Orthotopic liver transplantation (OLT) is associated with intraoperative bleeding and substantial red blood cell (RBC) transfusion requirements (1–4). Although blood safety has improved over the past 20 yr, adverse effects of RBC transfusion are still suspected, including such effects on outcome and graft survival in OLT (5–10). An important factor in accounting for blood loss in OLT appears to be enhanced fibrinolytic activity (11). Prophylactic aprotinin administration decreases intraoperative fibrinolysis, blood loss, and RBC transfusion requirements in patients undergoing OLT (3). Reports have suggested that, as a result of its antifibrinolytic effect, the use of aprotinin risks shifting the tight balance between coagulation and fibrinolysis towards unwanted thrombus formation and could actually promote thrombosis (12–20). Moreover, aprotinin, a bovine-derived protein, has been associated with hypersensitivity reactions (21–23). The present review was designed to survey the types of data that could indicate administration of aprotinin during OLT and the types of data that could indicate limiting the use of aprotinin in OLT with a view to producing an individualized approach to aprotinin administration (Table 1).
Effect of Aprotinin on Blood Loss and RBC Transfusion Requirement in OLT
Enhanced fibrinolytic activity occurs in 50%–70% of patients during the preanhepatic period and late during the anhepatic stage in patients undergoing OLT (11,24,25). It usually worsens soon after graft reperfusion and thereafter gradually decreases late after reperfusion (11,24,25). Increased fibrinolysis has been associated with a sharp increase in tissue-type plasminogen activator of fibrinolysis (t-PA) activity and a pattern of type-1 plasminogen activator inhibitor activity opposite to that of t-PA (11,24,25). The lack of t-PA hepatic clearance during the anhepatic period and t-PA release by the endothelial cells of the revascularized graft account for the increase in t-PA (26). In the 1990’s, these findings contributed to the widespread intraoperative administration of antifibrinolytic drugs, mainly aprotinin in Europe, to prevent or treat the activation of fibrinolysis in an attempt to decrease blood loss and the use of blood products during OLT (27–40). A large-dose regimen similar to that used in cardiac surgery was proposed (27). It included IV administration of 2 × 106 kallikrein-inhibiting units (KIU) as an initial dose followed by continuous IV administration of 5 × 105 KIU/h (27). Using this regimen, Neuhaus et al. (27) reported blood loss reduction of approximately 35% and RBC unit requirement reduction of 50% in 10 patients treated with aprotinin. However, until the year 2000, the beneficial effect of aprotinin on blood loss during OLT had only been suggested in adults and in children in small, retrospective, nonrandomized studies (27–41). Only two prospective randomized studies conducted in patients undergoing OLT concluded that aprotinin would have no beneficial effect (40), or a very limited beneficial effect (39) on RBC transfusion requirements. Finally, in 2000, Porte et al. (3) demonstrated that, independent of technical improvements, aprotinin reduces blood loss and RBC transfusion requirement in OLT. In the Porte et al. study (3), 137 patients undergoing OLT received either large doses of aprotinin, regular doses of aprotinin, or placebo. Intraoperative blood loss was 60% less in the large dose group and 44% less in the regular dose group compared with the placebo group. The total RBC unit (homologous and autologous) requirement was 37% less in the large dose group and 20% less in the regular dose group when compared with the placebo group. Aprotinin did not alter fresh-frozen plasma, platelet concentrate, cryoprecipitate, or fibrinogen requirements. Importantly, duration of intensive care unit (ICU) stay and postoperative ventilatory support were not altered by aprotinin therapy (3).
Effect of Aprotinin on Graft Reperfusion Syndrome
In OLT, graft reperfusion is often associated with significant hemodynamic changes, including decreased systemic vascular resistance and arterial blood pressure (42–44). Vasopressive drugs are often required to maintain adequate perfusion pressure during the early postreperfusion period (42–44). In three randomized studies, postreperfusion hemodynamic changes and the total amount of epinephrine required were smaller in patients who received aprotinin but with no effect on postoperative outcome (42–44).
