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5 Fibrinolysis, Antibrinolytic Agents, andPerioperative Considerations

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tors are plasminogen activator inhibitor-1 (PAI-1), plasminogen activator inhibitor-2 (PAI-2), and α2-antiplasmin (A2AP). A2AP acts to irreversibly inactivate plasmin by a suicide inhibition mechanism [15]. However, when plasmin is bound to brin, it is protected from this inhibition and can allow brinolysis [16]. PAI-1 and PAI-2 inhibit both tPA and uPA.However, PA-2 is only present in appreciable quantities during pregnancy [17]. C1-esterase inhibitor, α2-macroglobulin, and other aspects of the contact pathway of the coagulation cascade also represent less prominent non-serpin plasmin inhibitors.

Thrombin-activated brinolysis inhibitor (TAFI) is activated by thrombomodulin-associated thrombin. It is a carboxypeptidase that removes C-terminal lysine and arginine residues on brin. By doing so, it can decrease the number of available plasminogen-binding sites and help stabilize clots [18]. TAFI may play a key role in regulating the interplay between inammation and coagulation [18, 19].

Measuring Fibrinolysis

The development of methods to assess brinolytic activity has lagged behind the progress seen in coagulation testing, which is standardized for routine high-throughput screening [20]. Fibrinolysis, in normal blood and conditions, may take hours or days to develop and limits its clinical applications [21]. Coagulation reactions (international normalized ratio (INR) and activated partial thromboplastin time (APTT), for example) can take only seconds to minutes to run. To facilitate the assessment of brinolysis, one must add plasminogen activators or remove inhibitors. However, this will limit the applicability to an invivo scenario [20]. No “gold standard” assay exists to assess brinolytic activity, and the various methods available can be grouped according to a sample from whole blood, plasma, or euglobulin fraction of plasma [22].

Whole blood preparations are useful in that they can represent truly “global” activity, as the cellular components of blood have a signicant impact on coagulation and brinolysis [22]. These samples are often used perioperatively by point-of-care testing. However, this approach is limited by assay standardization, storage issues, the absence of endothelium, and the inability to use the sample in other types of assays [22]. The most studied perioperative tool to measure brinolysis is thromboelastography. This test is performed with a thromboelastograph (TEG) or rotation thromboelastometery (ROTEM) by measuring viscoelastic changes in whole blood over time with the addition of different activators like tissue factor and kaolin [22]. Thromboelastography can assess coagulation parameters but can also be modied to reect any endogenous brinolytic activity. In ROTEM, maximal lysis reects the percent decrease of maximal

amplitude over time. Small decreases can be due to tapering of the clot, allowing additional rotation of the sample [10,

22]. Maximal lysis of greater than 15% could indicate hyper-

brinolysis, whereas greater than 3% is an important benchmark to initiate antibrinolytic therapy in trauma [23, 24].

TEG and ROTEM are the most frequently utilized tools to assess brinolysis in trauma patients and have become increasingly popular [25]. However, there is controversy regarding the need to assess brinolysis in these patients given the frequent use of pre-emptive antibrinolytic therapy [10, 26]. Studies have suggested that they lack sensitivity to detect small changes in brinolytic activation, and there is questionable evidence to suggest that they would be helpful to guide antibrinolytic therapy [10, 26].

Plasma turbidity methods rely on the measurement of changes in optical density after the initiation of coagulation. Fibrin formation and lysis are reected by the optical density [18]. A common method utilized to measure brinolytic and coagulation activity is overall hemostasis potential. The assay relies on spectrophotometer readings in two sets of wells containing platelet-free plasma mixed with phosphatidylserine- containing phospholipids, calcium chloride, and tissue factor [22]. The other sample of wells has the addition of tPA.The readout will give an overall hemostasis potential and overall coagulation potential, allowing calculation of the overall brinolysis potential. Clot lysis time, the time from 50% of maximal clotting to 50% lysis, can also be obtained [27]. The overall brinolysis potential and clot lysis time can give insight for determining pro hemorrhagic and pro thrombotic states.

Lastly, the euglobulin fraction of plasma has been known for its strong brinolytic activity. It has greatly reduced amounts of PAI-1 with preserved levels of plasminogen activators when compared to untreated platelet free plasma [28]. This rebalanced plasminogen activator: PA-1 ratio allows the measurement of intrinsic brinolytic activity without exogenous activators [22]. The classic test is the euglobulin clot lysis time, which is a visual recording of the time it takes the euglobulin fraction to completely lyse [22].

