Antifibrinolytic Therapy and Perioperative Considerations

Review Article
Deborah J. Culley, M.D., Editor
Antifibrinolytic Therapy and Perioperative

Considerations
Jerrold H. Levy, M.D., F.A.H.A., F.C.C.M., Andreas Koster, M.D., Quintin J. Quinones, M.D., Ph.D.,
Truman J. Milling, M.D., Nigel S. Key, M.B., Ch.B., F.R.C.P.
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This article has been selected for the Anesthesiology CME Program. Learning objectives
and disclosure and ordering information can be found in the CME section at the front
of this issue.
ABSTRACT
Fibrinolysis is a physiologic component of hemostasis that functions to limit clot formation. However, after trauma or sur-
gery, excessive fibrinolysis may contribute to coagulopathy, bleeding, and inflammatory responses. Antifibrinolytic agents are
increasingly used to reduce bleeding, allogeneic blood administration, and adverse clinical outcomes. Tranexamic acid is the
agent most extensively studied and used in most countries. This review will explore the role of fibrinolysis as a pathologic
mechanism, review the different pharmacologic agents used to inhibit fibrinolysis, and focus on the role of tranexamic acid as
a therapeutic agent to reduce bleeding in patients after surgery and trauma. (Anesthesiology 2018; 128:657-70)
F IBRINOLYSIS is a physiologic component of hemo-

stasis that functions to limit clot formation.1 However,
after tissue injury associated with trauma or surgery, isch-
vascular injury, multiple hemostatic mechanisms are initi-
ated as shown in figure 1, resulting in thrombin generation,
platelet adhesion, cross-linking of platelets, and fibrin for-
emia and reperfusion, blood contact with large nonendothe- mation.1,2 As part of the hemostatic response to limit clot
lial surfaces such as cardiopulmonary bypass (CPB) circuits, formation, fibrinolysis is initiated. Fibrin, the end product
or as a contributing factor in other hemostatic disorders, of coagulation activation, becomes the cofactor for plasmin-
excessive fibrinolysis may contribute to coagulopathy, bleed- ogen activation by tissue plasminogen activator. Plasmin,
ing, and inflammatory responses. As a result, growing data the enzymatic factor in fibrinolysis, then lyses fibrin, but
have reported the efficacy of antifibrinolytic agents to reduce as a promiscuous enzyme with respect to substrate speci-
bleeding, allogeneic blood administration, and adverse clini- ficity, it can also mediate the proteolytic (in)activation of
cal outcomes. Of all the pharmacologic agents, tranexamic multiple hemostatic and inflammatory components when
acid is the agent most extensively studied in the literature present at concentrations that exceed the local and systemic
and used in most countries. This commentary will review inhibitors (most notably α2-antiplasmin), as shown in fig-
the role of fibrinolysis as a pathologic mechanism, review the ures 1 and 2.1,3,4 Overall, when regulated, fibrinolysis can
different pharmacologic agents used to inhibit fibrinolysis, be considered a protective physiologic response that appro-
and focus on the role of tranexamic acid as a therapeutic priately limits clot size. However, after major tissue damage
agent to reduce bleeding in patients. that occurs during surgical and traumatic injury, inhibit-
ing fibrinolysis may potentially inhibit other responses that
Fibrinolysis contribute to bleeding.2,5 Fibrinolysis also contributes to
Fibrinolysis regulates the extent of fibrin formation and coagulopathy by additional mechanisms beyond cleavage of
vascular obstruction during hemostasis. After tissue and fibrinogen and fibrin but also cleaving glycoprotein Ib and
This article is featured in “This Month in Anesthesiology,” page 1A. Figures 1 and 2 were enhanced by Sara Jarret, C.M.I.
Submitted for publication July 27, 2017. Accepted for publication October 2, 2017. From the Division of Cardiothoracic Anesthesiology
and Critical Care, Department of Anesthesiology, Duke University School of Medicine, Durham, North Carolina ( J.H.L, Q.J.Q.); Institute of
Anesthesiology, Heart and Diabetes Center North Rhine Westphalia, Bad Oeynhausen, Ruhr-University Bochum, Bochum, Germany (A.K.);
Seton Dell Medical School Stroke Institute, Austin, Texas (T.J.M.); and the Department of Medicine, Division of Hematology/Oncology, Uni-
versity of North Carolina, Chapel Hill, North Carolina (N.S.K.).
Copyright © 2018, the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc. All Rights Reserved. Anesthesiology 2018; 128:657–70
Anesthesiology, V 128 • No 3 657 March 2018
Copyright © 2018, the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
<zdoi;10.1097/ALN.0000000000001997>
Antifibrinolytic Therapy

Fig. 1. Simplified fibrinolysis pathway. For clot formation, the principal event is fibrin formation following vascular injury, tissue
factor binding to factor VIIa and activation of the Xase complex for hemostatic activation and thrombin generation. Thrombin
stimulates endothelial release of tissue plasminogen activator (tPA), but also increased vascular flow, kinins, and other factors
will release tissue plasminogen activator. Plasmin is released by formation of a plasminogen-tissue plasminogen activator
complex that assembles on fibrin and binds to lysine sites on fibrin clot. Once assembled, tissue plasminogen activator cleaves
plasminogen to its active form plasmin. Plasmin can also be generated by other mechanisms including urokinase, contact
activation, and kallikrein mediated protease activation. Fibrinolysis is inhibited by plasminogen activator inhibitors (PAI 1 and
PAI 2), and by thrombin binding to thrombomodulin to release and activate thrombin-activatable fibrinolysis inhibitor (not shown).
PAI = plasminogen activator inhibitor; TF = tissue factor.
IIb/IIIa receptors on platelets reducing platelet adhesion when activated by the thrombin-thrombomodulin complex,
and aggregation.6–8 removes lysine residues on fibrin, eliminating binding sites for
Thus, plasmin may exhibit multiple proinflammatory plasminogen, and may play an important role in regulating
responses that could stimulate pathophysiologic responses cross-talk between inflammation and coagulation.13
and multiorgan system failure. These adverse outcomes may With normal physiology, including an intact vascular
be attenuated with antifibrinolytic agents, and reports sug- and endothelial system, hemostatic balance is well preserved.
gest that antifibrinolytic therapy may improve mortality in However, after massive trauma, surgery, or extracorporeal cir-
high-risk patients undergoing cardiac surgery.9–11 culation, the ability to locally regulate fibrinolysis is exceeded,
such that plasmin generation and ensuing fibrinolysis become
Molecular Regulation of Fibrinolysis systemic, and coagulopathy ensues. This is the basis of phar-
The molecular activators of plasminogen are primarily tis- macologic administration of tranexamic acid that will be
sue-plasminogen activator but also urokinase-plasminogen reviewed. Although increasing data suggest the critical role
activator.2,6 Endothelial activation by a variety of agonists of hyperfibrinolysis as a pathologic cause of bleeding, there
releases tissue plasminogen activator from vascular endothe- is individual variability of fibrinolysis in all pathologic states.
lial cells, where it binds to fibrin and activates plasminogen This has led to potential concerns for an increase of plasmino-
to promote fibrinolysis at the site of clot formation. Activa- gen activator inhibitor 1 and a decrease of tissue plasminogen
tion of fibrinolysis is facilitated by sites in the plasminogen activator activity in some patients, a scenario that has been
molecule that bind to fibrin’s lysine residues.2,6 Tranexamic termed fibrinolytic shutdown.14,15 The theory is that patients
acid, a synthetic derivative of lysine, interferes with this step with fibrinolytic shutdown would not be expected to benefit
by occupying the lysine-binding sites in plasminogen. from an antifibrinolytic such as tranexamic acid, and may
The molecular inhibitors of fibrinolysis include plasmino- develop potential thrombotic effects. However, the clinical
gen activator inhibitor 1, which inhibits tissue plasmino- relevance of fibrinolytic shutdown is the subject of ongoing
gen activator, and plasminogen activator inhibitor 2, which debate and research.15–17
inhibits urokinase-plasminogen activator.2 The physiologic
inhibitor of plasmin is α2-antiplasmin but is currently called Laboratory Measurement of Fibrinolysis
plasmin inhibitor. Also, α2-macroglobulin functions as a plas- Over the years, multiple methods to assess fibrinolytic activity
min inhibitor. Factor XIIIa, a transglutaminase, cross-links in blood have been reported; however, there is no “gold stan-
fibrin to increase clot strength and render it more resistant dard” test.4 Available assays vary depending on whether whole
to fibrinolysis.12 Thrombin activatable fibrinolysis inhibitor, blood, plasma, or the euglobulin fraction of plasma is used for
Anesthesiology 2018; 128:657-70 658 Levy et al.
EDUCATION
the assessment of fibrinolysis. Point-of-care testing using whole acids such as lysine and its analogs inhibited the activation of
blood in a perioperative setting has the benefit of evaluating all plasminogen in vitro.23 Aprotinin, another fibrinolytic inhib-
plasma and cellular components including erythrocytes, plate- itor, is a broad-spectrum, naturally occurring protease inhibi-
lets, and mononuclear and polymorphonuclear leukocytes. tor that is only available in certain countries. Other molecular
The most extensively used tools for measuring fibrinoly- entities have been studied as potential fibrinolytic inhibitors
sis in a perioperative setting are thromboelastography and but are not approved for use, including nafamostat, MDCO-
rotational thromboelastometry that use different activators, 2010, and textilinins from Pseudonaja textilis.24–26 The three
including kaolin, tissue factor, or ellagic acid to measure vis- clinically available agents will be reviewed as follows.
coelastic changes in whole blood over time. Fibrinolysis is
measured by the rapidity of tapering of the clot over time Aprotinin
and is expressed as maximal lysis for rotational thromboelas-
Aprotinin is a protease inhibitor isolated from bovine lung

