Management of

Anticoagulation Agents in
Tra u m a P a t i e n t s
a, b
C. Cameron McCoy, MD *, Jeffrey H. Lawson, MD, PhD ,
Mark L. Shapiro, MDc

KEYWORDS
 Trauma  Anticoagulation  Thromboelastography  Hemorrhage  Hemostasis

KEY POINTS
 Early identification of anticoagulation status is key to injury management in the trauma
patient.
 Whereas some anticoagulant effects are detected on standard assays, such as prothrom-
bin time and activated partial thromboplastin time, the effect of other, newer agents is only
evident on specialized assays or thromboelastography.
 Knowledge of specific reversal strategies for individual agents such as direct thrombin
and factor Xa inhibitors is essential in managing acute, traumatic hemorrhage.
 Direct antidotes are not available for many newer anticoagulants; the management of
hemorrhage is complicated by these drugs, and is currently focused on resuscitation
and factor replacement.

INTRODUCTION

Anticoagulation adds additional complexity to the assessment and management of

the trauma patient.1,2 Trauma clinicians must act quickly to determine the patient’s
medications, complexity of injury, coagulation status, and the most appropriate
reversal strategy. The broad range of anticoagulants encountered includes antiplatelet
agents, low molecular weight heparin (LMWH), vitamin K antagonists (VKAs), and
newer, direct inhibitors of factors in the coagulation cascade. The use of particular
agents may suggest concurrent medical comorbidities that should be taken into

The authors have no disclosures or conflicts of interest to declare.

a
Department of Surgery, Duke University Medical Center, Duke University, Box 3443, Room
3581, White Zone, Duke South, Durham, NC 27710, USA; b Division of Vascular Surgery, Depart-
ment of Surgery, Duke University Medical Center, Duke University, Box 2622, Room 481 MSRB 1
Research Drive, Durham, NC 27710, USA; c Division of Trauma & Critical Care, Department of
Surgery, Duke University Medical Center, Duke University, 1557 F Duke South, Blue Zone
Box 2837, Durham, NC 27710, USA
* Corresponding author.
E-mail address: Christopher.mccoy@dm.duke.edu

Clin Lab Med - (2014) -–-

http://dx.doi.org/10.1016/j.cll.2014.06.013 labmed.theclinics.com
0272-2712/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
2 McCoy et al

consideration during the initial phase of trauma assessment and care. Once anticoag-
ulant medications are identified, the patient’s assessment should include laboratory
assessment of their coagulation state. Traditional studies such as activated partial
thromboplastin time (aPTT) and international normalized ratio (INR) may be
augmented by functional assays of coagulation such as thromboelastography
(TEG). Simultaneously, the patient’s complexity of injury should be assessed for any
indications to administer reversal. In addition to an accurate physical examination,
radiographic studies should be used to determine the presence of occult hemorrhage
in the setting of anticoagulation. Once the clinician has determined the patient’s anti-
coagulation status and complexity of injury, reversal of anticoagulation can be tar-
geted to specific agents and injuries. Failure to rapidly assess these factors can
result in delays in restoring hemostasis, and increased morbidity and mortality from
injury.

INITIAL ASSESSMENT OF THE ANTICOAGULATED TRAUMA PATIENT

The identification of injuries and determination of the extent of anticoagulation are

essential steps in the initial assessment of any trauma patient. The coagulation status
should be identified early during ascertainment of the medical history. Injuries exacer-
bated by therapeutic coagulation will also be identified on examination and will guide
further diagnostics. Laboratory studies should also be drawn to ensure their availabil-
ity at the earliest opportunity to guide possible reversal. Based on the patient’s history
and results from the primary survey and physical examination, radiographic studies
should be performed to identify occult injuries that could also be complicated by
the patient’s anticoagulation status.

Patient’s History and Physical Examination

It is essential to identify patients on therapeutic anticoagulation during the secondary
trauma survey. Special attention should be paid to current home medications to iden-
tify agents affecting coagulation. This information may be available from the patient,
the patient’s family, or prehospital care providers. Other clues to medical conditions
requiring anticoagulation treatment include previous surgical scars for procedures
such as valve replacement and medical alert badges. Suspicion of anticoagulation
based on clinical presentation and medical comorbidities may also be sufficient to
warrant further investigation of a patient’s coagulation status. Failure to obtain a com-
plete history, including medication, may result in serious complications from uncon-
trolled hemorrhage.