Factors Likely to Limit Aprotinin Administration in Patients Undergoing OLT
Clinical Thrombotic Events
The prevalence of postoperative venous thromboembolic events, prospectively studied by Ishitani et al. (45), was observed to be similar in OLT when compared with major abdominal surgery. However, an increasing number of reports of intraoperative intracardiac thrombotic events or pulmonary embolism have stoked a major controversy regarding the safety of aprotinin in OLT and raised the question of whether aprotinin could promote thrombosis in OLT (46). Intraoperatively, 19 case reports have documented untoward intravascular or intracardiac thrombus formation during the dissection, the anhepatic phase, or in the few minutes after reperfusion in patients undergoing OLT, followed by clinically significant pulmonary embolism (14–22). In only three of the 19 reports, patients had not received antifibrinolytics (14,20). Predisposing factors, such as the use of veno-venous bypass, low antithrombin III levels, an underlying cholestatic liver disease, or a septic state, were reported in all cases but one (17). An increased thrombotic risk did not come to light in the only large sample randomized study of aprotinin (3). However, this study had not been powered to assess thrombosis (3). Additional data, discussed below, suggest that these clinical reports may not be coincidental.
Some histological assessments also suggest the hypothesis of an activation of coagulation associated with OLT that aprotinin could potentially worsen (47,48). Gosseye et al. (47) reported the histological data of 10 of 219 children <15 yr of age undergoing OLT who died suddenly during the procedure. None had received aprotinin. Extensive obstruction of small lung vessels by platelet aggregates was found at necropsy. In contrast with disseminated intravascular coagulation, platelet aggregates were not found in the vessels of other tissues. In seven patients, pulmonary arterial pressure increased acutely before death, consistent with an acute obstruction of the pulmonary vascular bed. In another report of 100 adult patients undergoing OLT, Sankey et al. (48) reviewed the pathological data pertaining to the six perioperative deaths occurring up to the tenth postoperative day after OLT and to 13 patients who died within 10 days of a nontransplantation operation. Macroscopic pulmonary emboli were not identified in any of the transplant patients. However, extensive intravascular thrombi occluding small arterioles and alveolar capillaries of all pulmonary lobes were found in all OLT patients. These thrombi showed positive immunostaining for platelet markers and fibrinogen. In a similar manner to Gosseye et al.’s report, thrombi were not found in other organs in transplant recipients and thus did not seem to represent part of a widespread disseminated intravascular coagulation. A small premortem platelet count was recorded in all cases. In most cases a sudden and profound decrease in cardiac output associated with an increased pulmonary arterial pressure was consistent with the explanation that intrapulmonary obstruction by thrombi could be the reason for the failure of any resuscitation attempts (48).
Continuous intraoperative transesophageal echocardiographic assessments were performed by Ellis et al. (49) in 16 patients undergoing OLT using veno-venous bypass. No patients received aprotinin. Thrombi were detected in the hearts of all patients at all periods of OLT. In two patients paradoxical microthrombi were identified in the left heart at the time of reperfusion of the liver. A large thrombus seen in the right atrium of one patient during veno-venous bypass later embolized into the pulmonary circulation; transesophageal echocardiography revealed a dilated right heart (49). Suriani et al. (50) reviewed 62 intraoperative transesophageal echocardiographic examinations performed during OLT, as required by the anesthesiologist responsible for the patient’s care. Transesophageal echocardiography showed, for all patients, that a shower of venous microemboli entered the right ventricle and the pulmonary arteries on release of vena cava cross-clamping. Nineteen patients were observed to have pulmonary embolization of large materials. In one patient, thromboemboli proceeded into the systemic circulation (50).
