Version May 2024
INTRODUCTION — Fibrinolysis is an important physiologic response to bleeding that can contribute to coagulopathy. Prophylactic administration of an antifibrinolytic agent before surgery-induced tissue injury has occurred can reduce bleeding and allogeneic blood transfusions in cardiac surgery with cardiopulmonary bypass (CPB) and selected noncardiac procedures (eg, major orthopedic surgery, hepatic surgery). This topic will provide a review of the available intravenously (IV) administered antifibrinolytic agents (epsilon-aminocaproic acid [EACA], tranexamic acid [TXA], and aprotinin) and discuss their routine use in patients undergoing cardiac surgical procedures.
Prophylactic use of antifibrinolytics (primarily TXA) is also common during major orthopedic surgical elective procedures (eg, total knee or hip arthroplasty, spine surgery), as discussed in separate topic reviews. Antifibrinolytic therapy use after major trauma is discussed in the following topics:
Other perioperative blood conservation strategies are discussed separately. (See "Perioperative blood management: Strategies to minimize transfusions".)
AVAILABLE AGENTS — Fibrinolysis (conversion of plasminogen to plasmin) has a central role in restoring blood vessel patency following clot formation (see "Thrombotic and hemorrhagic disorders due to abnormal fibrinolysis", section on 'Overview of the fibrinolytic system'). Notably, plasmin generation during fibrinolysis also activates proinflammatory pathways [1].
Epsilon-aminocaproic acid (EACA) and tranexamic acid (TXA) are small molecular weight pharmacologic agents that are widely used to inhibit fibrinolysis. They bind to the lysine attachment site of the plasminogen molecule to prevent its binding to fibrin and its conversion to plasmin, thereby inhibiting fibrinolysis.
●Epsilon-aminocaproic acid – EACA was one of the first intravenous (IV) antifibrinolytic agents developed. It is commonly used during cardiac surgery in the United States but is not available in many other countries due to concerns regarding renal dysfunction [2-4]. (See 'Epsilon-aminocaproic acid-associated complications' below.)
●Tranexamic acid – TXA is the most widely used and extensively studied antifibrinolytic agent; it is used exclusively in most countries. TXA is approximately 10 times more potent than EACA [5].
TXA is also available for topical administration to inhibit local fibrinolysis at the site of bleeding, reducing bleeding with minimal systemic effects. Details are discussed in a separate topic [6]. (See "Overview of topical hemostatic agents and tissue adhesives", section on 'Tranexamic acid'.)
Oral preparations of TXA are also available. These have been used in major orthopedic surgical procedures. In studies of patients undergoing total knee arthroplasty, studies have noted similar efficacy after topical and/or oral administration of TXA compared with IV TXA, without differences in adverse effects [7-17] (see "Anesthesia for total knee arthroplasty", section on 'Dosing regimen'). Oral TXA is also used for treatment of menorrhagia when other options have been unsuccessful. (See "Managing an episode of acute uterine bleeding", section on 'Tranexamic acid'.)
●Aprotinin – Another antifibrinolytic agent, aprotinin, is a serine protease inhibitor. Aprotinin has been studied in cardiac and orthopedic surgery. Aprotinin is no longer available in the United States due to safety concerns [18-20]. However, aprotinin has been reintroduced for clinical use in Europe [2,20-22]. (See "Early noncardiac complications of coronary artery bypass graft surgery", section on 'Antifibrinolytic agents'.)
POTENTIAL ADVERSE EFFECTS
Thrombosis — It is uncertain whether the administration of tranexamic acid (TXA) or epsilon-aminocaproic acid (EACA) increases the risk of thromboembolic events. Antifibrinolytic agents are clot stabilizers that facilitate the normal hemostatic response to bleeding. Although hypercoagulability is a theoretical concern [2,23], there are differences between prohemostatic and prothrombotic properties. In fact, in the absence of antifibrinolytic agents, fibrinolysis can have prothrombotic effects due to plasmin-mediated platelet activation and thrombin generation [24]. Furthermore, multiple agents with prothrombotic properties are often administered to patients with active surgical bleeding, including antifibrinolytic agents, transfusions, and factor concentrates.
A higher risk of thrombotic complications and death was noted in retrospective observational studies with another antifibrinolytic agent, aprotinin, leading to its withdrawal from the market in the United States [18-20].
