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Abstract

  1. Top of page
  2. Abstract
  3. Epsilon-Aminocaproic Acid
  4. Tranexamic Acid
  5. Aprotinin
  6. Indications, Contraindications, and Drug Selection
  7. Adverse Effects
  8. Intraoperative Thromboembolism
  9. Summary
  10. Acknowledgements
  11. References

This article reviews the current status and controversies of the 3 commonly used antifibrinolytics—epsilon-aminocaproic acid, tranexamic acid and aprotinin—during liver transplantation. There is no general consensus on how, when or which antifibrinolytics should be used in liver transplantation. Although these drugs appear to reduce blood loss and decrease transfusion requirements during liver transplantation, their use is not supported uniformly in clinical trials. Aprotinin has been studied more extensively in clinical trials and appear to offer more advantages compared to two other antifibrinolytics. Because of the diverse population of liver transplant recipients and the potential adverse effects of antifibrinolytics, especially life–threatening thromboembolism, careful patient selection and close monitoring is prudent. Further studies addressing the risks and benefits of antifibrinolytics in the setting of liver transplantation are warranted. (Liver Transpl 2005;11:10–18.)

Enhanced fibrinolysis plays a significant role in the blood loss and transfusion requirements during orthotopic liver transplantation (OLT).1, 2 Enhanced fibrinolysis during OLT is caused by a disturbance of the balance between activators and inhibitors in the fibrinolytic system. Increased activities of fibrinolytic system activators, mainly tissue-type plasminogen activator and possibly urokinase-type plasminogen activator, and decreased activities of fibrinolytic system inhibitors, plasminogen activator inhibitors, and alpha-2 antiplasmin have been demonstrated during OLT.1–3 The net result of this imbalance is excessive degradation of the polymerized fibrin, which is manifested as generalized oozing in the surgical field. Laboratory tests such as shortened whole blood clot and euglobulin clot lysis times, reduced clot lysis index on thromboelastogram, elevation of fibrin degradation products and D-dimers, and decreased level of fibrinogen can assist in the diagnosis.1, 2, 4

Antifibrinolytics have been used since the early era of liver transplantation in an attempt to minimize blood loss, transfusion requirement, and associated risks and costs. However, despite their common use in clinical practice, there is no general consensus on how, when, or which antifibrinolytic should be used. Early studies on antifibrinolytics in liver transplantation suffered from design flaws and limitations of statistical power. More recent studies, including a multicenter, prospective, double-blinded trial from Europe, provide some new information on this topic. The purposes of this review are 2-fold. First, the pharmacology, efficacy, adverse effects, indications, and contraindications of 3 commonly used antifibrinolytics in OLT—epsilon-aminocaproic acid, tranexamic acid and aprotinin—were reviewed. Second, the controversies, including a possible link between intraoperative thrombotic events and antifibrinolytics were also examined.

Epsilon-Aminocaproic Acid

  1. Top of page
  2. Abstract
  3. Epsilon-Aminocaproic Acid
  4. Tranexamic Acid
  5. Aprotinin
  6. Indications, Contraindications, and Drug Selection
  7. Adverse Effects
  8. Intraoperative Thromboembolism
  9. Summary
  10. Acknowledgements
  11. References

Epsilon-aminocaproic acid (EACA) is a synthetic lysine analog that competitively inhibits the binding of plasminogen to lysine residues on the surface of fibrin and prevents conversion of plasminogen to plasmin. Recent studies have also indicated that EACA might inhibit prourokinase-induced plasminogen activation and prevent plasmin degradation of platelet glycoprotein Ib receptors, thus preserving platelet function.5, 6 There is a theoretical concern of dysrhythmia during rapid injection, but this is rarely seen in clinical practice. EACA is eliminated primarily from the kidney, 65% of the dose being found in the urine as unchanged drug. The terminal elimination half-life is about 2 hours.

