Secondary Logo

Journal Logo

REVIEW

Haemostatic disorders during liver transplantation

Ozier, Y.*; Steib, A.; Ickx, B.; Nathan, N.§; Derlon, A.; Guay, J.**; De Moerloose, P.††

Author Information
European Journal of Anaesthesiology: April 2001 - Volume 18 - Issue 4 - p 208-218

Abstract

Introduction

Orthotopic liver transplantation is widely regarded as the only effective treatment for many acute or chronic end-stage liver diseases. Improvements in immunosuppressive therapy, organ preservation, operative techniques and anaesthetic care have contributed to the reduction in morbidity and mortality. Difficulties in control of bleeding have been recognized since the early era of orthotopic liver transplantation. As anaesthetists began to better understand and regulate the circulatory and metabolic problems associated with orthotopic liver transplantation, it became apparent that massive bleeding and transfusion of stored blood was a particular issue. Problems included acute hypovolaemia, citrate loading, reduced ionized calcium, hyperkalaemia, acidosis, hyperosmolality and hypothermia. A significant relationship between large blood transfusion and postoperative morbidity and mortality has been recognized in many transplant centres.

Transfusion requirements have fallen among transplant centres as experience is gained. However, uncontrollable bleeding during surgery may still occur. Coagulation factor deficiencies due to liver disease, surgical dissection, specific and non-specific changes in the coagulation pattern and poor graft function may contribute to severe blood loss. This review describes the changes in the coagulation pattern during orthotopic liver transplantation, the different methods of coagulation monitoring with their predictive and/or diagnostic values and the available therapeutic approaches using blood component transfusion and pharmacological agents.

Coagulation changes in the recipient

Preoperative coagulation abnormalities

Complex and multifactorial derangements of haemostasis occur in patients with liver diseases (Table 1). In addition to the quantitative and qualitative defects of the coagulation factors, increased disseminated or intrahepatic consumption and loss into the extravascular compartment may contribute to their deficit. Evidence of coagulation activation has been demonstrated in advanced cirrhosis especially when sepsis or circulatory failure is present. The role of portal hypertension may be important particularly if a portosystemic shunt is present resulting in endotoxaemia. In keeping with the impairment of liver function and the clearance of activated clotting factors, decreased production of the natural anticoagulants antithrombin III and protein C may further enhance disseminated intravascular coagulation (DIC). Superimposed infection or surgical intervention may worsen a low grade DIC. In patients with fulminant hepatic failure, elevated markers of thrombin on the one hand and plasmin generation on the other may result from DIC or impaired clearance of endothelial derived tissue-plasminogen activator by the liver. Increased fibrinolytic activity in liver disease occurs as a distinct entity and is found in some but not all patients. Patients with primary biliary cirrhosis have less blood coagulation and fibrinolytic damage than patients with toxic or viral related liver cirrhosis [1]. Furthermore, patients with primary biliary cirrhosis and primary sclerosing cholangitis often exhibit a hypercoagulation profile in thromboelastography (TEG) [2].

Table 1
Table 1:
Haemostatic abnormalities in patients with liver disease

Intraoperative changes

Considerable progress has been accomplished in understanding intraoperative coagulation abnormalities. Ongoing debates focusing on their respective importance may result from differences in organ preservation, surgical techniques, transfusion protocols, pharmacological agents used or in preoperative alteration of haemostasis with respect to the underlying liver disease and the severity of liver failure.

Specific changes

The orthotopic liver transplantation procedure is conveniently divided into three stages. Stage I (the preanhepatic period) ends with the occlusion of the native liver blood flow. Stage II (the anhepatic period) continues until the donor liver is reperfused. An extracorporeal venovenous bypass may be used to reduce splanchnic blood pooling and circulatory disturbances associated with cross-clamping of the inferior vena cava. Stage III (reperfusion and the neohepatic period) lasts from the reperfusion of the grafted liver until the end of surgery.

Coagulation and fibrinolysis activation.