Laboratory Analysis
Laboratory analysis to determine the extent of anticoagulation in the trauma patient is
a crucial early assessment step. The initial laboratory analysis for most trauma pa-
tients, regardless of known coagulation status, often includes prothrombin time
(PT), aPTT, and platelet count as the sole indicators of coagulation status.3 For
some anticoagulants, such as VKAs, these data may be sufficient to determine the
level of anticoagulation and guide reversal. With other agents, such as direct thrombin
and factor Xa inhibitors, these assays provide unreliable means of identifying the level
of anticoagulation and drug activity. Details regarding the laboratory assessment of
specific anticoagulant medications during trauma are described in a subsequent
section.
Functional assays of coagulation such as TEG are also becoming more readily avail-
able and can guide care for patients on anticoagulants. TEG (TEG 5000; Haemonetics,
 Anticoagulation Agents in Trauma Patients 3

Braintree, MA, USA) and rotational thromboelastometry (ROTEM; TEM Systems Inc,
Durham, NC, USA) are increasingly used to provide a more complete assessment of
coagulation status for trauma patients.4–6 These newer assays provide results more
rapidly (15–20 minutes) than traditional assays such as aPTT or platelet count (45–
60 minutes).4,7 Originally described in 1948, TEG and ROTEM provide information
on clot formation, propagation, stabilization, and dissolution.6 Various therapeutic an-
ticoagulants produce distinct effects on these assays (Fig. 1). Thromboelastographic
changes specific to individual agents are discussed in a subsequent section.
Radiographic Studies
Following the initial assessment, and often run concurrently with laboratory assays,
radiographic studies are used to detect occult injuries and internal hemorrhage in
the anticoagulated trauma patient. Computed tomography (CT) is the most widely
used diagnostic method for this purpose.8,9 In particular, anticoagulated patients sus-
pected of traumatic brain injury should undergo a head CT scan to assess for occult
intracranial hemorrhage (ICH). Although the UK National Institute for Health and Care
Excellence guidelines suggest that routine head CT scanning is not necessary for all
patients on therapeutic anticoagulation with head trauma,10 multiple studies have
demonstrated missed ICH and current practice in many institutions is to obtain a
head CT scan on presentation for these patients.11,12 Demonstration of ICH by the
initial head CT scan of the anticoagulated trauma patient indicates the need for urgent
anticoagulation reversal, unless the risk is prohibitive owing to the likelihood of throm-
boembolic complications for an individual patient.

MANAGEMENT OF THE ANTICOAGULATED TRAUMA PATIENT

Vitamin K Antagonists
Some of the most commonly used therapeutic anticoagulants are VKAs such as
warfarin. Indications for warfarin use are some forms of atrial fibrillation, the presence
of a metallic valve or ventricular assist device, deep vein thrombosis, and pulmonary
embolism.13 Approximately 3% of patients presenting to Level 1 trauma centers in one
study were anticoagulated with this agent. In these patients, warfarin treatment was
associated with a 3-fold increase in mortality compared with those not taking warfarin
or antiplatelet agents.14 Based on this evidence, trauma patients on warfarin should
receive urgent reversal if an indication exists.
Warfarin’s anticoagulation effect is monitored via the INR. Some guidelines recom-
mend a target INR of 1.6 for anticoagulation reversal, with stepwise administration of

Fig. 1. Changes in thromboelastography secondary to anticoagulation. DFXaI, direct factor

Xa inhibitor; DTI, direct thrombin inhibitor; LMWH, low molecular weight heparin.
4 McCoy et al

a reversal agent followed by repeat INR measurement before additional administra-