Hemostatic Changes in Patients with Chronic Liver Disease
Hemostatic changes recorded in patients with chronic liver disease and/or undergoing OLT are shown in Table 2. Violi et al. (51) showed that there is a continuous prothrombotic state in the portal circulation of cirrhotic patients that is independent of the degree of liver disease. Eleven patients with various degrees of biopsy-proven cirrhosis and a control group were compared for plasma endotoxin, d-dimer, prothrombin fragment 1 + 2, and fibrinogen concentrations. Cirrhotic patients had significantly larger concentrations of endotoxin, d-dimers, and prothrombin fragment 1 + 2 and smaller fibrinogen concentration in the peripheral circulation than the controls. Samples taken from the portal vein had significantly larger endotoxin, d-dimer, and prothrombin fragment 1 + 2 concentrations and smaller fibrinogen concentration than found in the peripheral circulation (51). Other studies showed large concentrations of antiphospholipid antibodies, including Lupus anticoagulant and anticardiolipid immunoglobulin G and immunoglobulin M, in patients with chronic liver diseases (52–58). These factors are often associated with venous and arterial thrombosis (59). Chedid et al. (52) prospectively studied antiphospholipid antibody concentrations in healthy volunteers and in alcoholic patients with increasing degrees of liver disease. The antiphospholipid antibody prevalence increased from 15% in alcoholic patients with normal liver tests and normal clinical findings to 81% in patients with alcoholic hepatitis or cirrhosis. No antiphospholipid antibodies were found in the healthy control group (52). Elefsiniotis et al. (53) studied the prevalence of anticardiolipin antibodies in 32 healthy controls and in 107 untreated chronic hepatitis B virus (HBV) infected patients (negative for HBV early antigen [HbeAg] and positive for HBV DNA) with no previous thromboembolic complications. Anticardiolipin antibodies were present in 3% of the control population and 21.5% of the chronic HBV-infected patients. Moreover, in this series, a significant correlation was found between the presence of anticardiolipin antibodies and portal vein thrombosis (PVT) (53). Papatheodoridis et al. (54) studied 90 consecutive patients with chronic HBV and hepatitis C virus (HCV), for chronic hepatitis grading score and thrombophilic and coagulation factor evaluation. None had hepatocellular carcinoma or any other malignancy or a history of venous thrombosis. Protein C, protein S, antithrombin III, plasminogen deficiencies, activated protein C resistance, factor VIII increase, together with prothrombin 20210A mutation, and immunoglobulin G, immunoglobulin M anticardiolipin antibodies were investigated and considered as thrombophilic factors. At least one such factor was detected in 68% and 2 or more thrombotic risk factors in 37% of patients with chronic HBV and HCV. Decreased levels of coagulation factor IX, XI, or XII were found in only 16% of patients, and thus impairment of hepatocellular production cannot be exclusively to blame for the frequent prevalence of prothrombotic factor deficiencies (54). Fifteen to 50% of cirrhotic patients experienced PVT in Belli et al.’s review article (55). In a series of biopsy-proven cirrhotic patients investigated by Violi et al. (56), PVT was significantly associated with the presence of lupus anticoagulant (odds ratio [OR], 18.7; 95% confidence interval [CI], 2.8–143.5; P = 0.0008) and anticardiolipid antibodies (OR, 6.7; 95% CI, 1.3–37.9; P = 0.015). Because of the frequent prevalence of PVT in patients with chronic liver disease, one may assume that these markers are independently associated with an increased thrombotic risk rather than independent cofactors of nonpathogenic type in chronic liver disease (57). Ben-Ari et al. (58) preoperatively investigated thromboelastography in 47 patients with primary biliary cirrhosis, 21 patients with primary sclerosing cholangitis, 40 patients with noncholestatic cirrhosis confirmed by biopsy, and 40 healthy controls in a stable condition. Patients were considered to have a hypercoagulable state when three thromboelastographic abnormalities indicating hypercoagulability (short r time, increased maximal angle, and large α angle) were detected in the same patient on a single thromboelastographic measurement. Thromboelastographic hypercoagulability was detected in 13 of 47 (28%) patients with primary biliary cirrhosis and in nine of 21 (43%) primary sclerosing cholangitis patients but in only two of 40 (5%) patients with noncholestatic cirrhosis and in none of the healthy controls. The differences were statistically significant. In six patients with thromboelastographic hypercoagulability, low values of protein S, C, or antithrombin III levels as a result of poor hepatic synthesis could be responsible for the hypercoagulability. However, 16 of the remaining 62 patients had no other cause for hypercoagulability. In addition, hepatocellular carcinoma often recorded in patients with chronic liver disease increases the risk of venous thromboembolism, mainly PVT (60). During OLT, after reperfusion of the graft, the decrease in factors V and VIII together with the rapid increase in thrombin-antithrombin complexes suggests disseminated intravascular coagulation (25). Infection or surgery may worsen low grade disseminated intravascular coagulation (25,61).
