This document discusses the use of tranexamic acid (TXA) in trauma patients to reduce hemorrhage and mortality. It summarizes two major studies on TXA - the CRASH-2 trial and the MATTERs study. The CRASH-2 trial found TXA reduced mortality in trauma patients, though some critique the applicability of the results to severely injured patients in developed trauma systems. The MATTERs study in military patients also found reduced mortality with TXA. However, both studies found a potential increased risk of thrombosis with TXA use. Overall, the document examines the evidence for and criticisms of using TXA to reduce hemorrhage in trauma patients.

1. Greetings,
Welcome to the internal educational program (IEP) of the Vanderbilt University Division of Trauma,
Emergency Surgery and Surgical Critical Care. Our goal is to provide an opportunity to pursue topics
germane to trauma from all aspects of the team. My hope is to explore all areas of interest throughout the
course of the year including pre-hospital care, acute care issues, post-discharge requirements, as well as
injury prevention. We will attempt to outline the care provided to our trauma patient population from
point of injury until the patients care is completed.
As you know, the trauma team consists of the Chief of the Division, Dr. Rick Miller, our Trauma Program
Manager, Melissa Smith, RN, the Performance Improvement Director, Dr. Brad Dennis, the Outreach and
Prevention coordinator, Cathy Wilson, RN, the Trauma Resuscitation Manager, Kevin High, RN, as well as the
entire trauma faculty and Acute Care Surgery Fellows. Our multidisciplinary liaison team includes Tyler
Barrett (EM), Robert Boyce (Ortho), Reid Thompson (Neurosurgery), Shannon Kilkelly (Anesthesia), Peter
Bream (Radiology) and the LifeFlight team. Our goal is to improve the care of the trauma patient in a caring
and consistent manner and to help minimize injury in the Middle Tennessee region through outreach and
prevention efforts determined by the needs of the community. Please take a few minutes to review this
material and complete the survey.
Yours Truly,
Oscar Guillamondegui
Spring 2017
The ACS trauma education requirement (for faculty
who are not liaisons) may be met by documenting
acquisition of 16 hours of trauma-related CME per
year on average or by demonstrating participation in
an internal educational process (IEP) conducted by
the trauma program based on the principles of
practice-based learning and the PIPs program.

2. 1. Most common cause of bladder injury is caused by?
a. Motor vehicle accident
b. Falls
c. Crush Injury
d. Stab wound
2. Symptoms of bladder injury include?
a. Gross hematuria
b. Suprapubic pain and tenderness
c. Inability to void
d. All of the above
3. Indication for operative repair of extraperitoneal bladder injury?
a. Simple extraperitoneal rupture with properly draining catheter without clots.
b. Patient undergoing operative fixation of pelvis requiring hardware and vaginal injury.
c. No extravasation on retrograde cystography on day 10 after foley catheter drainage.
d. Grade I injury: contusion of bladder.
4. Retrograde cystography requires adequate bladder distension with how much contrast?
a. None
b. < 50cc
c. 350-400cc
d. 200cc
5. Bladder lacerations should be repaired with?
a. Absorbable suture
b. Silk suture
c. Prolene suture
d. Skin stapler
Answer Key for Winter 2017 Trauma IEP Newsletter
(answers are in bold and Italics below)