EACA was 1st used in clinical liver transplantation in 1966 by von Kaulla et al.7 (Table 1). In 1987, Kang et al.8 reported a study of 97 patients undergoing OLT. Of those patients, 20 developed severe fibrinolysis and were treated with 1 gm of EACA. All patients treated with EACA demonstrated complete inhibition of fibrinolysis with improved parameters on thromboelastogram. Later, the same group showed that a smaller dose of EACA (.25-.5 gm) was also effective in treating most fibrinolysis.9 In addition to a small single dose (.25-1.0 gm) recommended by Kang and his group,4, 8 a regimen consisting of a 5-gm bolus followed by a 1 gm/hour infusion has also been advocated in an attempt to maintain adequate blood levels of the drug. Later, several studies9, 10 showed no benefits of EACA in OLT, but the values of those studies were limited since they were retrospective and involved small numbers of patients. In a prospective, double-blind, randomized, controlled trial,11 in which 16 mg/kg/hour of EACA was compared to tranexamic acid and placebo, EACA reduced red blood cell transfusion requirements, though this reduction was not statistically significant compared to the placebo group.

Table 1. Antifibrinolytics in Orthotopic Liver Transplantation
ReferenceTotal Numbers of PatientsProspective StudyDoseResults
  1. Abbreviations: ECLT, euglobulin clot lysis time; EBL, estimated blood loss; RBC, red blood cells; KIU, kallikrein inactivator units; FFP, fresh frozen plasma; TEG, thromboelastogram; Cryo, cryoprecipitate; SVRI, systemic vascular resistance index; CI, cardiac index; DO2, oxygen delivery; t-PA, tissue-type plasminogen activator; TAT, thrombin-antithrombin III complex.

Epsilon-Aminocaproic Acid (EACA)
 Von Kaulla et al., 196673NoNot reportedPatients died of severe hemorrhage or thrombolic complications
 Kang et al., 1987820No1 gmFibrinolysis improved clinically and by laboratory tests
 McSorley and Taraporewalla, 1991936NoNot reportedNo significant difference in blood product use between the prophylactic EACA and the control groups
 Kang, 19934 No0.25 to 0.5 gmA single small dose is effective in treating most fibrinolysis
 Scudamore et al., 19951013NoNot reportedNo effects in reduction of transfusion
Tranexamic Acid (TA)
 Carlier et al., 19871433No15 mg/kg × 8 hours41% of patients with normal ECLT
 Boylan et al., 19961545Yes40 mg/kg/hour up to 40 gReduced EBL, plasma, platelet, and Cryo; no difference in RBC requirement, postoperative drain, hospital stay, or retransplant
 Kasper et al., 19971632Yes2 mg/kg/hourTA deceased fibrinolysis and need for EACA rescue but not transfusion requirements
Aprotinin
 Neuhaus et al., 19892320No2 million KIUSignificant reduction in RBC, FFP, and surgical time
 Cottam et al., 1991208Yes2 million KIU and followed by 500,000 KIU/hour, 50,000 KIU given to each unit of RBCReduce t-PA production and increase alpha-2 antiplasmin
 Grosse et al., 19912450NoLoad 280 mg plus 70 mg/hourReduce fibrinolysis (measured by TEG), RBC, FFP, and platelets
 Himmelreich et al., 1992310No500,000 KIU bolus before, during and after reperfusionSmaller increase in t-PA compared to other studies
 Soilleux et al., 199525189Yes2 million KIU load plus 500,000 KIU/hour infusion or 500,000 KIU load plus 150,000 KIU/hour infusionNo difference in RBC between the high and low dose aprotinin groups. No additional benefit for high dose aprotinin
 Scudamore et al., 19951066No1 million KIU bolus plus 500,000 KIU/hour infusionSignificant reduction in Cryo, FFP, RBC in the aprotinin but not in EACA treated group
 Milroy et al., 19953152YesLoad 280 mg plus 70 mg/hour infusion, additional 140 mg to bypass and 7 mg for each unit of RBCGreater SVRI, O2 extraction ratio and less C1, DO2 5 minutes after reperfusion
 Marcel et al., 19962644Yes200,000 KIU/hour infusionReduce FFP, Cryo but not RBC, platelets or postoperative drains, and less EACA rescue
 Garcia-Huete et al., 19972780Yes2 million KIU load plus 500,000 KIU/hour infusionNo difference in EBL, blood products, or t-PA, TAT and d-dimer levels in both groups
 Porte et al., 200029137YesHigh: 2 million KIU load plus 1 million KIU/hour plus additional 1 million KIU 30 minutes before reperfusion, low: 2 million KIU plus 500,000 KIU/hour60 and 44% EBL, 37% and 20% RBC reduction in high and regular dose groups, respectively compared to the placebo group
 Findlay et al., 20013063Yes1 million KIU load plus 250,000 KIU/hourReduce RBC requirement but not FFP, platelets or cryo requirements; no significant difference in any TEG parameters compared to placebo
Aprotinin
 Molenaar et al., 20014393YesHigh: 2 million KIU load plus 1 million KIU/hour plus additional 1 million KIU 30 minutes before reperfusion, low: 2 million KIU + 500,000 KIU/hourNo renal toxicity
 Molenaar et al., 200134137YesHigh: 2 million KIU load plus 1 million KIU/hour plus 1 million additional KIU 30 minutes before reperfusion, low: 2 million KIU + 500,000 KIU/hourBetter 1-month graft survival
 Molenaar et al., 20013267YesHigh: 2 million KIU load plus 1 million KIU/hour plus additional 1 million 30 minutes before reperfusion, low: 2 million KIU + 500,000 KIU/hourLess epinephrine use in high or low dose groups
 Rentoul et al., 20032824No15,000 KIU/kg load plus 5000 KIU/hour infusionReduce RBC and FFP requirements but not to a significant level in pediatric patients
 Findlay and Kufner, 20033363Yes1 million KIU load plus 250,000 KIU/hour infusionLess vasoactive infusion in the aprotinin group
Antifibrinolytics comparisons
 Dalmau et al., 200011124YesEACA 16 mg/kg/hourTA 10 mg/kg/hourTA but not EACA, decreased transfusion requirements, fibrinolysis (measured by TEG), and need for EACA rescue
 Dalmau et al., 200417127YesTA 10 mg/kg/hourAprotinin 2 million KIU bolus and 500,000 KIU/hour infusionNo difference was noticed between the TA and aprotinin groups