Average- versus high-risk patients — Decisions regarding use of TXA or EACA in patients deemed at higher risk for thrombotic events should be individualized, taking into consideration patient-related and surgical procedure-related risks for bleeding and transfusion, as well as the individual's risk for thrombotic events.
●Average-risk patients – Studies have not noted increased risk for thrombosis (eg, coronary graft occlusion, venous thromboembolism [VTE], pulmonary embolism) after routine prophylactic administration of antifibrinolytic agents during cardiac surgery [20,25,26], major joint arthroplasty (eg, total knee arthroplasty, total hip arthroplasty) [7-17,23,27-44], or spine surgery [45-49].
●Patients at high baseline risk – Data regarding the safety of TXA for surgical patients at high baseline risk of thromboembolic events are somewhat limited. Randomized clinical trials of antifibrinolytic agents have commonly excluded patients with prior thromboembolic events due to concerns regarding exacerbation of risk. Such patients are often chronically receiving anticoagulant agents, which are typically withheld during the perioperative period. The limited available data include the following studies:
•Orthopedic surgical patients with higher risk – Retrospective studies in orthopedic surgical patients with a prior thromboembolic history have not reported increased thromboembolic events or mortality after TXA administration [23,32-40].
•Other types of noncardiac surgery – One randomized trial included 9535 patients undergoing various noncardiac surgical procedures [50]. Either TXA 1 gram intravenous (IV) bolus or placebo was administered at the start and again at the end of surgery. The composite primary outcome (life-threatening bleeding, major bleeding, or bleeding into a critical organ) was less frequent in the TXA group (9.1 versus 11.7 percent; hazard ratio [HR] 0.76, 95% CI 0.67-0.87). The composite cardiovascular safety outcome of postoperative myocardial injury, nonhemorrhagic stroke, peripheral arterial thrombosis, or symptomatic proximal VTE at 30 days differed little in the TXA group (14.2 percent) compared with the placebo group (13.9 percent; HR 1.02, 95% CI 0.92-1.14) [50].
•Patients with coronary stents undergoing surgical procedures – In one retrospective study, the risk for major adverse cardiac events did not appear to be increased after intraoperative administration of an antifibrinolytic agent in patients with coronary stents [51].
•Across varied settings – A systematic review that included 216 randomized trials of IV TXA versus placebo in 125,550 surgical and nonsurgical patients did not find an increased risk for thromboembolism in studies that included patients with a history of thromboembolism [52]. Also, thrombotic complications have not been noted after other routes of antifibrinolytic administration [7-17].
Contraindications to antifibrinolysis — However, we avoid administration of antifibrinolytic agents in certain patient groups due to the potential increased risk of thrombosis:
●Known hypercoagulable conditions.
●Patients undergoing vascular anastomosis.
●Development of disseminated intravascular coagulation (DIC) – Although antifibrinolytic agents are appropriate in patients with severe bleeding due to a hyperfibrinolytic state, they are generally contraindicated in patients with DIC since inhibition of the fibrinolytic system may increase risk for thrombotic complications in this setting. (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults", section on 'Avoid antifibrinolytic agents and PCCs'.)
●Development of fibrinolytic shutdown – After major trauma, a potential concern is the risk of fibrinolytic shutdown, which increases the risk of thromboembolic complications due to an inhibition of fibrinolysis characterized by decreased tissue plasminogen activator (tPA) activity and increased circulating plasminogen activator inhibitor 1 (PAI-1) [53]. Diagnosis is with viscoelastic testing (eg, thromboelastography [TEG], rotational thromboelastometry [ROTEM]). In the United States (but not in Europe), antifibrinolytic agents are avoided after major trauma until these viscoelastic tests are available to guide administration of initial and additional doses, as discussed in separate topics [54]. (See "Etiology and diagnosis of coagulopathy in trauma patients", section on 'Viscoelastic hemostatic assays' and "Etiology and diagnosis of coagulopathy in trauma patients", section on 'Fibrinolysis shutdown' and "Ongoing assessment, monitoring, and resuscitation of the severely injured patient", section on 'Management of acute traumatic coagulopathy'.)