Stage I in itself does not induce specific changes in the haemostatic profile. Heavy blood loss may result from transection of collaterals resulting from previous surgery or portal hypertension. Intrinsic haemostatic deficiencies can be worsened by iatrogenic haemodilution or by extravasation of haemostatic proteins to the extravascular space. During the pre-anhepatic stage, 7-25% of patients exhibit enhanced fibrinolytic activity as monitored by TEG [3,4]. A hypercoagulable state has occasionally been reported in a few patients with neoplasm or Budd-Chiari syndrome [3,5]. Occurring late in stage II and usually worsening on the revascularization of the new liver, hyperfibrinolysis is the most striking abnormality of coagulation in orthotopic liver transplantation. Frank fibrinolysis with evidence of diffuse bleeding has been estimated to occur in about 20% of patients after graft reperfusion [3]. The mechanisms of increased fibrinolysis have been studied by several investigators [6, 7, 8]. It has been shown that tissue plasminogen activator activity levels rise sharply during the anhepatic period and culminate soon after reperfusion of the graft. Later in stage III, tissue plasminogen activator activity decreases gradually. Type-1 plasminogen activator inhibitor activity shows a pattern opposite to that of tissue plasminogen activator activity, with a decrease during the anhepatic period and a steady increase during the neohepatic period. The main factor underlying the increase in tissue plasminogen activator activity is the lack of hepatic clearance during the anhepatic period. Bakker and his colleagues have studied tissue plasminogen activator activity both in orthotopic liver transplantation and in heterotopic liver transplantation (the diseased liver is left in situ). In the latter situation, where a minimal hepatic function is maintained, tissue plasminogen activator activity levels remain within the normal range throughout the procedure [9]. Porte and his colleagues noticed a marked increase in tissue plasminogen activator activity after reperfusion of the graft in a subgroup of patients with severe fibrinolysis [8]. These investigators have suggested that this ‘second fibrinolytic burst’ was due to release of tissue plasminogen activator by the endothelial cells of the revascularized graft. Though no elevated tissue plasminogen activator activity has been observed in first hepatic graft venous outflow by others [9], the latter factor may be important in some situations. It has been suggested that hyperfibrinolysis may be secondary to thrombin formation as it occurs during DIC [10]. The clear decrease in platelet numbers and factors V and VIII, together with the rapid rise in thrombin-antithrombin complexes after reperfusion of the graft is suggestive of DIC. Low natural anticoagulants (antithrombin III, protein C) levels, chronic low-grade DIC and reduced hepatic clearance of activated factors may lead to intravascular fibrin formation and trigger a fibrinolytic reaction. Harper and his colleagues have suggested that ischaemic damage to the endothelium of the graft may play a role by impairing the anticoagulant effect of antithrombin III and protein C [10]. However, others have argued that there was no combined decrease in coagulation factors, no microthrombi on histopathological examinations of grafted livers, no increase in type-1 plasminogen activator inhibitor activity and no correlation between thrombin-antithrombin complex levels and tissue plasminogen activator activities [8] to support a clinically important role of DIC in orthotopic liver transplantation. An influence of the native liver disease on these changes has been suggested. A preserved capacity to generate thrombin and less fibrinolytic activation during the anhepatic phase has been shown in primary biliary cirrhosis compared with other cirrhotic states [1].

Platelets.

Platelet count decreases progressively during the procedure with a nadir at the time of reperfusion and a more pronounced decrease when grafted organs are severely damaged [11]. Early laboratory and human studies have suggested that the transplanted liver plays a major role in thrombocytopaenia. Intrahepatic platelet sequestration, local thrombin generation on the damaged graft endothelium, platelet extravasation into the spaces of Disse, and increased platelet phagocytosis by Kuppfer cells have all been hypothesized. The contribution of thrombocytopaenia to bleeding is not clear. However, it has been shown that highly sensitized orthotopic liver transplantation candidates required significantly more intraoperative blood transfusion than non-sensitized patients [12]. In alloimmunized patients, random platelet transfusions would not be effective and could even worsen blood loss. Pretransplant lymphocytotoxic antibody screening has been advocated to identify high-risk candidates who would benefit from HLA-matched platelet transfusions [12]. Besides a decrease in platelet count, dysfunction of platelet aggregation has been recognized after revascularization [11]. In vitro studies suggest that the adenosine contained in the University of Wisconsin fluid is able to reduce platelet aggregation even when given in small amounts.

Heparin activity may contribute to coagulopathy at reperfusion. This effect may be due to a release of exogenous heparin from the graft harvested after donor heparinization [13,14] or to endogenous heparin-like substances from the damaged ischaemic graft endothelium [15]. This effect is generally short lasting and does not require treatment. However, some orthotopic liver transplantation recipients may have a greater sensitivity to heparin and may not clear these substances adequately [16] supporting the use of protamine when heparin activity is well documented [14,15].