Tranexamic Acid

  1. Top of page
  2. Abstract
  3. Epsilon-Aminocaproic Acid
  4. Tranexamic Acid
  5. Aprotinin
  6. Indications, Contraindications, and Drug Selection
  7. Adverse Effects
  8. Intraoperative Thromboembolism
  9. Summary
  10. Acknowledgements
  11. References

Like EACA, tranexamic acid (TA) is also a synthetic derivative of the amino acid lysine that exerts its antifibrinolytic effects through the reversible blockade of the lysine-binding site on the plasminogen molecule. At high concentrations, TA may also act as a noncompetitive inhibitor of plasmin.12 TA has been suggested to have a higher antifibrinolytic activity than EACA in peripheral compartments, such as renal, intestinal, and prostatic tissues.13 TA is 6 to 10 times more potent than EACA and has a longer half-life. The kidney is the primary organ for drug excretion; more than 95% of the drug is eliminated unchanged in the urine.

Although use of TA in OLT was 1st reported in the 1980s,14 it was not tested in a prospective trial until 1996. In 1996, Boylan et al.15 reported a series of 45 OLT patients in a double-blinded, placebo-controlled study. Patients were randomized to receive placebo or TA at the rate of 40 mg/kg/hour to a maximum dose of 20 gm. A solution of dipyridamole-heparin was given simultaneously during the surgery because of a concern for thromboembolic complications caused by this relatively high-dose regimen. Patients receiving TA had significantly less intraoperative blood loss and reduced intraoperative plasma, platelet, and cryoprecipitate requirements compared to patients in the control group.15 In another trial, Kasper et al.16 failed to demonstrate efficacy of TA on reduction of transfusion requirements in a series of 32 patients, even though fibrinolysis was less severe as measured by thromboelastogram and less EACA rescue was needed in the TA treated group than in the control group. The small dose regimen (TA 2 mg/kg/hour) used may have contributed to the lack of efficacy of TA in this study. In a relative large prospective trial (124 patients), in which 2 lysine analogs (TA 10 mg/kg/hour and EACA 16 mg/kg/hour) were compared to placebo, Dalmau et al.11 demonstrated that fibrinolysis as assessed by thromboelastogram, and transfusion of red blood cells were significantly less in the TA group. EACA, used as a rescue drug, was given less frequently in the TA treated group (0 / 42) than in the EACA or control groups (6 / 42 and 7 / 40, respectively). Fresh frozen plasma (FFP), cryoprecipitate, and platelet requirements were similar intraoperatively among the 3 groups. Recently, the same group compared the efficacy of TA and aprotinin in a double-blinded, prospective, and randomized study.17 Of 127 consecutive patients undergoing OLT, 64 patients received TA (10 mg/kg/hour) and 63 patients received aprotinin (a 2 million kallikrein inactivator unit [KIU] bolus followed by a 500,000 KIU/hour infusion). There were no significant differences in coagulation test results (except for activated partial thromboplastin time [aPTT]) or transfusion requirements of red blood cells, FFP, or platelets between the 2 groups, intraoperatively or during the 1st 24-hour postoperative period. No significant differences were noticed in perioperative complications, such as thromboembolic events, reoperations, and mortality.