tometry. Maximal lysis greater than 3% is the critical value
for initiation of antifibrinolytic therapy in trauma, while a and is comprised of 58 amino acids with a molecular weight
value of greater than 15% suggests hyperfibrinolysis.4,18,19 of 6,512 Da. The molecular structure with its three kring-
Thromboelastography/thromboelastometry is the test les is structurally similar to tissue factor pathway inhibitor.
most often used clinically to determine fibrinolysis in trauma Aprotinin dosing is calculated in “kallikrein inhibiting units”
patients.20 With the increasing use of preemptive antifibrino- and protocols usually follow a “full-dose” (2 × 106 kallikrein
lytic therapy to reduce bleeding in trauma and surgery, there inhibiting units bolus followed by 5 × 105/h continuous
is some debate regarding the need for assessment of fibri- infusion) or a “half-dose” protocol. The agent is predomi-
nolysis. However, based on concerns regarding fibrinolytic nantly eliminated via proteolysis and only to a minor extend
shutdown in a subset of patients, there is growing interest via the kidneys. The initial plasma half-life is 150 min, with
in monitoring fibrinolysis in trauma.16 Thromboelastogra- a terminal half-life of approximately 10 h.27
phy and rotational thromboelastometry are frequently used Aprotinin is a broad-spectrum protease inhibitor that revers-
to assess fibrinolytic activation in trauma patients. How- ibly complexes with the active serine residue in various prote-
ever, they are not sensitive enough to detect minor degrees ases in plasma; reversibly inhibits trypsin, kallikrein, plasmin,
of fibrinolytic activation.15,18,21,22 There is ongoing debate elastase; and is the most potent antifibrinolytic agent.28 The
about their utility to detect fibrinolytic activation and guide propagation of fibrinolysis through Factor XIIa-mediated kal-
antifibrinolytic agent administration.19 likrein activation (contact activation) and plasmin generation
Other methods of evaluating fibrinolysis include plasma through tissue plasminogen activator–mediated plasminogen
turbidity methods based on measuring optical density activation is inhibited by ~4 µmol/l of aprotinin.28 However,
changes that reflect fibrin formation and lysis.4 The classic apart from these direct effects on the plasmatic coagulation
test for fibrinolysis is the euglobulin clot lysis time developed system, aprotinin also inhibits the protease-activated receptor
in the 1950s that acidifies citrated platelet-poor plasma to 1 thrombin receptor involved in both coagulation and inflam-
selectively precipitate certain factors including fibrin(ogen), mation.29 Aprotinin’s inhibition of protease-activated receptor
plasminogen, and tissue plasminogen activator, while 1 has been postulated to be a mechanism for stroke reduction
largely excluding the principal inhibitors of fibrinolysis after aprotinin administration for cardiac surgery.28,30,31
(plasminogen activator inhibitor 1, α2-antiplasmin, and α2- Despite multiple studies reporting its efficacy, several
macroglobulin). This “rebalancing” of plasma components reports questioned its safety, leading to its temporary removal
within the precipitate (the euglobulin fraction) allows the from the U.S. market. After a reanalysis of the data, the Euro-
measurement of endogenous fibrinolysis, which is normally pean Medicines Agency recommended in 2012 that its suspen-
inhibited by the large excess of fibrinolytic inhibitors. The sion in the European Union be lifted, and it is currently being
clot within the euglobulin fraction can be visually evalu- reintroduced in Europe. However, the European Medicines
ated until complete lysis occurs.4 Although there is no single Agency noted that aprotinin should only be given for “prophy-
gold standard assay for global measurement of fibrinolysis, lactic use to reduce blood loss and blood transfusion in adult
thromboelastography and rotational thromboelastometry patients who are at high risk of major blood loss undergoing
are the assays that are most often used in practice. isolated cardiopulmonary bypass graft surgery (i.e. coronary
artery bypass graft surgery that is not combined with other
Pharmacology of Antifibrinolytic Agents cardiovascular surgery” and “only after careful consideration
The two mainstay antifibrinolytic agents are the synthetic of the benefits and risks, and the consideration that alternative
lysine analogs tranexamic acid and ε-aminocaproic acid that treatments are available”) (http://www.ema.europa.eu/docs/
inhibit fibrinolysis by attaching to the lysine-binding site of en_GB/document_library/Referrals_document/Antifibrinol-
the plasmin(ogen) molecule, thereby displacing plasminogen ytic_medicines/WC500153601.pdf; accessed November 18,
from fibrin. Both tranexamic acid and ε-aminocaproic acid 2017). Additionally, the European Medicines Agency required
were developed and approved for use by regulatory agencies the establishment of a European registry for aprotinin use
more than 50 yr ago when it was found that some amino (http://www.ema.europa.eu/docs/en_GB/document_library/
Press_release/2012/02/WC500122914.pdf; accessed Novem- by glomerular filtration.39 Also similar to ε-aminocaproic acid,

ber 18, 2017). The European Society of Anaesthesiology task tranexamic acid is distributed throughout the intracellular and
force reported on aprotinin use in a perioperative setting and extracellular compartments.36 On a molar basis, tranexamic
has current suggestions for its use.32 acid is 7 to 10 times more potent than ε-aminocaproic acid
and has more sustained antifibrinolytic activity in tissues.36,40
ε-Aminocaproic Acid Intravenous dosing ranges from ~0.5 to 25 g depending on
the types of patients and procedures. In one of the largest stud-
ε-Aminocaproic acid is a synthetic inhibitor of plasminogen ies to date of tranexamic acid, the Clinical Randomization of an
activation with a molecular weight of ~131 Da. Pharmacoki- Antifibrinolytic in Significant Hemorrhage (CRASH-2) trial,
netic studies evaluating intravenous ε-aminocaproic acid of conducted in patients with posttraumatic bleeding, tranexamic
10 g or 100 mg/kg in volunteers produced an initial concen- acid was administered as a loading dose of 1 g intravenously
tration of about 1.5 g/l that decreased to 35 mg/l within 3 to