Non-specific changes

Haemodilution due to artificial fluid replacement may further reduce plasma concentrations of coagulation factors. An additional dilution effect due to the influx of preservation solution from the donor liver is often seen at graft reperfusion.

Hypothermia induces or enhances splanchnic platelet dysfunction. Moreover, hypothermia prolongs coagulation reaction time by reducing enzymatic activity. These abnormalities are inadequately reflected by the standardized laboratory coagulation testing performed at routine normothermic temperatures [17]. Circulatory failure may occur anytime during orthotopic liver transplantation and may worsen coagulopathy.

Perioperative monitoring of coagulation

Perioperative coagulation monitoring aims at analysing a clinically significant coagulopathy and guiding therapy.

Preoperative screening

Routine coagulation tests are usually performed preoperatively in order to assess the severity of the liver disease. In acute liver failure, some tests eventually help to decide the appropriate moment of emergency surgery. They include measurements of prothrombin time, activated partial thromboplastin time, thrombin time, activity of coagulation factors, fibrinogen concentration, platelet count, fibrin degradation products concentration, euglobulin lysis time, antithrombin III and D-dimer concentration.

From an anaesthesiologist's point of view, the first question is whether these results could help to predict blood loss and blood requirements during surgery, and therefore could lead to some kind of prophylactic therapy. Many investigators have looked for preoperative coagulation tests that correlate with intraoperative blood requirements in an attempt to determine which patients are at risk of massive bleeding. Differences in methods (anaesthesia, surgery, laboratory investigations), large differences in the amount of transfused blood products, variations in the selection of patients as well as in the administration of antifibrinolytic drugs and the small number of patients in some studies have made it difficult to compare the results. Table 2 summarizes some of these studies each of which comes from a different Institution involving a minimum of 50 patients with at least two haemostasis assays. None of these studies was prospective and/or randomized. Two studies found a relationship between abnormalities in some preoperative coagulation tests and blood requirements. Based on a coagulation score including platelet counts, prothrombin time, activated partial thromboplastin time, thrombin time, fibrinogen, antithrombin III, fibrin degradation products and euglobulin lysis time, Bontempo and his colleagues found that impairment of the coagulation score before orthotopic liver transplantation correlates with transfusion requirements and with patient's survival [18]. The authors suggested that immediate preoperative correction of the coagulation abnormalities might improve survival in these critically ill patients. Others have also proposed a preoperative correction of the coagulation defect before an orthotopic liver transplantation [26]. In another study performed on a relatively homogeneous population of cirrhotic patients, Steib and her colleagues found that patients with elevated levels of fibrinogen degradation products and a maximum amplitude (a reflection of the absolute strength of the fibrin clot) below 35mm in TEG before incision had 100% probability of developing hyperfibrinolytic activity during transplantation [4]. However, most authors failed to find any correlation between preoperative haemostatic profile and blood requirements in adults [23,24] or children [22,25]. Even if some statistical association were occasionally found, they were not strong enough to be of clinical value. For example, in the study of Mor and his colleagues, decreased platelet counts and prolonged activated partial thromboplastin time were statistically significant risk factors for intraoperative bleeding, but they could not be used as a result of their poor sensitivity and specificity (60% and 69% respectively) [24].

Table 2
Table 2:
Preoperative clotting data and intraoperative bleeding

Intraoperative evaluation

During surgery, coagulation tests are expected to be helpful either to lessen blood transfusion requirements or to prevent an intractable coagulopathy beyond all therapeutic resources.

Which tests should be used in clinical practice?