Comparison of different studies using TA in OLT is difficult because all trials used different dosage regimens ranging from low dosage (2 mg/kg/hour) to high dosage (40 mg/kg/hour). Nonetheless, it appears that TA suppresses fibrinolysis and may decrease blood loss and blood product requirements. The optimal dose of TA for OLT, however, is unknown.

Aprotinin

  1. Top of page
  2. Abstract
  3. Epsilon-Aminocaproic Acid
  4. Tranexamic Acid
  5. Aprotinin
  6. Indications, Contraindications, and Drug Selection
  7. Adverse Effects
  8. Intraoperative Thromboembolism
  9. Summary
  10. Acknowledgements
  11. References

Aprotinin is a naturally occurring protease inhibitor that is isolated from bovine and porcine lung. The mechanism of action of aprotinin is complex and has not been clearly defined. Its principal effect is the inhibition of a variety of proteases. In addition to inhibition of human plasmin, it also inhibits trypsin, kallikrein, chymotrypsin, activated protein C, and thrombin.18, 19 These enzymes play major roles in the complement system, the coagulation and fibrinolytic system, as well as roles in inflammation and hemodynamic regulation. Inhibition of these enzymes is due to formation of aprotinin-enzyme complexes on the active serine site of the enzyme. Each complex has a specific dissociation constant for aprotinin: highest with trypsin, moderate with plasmin, and lowest with kallikrein. Since the dissociation constant influences the concentration of aprotinin necessary to produce enzymatic inhibition, inhibition of kallikrein requires a higher dose of aprotinin than that required to inhibit plasmin.18 Following a bolus, aprotinin is redistributed into the extracellular compartments with an initial half-life of about 1 hour. The terminal half-life (7-10 hours) depends on the release of aprotinin from tissues like the kidneys and cartilage. It is eventually eliminated via the kidney as small peptides or amino acids.18, 19 Direct inhibition of plasmin is the major mechanism of the antifibrinolytic effects, while inhibition of the contact activation system via kallikrein inhibition is involved to a lesser extent.19 Several investigators suggested that suppression of fibrinolysis by aprotinin is due to inhibition of tissue-plasminogen activator production during OLT.20, 21 In addition to the antifibrinolytic property of aprotinin, there is some evidence suggesting that aprotinin may be antithrombotic. Its antithrombotic activity is believed to be achieved by selectively blocking the proteolytically activated thrombin receptors (PAR1) on platelets, while leaving other mechanisms of platelet aggregation unaffected.22

In 1989, Neuhaus et al.23 published the 1st description of aprotinin use in OLT. They found that 2 million KIU of aprotinin significantly decreased blood loss, transfusion of blood cells, FFP use, and duration of surgery when compared to a group without aprotinin. Their findings were supported by a subsequent report24 involving small numbers of patients.