3. Andrew Hopper, MD
Morbidity and mortality secondary to trauma is a global health problem. Over 4 million people die of
injuries every year.1 Estimates put deaths each year, as a result of road traffic injuries, at approximately a
million plus worldwide. It is also estimated that over 1.6 million people die every year because of
intentional acts of interpersonal, collective, or self-directed violence.1 Researchers believe that hemorrhage
is responsible for about a third of in-hospital trauma deaths. Hemorrhage shock is the most common cause
of shock in the injured patient. Hemorrhage has been shown to be a major contributing factor to the
mortality of trauma patients.
When bleeding occurs, the body activates the hemostatic system. This system can be broken up into
three components: primary hemostasis, fibrin formation, and removal of fibrin.2 Primary hemostasis
involves vasoconstriction of vessels (arachidonic acid, thromboxane A2, prostaglandins) followed by
formation of a platelet plug. With platelet plug formation, the coagulation cascade is activated. This then
leads to the combination of thrombin and fibrinogen, to ultimately form a stable fibrin clot. Finally, the
fibrin clot is removed via the fibrinolytic system. This occurs when plasmin cleaves the cross-linked fibrin,
causing clot dissolution. Trauma patients are at risk for the development of hyperfibrinolysis. This
phenomenon can potentially lead to continued bleeding in the severely injured. Antifibrinolytic agents
reduce blood loss in patients with both normal and exaggerated fibrinolytic responses.
The morbidity and mortality secondary to hemorrhage in the critically injured trauma patient is well
established in the literature. The body’s natural hemostatic system is important for control of hemorrhage
in the patient. Fibrinolysis, a component of the hemostatic system is designed to remove the clot. However,
in a trauma patient with on-going bleeding, removal of the clot is not ideal; instead, the patient needs clot
stabilization. One way to prevent hyperfibrinolysis is with the use of tranexamic acid (TXA). Tranexamic
acid is a synthetic derivative of the amino acid lysine. It is believed that tranexamic acid works by being a
competitive inhibitor for the activation of plasminogen to plasmin (Figure 1). Reports indicate that
tranexamic acid has eight times the antifibrinolytic activity of epsilon-aminocaproic acid.
Tranexamic acid is currently being used in trauma patients at hospitals around the world. Multiple
studies have examined the use of TXA in trauma patients. Two of the largest and most recognized studies
are the CRASH 2 and the MATTERs study.
CRASH-2 was a randomized, placebo-controlled trial. In this UK organized study, 20,211 adult
trauma patients from 274 hospitals and 40 countries were included. Patients were randomized to either
tranexamic acid (loading dose 1g over 10min then infusion of 1g over 8h) or matching placebo. Primary
outcome was measured as death in the hospital within 4 weeks of injury. Mortality was significantly
reduced with tranexamic acid vs. placebo (14.5% vs. 16%). The risk of death due to bleeding was
significantly reduced (4.9% vs. 5.7%). Also, the CRASH-2 authors found that early treatment (<1 hour from
injury) significantly reduced the risk of death due to bleeding (5.3% vs. 7.7%). Treatment given between 1
and 3 hours also reduced the risk of death due to bleeding (4.8% vs 6.1%). However, treatment given after
3 hours seemed to increase the risk of death due to bleeding (4.4% vs. 3.1%).3,4