Standard coagulation tests such as activated partial thromboplastin time, prothrombin time, fibrinogen and other coagulation factors levels are routinely used during orthotopic liver transplantation. All of them are performed at 37°C on plasma and not on whole blood, neglecting the role of temperature, platelets and red blood cells in the coagulation mechanism. They permit the identification of which part of the coagulation is altered. The usual tests of coagulation, such as fibrinogen degradation products and euglobulin lysis time, do not allow a quantitative evaluation of fibrinolysis. Euglobulin lysis time determines the activity of plasminogen but does not evaluate the net balance between plasminogen and antiplasmin. Fibrinogen degradation products become positive during major surgery because of resolution of blood clots in the capillaries or reabsorption of defibrinated blood from the surgical field. The increase in D-dimers suggests a fibrinolytic reaction after coagulation but is not able to determine whether this fibrinolysis is pathological or not. The results of these standard coagulation tests are usually obtained after a minimal lag time between 30 and 45min. Such a delay is deemed too long by several teams who thus have developed on-site monitoring of coagulation. On-site techniques include TEG and, rarely, Sonoclot. Both techniques evaluate the whole process of coagulation and fibrinolysis at 37°C [27,28]. Sonoclot results are more rapidly available but the TEG trace allows a better evaluation of fibrinolysis. TEG and Sonoclot may diagnose a qualitative or quantitative platelet dysfunction and fibrinogen deficiency. Both techniques may exhibit some discordant results in about 13% of cases for altered platelet function, in 11% for coagulation factor defect and in 17% for hyperfibrinolysis [29]. Because TEG is performed at 37°C, results may be overestimated when in vivo blood temperature is lower.

Diagnostic value.

The usual coagulation tests may not differentiate a decrease in coagulation factors resulting from extreme haemodilution from those resulting from a coagulopathy or hyperfibrinolysis. TEG may diagnose and quantify the severity of hyperfibrinolysis. In the study by Steib and her colleagues, a diagnosis of severe hyperfibrinolysis was obtained with TEG in all the 12 patients who developed severe bleeding [4]. TEG may diagnose a heparin-like effect after reperfusion and determine the efficient lowest dose of protamine to correct the prolongation of the reaction time representing the rate of initial fibrin formation [14, 15, 16]. Nevertheless TEG, which evaluates the overall coagulation process, may not diagnose which coagulation factor is specifically required to achieve an efficient coagulation. Clinical algorithms have been constructed on the basis of these correlations. Activated partial thromboplastin time is correlated with the reaction time and the coagulation time of the TEG and the onset time of the sonoclot (Sonoclot-ACT). Decreased fibrinogen levels are correlated with decreased maximum amplitude and alpha angle value (representing the clot formation rate) obtained at TEG. Low platelet count is associated with long reaction time and low maximum amplitude values on TEG. The whole blood clot lysis time of TEG has been correlated with euglobulin lysis time. Therefore platelet counts, fibrinogen levels and direct factor V determinations are probably the more useful tests to guide the administration of specific components during surgery. TEG and the usual coagulation tests are thus complementary.

Predictive value.

The prognostic value of intraoperative standard tests on bleeding or blood component requirements are poorly documented and controversial [30,31]. No correlation has been observed between intraoperative standard coagulation tests and blood loss [23]. On the contrary, Porte and his colleagues observed an increased fibrinolytic activity associated with increased blood volume requirements [8]. A reduction in bleeding associated with antifibrinolytic therapy has been observed in many circumstances (see below) and suggests a role of hyperfibrinolysis in the occurrence of abnormal bleeding. However, an abnormal trace is not always associated with abnormal bleeding and may resolve spontaneously without treatment [3,32]. During surgery, Kang and his colleagues reported that as many as 82% of cases may develop hyperfibrinolysis according to TEG criteria [3]. Hyperfibrinolysis resolved spontaneously at the end of surgery and only 20 of the 97 patients required antifibrinolytic therapy as a result of severe and diffuse bleeding. The detection of biological intraoperative hyperfibrinolysis is not predictive of diffuse oozing in the operative field [4,33]. Moreover a persistent hyperfibrinolytic activity has been observed in patients with prophylactic antifibrinolytic treatment [34]. This suggests that a low hyperfibrinolytic activity may have few consequences on bleeding. This also suggests that TEG may not be a reliable guide to administration of prophylactic antifibrinolytics in the absence of severe bleeding.

Management of coagulation disorders

Before liver transplantation

As preoperative coagulation abnormalities seem to be poorly correlated with intraoperative bleeding, their systematic correction before surgery is questionable. In fulminant hepatic failure, coagulation disorders are usually profound. Attempts to correct them by substitution of clotting factors are still under debate. The emerging role of new hepatic support systems may lead to new questions especially focusing on platelet function. In patients with end-stage chronic liver disease, no special preoperative coagulation management is necessary in the absence of bleeding. Replenishment of antithrombin III has not modified the baseline consumptive component of the haemostatic disorders observed in such patients in a recent randomized study [35].