In 1995, Soilleux et al.25 compared 2 doses of aprotinin (2 million KIU followed by an infusion of 500,000 KIU/hour and 500,000 KIU followed by an infusion of 150,000 KIU/hour) in 189 patients undergoing OLT. There was no difference in the amount of red blood cells transfused between the high dose group and the low dose group. Since there was no placebo group in this study, it is unclear if any benefit occurred. Marcel et al.26 compared low dose aprotinin infusion (200,000 KIU/hour) to placebo during OLT in a prospective trial. Transfusion of FFP and cryoprecipitate, but not red blood cells or platelets, was significantly reduced in patients who received low dose aprotinin infusion compared to patients treated with placebo. The efficacy of aprotinin was challenged by other investigators. Garcia-Huete et al.27 and Rentoul et al.28 failed to show a significant difference in the transfusion of red blood cells, FFP, cryoprecipitate, and platelets between the aprotinin-treated group and the placebo group.

In 2000, Porte et al.29 reported the 1st multicenter, prospective, double-blinded, controlled trial of aprotinin in OLT. A total of 141 patients were enrolled in the study. Patients were randomly assigned into 1 of 3 groups: group 1, high dose aprotinin (2 million KIU bolus followed by 1 million KIU/hour infusion, and an additional 1 million KIU before graft reperfusion); group 2, regular dose aprotinin (2 million KIU bolus followed by 500,000 KIU/hour infusion); and group 3, placebo. Transfusion criteria were standardized for all 6 liver transplant centers. Total blood loss in this study was significantly lower in the aprotinin treated groups (60% reduction in the high dose group and 44% reduction in the low dose group) than in the placebo group. The total blood loss was 2,030 mL (1,200-8,000 mL), 2,825 mL (1,244-7,525 mL), and 5,050 mL (2,100-9,000 mL) in the high dose aprotinin group, the regular dose aprotinin group, and the placebo group, respectively. The transfusion of red blood cells was 37% lower in the high dose group and 20% lower in the regular dose group than in the placebo group (1,800, 2,300, and 2,877 mL, respectively). In another prospective randomized controlled trial, Findlay et al.30 confirmed that aprotinin significantly reduced red blood cell transfusion in OLT when compared to placebo. Although intraoperative use of platelet, FFP, and cryoprecipitate was less in the aprotinin group than that in the placebo group, there was no statistical significance.

Some benefits, such as antiinflammatory and antioxidant effects, which have been shown in cardiac surgeries,19, 22 were also suggested in patients undergoing OLT. Milroy et al.31 1st reported more stable hemodynamics in patients who received aprotinin during OLT. In this study, 52 patients were randomized to receive either aprotinin or placebo. Significant differences between the 2 groups were noticed in cardiac index, systemic vascular resistance index, O2 delivery, and O2 extraction ratio 5 minutes after reperfusion. Molenaar et al.32 demonstrated that patients who were treated with either high or regular dose aprotinin showed more stable hemodynamic parameters and required less epinephrine for intervention compared to patients in the placebo group. However, some questioned the clinical relevance because of the small differences in epinephrine used. Findlay and Kufner33 demonstrated that infusions of vasoactive agents were used less frequently in the aprotinin group in a prospective, randomized, double-blinded study. Two possible mechanisms of hemodynamic stability by aprotinin were postulated: decrease in blood loss resulting in fewer hypotensive events and inhibition of the kallikrein-kinin system by high dose aprotinin, resulting in more stable hemodynamic state. Furthermore, 1-month graft survival was significantly higher in patients who received aprotinin (0 / 89 requiring retransplantation within 1 month) than in patients in the placebo group (4 / 48 requiring retransplantation). One-month recipient survival rate was similar among the 3 groups.34

Indications, Contraindications, and Drug Selection

  1. Top of page
  2. Abstract
  3. Epsilon-Aminocaproic Acid
  4. Tranexamic Acid
  5. Aprotinin
  6. Indications, Contraindications, and Drug Selection
  7. Adverse Effects
  8. Intraoperative Thromboembolism
  9. Summary
  10. Acknowledgements
  11. References

Antifibrinolytics are indicated in patients with bleeding caused by enhanced fibrinolysis. Antifibrinolytics are less effective in patients with bleeding caused by conditions other than enhanced fibrinolysis and may be harmful in patients with prothrombotic states. In addition to enhanced fibrinolysis during OLT, many other causes lead to blood loss: coagulopathy, thrombocytopenia, thrombocytopathy, dysfibrinogenemia, pretransplant fibrinolysis system disturbances, dilutional coagulopathy, hypothermia, bleeding secondary to technical difficulties, and variation in surgical experience and expertise.1, 2