Antibrinolytic Agents

By the 1950s, the amino acid lysine was known to inhibit the activation of plasminogen invitro, but the effect was too weak to be clinically relevant. In efforts to reduce maternal deaths from postpartum hemorrhage, investigations in 1953 by a Japanese team showed several mercaptoand aminocarbonic acids had antiplasminic effect [29]. During this work, they showed that epsilon-aminocaproic acid (EACA) was a strong inhibitor of plasminogen. EACA had been used clinically before this time, but the antiplasminic effect was not potent enough and required large

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doses. In 1962 a more potent compound was found: 4-amino-methyl-cyclohexane-carbonic acid [30]. The compound contains two stereoisomers of which the trans-form was discovered to be antibrinolytic (trans-4-aminomethylcyclohexanecarboxylic acid). This substance is now known as tranexamic acid (TXA) [31, 32]. EACA and TXA are synthetic lysine analogs that inhibit brinolysis by attaching to the lysine- binding site of the plasmin(ogen) molecule and displacing plasminogen from brin. TXA was found to be about 6–10 times more potent than EACA while also better tolerated [29]. Of countries that incorporate TXA into clinical practice, the United States has most strongly adapted the use of EACA, likely related to costs and early availability [10].

Aprotinin is another antibrinolytic which acts as a broadspectrum protease inhibitor. First isolated in cow parotid glands in 1930, its rst clinical use was in treating of hyperbrinolytic conditions, notably pancreatitis [33]. In the early 1980s, the Kirkland group in Alabama began using aprotinin in an attempt to attenuate the inammatory response after protamine administration. The surgical eld was found to be unusually dry after cardiopulmonary bypass (CPB), which led to a trial-and-error approach to developing aprotinin pro-

tocols and the further study of its interaction with the brinolytic system [34]. By 1993, aprotinin was approved by the FDA for use in coronary artery bypass grafting (CABG). Widespread use of aprotinin to reduce perioperative blood loss and transfusions also became popular in major orthopedic and hepatic surgery.

Other potential antibrinolytic agents, not approved for clinical use, include nafamostat, MDCO-2010, and textilinins from Pseudonaja textilis [10]. The three clinically used agents will be reviewed as follows.

Tranexamic Acid

TXA is a synthetic lysine analog with a molecular weight of 157Da that reversibly and competitively blocks the lysinebinding site on plasminogen, hence inhibiting brinolysis. Plasminogen is believed to have 4–5 low-afnity binding sites and one high-afnity binding site. TXA acts on the high-afnity binding site [35, 36].

The pharmacokinetics will vary based on the route of administration and overall renal function. TXA is produced under several brand names (see Table5.1) and can be admin-

Table 5.1 Antibrinolytic agents

Drug Tranexamic acid Epsilon-aminocaproic acid Aprotinin Composition Synthetic lysine analog Synthetic lysine analog Naturally occurring polypeptide,

Molecular weight 157Da 131Da 6512Da Mechanism of action

Elimination Renal Renal Proteolysis, renal Terminal elimination half-life Select adverse effects Prescription products (North America) Market approval USA

Abbreviations: IV intravenous

Antibrinolytic Inhibits conversion of plasminogen to plasmin through reversible, competitive blockade of plasminogen’s lysine-binding site

3h 2h 10h

Possible thrombosis Seizures Cyklokapron (IV, oral) Erfa-tranexamic (IV) Lysteda (oral)

Canada Europe

Antibrinolytic Inhibits conversion of plasminogen to plasmin through reversible, competitive blockade of plasminogen’s lysine-binding site

Possible thrombosis Possible thrombosis

Amicar (IV, oral) Trasylol (IV)

USA Canada

isolated from bovine lung tissue

Serine protease inhibitor Reversible inhibition of free plasmin, trypsin, chymotrypsin, kallikrein Inhibition of brinolysis, Factor XIIa-mediated kallikrein activation, thrombin-induced platelet activation Possible anti-inammatory effects

Renal dysfunction

Complete removal from market in 2008 Reintroduced in Canada in 2011 and Europe in 2012 Select availability in United Kingdom, the Netherlands, Sweden, Canada Still suspended in the USA

5 Fibrinolysis, Antibrinolytic Agents, andPerioperative Considerations

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istered intravenous (IV), intramuscular, oral, and topical. IV administration of a 10mg/kg bolus gives a plasma concentration of 10mg/L [37]. Additionally, the half-life is about 80min with 30% renal elimination within the rst hour, 55% by 3h, and 90% by 24h [38]. Oral TXA doses of 10–15mg/ kg give a peak plasma concentration within 3h [38]. In an in vitro tissue study, it has been shown that 100mg/L of TXA will reduce brinolytic activity by 98–100% [39]. TXA has little plasma-protein binding with minimal metabolism [36]. It passes through the placenta and equilibrates with fetal blood levels, with no adverse effects on the fetus. TXA is present in breast milk but at a concentration 100 times less than found in maternal blood, and does not have any effects on breast-fed babies [37, 40].