During liver transplantation

Coagulation therapy is based on the administration of blood components such as fresh frozen plasma, platelet and fibrinogen concentrates, and the use of pharmacological agents.

Blood components transfusion.

Guidelines for substitutive therapy are not clearly defined and practices vary widely between Institutions. Red blood cells usually are administered to maintain haematocrit close to 30%. Fresh frozen plasma is given to maintain prothrombin time below 1.2-1.5 times normal and platelets to keep the count above 50 × 109 L−1. A more rational approach could be the use of algorithms based on the results of intraoperative coagulation monitoring. TEG-based coagulation therapy was first described at the University of Pittsburgh [36]. The authors proposed the administration of a fluid mixture of red blood cells, fresh frozen plasma, crystalloids in a ratio of 3:2:2.5 for volume replacement, the infusion of platelets for maximum amplitude less than 40mm, cryoprecipitates for poor clot formation rate and additional fresh frozen plasma for prolonged reaction time (>12min). They argued that blood transfusion requirements decreased significantly in TEG-monitored patients compared with historical controls [36].

Other schemes have been described. Fresh frozen plasma administration was not deemed necessary by Dupont and his colleagues [37]. In that study, platelets and fibrinogen concentrates were given when platelet count and fibrinogen levels fell to below 50 × 109 L−1 and I g L−1, respectively; serum albumin was used as a volume expander and packed red blood cells were transfused when haematocrit was less than 35%. Antifibrinolytic prophylaxis was systematically and antithrombin III concentrates occasionally administered [37]. In another study, the administration of blood products was adjusted according to careful coagulation testing [38]. In contrast with the latter, some question the usefulness of coagulation monitoring to guide blood product transfusion during orthotopic liver transplantation. These studies rely on fresh frozen plasma infusion for blood volume expansion, and emphasize the major importance of avoiding haemodilution keeping haemoglobin levels stabile to manage haemostasis adequately [39]. However, the appropriateness of the transfusion thresholds and component administration schemes presented in the latter studies has not been evaluated prospectively in randomized studies. There is no evidence that one method leads to a better outcome that another. Thus, no definite useful recommendations can presently be issued with regard to blood component use during orthotopic liver transplantation and the importance of coagulation tests for guidance is apparent.

Antithrombin III.

Although antithrombin III concentrates have been used intraoperatively, their indications in the orthotopic liver transplantation setting are not clear. The aim of intraoperative use is to correct or to maintain normal antithrombin III level in order to increase its inhibition potential against thrombin formation. Moreover, through indirect inhibition of hyperfibrinolysis secondary to DIC, intraoperative blood loss and transfusion requirements may be reduced. Results of prospective, randomized controlled studies with a small number of patients are inconclusive [33,40,41].

Pharmacological agents.

As accelerated fibrinolysis is one of the main causes of excessive bleeding during orthotopic liver transplantation, the use of antifibrinolytics has been proposed to reduce blood loss and to treat or prevent the occurrence of intraoperative hyperfibrinolytic activity.