Factors Related to Blood Transfusion
Any blood-sparing technique, including aprotinin therapy, should have less risk than the risk of blood transfusion. At the present time, few transfusion fatalities attributable to misidentification, transmission of infectious disease, or acute lung injury are reported (5,6). However, in 1993, transfusion requirements of more than 10 RBC units were used by Mor et al. (8) to determine the impact of bleeding on the outcome of 205 patients undergoing OLT. In this series, the median transfusion requirement was 5 RBC units. Graft and patient cumulative survival rates were less in the bleeders. This assessment showed increases in septic episodes with positive blood cultures (40% versus 16%, P < 0.005) and longer stays in the ICU (13 versus 3 days, P < 0.005) in the bleeders. More recently Ramos et al. (9) prospectively assessed the number of RBC units that were significant from a prognostic point of view in 122 patients undergoing OLT (vena cava preservation in 111 of 122 patients). The median value of transfused RBC units was two. The number of RBC units transfused was associated with a longer ICU stay (cutoff = 6 RBC units; P = 0.047; risk ratio (RR), 3.1; 95% CI, 1.01–9.07), hospital stay (cutoff = 6 RBC units; P = 0.032; RR, 3.06; 95% CI, 1.1–8.5), and patient survival (cutoff = 6 RBC units; P = 0.05; RR, 2.76; 95% CI, 1–7.6) (11). Miki et al. (10) prospectively measured the concentrations of plasma endotoxin and proinflammatory cytokines in 30 patients undergoing OLT to investigate their relation to intraoperative blood loss and graft viability. All 24 patients whose operative RBC unit requirement was <10 U survived. Two patients whose operative RBC requirement was 10 U or more died. Increased interleukin 6 seemed to respond to the excessive intraoperative hemorrhage, to provoke the increase in endotoxin concentration, and to be associated with the graft viability (10). Preventing excessive intraoperative bleeding and the subsequent response of proinflammatory cytokines may be contributing factors to the success of OLT surgery.
Aprotinin is a naturally occurring single chain polypeptide protease inhibitor derived from bovine lung (62). More than 100 cases of allergy to IV aprotinin have been recorded, essentially after reexposure to the drug (21). Allergy to aprotinin may be life threatening and its detection is not always possible (22). In 25% of patients, no previous exposure was detected (23). Serious anaphylactic reactions were directly caused by a test dose or occurred after a negative test dose (21).
Rationalization of Aprotinin Administration During OLT
The assessment of preoperative factors likely to predict substantial blood loss in patients undergoing OLT would be relevant so that aprotinin is only administered when warranted. Indeed, a significant RBC-sparing effect of aprotinin was only reported when OLT was associated with significant blood loss (3). In this respect, Ramos et al. (9), Mor et al. (8), and Ozier et al. (1) recorded median transfusion requirements of approximately 5 RBC units. In Dalmau et al.’s (63) study, median transfusion requirements were 2 RBC units. Furthermore, factors likely to predict blood loss in OLT are diversely reported. Ritter et al. (64), Mallett and Cox (65), and Palareti et al. (66) observed that patients with chronic hepatitis, cirrhosis, and portal hypertension suffered a larger blood loss and were more prone to develop hyperfibrinolysis during OLT than patients with cholestatic disease. Coagulation, fibrinolytic factors, and their inhibitors were more preserved when compared with other causes of cirrhosis (66). Other studies conducted on large patient populations undergoing OLT, regardless of the underlying liver disease, failed to identify clinically relevant predictive factors for intraoperative bleeding (1,2,8,9,67). Based on data for 583 OLT, Findlay and Rettke (67) showed a significant association between blood loss and age, preoperative pseudo-cholinesterase, bilirubin, and creatinine concentrations in an univariate analysis. Finally, these criteria were of no predictive value in a multivariate regression analysis (67). Steib et al. (2) investigated at a single center a homogeneous population of 410 consecutive patients undergoing OLT for factors likely to predict large volume blood loss. Transfusion of 12 RBC units was the cut-off value for high blood loss. Patients with large and small blood loss differed with respect to preoperative hemoglobin