IV dosing can range from 0.5 to 25g based on patient and clinical conditions and must be adjusted for renal insufciency [10]. In earlier work, Nillson etal. describes a dose of 10mg/kg IV, 3–4 times hourly, in the treatment of systemic brinolysis with massive bleeding [37]. In a landmark study of TXA, the Clinical Randomization of an Antibrinolytic in Signicant Hemorrhage (CRASH-2) trial analyzed a group with major bleeding after severe trauma to receive a loading dose of 1g IV followed by an infusion of 1g over 8h [41]. In pediatric (less than 12-years-old) trauma, an expert consensus would dose TXA in a similar matter as adults at 15mg/kg (maximum 1g) followed by an infusion of 2mg/ kg/h for at least 8h until bleeding stops [42].

For the treatment of heavy menstrual bleeding, the U.S.Food and Drug Administration (FDA) recommends oral TXA (Lysteda; Ferring-Parsippany, New Jersey) 1.3g, three times daily for up to vedays [43]. Several other European agencies have similar protocols for oral TXA.Oral TXA formulation should be given 2h before any indicated surgical procedure.

Side effects are uncommon, and TXA has had a strong safety record. Mild nausea and diarrhea have been observed in a high-dose trial of TXA, but improve with a diminished dose [44]. Macroscopic hematuria from the upper renal tract is often considered a contraindication to TXA due to the risk of clot burden and ureteral obstruction. There are reports of acute renal cortical necrosis with oliguria and renal failure caused by TXA [29]. Patients on estrogens that have additional risk factors for thrombosis should take caution; however, evidence is lacking. Absolute contraindications include hypersensitivity, active thromboembolic disease, and brinolytic conditions with consumption coagulopathy.

Epsilon-Aminocaproic Acid

EACA is a synthetic, highly water-soluble crystal with a molecular weight of 131Da that acts as a lysine analog. Both

EACA and TXA act to block the conversion of plasminogen to plasmin resulting in the inhibition of brinolysis. Its volume of distribution is about 30L with IV dosing, and max serum concentrations are reached in 10min [ eventually distributes throughout both intravascular and extravascular compartments while penetrating blood and tissues [46]. Total body clearance is 169ml/min, and terminal half-life is about 2h [47–49].

Studies evaluating IV EACA of 10g or 100 mg/kg in humans produced an initial concentration of about 1.5g/L that decreased to 35mg/L within 3–4h, with 80–100% eliminated by urine ltration [10]. Patients with renal failure have markedly decreased total body clearance, and only 25% can be removed via hemodialysis [50]. EACA undergoes rapid excretion in the urine and thus needs to be administered as an IV infusion to achieve therapeutic levels. Studies have identied that an EACA concentration of about 130mcg/mL is required to inhibit systemic brinolytic activity. These studies recommend a dose of 0.1g/kg bodyweight every 3–4h or an initial loading dose of 10g to be followed by a continuous infusion of 1g/h [ brain barrier, but it is unclear whether it crosses the placenta or distributes in breast milk [46].

EACA is predominantly administered IV, with some case reports describing topical use [51, 52]. There are no standard guidelines for EACA dosing, and many dosing protocols have been developed for perioperative use. Like TXA, EACA has been studied most extensively in cardiac surgery. EACA protocols have shown reduced chest tube drainage following cardiac surgery, making EACA a preferred drug in many institutions in the United States [46].

Most safety concerns of EACA are based on the potential for promoting a prothrombotic state through action on the brinolytic pathway. Reports of adverse events are from isolated case reports or low-powered studies. To date, no trial has been able to show a signicant difference in thrombotic events when compared to TXA or aprotinin [46]. Caution should always be taken when considering the mechanism of the drug and any pre-existing patient coagulopathies. Overall, EACA is well tolerated.

47–49]. EACA likely crosses the blood-

45]. The drug

Aprotinin

Aprotinin is a naturally occurring 58 amino acid polypeptide, with a molecular weight of 6512 Da, isolated from bovine lung but currently manufactured by recombinant technology. It is a serine protease inhibitor with its antibrinolytic effect via direct noncompetitive inhibition of plasmin. The structure is similar to tissue factor pathway inhibitor, and its dosing is calculated in kallikrein-inhibiting units [10]. Aprotinin may falsely elevate or prolong partial

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thromboplastin time and celite-activated clotting time (ACT) measurements. Therefore these should not be used to monitor heparin anticoagulation during surgery. If ACT monitoring is necessary after aprotinin administration, a minimal ACT of 750s or kaolin-ACT of 480s is recommended by the European Society of Anesthesiology task force [33].

Due to its nonspecic nature, aprotinin is also an inhibitor of trypsin, chymotrypsin, platelet protease-activated receptor- 1, and kallikrein. The inhibition of protease-activated receptor-1 is a possible mechanism for stroke reduction during cardiac surgery after aprotinin administration [10]. Additionally, aprotinin inactivates free plasmin but does not greatly affect bound plasmin. Aprotinin is renally excreted with a plasma half-life of 150min and an elimination halflife of 5–10h after lysosomal enzyme metabolization [53].