followed by an infusion of 1 g over 8 h. In orthopedic surgery,
4 h, and 80 to 100% was eliminated in the urine by filtra- tranexamic acid doses usually range from 0.5 to 2 g. Recent
tion.33–35 In vitro experiments and clinical studies report that studies have utilized a loading dose of 4 g intravenously over 1 h
a plasma ε-aminocaproic acid concentration of ~130 µg/ml followed by infusion of 1 g/h over 6 h.41,42 For excessive men-
is required to inhibit systemic fibrinolytic activity.33–35 Since strual bleeding, based on the U.S. prescribing information,
ε-aminocaproic acid is rapidly excreted in the urine, it must tranexamic acid is given orally (Lysteda; Ferring-Parsippany,
be administered intravenously as an infusion to maintain New Jersey) at doses of 1.3 g every 8 h for up to 5 days.
therapeutic concentrations. Nilsson et al. recommended a Despite the potential toxicity concerns, side effects are
dose of 0.1 g/kg bodyweight every 3 to 4 h, whereas McNicol uncommon, as noted in patients with heavy menstrual bleed-
and Douglas recommended an initial loading dose of 10 g ing receiving oral doses of 1.3 g three times daily for 4 to 5
followed by a continuous intravenous infusion of 1 g/h to days.43 Oral tranexamic acid is currently approved by the
maintain a plasma concentration of ~130 µg/ml.33,35,36 Food and Drug Administration and in other countries, with
After intravenous administration, the volume of distribu- an impressive safety record, for reducing bleeding in women
tion is reported to be 30.0 ± 8.2 l and is primarily eliminated by with idiopathic menorrhagia. Its efficacy is thought to be
the kidneys, with 65% recovered unchanged, and 11% appear- explained by inhibition of increased fibrinolytic activity in the
ing as adipic acid.33–35 The total body clearance is 169 ml/min endometrium during the initial days of menstruation. How-
with a terminal elimination half-life of ~2 h33–35 (http://www. ever, macroscopic hematuria with bleeding from the upper
accessdata.fda.gov/drugsatfda_docs/label/2004/15197scm0 renal tract is considered a contraindication to tranexamic acid
36,scf037,scp038,scm039_amicar_lbl.pdf; accessed Novem- due to concerns for clot obstruction in the ureters and reports
ber 18, 2017). The concentration of ε-aminocaproic acid of acute renal cortical necrosis with renal failure.23
required to inhibit fibrinolysis is ~1 mM or 0.13 mg/ml, which
is achieved with a 5-g load followed by 1 to 1.25 g/h, which Antifibrinolytic Therapy and Risk of
should maintain plasma concentrations of 0.13 mg/ml. Thrombosis
ε-Aminocaproic acid is most extensively used in
The potential role of antifibrinolytic therapy producing hyper-
the United States compared to most countries that use
coagulability is a potential concern among clinicians.44 There
tranexamic acid. This may be related to costs and that it was
may be a prothrombotic effect of plasmin during therapeutic
the first agent that was widely available. Side effects reported
fibrinolysis that is explained by plasmin-mediated prothrom-
from ε-aminocaproic acid include hypotension, cardiac
bin and platelet activation.45 Multiple studies have reported
arrhythmias, rhabdomyolysis, and renal dysfunction.37,38
that fibrinolysis and fibrinolytic therapy activate platelets
and/or the plasma coagulation components both in vitro and
Tranexamic Acid in vivo.46–48 Despite concerns about the potential for a pro-
Tranexamic acid is a lysine analog with a molecular weight of thrombotic effect of fibrinolytic inhibitors, thrombosis has
~157 Da that reversibly binds to the lysine-binding sites on not been a significant clinical issue. In randomized controlled
plasminogen to inhibit its affinity to bind to multiple pro- trials of antifibrinolytics in major orthopedic surgery, cardiac
teins including fibrin. After a 10 mg/kg intravenous dose of surgery, or trauma (CRASH-2 trial), there were no increases in
tranexamic acid, the half-life is ~80 min with 30% renal elim- thrombotic complications compared to controls.49 Of note is
ination within the first hour, while after oral administration that in meta-analyses of tranexamic acid in orthopedic surgical
of 10 to 15 mg/kg, peak plasma concentrations occur within patients, who are at particularly high risk for venous thrombo-
3 h.39 Andersson et al. reported that 98 to 100% reduction of embolism, no increased incidence of venous thromboembo-
fibrinolytic activity required concentrations of ~100 mg/l.40 lism was observed compared to controls.50–52 Moreover, one
After intravenous administration of 10 mg tranexamic analysis reviewed thrombotic events as an outcome in 5,049
acid/kg body weight, 30% was recovered in the urine by 1 h, subjects from 57 studies of patients treated with tranexamic
55% by 3 h, and 90% within 24 h. Further studies indicated acid, ε-aminocaproic acid, or aprotinin for various types of
that tranexamic acid, like ε-aminocaproic acid, is eliminated bleeding not related to trauma or surgery.53 A total of 3,616
EDUCATION
(72%) had subarachnoid hemorrhages, of whom 3,414 (68%) and vascular remodeling leading to abdominal aortic aneu-
patients received tranexamic acid and 1,635 (32%) received rysm could be restored by injecting plasminogen knockout
ε-aminocaproic acid. The frequencies of limb ischemia and animals with activated plasmin. The dependence of these
myocardial infarction were less than 1% for tranexamic acid murine models of inflammation and vascular remodeling on
and ε-aminocaproic acid. The frequency of deep vein throm- the proteolytic activity of plasmin highlights its importance
bosis or pulmonary embolism was 1.9% for tranexamic acid to innate immunity and inflammation.
and 3.0% for ε-aminocaproic acid.53 The relationship between plasmin activity and inflamma-
In orthopedic surgical patients undergoing total hip tion has been studied in humans primarily during the use of
replacement or total knee arthroplasty, randomized con- antifibrinolytic drugs (tranexamic acid, ε-aminocaproic acid,
trolled trials have compared the effect of tranexamic acid, and aprotinin) to inhibit plasmin and decrease bleeding. In
ε-aminocaproic acid, or aprotinin with placebo on bleeding, cardiac surgery, the effects of tranexamic acid and aprotinin