tion.15 Indications for the reversal of warfarin in trauma patients include ICH and un-
controlled hemorrhage elsewhere in the body. The Eastern Association for the
Surgery of Trauma guidelines state that patients with posttraumatic ICH should
begin therapy to correct their INR to less than 1.6 within 2 hours of arrival, and reach
an INR of less than 1.6 within 4 hours.15 Early reversal has been demonstrated to
reduce hemorrhage progression and mortality.16 Anticoagulated patients with head
trauma but without radiographic evidence of ICH should not receive preventive
reversal. Patients presenting with a hemorrhage in other locations aside from the
brain should have reversal considered on a patient-by-patient basis, taking into ac-
count the extent of injury and the potential risks associated with anticoagulation
reversal.
Fresh frozen plasma (FFP) has been the traditional reversal agent for warfarin in
trauma patients.17 FFP, as a blood product, requires frozen storage and associated
thawing time in addition to ABO compatibility testing, and carries a risk of
transfusion-related complications.18,19 Thawing time and ABO compatibility testing
may not pose a delay at centers capable of maintaining thawed FFP stores of type
AB, but availability in large volumes or at smaller centers is not guaranteed.16 In addi-
tion, multiple doses of FFP are often required to reduce the INR to levels necessary for
normal hemostasis. Administration of large volumes of FFP poses a risk for patients
with medical comorbidities such as congestive heart failure who do not require volume
resuscitation. Because of these issues, prothrombin complex concentrate (PCC) has
gained favor as the agent of choice for emergent warfarin reversal.
PCCs are available as 3-factor (factors II, IX, X) or 4-factor (factors II, VII, IX, X) con-
centrates. These agents have a low risk of infection because of viral inactivation, do
not require cross-matching, and are administered in low volumes; moreover, thera-
peutic doses can be infused within 15 to 30 minutes.20,21 The current American Col-
lege of Chest Physicians guidelines recommend the use of PCC over FFP for
reversal of warfarin in patients with serious hemorrhage.22 Kcentra (CSL Behring,
King of Prussia, PA, USA), a 4-factor PCC, has recently been licensed for urgent
warfarin reversal in the United States.23 The lack of cross-matching and speed of
correction make PCCs the ideal agents for correction of warfarin anticoagulation in
trauma patients (Table 1).
Limited evidence exists regarding the use of recombinant activated factor VII
(rFVIIa) for reversal of VKA-related hemorrhage.17 Use of rFVIIa in VKA-
anticoagulated patients presenting with a traumatic hemorrhage should be reserved
for cases when first-line agents are not available.24 rFVIIa carries a significant risk of
thrombosis. By comparison, PCCs contain minimal levels of activated clotting factors
in addition to some level of Protein C and S. As a result, PCCs carry a theoretically
lower risk of thrombosis than rFVIIa.

Direct Thrombin Inhibitors

Direct thrombin inhibitors (DTIs) are reversible, competitive inhibitors that block the
active site of thrombin, and do not require a cofactor to exert their effect on the coag-
ulation cascade. As DTIs are relatively new oral anticoagulants, fewer data exist
regarding the management of posttraumatic hemorrhage in patients taking these
agents. One such agent, dabigatran etexilate, is approved in several countries for
the prevention of venous thromboembolism in patients undergoing total hip or knee
replacement and the prevention of stroke or embolism in patients with nonvalvular
atrial fibrillation.25–27 Dabigatran is mainly eliminated by renal clearance, and blood
levels can be decreased through diuresis and dialysis.28
 Anticoagulation Agents in Trauma Patients 5

Table 1
Anticoagulants and urgent reversal strategies

Anticoagulant Mechanism Urgent Reversal Strategy

VKA (eg, warfarin)
Oral DTI (eg, dabigatran)
Direct factor Xa inhibitor
(eg, rivaroxaban)
LMWH (eg, enoxaparin)
Aspirin
Clopidogrel
Epoxide reductase
inhibition
Competitive, reversible direct
inhibition of thrombin
Competitive, reversible direct
inhibition of factor Xa
Potentiation of
antithrombin III
Cyclooxygenase-1
inhibition
Irreversible inhibition of
platelet P2Y12 ADP
receptor
First line: PCC
Second line: FFP
First line: PCC including
FEIBA, rFVIIa
Second line: hemodialysis
Pending: direct inhibitors
(eg, anti-Dabi Fab)
First line: PCC
Poorly removed by
hemodialysis
First line: protamine
(temporary, partial), rFVIIa
First line: platelet transfusion
Second line: desmopressin
First line: platelet transfusion
Second line: desmopressin

Abbreviations: ADP, adenosine diphosphate; DTI, direct thrombin inhibitor; FEIBA, factor VIII inhib-
itor bypassing activity; FFP, fresh frozen plasma; LMWH, low molecular weight heparin; PCC, pro-
thrombin complex concentrate; rFVIIa, recombinant activated factor VII; VKA, vitamin K
antagonist.