Tranexamic acid-associated complications
Seizures — Convulsive seizures have been reported after administration of high doses of IV TXA during cardiac surgery with cardiopulmonary bypass (CPB), although overall risk is low and is minimized by avoiding high doses (eg, >4 grams) [25,26,55-59]. It is particularly important to avoid higher doses of TXA in patients with moderate to severe renal dysfunction who may accumulate higher blood levels of TXA [60]. Since TXA can pass into the cerebrospinal fluid, this agent is typically avoided in patients with a seizure history [2,21]. If available, we use EACA rather than TXA in patients with known history of seizures. If EACA is not available, decisions to use TXA are individualized based on procedure-related factors.
Data in cardiac surgical patients note a risk of seizures between 0.4 and 1.6 percent after administration of TXA [2,25,26,55-57,59,61-63]. In one randomized trial of 4631 patients undergoing cardiac surgery, seizures occurred in more patients who received TXA compared with placebo (0.7 versus 0.1 percent), but the overall risk was low [25]. A post hoc analysis noted that patients with seizures were more likely to have a stroke (relative risk [RR] 21.9, 95% CI 10.1-47.6) or die (RR 9.52, 95% CI 2.5-35.9) [25]. Another randomized trial in 3031 patients compared TXA dosing regimens during cardiac surgery (a 30 mg/kg bolus followed by 16 mg/kg per hour infusion plus 2 mg/kg in the CPB prime versus a 10 mg/kg bolus followed by a 2 mg/kg per hour infusion plus 1 mg/kg in the CPB prime) [26]. Seizure incidence was slightly higher in patients who received the higher TXA dose (1.0 versus 0.4 percent; risk difference [RD] 0.6 percent, 95% CI 0.0-1.2 percent). Older meta-analyses and observational studies have also noted that risk for seizures is higher after IV administration of higher doses of TXA compared with lower doses, controls, or other antifibrinolytic agents [55,56,59].
Potential mechanisms for seizures include induced neuronal excitation by TXA inhibition of γ-aminobutyric acid (GABA) neurotransmission [62-64]. During cardiac surgery, the occurrence of cerebral emboli may contribute to blood-brain barrier or ischemic injury and potential for seizure activity.
Wrong site administration — There have been multiple case reports of unintentional intrathecal administration of TXA, often attributed to the similar appearances of ampules of TXA and local anesthetic (particularly hyperbaric bupivacaine 0.5%) [65,66].
Reported signs and symptoms of intrathecal administration included back, buttock, and leg pain. Myoclonus, seizures, tachycardia, hypertension, and in some cases ventricular fibrillation have also been noted. Death occurred in approximately one-half of the reported cases. Vigilance is required when administering any pharmacologic agent during anesthetic care and is particularly important when neuraxial medications are used. (See "Prevention of perioperative medication errors", section on 'Wrong route errors'.)
Epsilon-aminocaproic acid-associated complications
Renal dysfunction — Cases of postoperative renal dysfunction have been reported after EACA administration [2,3]. In a small randomized trial conducted in 64 consecutive adult patients undergoing thoracic aortic surgery with CPB, a numerically higher but nonsignificant increase in the incidence of renal failure was noted after EACA (3/30 patients) compared with TXA (0/31 patients) [58]. In a retrospective study of 448 children with life-threatening hemorrhage, most did not receive an antifibrinolytic [4]. Acute kidney injury (AKI) developed in 17 percent of those who received no antifibrinolytic agent, in 16 percent of 37 patients who received TXA, and in 50 percent of 18 patients who received EACA (adjusted odds ratio [OR] 3.3, 95% CI 1.0-10.3 for EACA compared with placebo).
USE OF ANTIFIBRINOLYTIC AGENTS IN CARDIAC SURGERY — We recommend administration of prophylactic antifibrinolytic therapy for cardiac surgery with cardiopulmonary bypass (CPB). This is consistent with several professional society guidelines [67-71].
Fibrinolysis is a major contributor to coagulopathy and bleeding during cardiac surgery with CPB (figure 1). Administration of intravenous (IV) antifibrinolytic agents is associated with decreased bleeding, allogeneic red blood cell (RBC) transfusions, and risk for postoperative mediastinal re-exploration in cardiac surgical patients [1,2,18,20,23,25,26,52,59,72,73].