transfusion, or venous thromboembolic events. Tranexamic were studied using whole blood mRNA expression profiling
acid was used in the majority of trials, where patients also of inflammatory genes.60 Of the 114 genes studied, eight pro-
received routine mechanical and/or pharmacologic prophy- duced less transcript in the presence of aprotinin, while three
laxis for deep vein thrombosis.54 The mean age of patients genes were inhibited by tranexamic acid and aprotinin, the
ranged from 55 to 76 yr. The analyses showed no significant broader spectrum of aprotinin most likely owing to its broader
difference in risk of venous thromboembolism in patients inhibitory activity against serine proteases and its effects on the
receiving antifibrinolytic therapy compared to those receiv- protease-activated receptor 1/thrombin receptor of platelets.
ing placebo in 1,637 patients. Additional subgroup analyses Apart from cardiac surgery, inflammation secondary to
according to the antifibrinolytic therapy reported no signifi- bacterial infection and exposure to lipopolysaccharide results
cant differences in venous thromboembolic events between in plasmin generation, which may contribute to disseminated
the treated and control groups. intravascular coagulation in septic shock. Macrophages and
In liver transplantation, from 23 studies involving 1,407 dendritic cells have several receptors for binding and activat-
patients who received tranexamic acid or aprotinin, despite ing plasminogen to plasmin11 that in turn activate other pro-
reduced bleeding and the need for transfusion, there was no teases, digest extracellular matrix, and initiate an inflammatory
increased risk for hepatic artery thrombosis, venous throm- response needed to fight infection. One study in humans has
boembolic events, or perioperative mortality.55 attempted to address the ability of systemically administered
antifibrinolytic drugs to counteract the inflammation associ-
Antiinflammatory Effects of Inhibiting ated with lipopolysaccharide exposure. Healthy volunteers were
Fibrinolysis given an intravenous bolus of Escherichia coli–derived lipopoly-
One of the proposed benefits of inhibiting fibrinolysis is saccharide 4 ng/kg, preceded either by a 30-min infusion of
that plasmin and plasminogen have broad-spectrum inflam- tranexamic acid (2 g) or placebo.61 In normal humans, lipopoly-
matory effects due to cellular binding, proteolytic activity, saccharide induces rapid increases in plasma of concentrations
and generation of inflammatory mediators as shown in D-dimers and plasmin-α -antiplasmin complexes. Pretreatment
2
figure 1.56 Plasmin, particularly when bound to the surface with tranexamic acid before lipopolysaccharide administration
of macrophages, plays a critical role in monocyte activa- greatly attenuates D-dimer and plasmin-α2-antiplasmin com-
tion and inflammation including exit from circulation into plexes, indicating a reduction in the activity of free plasmin
injured or infected tissue, cytokine production, and proteo- and protection against fibrinolysis. However, tranexamic acid
lytic activation of matrix-metalloproteases with subsequent pretreatment did not affect lipopolysaccharide-induced throm-
degradation and remodeling of extracellular matrix. Acti- bin generation; expression of lipopolysaccharide-induced mark-
vated plasmin elicits chemotaxis and actin polymerization in ers of leukocyte activation CD11b and CD66b on leukocytes;
monocytes including the release of cytokines downstream of lipopolysaccharide-induced release of von Willebrand factor
the transcription factors nuclear factor-κB, activator protein and E-selectin from endothelial cells; or lipopolysaccharide-
1, and signal transducer and activator of transcription.57,58 induced production of tumor necrosis factor–α, interleukin-6,
Much of the data that demonstrate the role of plasmin interleukin-8, and interleukin-10. Taken together, these results
and plasminogen in inflammation have been generated in seem to suggest that tranexamic acid can inhibit the activity of
experimental animal models that have included plasmino- free plasmin and fibrinolysis; however, many of the inflamma-
gen knockout mice. Plasminogen null mice were found to tory effects are mediated by plasmin bound to the surface of
have reduced macrophage infiltration into sites of inflam- leukocytes, where it is relatively protected from antifibrinol-
mation after peritoneal thioglycollate injection as well as ytic drugs. Plasmin’s importance in initiating inflammation,
reduced abdominal aortic aneurysm formation after calcium leukocyte chemotaxis, and extracellular matrix remodeling is
chloride injection.59 Reduction in macrophage infiltra- indisputable given the dramatic phenotype induced in plas-
tion and abdominal aortic aneurysm were associated with minogen knockout mice. What is not fully clear is the degree
reduced matrix metalloprotease–9 activity. In this model, to which antifibrinolytic drugs can modulate inflammation
macrophage infiltration, matrix metalloprotease–9 activity, by limiting plasmin’s proteolytic activity. Expression of several
inflammatory genes is altered by the administration of antifibri- event occurred in 386 tranexamic acid patients (16.7%) and
nolytic drugs in the setting of cardiac surgery. However, several 420 placebo patients (18.1%). Tranexamic acid reduced
lipopolysaccharide-induced aspects of plasmin activation are transfusion during hospitalization from 7,994 total units
not affected by pretreatment with antifibrinolytics. in placebo to 4,331 in the tranexamic acid group. Adverse
events including hemorrhage or cardiac tamponade requir-
Clinical Uses ing reoperation occurred in 2.8% of placebo and 1.4% of
tranexamic acid, and seizures occurred in 0.1% of placebo
Cardiac Surgery and 0.7% of tranexamic acid–treated patients.68
Cardiac surgery including CPB but also off-pump is argu-
ably one of the most studied scenarios of antifibrinolytic use. Seizures and Tranexamic Acid
Treated patients consistently demonstrate reduced bleeding In 2010, clinicians began to report convulsive seizures after

and allogeneic transfusion requirements. We have previously cardiac surgery with CPB using high-dose tranexamic acid
reviewed the use of antifibrinolytic agents in cardiac surgery initially, and from retrospective evaluations at lower doses.69
in this journal, as shown in table 1, and have noted that these In a recent meta-analysis of randomized controlled trials and
drugs are an important part of perioperative blood conserva- retrospective studies, the use of tranexamic acid was asso-
tion management.27 ciated with a 4.1-fold increased risk of clinical seizures.70
Despite this, the optimal dose of tranexamic acid is still Suggested mechanisms for tranexamic acid–induced seizures
not established. In a prospective, blinded dosing study, 148 include increased neuronal excitation mediated by antagoniz-
patients were randomized to placebo, while five groups ing inhibitory γ-aminobutyric acid neurotransmission and
received intravenous tranexamic acid as loading doses that neural glycine receptors.67 Tranexamic acid, γ-aminobutyric
ranged from 2.5 to 40 mg/kg before incision, followed by an acid, and glycine have similar molecular structures. However,
infusion of one-tenth the loading dose for 12 h.62 The authors despite the similarities, ε-aminocaproic acid, another lysine
reported that patients receiving an initial 10 mg/kg loading analog antifibrinolytic agent, has not been reported to pro-
dose followed by an infusion had significantly less chest tube duce seizures. Tranexamic acid’s structure is similar to gly-
drainage than with lower doses, but did not alter transfusions, cine that functions as an inhibitory neurotransmitter in the
and higher doses did not provide additional reductions in brain and spinal cord. In cardiac surgical patients, seizures
bleeding. Fiechtner et al. reported that a bolus 10 mg/kg dose are primarily observed in older patients after CPB for open
with an infusion of 1 mg · kg–1 · h–1 was provided a tranexamic heart surgery, where multiple other mechanisms including
acid plasma concentration that inhibited fibrinolytic activity cerebral emboli may be responsible. With emboli, vascular
in vitro.63 Dowd et al. calculated a loading dose of 30 mg/kg injury may cause local disturbances of the blood–brain bar-
followed by 16 mg · kg–1 · h–1 for 6 h and 2 mg/kg added to the rier, increase tranexamic acid concentrations at the site of
pump prime to achieve 100% inhibition of fibrinolytic activ- injury in the brain, and potentially promote seizures, as we
ity (table 1).64 Using this dosing strategy, Sharma et al. found have previously speculated in an editorial in the journal.69
mean plasma tranexamic acid concentration was consistently Therefore, additional mechanisms may be responsible for
higher than the previously suggested threshold.65 producing seizures. This is particularly important because
With the increasing use of tranexamic acid in cardiac the risk of seizures seems insignificant in women receiving
surgery and at higher doses, reports emerged about gener- approximately 4 g a day of tranexamic acid for menstrual
alized convulsive seizures in the absence of new ischemic bleeding, in trauma patients in the large CRASH-2 trial who
lesions on brain imaging, often in patients receiving higher received 2 g of tranexamic acid, and in noncardiac surgical
tranexamic acid doses of 100 mg/kg intravenously fol- patients.
lowed by 20 to 50 mg · kg–1 · h–1 with a total dose up to However, the impact of tranexamic acid–associated seizures
259 mg/kg.66 Experimental models noted that hyperexcit- after cardiac surgery on clinical outcomes is not well under-
ability and seizures appeared in a dose-dependent fashion stood. Assuming a transient pharmacologic mechanism, one
when tranexamic acid was applied topically onto central would expect only a minor effect on clinical outcomes, pre-
nervous system tissue. However, these concentrations are sumably with the exception of some critically ill patients where
unlikely to be achieved in clinical practice.67 weaning from mechanical ventilation may be delayed. This
In the largest randomized clinical trial of tranexamic acid consideration is consistent with an analysis of a large national
in cardiac surgery, Myles et al. randomized 4,631 coronary database of more than 11,000 pediatric patients undergoing
artery surgical patients to receive aspirin or placebo and surgery for congenital heart disease.71 The propensity match-
tranexamic acid or placebo with a primary composite out- ing resulted in more than 3,700 pairs of patients and reported
come of death and thrombotic complications that included the incidence of seizures was 8-fold increased (1.6% vs. 0.2%)
nonfatal myocardial infarction, pulmonary embolism, in patients who received tranexamic acid, while all other clini-
stroke, renal failure, or bowel infarction within 30 days after cal outcomes were comparable between groups. In contrast, in
surgery.68 A total of 2,311 patients received tranexamic acid the aforementioned large randomized clinical trial in coronary
and there were 2,320 placebo patients. The primary outcome artery bypass patients, the seizure rate in the tranexamic acid
EDUCATION
group was 7-fold increased (15 patients [0.7%] vs. 2 patients
In the U.S. still suspended