EACA has long been used in the field of OLT and it is inexpensive. Many people are comfortable with the drug; this is partially reflected in the fact that EACA was used as a “rescue” drug in many clinical trials.11, 16, 17, 26 The failure to demonstrate a beneficial effect of EACA in a prospective trial in OLT is surprising and not totally understood. Reasons for a lack of benefit in OLT include: 1) EACA has not been carefully studied in OLT. This lack of interest, which is also true in cardiac surgery,35 may reflect a reality that pharmaceutical companies tend to sponsor more expensive drugs in clinical research; 2) liver transplant patients may have more heterogeneous coexisting diseases than other patient populations in antifibrinolytic studies; therefore a large study sample is needed to demonstrate efficacy of EACA in OLT; 3) EACA may be indeed less efficacious than other antifibrinolytics, as suggested by pooled cardiac data.36 Until more definitive studies are performed, the controversy over whether EACA is effective in reducing blood loss and transfusion requirements in OLT will likely remain.

Use of aprotinin is certainly supported by many prospective trials and its potential antiinflammatory and antioxidant effects also seem attractive during OLT.29–34 However, it is more expensive compared to other antifibrinolytics and its nonantifibrinolytic effects and its clinical significance need to be confirmed in future studies. Recently, TA was demonstrated to be equally effective compared to aprotinin; it may provide some advantage since it is less expensive and it is associated with lower incidence of allergic reactions than aprotinin.17 While the debate on whether or which antifibrinolytic should be used during OLT continues, the issue of when it should be used is also far from settled. Prophylactic application of antifibrinolytics has been used in many practices and in many clinical trials,11, 17, 29, 30 while selective use after diagnosis of enhanced fibrinolysis has been advocated by others.8

In many prospective trials, patients with diseases possibly related to prothrombotic states were excluded. However, exclusion criteria were not uniform and vary from study to study. Pediatric patients, patients with Budd-Chiari syndromes were excluded from many studies.11, 15, 17, 29, 30 Other exclusion criteria included multiorgan transplantation, retransplantation, fulminant liver diseases, primary amyloidotic neuropathy, primary sclerosing cholangitis, renal failure, primary biliary cirrhosis, malignant disease, preexisting thrombotic disease such as portal vein thrombosis, and previous exposure to aprotinin.

Patients with impaired kidney function and retransplantation present unique challenges and are worth mentioning in more detail. In patients with impaired kidney function, platelet dysfunction caused by uremia may lead to diffuse bleeding. Fluid and electrolyte management is more difficult intraoperatively. The duration of antifibrinolytic agents is prolonged for all 3 antifibrinolytics due to their renal excretion. Dosage adjustment in patients with renal insufficiency or failure during OLT has not been explored. In addition, there is a concern regarding potential renal toxicity by antifibrinolytics (discussed below). Intraoperative hemodialysis further complicates dosing because of the potential decrease in concentration of the drug by dialysis. Massive blood loss and transfusion are common in patients undergoing liver retransplantation.37 While, in theory, antifibrinolytics may offer some advantages by reducing blood loss and transfusion requirements, whether they are effective or safe in such subpopulation is unknown since this subpopulation is often excluded from clinical trials.

Disseminated intravascular coagulation, a disease characterized by microcoagulation, leads to the consumption of clotting factors and presents with diffuse bleeding. Thus, the prothrombotic property of antifibrinolytics contraindicates their use in disseminated intravascular coagulation. The real challenge is differentiating disseminated intravascular coagulation from enhanced fibrinolysis, since both present with very similar clinical pictures.

Adverse Effects

  1. Top of page
  2. Abstract
  3. Epsilon-Aminocaproic Acid
  4. Tranexamic Acid
  5. Aprotinin
  6. Indications, Contraindications, and Drug Selection
  7. Adverse Effects
  8. Intraoperative Thromboembolism
  9. Summary
  10. Acknowledgements
  11. References

The adverse effects of antifibrinolytics described in this article have been primarily observed outside of the transplant setting since there are few studies designed to investigate the adverse effects of antifibrinolytics during OLT.