Aprotinin, a serine protease inhibitor derived from bovine lung, is widely used to prevent and/or treat hyperfibrinolysis during orthotopic liver transplantation. The compound has to be administered by continuous infusion in order to achieve stable plasma concentration. Aprotinin acts as an inhibitor of human trypsin, plasmin, plasma kallikrein and tissue kallikreins. The result is the formation of aprotinin-enzyme complexes at the active serine site of the enzyme. The plasma concentration required to inhibit plasmin and kallikrein activities are, respectively, 100 kallikrein inhibitory unit (KIU) mL−1 and 200-500 KIU mL−1. The drug has a high affinity for renal tissue and is freely filtered by the glomeruli after lysosomal breakdown. Despite anecdotal reports of renal failure, aprotinin did not show deleterious effect on renal function in randomized placebo-controlled studies. Because this drug is an animal protein, allergic response to a second exposure may be expected. The incidence of acute hypersensitivity is not known during orthotopic liver transplantation. Even if aprotinin is widely used in many liver transplant centres, its efficacy and the best way to use it are open to debate. A high-dose regimen (1-2 × 106 KIU initial dose and 0.5 × 106 KIU h−1 infusion), similar to the protocol used in cardiac surgery has initially been suggested. The first results published in the literature showed a significant decrease in the need for blood products during surgery. However, in all of those studies, treated patients were compared with an historical control group. Immediately available laboratory tests such as TEG and euglobulin lysis time might reveal a preventive effect of aprotinin against hyperfibrinolytic activity [42]. Himmelreich and his colleagues reported typical signs of hyperfibrinolysis revealed by TEG in patients receiving aprotinin either by continuous infusion or in bolus form [43]. More sophisticated tests used for clinical investigations including serial dosages of tissue plasminogen activator, type-1 plasminogen activator inhibitor, thromboplastin activation time showed abnormal results even with high dose therapy. Tissue plasminogen activator increased at time of reperfusion in most cases [34,42,44]. However, these changes were less pronounced in treated patients. Initial controlled randomized trials included a small number of patients and failed to demonstrate a significant difference between high-dose treated patients and untreated patients. A prospective, randomized placebo-controlled study including 80 patients showed similar intraoperative requirements for packed red blood cells, fresh frozen plasma, platelets and cryoprecipitate in both groups [34]. However, the proportion of cirrhotic patients was higher in the aprotinin group. A further attempt to compare a low dose regimen (0.2 × 106 KIU h−1) to a placebo failed to show a significant reduction in transfused packed red blood cells although the need for cryoprecipitate and fresh frozen plasma units was significantly lower in the treated group [38]. The results may have been distorted by the concomitant use of other antifibrinolytics or protamine. Recently, a European multicentre placebo-controlled randomized study (EMSALT study) tested the efficacy of a plasmin-inhibiting dose and of a kallikrein-inhibiting dose of aprotinin [45]. The median amount of homologous and autologous unit of blood transfused was significantly lower than the median value in the placebo group (37% lower in the high-dose group and 20% lower in the low-dose group). These controversial reports suggest that some factors may influence effectiveness of aprotinin. For example, specific surgical factors and Institutional transfusion practices probably contribute to the blood requirements. Regarding the indications for aprotinin therapy, the following questions remain open.

(a) Should the real goal and efficacy of treatment be evaluated on clinical signs or on biological grounds?

(b) Is the putative effect of the drug related to plasma concentration? If the main effect during orthotopic liver transplantation is linked to plasmin inhibition, high-dose therapy should not be mandatory. Ickx and his colleagues [46] and Soilleux and his colleagues [47] reported comparable results between highdose and low-dose therapy.

(c) Do all patients carry the same risk for intraoperative hyperfibrinolysis? Some patients seem to possess a latent hyperfibrinolytic state which could explode during surgery [4], whereas others have a better preserved coagulation and fibrinolytic balance [1,2].

(d) Should the drug be used preventively or injected only to treat clinical or biological signs?

Further evaluation is required for giving an appropriate answer to all these questions.

Epsilon aminocaproic acid was the first agent used in this indication [3]. It acts by saturating a high affinity lysine binding site of plasminogen, resulting in a delay in fibrinolysis. This drug is cheap and has few adverse effects. The short elimination half-life requires continuous infusion of relatively large doses. However, the infusion dose should be adjusted in case of elevated serum creatinine. Kang and his colleagues reported successful treatment of hyperfibrinolysis assessed on clinical generalized oozing and TEG changes in 20 patients receiving a bolus dose of 1 g epsilon amino caproic acid compared with 77 previous untreated patients [3].

Tranexamic acid is another lysine analogue. A double-blind, randomized placebo-controlled study using high-dose tranexamic acid (maximum of 20 g) showed that prophylactic administration significantly reduced intraoperative blood loss [48]. However, the intraoperative use of packed red blood cells was not significantly different between groups. A marked reduction in platelets and cryoprecipitate was observed in patients receiving tranexamic acid. The authors concluded that tranexamic acid is an acceptable alternative to aprotinin therapy. Kaspar and his colleagues, using small-dose tranexamic acid (2 mg kg−1 h−1), reported a decrease in hyperfibrinolytic activity whereas transfusion requirements were small and similar in the control group [49]. A recent randomized placebo-controlled study has shown that the prophylactic administration of tranexamic acid (10 mg kg−1 h−1) can reduce intraoperative blood requirements [50]. A reduction in the dose is recommended in patients with preoperative renal dysfunction.