Suspended since 2008 [0.1%]) and seizures were associated with a 9.52-fold risk of
Canada in 2011 and
U.S., Canada, Europe

Suspension lifted in 30-day mortality.68 However, in these patients, the relative risk
Approval
Europe in 2012 for stroke was nearly 22-fold. Patient numbers are too small to
draw any definitive conclusions. However, these data suggest
U.S., Canada
that besides temporal pharmacologic effects, other mechanisms
contributed to the seizures and persisting neurologic damage.
Liver Surgery
Bleeding and coagulopathy in patients undergoing liver sur-
2 × 106 KIU bolus CPB, continuous
1 × 106 KIU bolus CPB, continuous
2 mg/kg CPB, continuous infusion

Half dose: 1 × 106 KIU bolus patient,
Full dose: 2 × 106 KIU bolus patient,
1–2 mg CPB, continuous infusion

High dose: 30 mg/kg bolus patient,
Low dose: 10 mg/kg bolus patient,

gery or transplantation are common. In patients with hepatic
100 mg/kg bolus patient, 5 mg/kg
Suggested Dosing in Adults

dysfunction, complex alterations in hemostatic function are
CPB, continuous infusion of common due to multiple causes, and excessive bleeding is
infusion of 2.5 × 105 KIU
infusion of 5 × 105 KIU
common during these procedures. Hyperfibrinolysis is also

common during liver transplantation.72 During the early
development of liver surgery and transplantation, hyper-
of 16 mg/kg
fibrinolysis was reported using thromboelastography, and

of 1 mg/kg
30 mg/kg
empiric antifibrinolytics were initially used by transplant

pioneer Dr. Thomas Starzl to reduce bleeding. Several years
later, when further evaluating coagulopathy associated with
liver transplantation, potential concerns regarding venous
Pharmacodynamics
thromboembolism and increased mortality were reported.

150 min, terminal
Plasma T½ life 2 h
Plasma ½ life 3 h
Initial plasma T½
The routine use of tranexamic acid and antifibrinolytic

T½ life 10 h
agents overall is variable. During hepatic transplantation, tis-

sue plasminogen activator concentrations may be increased
during the anhepatic phase of transplantation due to vas-
cular injury and reduced clearance. After reperfusion of the
transplanted liver, tissue plasminogen activator clearance
Predominantly
Elimination
~60% renal
proteolysis,
and plasminogen activator inhibitor 1 release often correct

Renal
Renal
the hyperfibrinolysis. Most liver transplant centers use vis-

Table 1. Antifibrinolytic Agents: Drug Descriptions, Doses, and Mechanisms of Action
coelastic monitoring with rotational thromboelastometry or

thromboelastography as a guide for the use of tranexamic
acid for hyperfibrinolysis.
thrombin-induced platelet activation,
Reversibly complexes with the active
of the activation of plasminogen to
of the activation of plasminogen to

Antifibrinolytic; competitive inhibition
Antifibrinolytic: competitive inhibition
Molenaar et al. reported a meta-analysis of safety and effi-

XIIa–induced contact activation,
cacy in randomized clinical trials of antifibrinolytics used in

sites of plasmin, kallikrein, and
Inhibition of fibrinolysis, Factor

Mechanism of Action
liver transplantation up to 2007 that included tranexamic

and inflammatory response
acid, aprotinin, and ε-aminocaproic acid. A total of 23 stud-

ies with 1,407 patients were analyzed and found that both
aprotinin and tranexamic acid reduced the need for allo-
Protease inhibitor
geneic transfusions, without safety concerns that included

hepatic artery thrombosis, venous thromboembolic events,
plasmin
plasmin
or perioperative mortality.55
trypsin
Additional studies include a randomized multicenter

evaluation of primary liver transplantation in 137 patients
Modified with permission from Koster et al.27
with high- and low-dose aprotinin published in 2000.73

Protein, isolated
Composition
Synthetic lysine
ε-Aminocaproic Synthetic lysine
Blood loss was reduced in the aprotinin-treated patients by

from bovine
lung tissue
44 to 60%, transfusion requirements were 20 to 37% lower,

CPB = cardiopulmonary bypass.
analog
analog
and there were no differences in mortality or thromboem-

bolic events among the groups.73 In another trial of 132
patients undergoing hepatic transplantation, patients were
randomized to tranexamic acid, ε-aminocaproic acid, or
placebo. Transfusions were reduced in the tranexamic acid–
Tranexamic
treated patients, and there was no benefit of ε-aminocaproic

Aprotinin
acid
acid
acid, and no intergroup difference with regard to transfusion