concentration, prothrombin time, indicators of fibrinolysis, and previous abdominal surgery. However, a low positive predictive value was associated with these criteria (29% for previous surgery, 40% for preoperative hemoglobin concentration, 43% for fibrinolysis activation, <60% for two combined criteria, and 70% for the combined three criteria) (2). Ozier et al. (1) prospectively recorded the data of 303 OLTs conducted in 8 French institutions over a 12-month period in 1999. In the Ozier et al. (1) evaluation, variables found to be associated with RBC transfused in excess of the median were preoperative hemoglobin and creatinine concentrations, duration of surgery, prothrombin time, and previous abdominal surgery. However, an important “effect center” was observed so that any prediction rules validated in one center were precluded from generalization to other situations. Mor et al. (8) and Ramos et al. (9), investigating 122 and 92 patients, respectively, did not identify any predictive factor for intraoperative bleeding, including previous upper abdominal surgery. Consequently, transfusion requirements in OLT can only be anticipated on an individual basis from data indicating local blood loss and triggers for RBC transfusion in a given institution (1).
OLT Conducted in Patients with Acute Liver Failure
Coagulation disorders recorded in patients with acute liver failure are mainly attributable to impaired liver synthesis and first require specific replacement therapy (68). Hyperfibrinolysis does not appear to be a noteworthy occurrence in patients with acute liver failure, except in the case of bacterial superinfection (61,68). In patients with acute liver failure, the OLT procedure is generally technically easy because of the absence of previous liver surgery and of collateral portosystemic circulation (69). Aprotinin administration, therefore, has limited indications in patients with acute liver failure undergoing OLT and should thus be decided on an individual basis depending on preoperative coagulation tests and any anticipated technical problems.
Aprotinin Among Antifibrinolytic Drugs
The lysin-analogs, tranexamic acid and ε-aminocaproic acid, are synthetic molecules with antifibrinolytic properties (62). Randomized studies have demonstrated that lysin-analogs decrease blood loss and RBC transfusion requirement, similar to aprotinin in OLT when there is significant intraoperative bleeding (4,63,70–72). Thrombotic events have been reported with lysin analogs (14,18). Similar to aprotinin, the thrombotic risk associated with lysin analogs has not been specifically evaluated. Aprotinin administration in OLT was initially favored among antifibrinolytic drugs in Europe because it was believed that both its weaker antifibrinolytic effect and its shorter half-life compared with tranexamic acid would reduce the perceived prothrombotic risk (62). The charges for a 4-h course of large dose aprotinin or tranexamic acid and the cost of three RBC units were 216 euros, 26 to 100 euros, and 516 euros, respectively, in French University Hospitals in 2003. A 4-h course of ε-aminocaproic acid was 30 euros when this drug was still available.
Conclusions and Clinical Implications
At the present time, median transfusion requirements of 2–5 RBC units are expected in OLT. RBC transfusion has been correlated with increased morbidity and reduced survival rates in OLT. The cutoff value is 5–6 RBC units for adverse effects associated with RBC transfusion in OLT. Guidelines for predicting intraoperative bleeding and RBC transfusion requirements developed for one OLT center cannot be generalized to others. Prophylactic use of large-dose aprotinin decreases blood loss and transfusion requirements only when OLT is associated with significant blood loss. However, aprotinin did not alter the postoperative outcome in patients undergoing OLT, is likely to cause allergy, and could be associated with thrombotic events, mainly in patients with thrombophilic factors, preexisting sepsis, cholestatic liver disease, cancer, and portal, suprahepatic or peripheral venous thrombosis. Until contrary data are available, prophylactic aprotinin should not be systematically administered to patients undergoing OLT. Each center needs to identify patients requiring specific attention in the area of blood loss, including the use of antifibrinolytics. Limiting transfusion requirements to less than 5–6 RBC units may be warranted in OLT.
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