nism contributes to immediate hemostasis, if at all. To the best Disclosure
of our knowledge, unlike INK, TXA in intranasal absorption There are no financial support or funding disclosures to report.
has not been studied versus placebo or compared with IV dos-
age. Thus, the exact effective formulation and dose, as well as References
ATXA’s effectiveness on specific blood vessels of varying di- 1. Gifford TO, Orlandi RR. Epistaxis. Otolaryngol Clin North
Am. 2008;41(3):525-536.
ameter, are key questions that need to be answered. A clinical 2. Viehweg T, Rogerson J, Hudson JW. Epistaxis: diagnosis and
trial of ATXA versus placebo for epistaxis in the ED is ongoing treatment. J Oral Maxillofac Surg. 2006;64:511–518.
(ClinicalTrials.gov identifier: NCT02930941) at University of 3. Sethi RKV, Kozin ED, Abt NB, et al. Treatment disparities in
California-Davis and hopefully will shed some light on some the management of epistaxis in united states emergency de-
of these questions. partments. Laryngoscope. 2018;128:356–362.

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