In the mid-2000s, concerning reports regarding the safety of aprotinin were widely published, which suggested multiple adverse events and increase in 5-year mortality [46]. By 2006, the FDA added renal dysfunction, stroke, graft occlusion, and anaphylaxis to aprotinin’s list of safety issues [33]. Further research in 2007 gave conicting evidence surrounding aprotinin’s safety but only cast doubt on the drug.

In 2008, the Blood Conservation Using Antibrinolytics in a Randomized Trial (BART) was published [54]. This blinded, randomized controlled trial (RCT) compared aprotinin, TXA, and EACA in patients undergoing high-risk cardiac surgery. The trial was stopped by the safety committee in October 2007 due to nonsignicant increased mortality associated with aprotinin. Results from BART, previous studies, and the FDA warning led to the withdrawal of aprotinin from the United States in late 2007 and from Canada and Europe in 2008. Subsequent criticism and reanalysis of the data eventually convinced Health Canada in 2011 to allow aprotinin for patients undergoing isolated CABG.The European Medicines Agency also lifted its suspension in the European Union in 2012 but enforced the establishment of a European registry for aprotinin use [55]. Aprotinin is currently available in the United Kingdom, the Netherlands, Sweden, and Canada.

Perioperative Considerations

Cardiac Surgery

Cardiac surgery is the most studied area in the brinolytic literature. TXA became key in antibrinolytic therapy after its comparative safety was shown in the BART trial, and has been extensively examined in cardiac surgery, CPB, or offpump [54]. TXA has been consistently shown to be efcacious in reducing blood loss and transfusion requirements

during cardiac surgery. The Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists blood conservation guidelines strongly (class IA) recommend the use of TXA or EACA in cardiac surgery [

There is no optimal dose of TXA, and large variations in dosing recommendations have been cited. In a prospective, double-blinded dosing study on CPB by Horrow etal. [57], 148 patients were given placebo, while ve groups received TXA IV with a loading dose before incision (2.5–40mg/kg) and followed by infusion of one-tenth the loading dose for 12h. A major nding was a signicant reduction in chest tube drainage from the patients who received a 10mg/kg loading with additional maintenance dose (now referred to as the “Horrow low dose” regimen). However, TXA did not change transfusion requirements. Increasing the dosage (20 and 40mg/kg bolus) did not provide additional reductions in bleeding. Fiechtner etal. [58] showed that a bolus 10mg/kg dose followed by an infusion of 1mg/kg/h gave a TXA concentration sufcient to inhibit brinolytic activity invitro. Dowd etal. [ followed by 16mg/kg/h for 6h, and 2mg/kg added to the pump prime would get a 100% inhibition of brinolytic activity. Using this regimen, Sharma etal. [60] found that the mean plasma TXA concentration was consistently higher than the previously suggested threshold.

After FDA withdrawal of aprotinin in 2007 and the implementation of TXA during cardiac surgery, there were increased reports of postoperative generalized convulsive seizures in the absence of new ischemic lesions on brain imaging [10]. In retrospective analysis, it was found that patients were receiving doses of 100 mg/kg followed by 20–50mg/kg/h with a total dose up to 259mg/kg during surgery [61]. Given concern for seizure activity at these high doses, lower dose guideline modications were made with 30mg/kg loading followed by 15mg/kg/h plus 2mg/kg in the CPB priming solution. It was recommended not to exceed a maximum TXA total dose of 100mg/kg in patients over 50 years old who underwent CPB open-heart procedures [62].

A recent, large RCT that gives the strongest evidence of the benets of TXA in cardiac surgery is from Myles etal. [63]. The administration of a single initial bolus of 50 or 100 mg/kg of TXA was associated with a decreased incidence of transfusion of RBCs and other blood products and a reduction of redo surgery for major hemorrhage for tamponade. The incidence of seizures was 0.7% with TXA-treated patients compared to 0.1% of patients given placebo.

TXA has also been specically studied for use in offpump CABG, with several studies showing a reduction in perioperative bleeding when compared to placebo without increased thrombotic complications [46].

59] calculated a bolus of 30mg/kg TXA IV,

56].