Drug
requirements, thromboembolic events, and mortality.74

Fig. 2. Multiple pathways are responsible for generation of plasmin, including endothelial activation and release of tissue plas-
minogen activator (tPA), contact activation, and kallikrein-mediated plasmin activation. Plasmin generation and activity are also
inhibited by plasminogen activator inhibitor 1 (PAI1), thrombin-activatable fibrinolysis inhibitor (TAFI), lysine analogs (tranexamic
acid and ε-aminocaproic acid [EACA]), and α2-antiplasmin. Plasmin generation after tissue injury can induce many other re-
sponses, including thrombin generation and cleavage of fibrinogen to fibrin. Plasmin also binds and activates monocytes,
neutrophils, platelets, and endothelial cells, to increase proinflammatory responses and multiorgan system failure. Attenuation
of these pathophysiologic responses with tranexamic acid might provide additional mechanisms to restore hemostatic balance
and control of plasmin generation and fibrinolysis, as shown in the Clinical Randomization of an Antifibrinolytic in Significant
Hemorrhage (CRASH–2) trial. After trauma, tissue injury shifts the complex balance of fibrinolysis to additional plasmin genera-
tion, and activation that increases coagulopathy, inflammatory responses, and bleeding. Modified with permission from Levy.5
PMN = polymorphonuclear leukocyte.
There are fewer data for antifibrinolytic use in patients a meta-analysis examining efficacy for reducing perioperative
undergoing hepatic resection. In a prospective randomized allogeneic erythrocyte transfusion from 43 randomized con-
trial for hepatic tumor resections, tranexamic acid was com- trolled trials in total hip and knee arthroplasty, spine fusion,
pared to placebo in 214 hepatectomies with continuation of musculoskeletal sepsis, or tumor surgery performed before
therapy every 6 h for 3 days. The authors noted lower blood July 2005.76 The report included 23 trials with 1,268 patients
losses, transfusions, shorter operative times, and lower hospi- receiving aprotinin, 20 trials with 1,084 patients receiving
tal costs in the tranexamic acid–treated patients. There were tranexamic acid, and 4 trials with 171 patients receiving
no differences in adverse outcomes including thromboem- ε-aminocaproic acid. Both aprotinin and tranexamic acid
bolic events or mortality.75 significantly reduced patient need for erythrocyte transfu-
sions with an odds ratio of 0.43 for aprotinin and 0.17 for
Orthopedic Surgery tranexamic acid.76
Multiple clinical trials have reported the efficacy of antifi- Additional randomized clinical trials in patients under-
brinolytic therapy in reducing bleeding and transfusion going primary total hip arthroplasty using only tranexamic
requirements in orthopedic surgery. Zufferey et al. reported acid at doses of 0.5 to 2 g reported on 505 patients from
EDUCATION
11 studies for total hip arthroplasty. Tranexamic acid reduce blood loss and need for allogeneic transfusions in a
significantly reduced perioperative bleeding and allogeneic randomized, blinded, prospective study of 168 patients for
transfusion requirements compared to the control group, primary hip arthroplasty.81 A 1-g tranexamic acid loading
with no differences in venous thromboembolism or other dose was initially administered followed by a continuous
adverse events using dosing strategies of ~1 g before incision infusion of 1 g or placebo for 8 h along with a restrictive
(10 to 15 mg/kg), with or without additional dosing by con- transfusion algorithm. There were no differences between
tinuous infusion or repeat dosing.50 the groups, and the authors also performed a meta-analysis
For primary total knee arthroplasty, a meta-analysis up combining this study with five other similar trials and found
to 2012 reported 1,114 patients from 19 randomized clini- no differences in bleeding or transfusion rates.
cal trials and noted tranexamic acid reduced postoperative
bleeding and transfusion requirements without differences Postpartum Hemorrhage

in venous thromboembolism or other adverse events in the Postpartum hemorrhage is a leading cause of maternal mor-
immediate postoperative period.77 In a meta-analysis of 411 bidity and mortality worldwide. Hematologic changes in
patients from six randomized clinical trials, tranexamic acid pregnancy at the time of delivery include decreased plasmin-
at doses of greater than or equal to15 mg/kg reduced bleed- ogen activator inhibitor 2 synthesis and tissue plasminogen
ing and the need for transfusion without safety concerns, activator release and hyperfibrinogenemia at concentrations
including venous thromboembolism.78 of 500 to 600 mg/dl. Multiple studies in different patient
Multiple studies have reported that tranexamic acid populations have evaluated tranexamic acid as a therapeutic
reduces blood loss and transfusions in patients undergoing agent to reduce bleeding and improve outcomes. In two ini-
total knee arthroplasty. Tranexamic acid is routinely used tial randomized clinical trials, tranexamic acid was given as
for total knee arthroplasty, whereas ε-aminocaproic acid is 1 g or 0.5 g intravenously 2 to 3 min after vaginal delivery, or
less frequently used. As a result, a multicenter retrospective 1 g intravenously before incision for cesarean section.82 The
chart review of elective unilateral total knee arthroplasty authors reported blood loss was reduced with tranexamic
from April 2012 through December 2014 was performed acid but there were no differences between the chosen
that included five hospitals within a healthcare system.79 doses.82 In an analysis of more than 1,000 women from five
The authors collected age, severity of illness score, sex, use randomized clinical trials undergoing elective cesarean sec-
of antifibrinolytic agent and dose, erythrocyte transfu- tion, tranexamic acid at doses of 1 g intravenously before
sions, and preadmission and discharge hemoglobin. There incision reduced bleeding.83
were a total of 2,922 primary unilateral total knee arthro- For a more definitive answer, the recently reported World
plasty cases of which 820 patients received 5 or 10 g of Maternal Antifibrinolytic trial was a randomized, double-
ε-aminocaproic acid, 610 patients received tranexamic blind, placebo-controlled trial evaluating early administration
acid, and 1,492 patients received no antifibrinolytic ther- of tranexamic acid on mortality, hysterectomy, and other rel-
apy (control group).79 The proportion of patients trans- evant outcomes with postpartum hemorrhage. Recruitment
fused with ε-aminocaproic acid was 2.8%, tranexamic acid was from March 2010 to April 2016 in 20,060 women after
3.2%, and controls 10.8% with lower mean erythrocyte vaginal delivery or caesarean section from 193 hospitals in 21
units transfused per patient. However, there were no dif- countries.84 Tranexamic acid was administered as a 1-g intrave-
ferences between the ε-aminocaproic acid and tranexamic nous dose, but if bleeding persisted or restarted within 24 h of
acid groups in the number of erythrocyte units transfused the first dose, a second 1-g dose could be given. The composite
per patient, percentage of patients transfused, or discharge primary endpoint was death from all causes or hysterectomy
hemoglobin concentrations.79 within 42 days and was analyzed on an intention-to-treat
The same investigators similarly evaluated antifibrinolytic basis. Death due to bleeding was reduced in tranexamic acid–
use in total hip arthroplasty in a retrospective chart review treated women (1.5%, 155/10,036 patients compared to
of 1,799 primary unilateral total hip arthroplasty cases from 1.9%, 191/9,985 in the placebo group; risk ratio, 0.81; P =
April 2012 through December 2014, of whom 711 received 0.045). When tranexamic acid was given within 3 h of deliv-
ε-aminocaproic acid, 445 received tranexamic acid, and 643 ery, mortality was 1.2% compared to 1.7% in placebo (risk
received no antifibrinolytic agent.80 Erythrocyte transfusions ratio, 0.69; P = 0.008), and there were no differences in hys-
were 6.8% in the ε-aminocaproic acid–treated patients, 9.7% terectomy in tranexamic acid–treated patients versus controls
in the tranexamic acid group, and 24.7% in patients receiv- (3.6% vs. 3.5%). The composite primary endpoint of all-cause
ing no therapy, although no differences were noted in mean mortality or hysterectomy was not reduced with tranexamic
erythrocyte units per patient and percentage of patients trans- acid (5.3% vs. 5.5%), and there were no differences in adverse
fused between the antifibrinolytic-treated patient groups. events between the groups.84
Antifibrinolytic therapy in most surgical procedures,
including orthopedic surgery, is limited to intraoperative Traumatic Injury
use. In a recent study, Zufferey et al. examined whether addi- Despite the extensive use of antifibrinolytic therapy and
tional postoperative tranexamic acid infusion could further tranexamic acid for multiple other indications, its use in
trauma has significantly increased only in recent years. Fibri- participants with a closure date of 2018. The protocol for
nolysis follows tissue injury as initially noted. However, tranexamic acid/placebo is the same as in CRASH-2 (http://
multiple studies have helped better define fibrinolysis after www.controlled-trial.com/ISRCTN50867461; accessed
trauma. In a study of 303 trauma patients, rotational throm- November 19, 2017). Another trial in progress is CRASH-3:
boelastometry, D-dimer, and plasmin-antiplasmin com- tranexamic acid for the treatment of significant traumatic brain
plexes were used to better define implications of traumatic injury (http://www.isrctn.com/ISRCTN93732214; accessed
injury. Fifty-seven percent had “moderate” hyperfibrinolysis November 18, 2017). Ten thousand patients within 8 h of
detected by the biomarker concentrations but not rotational injury with any intracranial bleeding on computerized tomog-
thromboelastometry, while 5% had severe hyperfibrinolysis, raphy will be recruited. Finally, a trial of prehospital tranexamic
detected by the biomarkers and rotational thromboelastom- acid treatment in moderate to severe traumatic brain injury is
etry. The combined hyperfibrinolysis groups had increased expected to enroll 967 patients (NCT01990768). The trial will