DTIs affect multiple coagulation studies, including thrombin clotting time (TCT), PT,
aPTT and ecarin clotting time (ECT).29,30 The aPTT does not provide a linear repre-
sentation of plasma DTI levels. The aPTT underestimates DTI activity at high plasma
concentrations, whereas TCT may overestimate DTI levels; its use should be
reserved to ruling out the presence of any residual DTI activity, as a normal TCT en-
sures that no DTI anticoagulation effect is present. The preferred assay for quantita-
tive assessment of DTI activity is ECT, which was originally developed to monitor
hirudin-type DTI activity. ECT is the only dose-responsive assay for DTIs. Unfortu-
nately, it is uncommon and its availability in smaller institutions may be limited.
DTIs such as dabigatran and argatroban produce dose-dependent increases in clot-
ting time on InTEM (ellagic acid–activated intrinsic pathway thromboelastometry) (see
Fig. 1).31 These changes in clotting time are based on direct inhibition of thrombin by
the drug.
Initial management of uncontrolled bleeding complicated by DTIs should focus on
volume and blood product resuscitation. Although the manufacturer recommends
FFP to assist with restoring circulating coagulation factors, it is unlikely to reverse
the drug effect based on its mechanism.32,33 Animal models and case study reports
suggest that rFVIIa significantly reduces bleeding time and may be useful in treating
hemorrhage in subjects receiving a DTI, but this effect is agent-dependent and
dose-dependent.34–38
Both activated and nonactivated PCCs have also been evaluated as agents for
emergency reversal of dabigatran (see Table 1). Animal models suggest that these
agents significantly reduce dabigatran-induced prolongation of bleeding time. How-
ever, clinical data regarding their use in hemorrhaging patients are limited to case
reports.39,40 Further details on results from these case reports are available in the
article by Levy and Levi elsewhere in this issue. Looking forward, a true antidote
6 McCoy et al

(anti-Dabi Fab), which complexes with dabigatran in a similar manner to that of

thrombin and functions as a high-affinity competitive inhibitor, is under development
for emergency reversal of dabigatran anticoagulation.41 At present, PCCs are the
agent of choice to treat posttraumatic hemorrhage in patients on DTIs.

Direct Factor Xa Inhibitors

Another class of new oral anticoagulants, direct factor Xa inhibitors, are associated
with many of the same difficulties in controlling posttraumatic hemorrhage as DTIs.
Direct factor Xa inhibitors, like DTIs with thrombin, are capable of accessing not
only free factor Xa but also factor Xa associated with the prothrombinase complex
and established clot.42,43 One direct factor Xa inhibitor, rivaroxaban, is currently
approved in the United States for the prevention of venous thromboembolism in pa-
tients undergoing total hip or knee replacement surgery.44,45 In clinical practice, rivar-
oxaban is replacing LMWH as the agent of choice in this role.
Treatment with direct factor Xa inhibitors results in prolongation of the PT and aPTT.
Platelet aggregation does not seem to be affected.46 Direct factor Xa inhibitor treat-
ment also produces dose-dependent increases in clotting time on InTEM (see
Fig. 1). These changes in clotting time also mirror dose-dependent changes in PT
and are similar to changes seen with DTIs.47,48
FFP is unlikely to provide direct factor Xa reversal, but will help to maintain coagu-
lation factor levels during an ongoing hemorrhage. High-dose PCC (50 IU/kg) and acti-
vated PCC (50 IU/kg) administration have demonstrated efficacy in normalizing
bleeding time in an animal model (see Table 1).49 This dose is approximately twice
the amount of PCC administered to reverse hemorrhage secondary to VKAs in pa-
tients with a pretreatment INR of 2 to 4 (25 IU/kg).23 High-affinity competitive inhibi-
tors, such as those for DTIs, are also under development and are being tested in
animal models, with promising results showing complete PT normalization. Similarly
to DTI reversal, PCCs are currently the best available agents for reversal of direct fac-
tor Xa inhibitors.

Low Molecular Weight Heparin

Enoxaparin is the most widely used LMWH for outpatient anticoagulation, and the
heparinoid most likely to be encountered in the setting of acute trauma.50 Owing to
their lighter weight compared with unfractionated heparin, LMWHs exhibit anti-
thrombin III–dependent coagulation factor inactivation but also significant anti–factor
Xa activity.
LMWH activity may be assessed using an anti–factor Xa assay, available in many
hospital clinical laboratories.51 Unfortunately, this assay takes a minimum of 1 to
2 hours to complete and does not provide timely data in acute trauma care. Patients
taking heparinoid anticoagulation demonstrate prolonged clotting time on the InTEM
assay of ROTEM and prolonged reaction time on TEG (see Fig. 1). These changes
represent inhibition of thrombin burst formation by the circulating anticoagulant.52
This finding can be confirmed in ROTEM by performing the HEPTEM (heparinase-
modified thromboelastometry) test.
There is no US Food and Drug Administration (FDA)-approved antidote for LMWHs,
but protamine sulfate exhibits partial, temporary reversal of anti–factor IIa activity (see
Table 1).20,53 Anticoagulant activity may return as soon as 3 hours following reversal,
so ongoing administration is vital. Case reports, small series, and in vitro studies have
documented successful outcomes and laboratory assay normalization using rFVIIa.54
However, the risk of thrombosis must be balanced with the possibility of ongoing hem-
orrhage when using this agent for the reversal of LMWHs.
 Anticoagulation Agents in Trauma Patients 7