Renal complications have been reported with the use of EACA. Acute renal failure related to use of EACA has been postulated to be due to acute tubular necrosis, renal infarction, myopathy / pigment-induced renal complications, glomerular capillary thrombosis, and obstruction of the upper urinary tract.38 Severe proteinuria has been reported with the use of EACA. A recent study has suggested that EACA is associated with elevated excretion of beta-2 microglobulin, a protein linked to specific tubular injury and damage.39 A case of acute hyperkalemia was reported in a patient with underlying chronic renal insufficiency who underwent coronary artery bypass grafting treated with EACA.40 A possible explanation is that EACA, a synthetic amino acid structurally similar to lysine and arginine, can enter muscle cells in exchange for potassium. EACA can act as a source of protons and unmeasured anions and is suggested to cause anion gap metabolic acidosis.38 Fatty degradation of the myocardium has been reported in dogs. Skeletal muscle weakness and fibrosis have been reported following prolonged administration. A total of 31 cases of EACA-induced myonecrosis or myoglobinuria were reported in the literature between 1972 and 1995; all patients received high doses of oral EACA for a long period of time.41 No treatment for overdose is known, although evidence exists that EACA is removed by hemodialysis.

TA is well tolerated and adverse events are uncommon. Nausea, diarrhea, and orthostatic reactions have been reported most often.42 Retinal changes have been reported in an animal study during long-term oral administration of the drug. Disturbance in color vision has been documented in patients. Like EACA, TA is contraindicated in patients with a history of thromboembolic disease or disseminated intravascular coagulation.

The most common side effects reported with aprotinin include renal dysfunction, hypersensitivity reactions, and arterial thrombosis. There is evidence suggesting an increase in creatinine level during the postoperative period following coronary artery bypass grafting. Increase of beta-2 microglobulin excretion is noted after administration of aprotinin, as with EACA.39 Aprotinin has a high affinity for renal tissue. It is hypothesized that aprotinin causes a reversible overload of the tubular reabsorptive mechanisms, resulting in transient renal dysfunction. Aprotinin may also have a direct toxic effect on the proximal tubular cells or alter intrarenal blood flow through inhibition of renin and kallikrein activity.6 Despite several clinical trials reporting a mild to moderate increase in postoperative serum creatinine levels in coronary artery bypass grafting and OLT using high dose aprotinin, Molenaar et al.43 not only showed no increased incidence of postoperative renal insufficiency, but a possible protective effect on renal function when aprotinin was used during OLT in a multicenter, prospective trial.

Published evidence of hypersensitivity and/or anaphylactic reactions to EACA or TA is sparse. In contrast, there have been a number of such reports after aprotinin administration. Since aprotinin is a naturally occurring protein isolated from bovine or porcine lung, it is not surprising that hypersensitivity reactions are seen. Reactions range from rash, urticaria, or itching, to bronchospasm, tachycardia, and cardiovascular collapse.18 Hypersensitivity reactions are rarely reported in patients without prior exposure to aprotinin. The incidence in patients who had previous exposures to aprotinin was reported to be 2.5% and fell significantly in the patients with an exposure to the drug greater than 6 months earlier.44

In clinical settings other than OLT, the use of antifibrinolytics was reported to be associated with cases of cerebral thrombosis, arterial thrombosis, graft thrombosis, and pulmonary artery catheter thrombosis. Rapid injection of aprotinin may cause histamine release leading to hypotension.18 A possible potentiation of muscle relaxants (suxamethonium and tubocurarine) by aprotinin was published in a case report.45

Intraoperative Thromboembolism

  1. Top of page
  2. Abstract
  3. Epsilon-Aminocaproic Acid
  4. Tranexamic Acid
  5. Aprotinin
  6. Indications, Contraindications, and Drug Selection
  7. Adverse Effects
  8. Intraoperative Thromboembolism
  9. Summary
  10. Acknowledgements
  11. References

A link between thromboemboli and antifibrinolytics has been a longstanding concern.7 Although bleeding diathesis is a common problem for patients undergoing liver transplantation, occasionally thromboembolism is encountered.46 Kang et al.8 in 1987 reported 2 cases of massive pulmonary emboli during the anhepatic stage of OLT. Navalgund et al.47 gave the 1st detailed description of the incidence of intraoperative thromboembolism and failed resuscitation in 1988. Since then, several case reports of devastating intraoperative intracardiac or pulmonary thromboembolism events have appeared.48–58 Most cases presented with sudden onset of systemic hypotension along with elevation of central venous pressure (CVP), pulmonary artery pressure, or right ventricular dysfunction. Many patients died shortly after the incident.