4. The CRASH2 trial is not without critique however. First, concerns exist regarding the study
population. Many argue that the study population does not represent a truly sick trauma population, with
potential that the inclusion criteria diluted out the sick bleeding patients. The data shows that only about a
third of the patients were hypotensive and only half actually required blood transfusions. Furthermore, only
about 5% of patients died from bleeding. Thus, there is debate about the applicability of the results to a truly
sick, bleeding trauma patients. Second, 68% of the patients were blunt trauma patients - which also raises
questions as to how these results apply to sick penetrating trauma patients.5 Third, about 75% of patients
were enrolled in third-world countries. These countries do not have the same training, resources, or
infrastructure typically associated with more developed countries and trauma systems.
In addition to the CRASH-2 trial, there is also the Military Application of Tranexamic Acid in Trauma
Emergency Resuscitation (MATTERs) Study. This study is in military patients and attempts to address some
of the critiques of the CRASH-2 trial. MATTERs is a retrospective observational study that examined 896
consecutive admissions with combat injury. Of the 896 patients reviewed, 293 received TXA. The
investigators used mortality at 24 hours, 48 hours, and 30 days as well as the influence of TXA
administration on postoperative coagulopathy and the rate of thromboembolic complications as their major
outcomes. The TXA group had lower unadjusted mortality than the no-TXA group (17.4% vs 23.9%,
respectively; P=.03). This lower mortality was in spite of being more severely injured: (mean [SD] Injury
Severity Score, 25.2 [16.6] vs 22.5 [18.5], respectively; P<001). The researchers also examined patients that
received massive transfusions. The mortality benefit of TXA was even more pronounced in the massive
transfusion group: (14.4% vs 28.1%, respectively; P=.004). The authors concluded that treatment with TXA
should be implemented into clinical practice as part of a resuscitation strategy following severe wartime
injury and hemorrhage.6 However, this was a retrospective study and therefore has the potential pitfalls
associated with any retrospective study. Also, the patient population was primarily young, healthy, military
patients. Again, how well does this patient population apply to our civilian patient population? Finally, there
was a higher risk of pulmonary embolism (PE) and deep vein thrombosis (DVT) with the TXA group. PE was
more common in the TXA group vs. non-TXA group [8 (2.7%) vs. 2 (0.3%]. This result was also seen with
DVTs [ 7 (2.4%) vs. 1 (0.2%)]. The authors attempt to justify this increased risk of thrombosis because of the
higher injury burden in the TXA group. However, it’s unclear if the higher risk of thrombosis is secondary to
higher injury burden or a side effect of TXA treatment.
The most common side effects seen with tranexamic acid are nausea, vomiting, diarrhea, rash, and
muscle pain. Since tranexamic acid prevents clot dissolution, there is also concern for deep vein thrombosis
and pulmonary vein thrombosis. Garg et. Al. wrote a case report of a patient with ST segment elevation after
receiving a dose of 10 mg/kg of tranexamic acid. The patient had emergent coronary angiography which
demonstrated complete occlusion of the distal right coronary artery. The patient was successfully treated
with thrombectomy and percutaneous coronary intervention.7
Despite these few case reports, overall TXA may be safe to administer. A 2015 Cochrane update on
TXA says that it safely reduces mortality in trauma patients with bleeding without increasing the risk of
adverse events. Per the results of the CRASH-2 trial, the Cochrane editors recommend that TXA should be
given as early as possible and within three hours of injury.1
As emphasized, hemorrhage is a leading cause of morbidity and mortality in trauma patients. The
body’s natural coagulation cascade attempts to control the bleeding. However, in severely injured and
bleeding trauma patients, sometimes the coagulation system gets reversed too soon as the body proceeds to
the fibrinolysis stage. TXA, a lysine analog, appears to disrupt the fibrinolysis system. The two largest
studies using TXA in trauma patients seem to demonstrate that its use is safe and can lead to improved
mortality rates. However, neither study is without critique. There is an ongoing study from the University of
Pennsylvania called the Study of Tranexamic Acid during Air Medical Prehospital transport trial (STAAMP).
The authors will study the effect of infusing TXA during air medical transport on 30 day mortality in patients

5. at risk of bleeding as compared to placebo. They will also examine the effects of TXA on other clinical
outcomes (clotting measurements on arrival to trauma center, total blood transfusion requirements during
the first 24 hours, the development of multiple organ failure, hospital-acquired infection, acute lung injury
and abnormal clotting throughout the body). Ultimately, more prospective, randomized trials in severely
injured trauma patients are needed to provide a more detailed and thorough analysis.
Figure 1: Schematic illustrating the mechanism of action of tranexamic acid and epsilon-aminocaproic acid.
Due to structural similarities to lysine, both tranexamic acid and epsilon-aminocaproic acid moieties
competitively inhibit binding of fibrin to plasminogen via interaction at an active lysine-binding site. The
binding of fibrin to plasminogen is facilitated by a tissue plasminogen activator (t-PA). When either
tranexamic acid or epsilon-aminocaproic acid is bound to the lysine-binding site on plasminogen,
fibrinolysis is prevented, with concomitant stabilization of the fibrin clot over the bleeding vessel. Dunn CJ,
Goa KL: Tranexamic acid: a review of its use in surgery and other indications. Drugs. 1999 Jun;57[6]:1005-
32.) http://reviews.jbjs.org/content/3/6/e1.figures-only