5 Fibrinolysis, Antibrinolytic Agents, andPerioperative Considerations

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Tranexamic Acid andtheRisk ofSeizures

Seizures are a major concern with the use of TXA as they have been an associated complication with cardiac surgery. A recent meta-analysis of 28 RCTs of TXA administration, in patients undergoing CABG, found an increase in the incidence of postoperative seizures with a relative risk of 6.67 [64]. The mechanism for the increased risk of seizures is unknown but may involve the competitive antagonism of TXA on hippocampal gamma-aminobutyric acid type A (GABA/A) and the glycine receptor [65]. TXA, GABA, and glycine have similar molecular structures. The proconvulsant properties of TXA are likely via direct effects on the central nervous system, as the application of TXA in experimental animal models will cause systemic, as well as intracranial, hypertension, and seizures [66]. Case reports have found that maximal TXA concentrations from the cerebral spinal uid occurred after the termination of drug infusion [65]. EACA has not been known to cause seizure activity, although there is inadequate data.

The incidence of seizures associated with TXA is likely dose-related, particularly with doses greater than 50mg/kg [67]. Studies have shown that predictors of seizure activity include: open chamber cardiac surgery, advanced age, female sex, redo surgery, ascending aortic disease, deep hypothermic circulatory arrest, cross-clamp time, chronic renal dysfunction, and TXA [68–71]. It has been speculated that cerebral emboli causing local blood-brain barrier disturbances leading to seizure activity could be an alternate or contributory mechanism for these ndings. In other scenarios, such as TXA loading in menstrual or traumatic bleeding, seizure activity is much less signicant [10, 72].

Although shown to occur, the signicance of seizures associated with cardiac surgery and TXA is not known. A Japanese database of pediatric cardiac surgeries showed a signicant increase in the incidence of seizures (1.6% versus

0.2%) in patients who received TXA but no difference in outcomes [73]. In contrast, Myles etal. [63] showed an increased incidence of stroke and death associated with TXA.Overall, it is unclear if TXA is the direct cause of stroke after cardiac surgery or if it only enables other mechanisms to exert their effects on the central nervous system.

Trauma, theRole ofFibrinolysis, andTraumatic Brain Injury

Trauma and traumatic bleeding is a leading cause of death and disability worldwide, with an estimated 400,000 deaths every year [74]. The past decade has seen the growing popularity of utilizing antibrinolytic agents in traumatic bleeding after the CRASH-2 and Military Application of Tranexamic Acid in Trauma Emergency Resuscitation Study

(MATTERs) trials [ mark studies, TXA was added to the World Health Organization’s list of essential medicines.

The CRASH-2 trial was a randomized trial to evaluate the effects of TXA in 20,211 adult trauma subjects who experienced or were at risk of signicant bleeding. Subjects were randomized within 8h of injury to 1g IV over 10min followed by a 1g infusion over 8h, or matching placebo. The primary outcome was 28-day in-hospital mortality. All-cause mortality was 14.5% in the treatment group and 16% in the placebo group (RR 0.91, 95% CI 0.85–0.97, P= 0.0035). Additionally, there was a reduction in risk of death due to bleeding of 4.9% vs. 5.7% (RR 0.85, 95% CI 0.76–0.96, P = 0.0077). Other cardiothoracic and thromboembolic events were similar between the groups. There was no signicant difference in the number of transfusions or need for surgery. Post hoc analysis of the 35% of patients that died from bleeding suggested that the benet of TXA was greatest when injected within the rst hour after injury. However, treatment that was started 3 h after injury paradoxically increased the risk of death from bleeding.

CRASH-2 was the rst trial to demonstrate a mortality benet using TXA in trauma, however, the results were controversial considering these results were not obtained in the setting of an advanced trauma network [ cerns about subjects being treated in facilities with limited resources, no protocols for identifying thromboembolic events, and no insight into the mechanism of TXA’s protective effect. More trials are being conducted to give answers to these lingering questions, including the Pre hospital Antibrinolytics for Traumatic Coagulopathy and Hemorrhage (PATCH) trial [77].

The MATTERs trial was a retrospective observational study designed to evaluate TXA in combat injury and to assess the effects of its administration on total blood product use, thromboembolic complications, and mortality. In the patient group treated with TXA, there was an unadjusted inhospital mortality of 17.4% vs. 23.9% in the nonTXA-treated group, as well as an independent association of TXA-treated patients with greater survival and less coagulopathy. Conicting with the CRASH-2 study, MATTERs reported an associated increased risk of thromboembolic events in TXA subjects, however with further analysis, no association was found. Future studies will aim to clarify these ndings.

The concept of acute traumatic coagulopathy (ATC) began to emerge in the literature after theorizing that another form of coagulopathy exists in patients, unrelated to uid and blood product administration, related to tissue injury and bleeding [78]. During the response to traumatic injury, there arises a primary coagulopathy that has been associated with increased activated protein C.Shock and tissue injury results in a large tPA release from intracellular endothelial stores. A resultant sympathetic surge and “endotheliopathy”

41, 75]. Based on ndings in these land-

76]. There were con-

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with glycocalyx damage further exacerbate coagulopathy and stimulate hyperbrinolysis [79]. Additionally, the response is characterized by dysbrinogenemia, endothelial dysfunction, and thrombocytopathia [80]. Hyperbrinolysis has been identied as a signicant contributor to mortality in adult trauma patients [76]. Although data suggests an important role of hyperbrinolysis as a pathological cause of bleeding, there can be individual variability in brinolysis.