Antiplatelet Agents
Antiplatelet agents such as aspirin and clopidogrel are used individually and in com-
bination for the treatment of cardiovascular disease.55,56 Patients who have under-
gone percutaneous coronary intervention are often temporarily or permanently
dependent on these medications to maintain stent patency. As a result, caution
must be used during attempted reversal of traumatic hemorrhage, owing to the risk
of stent thrombosis and subsequent myocardial infarction. Numerous studies have
demonstrated a greater degree of progression of ICH and worse outcomes in trauma
patients taking antiplatelet agents.57,58
Aspirin irreversibly acetylates a specific serine moiety of platelet cyclooxygenase
(COX)-1, thereby reducing the synthesis of thromboxane A2.59 Thromboxane A2
acts as a potent platelet aggregator and vasoconstrictor. Aspirin’s effect is clinically
evident in arachidonic acid (AA)-based or collagen-based aggregation assays, but
bleeding time is rarely prolonged.60 The platelet function assay using collagen-
based and adenosine diphosphate (ADP)-based activation also demonstrates aspirin
inactivation, but results are not available in the acute setting owing to the test duration.
Newer assays, such as VerifyNow (Accumetrics, San Diego, CA, USA), aim to provide
faster results that reflect the true bleeding potential of patients taking antiplatelet
agents.61
Clopidogrel irreversibly blocks the binding of ADP to platelet P2Y12 receptors and
thereby inhibits further release of ADP from platelets.59 ADP is a potent platelet acti-
vator, and clopidogrel interrupts the self-feedback activation loop normally estab-
lished by ADP release from platelet dense bodies.62 Unlike aspirin, clopidogrel
demonstrates both inhibition of platelet aggregation assays and a prolongation in
bleeding time.59 Early TEG poorly detected changes in platelet activation secondary
to antiplatelet agents such as aspirin and clopidogrel. Modern TEG for platelet func-
tion uses platelet-specific activators. TEG Platelet Mapping (Haemonetics) using
AA-based or ADP-based assays of blood from patients taking as little as 75 mg of
aspirin daily for 1 week demonstrates significant time-dependent reductions in
maximum amplitude and curve area (see Fig. 1).63,64 Similar reductions are seen in pa-
tients on clopidogrel using the ADP-based assay, but not the AA-based assay.
Owing to their irreversible mechanisms of action, aspirin and clopidogrel do not
have direct antidotes. When traumatic hemorrhage is present, the traditional belief
is that platelet function may be reestablished by the transfusion of nonacetylated
platelets. Some studies have demonstrated restoration of platelet activity with trans-
fusion for patients on a low-dose (75–81 mg/d) aspirin regimen, whereas others have
demonstrated failure of transfusion to halt ICH progression in patients on a high-dose
(325 mg/d) aspirin regimen.61,65 In the event of clinically significant bleeding, such as
traumatic ICH, older literature recommends the urgent transfusion of multiple units of
platelets for patients on clopidogrel.20
Numerous subsequent studies and reviews have now demonstrated that platelet
transfusion is not effective in reducing mortality or altering outcomes from traumatic
ICH complicated by some antiplatelet agents.65,66 Because many of these studies
were based at institutions without specific protocols for platelet transfusion, recent
studies have hypothesized that the extent and duration of platelet transfusion were
insufficient to affect outcomes.57 As a result a new protocol was developed, recom-
mending 5 platelet concentrate units for patients with small ICH on aspirin and 10
platelet concentrate units for patients with small ICH on clopidogrel. In more severe
cases of ICH, this protocol recommends the addition of desmopressin and serial
platelet transfusions every 12 hours for 48 hours (see Table 1). Additional platelet
8 McCoy et al

transfusion for up to 5 days may be necessary in patients on clopidogrel, owing to the

persistence of the drug’s active metabolite.

SUMMARY

Therapeutic anticoagulation presents unique challenges during the care of trauma

patients. Failure of normal hemostatic measures secondary to pharmacologic
blockade may turn clinically insignificant hemorrhage into an organ-threatening or
life-threatening situation. The spectrum of agents encountered by trauma clinicians
requires familiarity with coagulation physiology, drug mechanisms, and appropriate
reversal strategies. The advent of new anticoagulation agents poses additional
challenges because of the lack of adequate reversal agents. To provide optimal
trauma care for the anticoagulated patient, research and clinician education must
continue to match pace with drug development and transition to these newer
agents.

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