6. References:
1. Ker K, Roberts I, Shakur H, Coats TJ. Antifibrinolytic drugs for acute traumatic injury. Cochrane Database
of Systematic Reviews 2015, Issue 5. Art. No.: CD004896. DOI: 10.1002/14651858.CD004896.pub4.
2. Pieracci Fredric M, Kashuk Jeffry L, Moore Ernest E. “Postinjury Hemotherapy and Hemostasis.” Trauma.
Editors: Mattox Kenneth, Moore Ernest, Feliciano David. McGraw-Hill Companies. 7th edition. Pages: 216-
235.
3. Shakur H, Roberts I, Bautista R, et al; CRASH-2 Trial Collaborators. Effects of tranexamic acid on death,
vascular occlusive events, and blood transfusion in trauma patients with significant hemorrhage
(CRASH-2): a randomized, placebo-controlled trial. Lancet. 2010;376(9734):23-32.
4. Roberts I, Shakur H, Coats T, Hunt B, Balogun E, Barnetson L, et al. “The CRASH-2 trial: a randomized
controlled trial and economic evaluation of the effects of tranexamic acid on death, vascular occlusive
events and transfusion requirement in bleeding trauma patients.” Health Technol Assess 2013;17(10).
5. Inaba, Kenji. “Antifibrinolytics in Trauma Patients. Published Online: October 17, 2011. Arch Surg.
doi:10.1001. /archsurg.2011.286
6. Morrison JJ, Dubose JJ, Rasmussen TE, Midwinter MJ. Military Application of Tranexamic Acid in Trauma
Emergency Resuscitation (MATTERs) Study [published online October 17, 2011]. Arch Surg.
doi:10.1001/archsurg.2011.287
7. Garg, Jalaj MD*; Pinnamaneni, Sowmya MD; Aronow, Wilbert S. MD; Ahmad, Hasan MD. “ST Elevation
Myocardial Infarction After Tranexamic Acid: First Reported Case in the United States.” American Journal
of Therapeutics: November/December 2014 - Volume 21 - Issue 6 - p e221–e224.
8. Virgilio, Christian de, Yahoubian Arezou, Smith Jennifer. “Hemostasis.” Review of Surgery for Absite and
Boards. Saunders Elsevier 2010. P107-113.

7. Stop the Bleed Resources:
https://www.dhs.gov/stopthebleed
http://www.bleedingcontrol.org/
http://bulletin.facs.org/2016/03/the-hartford-consensus-iv-a-call-for-increased-national-resilience/
http://bulletin.facs.org/2013/06/improving-survival-from-active-shooter-events/
2017 National Trauma
Awareness Month
The month of May is National Trauma
Awareness Month. This May, National
Trauma Awareness Month celebrates
its 29th anniversary supporting efforts
to StopTheBleed. StopTheBleed is a
nationwide campaign to empower
individuals to act quickly and save
lives. Uncontrolled bleeding injuries
can result from natural and manmade
disasters and from everyday accidents.
If this bleeding is severe, it can kill
within minutes, potentially before
trained responders can arrive.
Providing bystanders with basic tools
and information on the simple steps
they can take in an emergency
situation to stop life threatening
bleeding can save lives. Similar to the
use of CPR or automatic defibrillators,
improving public awareness about
how to stop severe bleeding and
expanding personal and public access
to Bleeding Control Kits can be the
difference between life and death for
an injured person.
Vanderbilt Trauma’s Mission
The Vanderbilt Trauma team will be
providing several StopTheBleed classes
throughout the month of May. Anyone can
attend these classes. It is important for
staff with no medical knowledge to attend
this course as it is designed to help those
individuals control life threatening
hemorrhage.
The class dates will be sent out closer to
the event month and will also be on Nurse
Alerts.

8. Division of Trauma and Surgical Critical Care
For any questions in regards to the IEP or Trauma
cases please contact:
Melissa Smith: 322.6745
or
Brad Dennis: 936.0286
Melissa Smith – Trauma Program Mgr
melissa.d.smith@vanderbilt.edu
Oscar Guillamondegui – Trauma Medical
Director
Oscar.guillamondegui@vanderbilt.edu
Brad Dennis – Trauma PI Director
Bradley.m.dennis@vanderbilt.edu
Cathy Wilson – Trauma Outreach & Injury
Prevention Coordinator
Catherine.s.wilson@vanderbilt.edu
Andrew Hopper– ACS Fellow/IEP editor
julie.valezuela@vanderbilt.edu
Upcoming Courses
2017 Courses:
ASSET- April 11
ATLS Provider – April 20/21
ATLS Instructor – May 11
RTTDC- May 25 (Jennie Stuart)
ATLS Provider (residency course) –
June 8-9