With this in mind several investigators have raised caution to the practice of giving TXA, or other antibrinolytics, to all trauma patients due to the concern of brinolytic shutdown, or reduced brinolytic activity [81]. Giving TXA to these patients may cause unwanted thrombotic effects. In one study, Moore etal. [81] describe three brinolytic phenotypes: hyperbrinolysis, physiologic, and shutdown. Using a TEG databank from trauma subjects presenting to the emergency department over threeyears, they grouped subjects by lysis measurement 30min after maximum amplitude (LY30, percent). The most common phenotype was brinolysis shutdown (46%), while hyperbrinolysis (18%) independently increased risk of mortality (OR 3.3, 95% CI 2.4–4.6, P<0.0001). Acute blood loss was the leading cause of death in the hyperbrinolysis group, while multiple organ failure was most common in brinolysis shutdown. Possible mechanisms to explain these results have been put forward, but none have been proven invivo [82]. There is ongoing debate concerning the relevance of brinolytic shutdown.

Traumatic brain injury (TBI) is a leading cause of death after trauma and commonly presents with coagulopathy. Coagulopathy is a poor prognostic indicator for patients with TBI and is associated with hemorrhagic injury and high mortality [83]. Hyperbrinolysis is also present in these patients with a mechanism likely similar to patients that present with other traumas. What is known is that patients with TBI will have increased release of tissue factor in the circulation from injured brain tissue, temporal changes in tPA and uPA, and depletion of antiplasmin [84]. Evidence of the efcacy of antibrinolytics on TBI is lacking, but several trials are attempting to address this issue. CRASH-3: tranexamic acid for the treatment of signicant traumatic brain injury, is estimated to be completed in 2020 [85].

Orthopedics

[

87]. The total blood loss in THA averages 1600mL, depend-

ing on surgical technique. About 30% of patients receive at least one blood transfusion with a median of 2.2units [87].

Overall, TXA is efcacious in reducing perioperative blood loss and transfusion requirements over a range of procedures. Intraoperative dosing of TXA for joint arthroplasty varies greatly. Many centers administer 10–15mg/kg TXA prior to the release of the tourniquet, or prior to skin incision for THA, followed by 1 or more repeat 10–15mg/kg boluses 3–8h later. A 2015 meta-analysis of 2720 TKA and THA procedures found that TXA signicantly reduced blood loss and transfusion requirements [88]. For both TKA and THA, the number of patients receiving at least one unit of packed red blood cells were decreased in the TXA group compared to the control group. These results have been supported in several studies involving TKA and THA patients [89, 90]. Having established the efcacy of TXA in major joint surgeries, Xu etal. [91] conducted a systemic review and metaanalysis of 211 publications to investigate the safety of different routes of TXA, with a secondary aim to identify the safest and most efcacious route of TXA.Studies were examined with drug administration via: IV, intra-articular, topical, oral, and their combinations. TXA via IV and topical had the lowest risk ratio (RR=0.11, 95% CI 0.03–0.41) with all routes showing signicantly lower transfusion rates compared to placebo.

Spine surgery has also been studied in single and multilevel procedures. A 2015 meta-analysis with a total of 644 patients concluded that TXA reduced intraoperative blood loss by 219mL (95% CI −116mL to −322mL, P<0.05) [92]. They did not nd an associated increased incidence of pulmonary embolism, deep venous thrombosis, or myocardial infarction. A more recent review and meta-analysis of TXA looking at blood loss and blood transfusion in multilevel spine surgery showed a decrease in blood loss and transfusion compared to controls, as well as a higher hemoglobin value post-surgery [93]. The RCTs in the analysis reviewed several different dosing regimens with many following 10–15mg/kg TXA loading dose IV with an infusion of 1–2mg/kg/h [93]. Recent studies show promising results utilizing high-dose TXA with a 50mg/kg loading dose IV followed by an infusion of 5mg/kg/h. Current literature and future studies in orthopedic surgery focus on the role of TXA in intertrochanteric fractures, total shoulder replacement, pediatrics, and topical TXA application.