28-day mortality compared to patients without hyperfibri- randomize patients to three groups dosed by ambulance crews
nolysis (12% vs. 1%; P < 0.001).21 with 1 g tranexamic acid, 2 g tranexamic acid, or placebo.
In the CRASH-2 trial, adult trauma patients were ran-
domized within 8 h of injury to a 1-g intravenous loading Fibrinolytic Shutdown in Trauma
dose of tranexamic acid followed by a 1-g infusion over 8 h One of the major arguments surrounding the routine use
compared to placebo. The primary outcome was in-hospi- of antifibrinolytic agents in trauma is the concern about
tal 28-day mortality. From 10,060 patients randomized to fibrinolytic shutdown. As previously mentioned, although
receive tranexamic acid compared to 10,067 receiving pla- hyperfibrinolysis in an important pathologic cause of bleed-
cebo, mortality was reduced with tranexamic acid (14.5 vs. ing, considerable individual variability in the fibrinolytic
16.0%; P = 0.0035), and the risk of death due to bleeding profile at baseline has been noted. This includes a subgroup
was also significantly reduced. Additional analyses of the with increased circulating plasminogen activator inhibitor 1
35% of patients who died from bleeding reported that the and decreased tissue plasminogen activator activity, a profile
benefit from tranexamic acid was greatest when administered that is termed fibrinolytic shutdown.14,15
within the first hour of injury, but if given more than 3 h As a result of the recent widespread use of thromboelas-
after injury, mortality was paradoxically increased. Despite tography and rotational thromboelastometry in trauma,
the novelty and the results of CRASH-2, the mortality differ- hyperfibrinolysis has been identified in a subgroup of severely
ence of 1.5% was rather small and statistically significant due injured patients, and this has been proposed as a contribut-
to a large number of patients studied. The performance and ing cause of bleeding in trauma-induced coagulopathy.86
results of this large trial have been the subject of an intensive Acutely injured patients with severe hyperfibrinolysis after
controversial debate.85 Only approximately 5% of patients 30 min based on thromboelastography findings are reported
died because of bleeding, and only 50% of patients received to have mortality rates exceeding 70%.18,22,87 Based on the
blood transfusions. Most of the patients were studied in CRASH-2 trial, many trauma centers throughout the world
countries where rapid access to blood products, damage-con- use tranexamic acid for all major trauma patients. However,
trol surgery, angiography, laboratory testing, and advanced among patients with trauma-induced coagulopathy, pheno-
critical care were not available. As there was no difference in typic distinction between those with global factor deficiency
the amount of blood transfused between groups, the mecha- versus those with hyperfibrinolysis is apparent.14,15 Moore
nism of the effect of tranexamic acid on outcomes remains et al. hypothesize that tissue injury and hemorrhagic shock
undetermined. Additional trials are underway, including produce distinct and opposing phenotypic effects on fibri-
Pre-hospital Anti-fibrinolytics for Traumatic Coagulopathy nolysis, such that untimely inhibition of fibrinolysis in those
and Hemorrhage (PATCH), a prospective, randomized, with fibrinolytic shutdown may result in increased mortal-
placebo-controlled multicenter study that will include 1,200 ity.15 Despite these concerns, we believe the overwhelming
patients in Australia and New Zealand. Modern trauma care, safety of antifibrinolytic therapy, the variability of fibrinolytic
examination of coagulation, fibrinolysis, transfusion require- phenotype at different times after tissue injury for a given
ments, and incidence of vascular occlusive complications as individual, and the potential for clotting factor and blood
well as effects on inflammation, immune function, and sep- product administration to worsen hypercoagulability con-
sis will be examined to advance knowledge regarding the role tinue to make this perspective controversial.
of tranexamic acid in trauma (https://clinicaltrials.gov/ct2/
show/NCT02187120; accessed November 18, 2017). Intracranial Hemorrhage and Neurosurgery
A post hoc evaluation of CRASH-2 evaluated outcomes in In patients with intracranial hemorrhage, continued bleeding
270 participants with intracranial bleeding. Although either or expansion of the hematoma is a major cause of morbidity
benefits or harmful effects could not be excluded, the results and mortality. After a subarachnoid hemorrhage, a recurrence
suggested tranexamic acid warranted further research. The of bleeding within the first 24 h is reported to occur in 9 to
ongoing study in the United Kingdom’s Tranexamic acid in 17% of patients and is associated with a mortality of ~60%.88,89
IntraCerebral Hemorrhage (TICH) trial will include 2,000 Antifibrinolytic therapy after subarachnoid hemorrhage is
EDUCATION
reported to reduce rebleeding by 35 to 40%, although outcomes Topical Administration of Tranexamic Acid
are not improved due to delayed cerebral ischemia after injury, A recent Cochrane review addressed the topical application
and overall due to adverse effects of intracranial hemorrhage.90,91 of tranexamic acid in a large variety of clinical settings such
A Cochrane review of nine studies between 1973 and as cardiac surgery, knee arthroplasty, and spinal surgery.96 The
2000 reported that with antifibrinolytic therapy, outcomes authors concluded that topically administered tranexamic
were not improved because of cerebral ischemia.90 How- acid may reduce bleeding and transfusions, but expressed
ever, eight of the nine trials were published before 1990, concern that safety data, particularly with regard to thrombo-
and current standard therapies including calcium channel embolic complications, are unknown. Topical administration
blockers and other interventions including triple H therapy of tranexamic acid may lead to lower plasma concentrations
(hypertension, hypervolemia, and hemodilution) for vaso- but variability depending on the dose used, the application
spasm prophylaxis were not used, which might account for site, and local readsorption, and may achieve plasma concen-