Efficacy
●Tranexamic acid (TXA) – Most of the large studies and meta-analyses evaluating efficacy and safety of lysine analog antifibrinolytics in cardiac surgical patients are from studies of TXA [18,20,25,26,52,59,73]. In a placebo-controlled randomized trial of 4662 patients undergoing coronary artery bypass grafting (CABG) surgery, patients who received a bolus dose of TXA (either 100 or 50 mg/kg) administered 30 minutes after anesthesia induction had a lower rate of blood transfusion (37.9 versus 54.7 percent; risk ratio 0.69, 95% CI 0.65-0.74) [25]. Major hemorrhage or cardiac tamponade leading to reoperation was also less common (1.4 versus 2.8 percent; risk ratio 0.49, 95% CI 0.32-0.75). Although rare, seizures were more common in the TXA group (0.7 versus 0.1 percent) [25].
A 2021 model-based meta-analysis of 64 randomized trials and 18 observational studies included nearly 50,000 cardiac surgical patients and 73 different dosing regimens of TXA (ranging from 5.5 mg/kg to 20 grams total) [59]. The estimated probability of transfusion in the absence of TXA exposure was 62 percent (95% CI 53-72 percent). Both lower and higher dosing regimens reduced transfusion risk, with a maximum reduction of 33 percent (95% CI 25-42 percent) [59]. Another meta-analysis of placebo-controlled trials in patients undergoing cardiac surgery, major noncardiac surgery, or nonsurgical medical interventions noted that TXA reduced mortality due to bleeding (2.9 versus 3.8 percent; risk difference [RD] 0.008, 95% CI 0.011-0.005; 46,702 patients; 49 studies) [52].
●Epsilon-aminocaproic acid (EACA) – Data regarding efficacy of EACA are more limited. A 2009 meta-analysis of randomized trials of the three antifibrinolytic agents (aprotinin, TXA, and EACA) included only cardiac surgical patients, with 5 trials (672 patients) comparing EACA versus controls, and 19 trials (1802 patients) comparing TXA versus controls [18]. Similar efficacy of both agents was reported; compared with placebo, relative risk for TXA was 0.70 (95% CI 0.61-0.80) and for EACA was 0.75 (95% CI 0.58-0.96).
A post hoc analysis of a 2011 study in cardiac surgical patients included direct comparisons of those receiving EACA (n = 780) versus those receiving TXA (n = 770) [74]. Risks for bleeding requiring reoperation and requirements for transfusion of blood products were similar except for fresh frozen plasma (FFP); 37.8 percent of patients receiving TXA needed FFP compared with 45.4 percent of those receiving EACA (relative risk 0.83, 98.33% CI 0.72-0.96).
A 2011 meta-analyses (52 randomized trials; 25,000 participants) reported efficacy of three antifibrinolytic agents (aprotinin, TXA, and EACA) compared with placebo in various types of cardiac and noncardiac surgery [20]. Overall, RBC transfusions were less frequent in patients receiving TXA compared with EACA (30 versus 45 percent); relative risk compared with placebo for TXA was 0.61 (95% CI 0.53-0.70) and for EACA was 0.81 (95% CI 0.67-0.99).
Timing of administration — The antifibrinolytic agent is typically administered after anesthetic induction and always before initiation of CPB [2,75,76]. However, institutional protocols for precise timing of initial administration vary. Examples include just before skin incision, over a 30-minute period after anesthetic induction, or shortly after systemic heparinization. Administration of prophylactic antifibrinolytic agents before the occurrence of significant tissue injury is ideal but not always feasible (eg, traumatic cardiac injury).
The antifibrinolytic infusion is continued throughout the postbypass period until the completion of the procedure (ie, skin closure). If ongoing clinical bleeding is a concern, we continue the antifibrinolytic infusion for several postoperative hours [2,25,76-79].
Dosing and administration
Tranexamic acid — Typically, 10 to 30 mg/kg of IV TXA is administered as an initial loading dose, followed by an infusion of 1 to 16 mg/kg per hour throughout CPB until skin closure. Some centers include a dose of 1 to 2 mg/kg in the CPB prime. In patients with normal renal function, the half-life is approximately 80 minutes after the bolus dose. For this reason, the infusion is continued until the end of surgery or longer if necessary [2]. (See 'Timing of administration' above.)