Antibrinolytics have been studied extensively in orthopedic surgery, particularly in the most common procedures like total knee arthroplasty (TKA) and total hip arthroplasty (THA). During TKA, blood loss can be signicant and under estimated, averaging between 762 and 1789 mL in the absence of TXA [86]. In a recent study, 25% of patients required red blood cell transfusion with a median of 2.2units

Liver Surgery andTransplantation

Patients undergoing hepatic surgery face a unique challenge due to potential alterations in hemostatic function leading to coagulopathy and excess bleeding. Hemostatic function is determined by a complex relationship between vascular

5 Fibrinolysis, Antibrinolytic Agents, andPerioperative Considerations

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endothelium, platelets, coagulation, and brinolytic activity [94]. Patients with compromised liver function often have derangement in hemostasis and can develop a primary hyperbrinolysis from the inammation and trauma of surgery. Hyperbrinolysis is particularly common during liver transplantation [95]. Early reports of hyperbrinolysis during transplant, diagnosed by thromboelastography, spurred the use of antibrinolytics for treatment until reports gave concern over increases in venous thromboembolism and mortality [10]. During hepatic transplantation, tPA levels increase during the anhepatic phase due to vascular trauma and reduced clearance. This perturbation is usually corrected after hepatic reperfusion, as PAI-1 is released and tPA is cleared.

RCTs have shown that TXA reduces blood loss and transfusion requirements during orthotopic liver transplantation (OLT) by 30–40% compared to placebo [96]. Subsequently, most liver transplant centers have developed protocols that determine when TXA and other antibrinolytics are appropriate during transplantation. TXA use is not universal due to lingering concerns about safety and thromboembolic complications. Large-scale safety data exist for aprotinin but are lacking for TXA, particularly in subgroups that are low risk for blood loss or high risk for thromboembolic complications. Additionally, there has been great change in surgical and anesthetic technique for OLT over the last 15years that may change blood management practices.

A propensity score matched study by Badenoch etal. [96] looked to describe the clinical use of TXA and to appraise effectiveness and safety. Data was collected from 1799 liver transplant patients and retrospectively analyzed using propensity matching to account for thrombotic risk and transfusion confounders. In matched pairs, patients exposed to TXA received less red blood cell and fresh frozen plasma transfusions. No difference in thromboembolic events were found between matched groups. They concluded that TXA is effective in modern clinical practice. However, the magnitude of effectiveness was reduced when compared to previous studies, possibly accounting for the improvements in modern practice.

The efcacy of TXA in hepatic resection is less studied. Resection is the optimal treatment for primary metastatic liver malignancies, benign liver tumors, and some biliary disease [94]. Like OLT, bleeding is a regular obstacle in hepatic resections and would seem amenable to antibrinolytic therapy. A prospective, randomized trial in 2006 found that TXA lowered blood loss and operative times in hepatic tumor resections [97]. In a 2016 prospective cohort study, 18 patients undergoing major hepatic resection were sequentially assigned to one of three cohorts: control, TXA dose I (1g bolus followed by 1g infusion over 8h), and TXA dose II (1g bolus followed by 10mg/kg/h until the end of surgery) [94]. Blood samples were collected for TEG, coagulation

components, and TXA concentration. They concluded that there was no thromboelastographic evidence of hyperbrinolysis in these major liver resections and that TXA did not inuence a change in systemic brinolysis. Further research is warranted in this area.

Obstetrics

Postpartum hemorrhage (PPH) is an obstetric emergency and the leading cause of maternal death worldwide. At delivery, PAI-2 synthesis stops and tPA is rapidly increased, causing hyperbrinogenemia to levels of 500–600mg/dL [29]. Based on previous work, World Health Organization (WHO) guidelines recommend TXA in PPH if uterotonics fail to stop bleeding, or if bleeding is thought to be from trauma [98]. However, the efcacy of TXA in this scenario is uncertain, and a 2016 analysis of 26 RCTs was inconclusive due to poor study design and serious aws [99]. Many of the studies used a 1g IV dose of TXA before incision for cesarean section, or 1g IV after vaginal delivery.

A recent, large trial published in 2017 was able to add to our understanding of TXA in PPH [100]. The study aimed to analyze the effects of TXA on death and hysterectomy in woman with PPH. Woman aged 16 years and older from 193hospitals in 21 countries were recruited after being diagnosed with PPH after vaginal birth or caesarean section. Subjects were assigned to either 1g IV TXA or matching placebo, but if bleeding persisted or restarted within 24h of the rst dose, a second 1g dose or placebo could be given. The composite primary endpoint was death from all-causes or hysterectomy within 42days of giving birth. They found that death due to bleeding was signicantly reduced in women given TXA, especially when given within 3h of birth where deaths were reduced by nearly one-third. There were no signicant differences in other causes of death between groups. Hysterectomy was not reduced with TXA, although it did substantially reduce the number of laparotomies to control bleeding. The composite primary endpoint of allcause mortality or hysterectomy was not reduced with TXA.

Subarachnoid Hemorrhage

When a patient suffers a subarachnoid hemorrhage (SAH), rebleeding is a signicant cause of morbidity and mortality. Currently, the rate of rebleeding has decreased to about 15% due to more sophisticated endovascular and surgical techniques early in the hospital course. The highest risk of rebleed is during the rst 24h after SAH, peaking in the rst 6h. After rebleed, approximately 60% of patients will die, and another 30% will remain dependent for activities of daily living [101].