the higher number of ischemic events. However, even with trations that effectively inhibit systemic hyperfibrinolysis.96
current therapies for vasospasm, studies suggest rebleeding is
reduced but without benefit on neurologic outcomes.92 Summary
In a study from three Swedish hospitals published in The use of antifibrinolytic therapy in the perioperative setting
2002 not included in the mentioned Cochrane review, Hill- has been extensively studied. Most studies report that tranexamic
man et al. studied 596 patients with subarachnoid hemor- acid and aprotinin are consistently associated with a reduction
rhage randomized to receive tranexamic acid at 1 g every 6 h in bleeding and need for allogeneic transfusions. Despite the
until the aneurysm was clipped, coiled, or secured.93 A total extensive use of ε-aminocaproic acid primarily in the United
of 70% of aneurysms were treated within 24 h of admis- States, there are far less safety and efficacy data regarding this
sion. Although the study was not blinded, the tranexamic agent. Although theoretical concerns about the potential for
acid–treated patients had a lower rebleeding rate within the hypercoagulable effects of antifibrinolytic agents remain, the
first 24 h of 2.4% versus 10.8% for controls. Also, rebleed- scientific data and clinical experience suggest the relative safety
ing occurred in 30 of the 33 patients within the first 8 h. of these agents regarding thromboembolic complications. How-
However, there were only nonsignificant trends of improved ever, most of the available data are related to tranexamic acid. In
mortality (16.3 vs. 12.9%) and outcomes (Glasgow outcome patients undergoing cardiac surgery, the efficacy of tranexamic
score 4 or 5, 70.5 vs. 74.8%) in the tranexamic acid–treated acid and aprotinin to reduce blood loss and transfusion is estab-
patients, albeit without other concerns for adverse events.93 lished. Although tranexamic acid–associated seizures occur only
Starke et al. reported a similar study but with in cardiac surgical patients, their impact on clinical outcomes
ε-aminocaproic acid94 in 248 patients with subarachnoid needs further investigation. The reintroduction of aprotinin in
hemorrhage who received a 4-g loading dose followed by a Europe will be accompanied by a large registry that hopefully
1 g/h infusion. A total of 73 patients received ε-aminocaproic will provide more data regarding previously raised safety con-
acid with a lower rebleeding rate in treated patients of 2.7% cerns. In trauma patients, the extensive use of tranexamic acid is
compared to 11.4% in controls but with an increased inci- based on the CRASH-2 study that reported a reduced mortality
dence of lower extremity deep vein thrombosis.94 with early tranexamic acid administration. Controversy regard-
Harrigan et al. retrospectively analyzed 356 patients with ing fibrinolytic shutdown in a subset of patients with traumatic
subarachnoid hemorrhage treated with ε-aminocaproic acid injury and potential adverse effects of antifibrinolytics has limited
on intensive care unit admission.95 Treatment of the ruptured routine administration of tranexamic acid in the United States.
aneurysm occurred an average of 47.4 h after hospital admis- For orthopedic surgery, antifibrinolytic treatment is associated
sion, and patients received an average ε-aminocaproic acid dose with clear reductions in bleeding and variable effects on reduc-
of 40.6 g over 35.6 h. The overall rebleeding rate was low, 1.4%, tion of allogeneic blood transfusions. There is good evidence for
and the rate of rehemorrhage per 24-h period was 0.71%. Vaso- a reduction in transfusion requirements in liver transplantation
spasm occurred in 11.5% of patients, and permanent neuro- for both aprotinin and tranexamic acid with no indication of an
logic deficits from ischemic stroke were seen in 7.2%.95 increased risk of thrombotic complications. The recently pub-
Overall, with the administration of antifibrinolytic ther- lished data for the prevention of postpartum hemorrhage with
apy to prevent early rebleeding in subarachnoid hemorrhage, antifibrinolytics are also further supported by the World Mater-
there appears to be no increased risk of ischemic events or nal Antifibrinolytic study.
adverse outcomes. Despite reduced rebleeding rates, addi-
tional improvement of outcomes with antifibrinolytic agents Research Support
has not been established, likely due to the complexity of Support was provided from institutional and/or departmen-
the original bleeding event, neurologic injury, and location tal sources and grant No. NIGMS T32 GM08600 from Duke
University Medical Center, Durham, North Carolina (to Dr.
of the bleed. Further complicating outcomes are concerns Quinones) and grant No. NHLBI K23 1K23HL127227-01A1
about optimal times to restart venous thromboembolic pro- from Seton Dell Medical School Stroke Institute, Austin, Tex-
phylaxis in these immobile patients. as (principal investigator: Truman J. Milling, Jr., M.D.).
Competing Interests shutdown: Rationale for selective tranexamic acid. J Trauma

Acute Care Surg 2015; 78(6 suppl 1):S65–9
Dr. Levy serves on steering committees for Boehringer In-
17. Moore EE, Moore HB, Gonzalez E, Sauaia A, Banerjee A,

gelheim, CSL Behring, Grifols, and Instrumentation Labs, Silliman CC: Rationale for the selective administration of
and on advisory committees for Leading Biosciences, Oc- tranexamic acid to inhibit fibrinolysis in the severely injured
tapharma, Pfizer, and Portola. Dr. Milling is a member of a patient. Transfusion 2016; 56(suppl 2):S110–4
steering committee for Portola and is a consultant for CSL 18. Schöchl H, Frietsch T, Pavelka M, Jámbor C: Hyperfibrinolysis
Behring. Dr. Key is a consultant for Bayer and CSL Beh- after major trauma: Differential diagnosis of lysis patterns and
ring and receives research support from Baxalta US Inc. The prognostic value of thrombelastometry. J Trauma 2009; 67:125–31
other authors declare no competing interests. 19. Chapman MP, Moore EE, Ramos CR, Ghasabyan A, Harr JN,
Chin TL, Stringham JR, Sauaia A, Silliman CC, Banerjee A:
Fibrinolysis greater than 3% is the critical value for initiation
Correspondence of antifibrinolytic therapy. J Trauma Acute Care Surg 2013;
Address correspondence to Dr. Levy: Department of An- 75:961–7; discussion 967

esthesiology, 2301 Erwin Road, Box 3094, Duke Universi- 20. Theusinger OM, Levy JH: Point of care devices for assessing
ty Medical Center, Durham, North Carolina 27710. jerrold. bleeding and coagulation in the trauma patient. Anesthesiol
[email protected]. Information on purchasing reprints may be Clin 2013; 31:55–65
found at www.anesthesiology.org or on the masthead page 21. Raza I, Davenport R, Rourke C, Platton S, Manson J, Spoors
at the beginning of this issue. ANESTHESIOLOGY’s articles are C, Khan S, De’Ath HD, Allard S, Hart DP, Pasi KJ, Hunt BJ,
made freely accessible to all readers, for personal use only, Stanworth S, MacCallum PK, Brohi K: The incidence and
6 months from the cover date of the issue. magnitude of fibrinolytic activation in trauma patients. J
Thromb Haemost 2013; 11:307–14
22. Cotton BA, Harvin JA, Kostousouv V, Minei KM, Radwan

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Review Article

Deborah J. Culley, M.D., Editor

Antifibrinolytic Therapy and Perioperative

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F IBRINOLYSIS is a physiologic component of hemo-

Anesthesiology, V 128 • No 3 657 March 2018

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Anesthesiology 2018; 128:657-70 658 Levy et al.

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Anesthesiology 2018; 128:657-70 659 Levy et al.

Press_release/2012/02/WC500122914.pdf; accessed Novem- by glomerular filtration.39 Also similar to ε-aminocaproic acid,

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Anesthesiology 2018; 128:657-70 660 Levy et al.

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Anesthesiology 2018; 128:657-70 661 Levy et al.

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Anesthesiology 2018; 128:657-70 662 Levy et al.

group was 7-fold increased (15 patients [0.7%] vs. 2 patients

In the U.S. still suspended

U.S., Canada, Europe

1 × 106 KIU bolus CPB, continuous

2 mg/kg CPB, continuous infusion

1–2 mg CPB, continuous infusion

Low dose: 10 mg/kg bolus patient,

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common during these procedures. Hyperfibrinolysis is also

fibrinolysis was reported using thromboelastography, and

empiric antifibrinolytics were initially used by transplant

thromboembolism and increased mortality were reported.

The routine use of tranexamic acid and antifibrinolytic

agents overall is variable. During hepatic transplantation, tis-

and plasminogen activator inhibitor 1 release often correct

the hyperﬁbrinolysis. Most liver transplant centers use vis-

coelastic monitoring with rotational thromboelastometry or

of the activation of plasminogen to

of the activation of plasminogen to

Antifibrinolytic: competitive inhibition

Molenaar et al. reported a meta-analysis of safety and effi-

cacy in randomized clinical trials of antifibrinolytics used in

Inhibition of fibrinolysis, Factor

liver transplantation up to 2007 that included tranexamic

acid, aprotinin, and ε-aminocaproic acid. A total of 23 stud-

geneic transfusions, without safety concerns that included

Additional studies include a randomized multicenter

with high- and low-dose aprotinin published in 2000.73

ε-Aminocaproic Synthetic lysine

Blood loss was reduced in the aprotinin-treated patients by

44 to 60%, transfusion requirements were 20 to 37% lower,

and there were no differences in mortality or thromboem-

treated patients, and there was no benefit of ε-aminocaproic

acid, and no intergroup difference with regard to transfusion

requirements, thromboembolic events, and mortality.74

Anesthesiology 2018; 128:657-70 663 Levy et al.

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Anesthesiology 2018; 128:657-70 664 Levy et al.

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Anesthesiology 2018; 128:657-70 665 Levy et al.

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Anesthesiology 2018; 128:657-70 666 Levy et al.