Various other dosing strategies have been reported (figure 2) [79]. Although the IV dose of TXA required to inhibit fibrinolytic activity by 98 to 100 percent is approximately 100 mcg/mL, a lower dose of 22.4 mcg/mL provides an 80 percent effective concentration [59]. Once the concentration exceeds the 80 percent effective concentration, further changes in drug concentration have little clinically relevant impact on efficacy [20]. For example, a randomized trial compared TXA dosing regimens in 3031 patients undergoing cardiac surgery (a 30 mg/kg bolus followed by 16 mg/kg per hour infusion plus 2 mg/kg in the CPB prime versus a 10 mg/kg bolus followed by a 2 mg/kg per hour infusion plus 1 mg/kg in the CPB prime) [26]. Only a slightly lower incidence of allogeneic blood transfusion was noted in patients receiving the higher TXA dose (21.8 versus 26.0 percent) [26]. However, as noted above, the seizure incidence was slightly higher in those receiving the higher TXA dose (1.0 versus 0.4 percent) [26]. (See 'Seizures' above.)
Epsilon-aminocaproic acid — Typically, an initial loading dose of 5 to 10 grams is followed by a continuous infusion of 1 gram/hour to maintain plasma concentration of approximately 0.13 mg/mL [79]. Some centers include an additional 5 to 10 mg dose in the CPB prime. Other dosing strategies have been reported [79-81].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Transfusion and patient blood management".)
SUMMARY AND RECOMMENDATIONS
●Available agents – In intraoperative settings, epsilon-aminocaproic acid (EACA) and tranexamic acid (TXA) are the two widely used intravenous (IV) agents that inhibit fibrinolysis. (See 'Available agents' above.)
•EACA – EACA is commonly used during cardiac surgery in the United States.
•TXA – TXA is used in most other settings and is used exclusively in many countries. TXA is approximately 10-fold more potent than EACA.
TXA is also available for oral administration, and in topical preparations to inhibit local fibrinolysis at the site of bleeding. (See "Overview of topical hemostatic agents and tissue adhesives", section on 'Tranexamic acid'.)
•Aprotinin – Another antifibrinolytic agent, aprotinin, is no longer available in the United States and is rarely used elsewhere due to safety concerns.
●Potential adverse effects
•Thrombosis – Although hypercoagulability is a theoretical concern, increased thrombosis risk (eg, coronary graft occlusion, venous thromboembolism [VTE], pulmonary embolism) has not been noted after routine prophylactic administration of antifibrinolytic agents during cardiac surgery, during noncardiac surgery such as major orthopedic procedures, or in nonsurgical settings.
However, we avoid IV antifibrinolytics in patients with a known hypercoagulable condition, those undergoing vascular anastomosis, and after development of disseminated intravascular coagulation (DIC) or trauma-induced fibrinolytic shutdown. (See 'Thrombosis' above.)
•TXA-associated complications
-Seizures with high doses of TXA – Convulsive seizures have been reported after administration of higher doses of TXA (eg, >4 grams) during cardiac surgery. Patients with moderate to severe renal dysfunction are at particular risk because they may accumulate higher blood levels of TXA. (See 'Seizures' above.)
-Wrong site administration – Inadvertent intrathecal administration of TXA has occurred due to the similar appearances of ampules of TXA and hyperbaric bupivacaine, causing severe adverse effects. (See 'Wrong site administration' above.)
•EACA-associated renal dysfunction – Rare cases of postoperative renal injury have been reported after IV EACA administration. (See 'Epsilon-aminocaproic acid-associated complications' above.)
●Use of antifibrinolytic agents in cardiac surgery
•We recommend administration of prophylactic antifibrinolytic therapy (EACA or TXA) before initiation of cardiopulmonary bypass (CPB) (Grade 1B). We administer an initial loading dose followed by an infusion continuing throughout CPB until skin closure. If ongoing clinical bleeding is a concern, we continue the infusion for several postoperative hours. Randomized trials demonstrate that such treatment reduces risks for perioperative transfusion and postoperative mediastinal re-exploration. (See 'Timing of administration' above and 'Efficacy' above.)
•Dosing and administration
-TXA – Typically, an initial loading dose of 10 to 30 mg/kg is administered, followed by an infusion of 1 to 16 mg/kg per hour. Some centers include a dose of 1 to 2 mg/kg in the CPB prime. Various other dosing strategies have been reported (figure 2). (See 'Tranexamic acid' above.)
-EACA – Typically, an initial loading dose of 5 to 10 grams is administered, followed by a continuous infusion of 1 gram/hour. Some centers include a dose of 5 to 10 grams in the CPB prime. (See 'Epsilon-aminocaproic acid' above.)
آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟