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A. N. Primm

The literature supports considering a short-course use of TXA to prevent rebleeding after SAH, with studies reporting a reduction in rebleeding by 35–40% [46, 102, 103]. However, these studies emphasized that outcomes were diminished by cerebral ischemia. A 2017 systematic review to assess the evidence for the role of TXA in the treatment of SAH and subdural hemorrhage found that TXA signicantly reduced rebleeding in SAH patients and trended toward reducing mortality, but did not improve Glasgow Outcome Scale scores [104].

Initiated in 2013, the ultra-early tranexamic acid after subarachnoid hemorrhage (ULTRA) trial will aim to determine whether ultra-early and short-term administration of TXA (1g bolus as soon as possible after randomization followed by 1g over 8h infusion to maximum of 24h), in addition to standard SAH management will lead to better functional outcome scores at six months [105]. The TXA dose used in this trial will be lower than in previous studies in an effort to prevent delayed cerebral ischemia.

Pediatrics

Antibrinolytic drugs, particularly TXA, are effective when used in both adult and pediatric surgical patients. Prospective RCTs in children undergoing cardiac surgery, spinal fusion, and craniosynostosis repair have shown that IV TXA is effective in reducing blood loss and transfusions [106]. Although without signicant evidence, TXA has been used clinically in major pediatric plastic and maxillary procedures, organ transplantation, trauma, and major abdominal surgeries. Additionally, the WHO, American Society of Anesthesiologists, European Society of Anesthesiology, and Australian National Blood Authority have comprehensive blood management guidelines that suggest prophylactic TXA administration.

Pharmacokinetic studies over the past 10years have elucidated TXA dosing regimens for children. These regimens are mostly based on the assumption that plasma TXA concentrations should target between 20 and 100 mcg/ mL.However, these assumptions are based on invitro models of brinolysis inhibition, and further studies are needed to validate this concept invivo [106].

Topical Tranexamic Acid

Given the potential benets of decreased risk of adverse events compared to systemic TXA, there is increased interest in utilizing the topical form of TXA [107]. When applied topically, the plasma concentration of TXA is 90% less than when administered IV [36]. However, local tissue drug concentrations from the topical application may also increase

the risk of adverse events. A previous Cochrane review, covering a wide range of procedures, concluded that locally applied TXA might reduce bleeding and transfusions, but had concerns about the lack of safety data [108].

A recent systematic review and meta-analysis were conducted to evaluate the efcacy and safety of topically administered TXA [107]. A total of 67 studies were included, the majority of which evaluated orthopedic procedures. Administration of topical TXA, compared to placebo, signicantly reduced the odds of receiving a blood transfusion (OR 0.28, 95% CI 0.20–0.38; P<0.001) and signicantly reduced mean blood loss. When compared to IV administration, there was no difference in transfusion requirements or blood loss. There was also no difference in the odds of developing a venous thromboembolic complication between topical TXA and control groups, or the topical and IV groups. No major differences were found between topical and systemic TXA concerning safety and efcacy. However, most of the included trials were not powered sufciently to detect these differences. Besides orthopedic surgery, comparisons between systemic and topical TXA warrant further exploration.

Conclusions

The antibrinolytic agents, particularly TXA, have been studied widely in a variety of perioperative settings. Most concerns about potential thromboembolic events using the antibrinolytics have not been seen in the literature, although many studies are underpowered to detect them. The efcacy of aprotinin has been shown in cardiac surgery, but early safety concerns shelved its use in the United States. The reintroduction of aprotinin in Europe, along with a large safety registry, will be closely examined. The three described antibrinolytics had shown reduced blood loss and transfusion rates in cardiac surgery, but concern over seizure activity in patients treated with TXA remain. Seizures in cardiac surgery are likely related to higher dosages, and it will be important to investigate the real impact on outcomes. CRASH-2 was a landmark trial showing reduced mortality in patients treated early with TXA after traumatic injury. The controversy surrounding measuring brinolytic shutdown and its impact on therapy is an area requiring further work. Several on-going trials will further enlighten the use of TXA in trauma, including CRASH-3 for traumatic brain injuries. Orthopedic surgery has established the benets of perioperative TXA administration and continues to investigate alternate routes of administration to improve safety. Liver transplant has clear reductions in blood loss with antibrinolytic treatment, although the magnitude of such reductions may be explained by improved surgical and blood management practices. There is no clear evidence for improved out-

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comes with TXA administration after SAH, and the results of the ULTRA trial are highly anticipated. Death due to bleeding is signicantly reduced in women given TXA during PPH, particularly within the rst 3h. Like adults, antibrinolytic therapy is effective in pediatric surgery, but optimum dosages are still under investigation.

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