There have been at least 30 reported cases of intraoperative, intracardiac or pulmonary thromboembolism during OLT.8, 47–58 These events occurred at various stages of the operation: in the preanhepatic stage in 4 patients; in the anhepatic stage in 10 patients; in the postreperfusion stage in 9 patients; and in the other 7 patients the timing was not described. The majority of the patients received antifibrinolytics (24 / 30 patients; 11 patients received aprotinin, 10 patients received EACA, 3 patients received both EACA and aprotinin, no patient received TA); 5 patients did not receive antifibrinolytics; whether antifibrinolytics were used was not reported in 1 patient. Many possible causes have been postulated, but no definite cause and effect relationship between thromboembolic events and antifibrinolytic use can be drawn from these case reports. Although there is evidence showing that aprotinin has an antithrombotic, rather than prothrombotic effect,59 the question still remains unanswered for all antifibrinolytics in the setting of liver transplantation. To answer this question, a considerable numbers of patients are needed, as the incidence of thromboembolic events is so low. Additionally, the problem is complex, since other conditions could be responsible for thrombotic events, as suggested in these case reports. Other possible causes include migration of preexisting thrombi, immune complex formation by injection of hyperimmune globulin, disseminated intravascular coagulation, protein C or S deficiency, multiorgan failure, sepsis, clotting pathway activation by endotoxin, and massive transfusion of stored bank blood. The intraoperative application of transesophageal echocardiogram in OLT has increased in recent years. The use of transesophageal echocardiogram may increase the accuracy and the sensitivity of diagnosis of intraoperative thrombotic events.48 However, whether the increased use of intraoperative transesophageal echocardiogram is responsible for the increased number of reports of intraoperative thrombotic events in recent years is not known.

Summary

  1. Top of page
  2. Abstract
  3. Epsilon-Aminocaproic Acid
  4. Tranexamic Acid
  5. Aprotinin
  6. Indications, Contraindications, and Drug Selection
  7. Adverse Effects
  8. Intraoperative Thromboembolism
  9. Summary
  10. Acknowledgements
  11. References

Antifibrinolytics appear beneficial in reducing blood loss and decreasing transfusion requirements during OLT, although uniform supporting data are lacking. Aprotinin has been studied more extensively in clinical trials and appears to offer more advantages compared to two other antifibrinolytics. However, because of the diverse population of liver transplant patients, the complicated coexisting medical conditions, the complex derangements of coagulation and fibrinolysis, and the potential adverse effects of antifibrinolytics, especially severe or life-threatening thromboembolism, careful patient selection and close monitoring of patients receiving antifibrinolytics is prudent. Further studies on the risks and benefits of antifibrinolytics in the setting of liver transplantation are warranted.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Epsilon-Aminocaproic Acid
  4. Tranexamic Acid
  5. Aprotinin
  6. Indications, Contraindications, and Drug Selection
  7. Adverse Effects
  8. Intraoperative Thromboembolism
  9. Summary
  10. Acknowledgements
  11. References

We thank Michelle Braunfeld, M.D. and Robert Kaufman, M.D. (Department of Anesthesiology, David Geffen School of Medicine at UCLA, Los Angeles, CA) for reviewing the manuscript and for their constructive comments, and we thank Phillip Sanders for his excellent support.

References

  1. Top of page
  2. Abstract
  3. Epsilon-Aminocaproic Acid
  4. Tranexamic Acid
  5. Aprotinin
  6. Indications, Contraindications, and Drug Selection
  7. Adverse Effects
  8. Intraoperative Thromboembolism
  9. Summary
  10. Acknowledgements
  11. References
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