As antifibrinolytic therapy will induce a shift of the haemostatic balance towards coagulation, thrombotic complications may be feared at the outset. Thrombosis of the arterial axis of the liver graft is a devastating complication, often leading to fulminant graft necrosis and death unless an emergency retransplantation can be performed. This life-threatening complication is more common in paediatric orthotopic liver transplantation, where it occurs in over 10% of cases. Thrombosis of the portal vein is just as devastating, but much less common. Postoperative thrombotic complications have been described in the early experience of orthotopic liver transplantation when epsilon amino caproic acid had been used in patients with hepatic neoplasms. Use of antifibrinolytic agents has since been considered as potentially harmful. Yet, no increase in the rate of graft vascular thrombosis has been reported with aprotinin or synthetic antifibrinolytics [45,50]. However, this point has not been specifically studied with appropriate methods. Lethal venous thromboembolic complications have been suspected in some cases [51,52]. Some orthotopic liver transplantation recipients such as patients with cancer or primary biliary cirrhosis may be at increased risk of developing thrombotic complications. This consideration supports the view that the decision to use antifibrinolytics should be taken on an individual basis.

Conclusion

Uncontrollable bleeding remains a challenging complication of liver transplantation. Profound coagulation disorders are probably contributors, but anatomical and technical considerations are important varying determinants of high blood loss. As Bontempo has pointed out, the question of which and how much coagulation testing needs to be done remains unanswered [53]. So far, no conclusion can be reached whether less monitoring leads to more bleeding. The use of antifibrinolytic agents such as aprotinin and tranexamic acid seems attractive, but the decision to use one should take into account individual and Institutional considerations. Disorders of coagulation related to orthotopic liver transplantation will undoubtely continue to generate intense interest and active research.

References

1 Segal H, Cottam S, Potter D, Hunt BJ. Coagulation and fibrinolysis in primary biliary cirrhosis compared with other liver disease and during orthotopic liver transplantation. Hepatology 1997; 25: 683-688.
2 Ben-Ari Z, Panagou M, Patch D et al. Hypercoagulability in patients with primary biliary cirrhosis and primary sclerosing cholangitis evaluated by thrombelastography. J Hepatol 1997; 26: 554-559.
3 Kang Y, Lewis JH, Navalgund A et al. Epsilon-aminocaproic acid for treatment of fibrinolysis during liver transplantation. Anesthesiology 1987; 66: 766-773.
4 Steib A, Gengenwin N, Freys G, Boudjima K, Levy S, Otteni JC. Predictive factors of hyperfibrinolytic activity during liver transplantation in cirrhotic patients. Br J Anaesth 1994; 73: 645-648.
5 Lewis JH, Bontempo FA, Awad SA et al. Liver transplantation: Intraoperative changes in coagulation factors in 100 first transplants. Hepatology 1989; 9: 710-714.
6 Dzik WH, Arkin CF, Jenkins RL, Stump DC. Fibrinolysis during liver transplantation in humans: role of tissue-type plasminogen activator. Blood 1988; 71: 1090-1095.
7 Arnoux D, Boutière B, Houvenaeghel M, Rousset-Rouviere A, Le Treut P, Sampol J. Intraoperative evolution of coagulation parameters and t-PA/PAI balance in orthotopic liver transplantation. Thromb Res 1989; 55: 319-328.
8 Porte RJ, Bontempo FA, Knot EA, Lewis JH, Kang YG, Starzl TE. Systemic effects of tissue plasminogen activator-associated fibrinolysis and its relation to thrombin generation in orthotopic liver transplantation. Transplantation 1989; 47: 978-984.
9 Bakker CM, Metselaar HJ, Groenland TN et al. Increased tissue-type plasminogen activator activity in orthotopic but not heterotopic liver transplantation: the role of the anhepatic period. Hepatology 1992; 16: 404-408.
10 Harper PL, Luddington RJ, Jennings I et al. Coagulation changes following hepatic revascularization during liver transplantation. Transplantation 1989; 48: 603-607.
11 Himmelreich G, Hundt K, Neuhaus P, Roissant R, Riess H. Decreased platelet aggregation after reperfusion in orthotopic liver transplantation. Transplantation 1992; 53: 582-586.
12 Weber T, Marino IR, Kang YG, Esquivel CD, Starzl TE, Duquesnoy RJ. Intraoperative blood transfusions in highly alloimmunized patients undergoing orthotopic liver transplantation. Transplantation 1989; 47: 797-801.
13 Bakker CM, Stibbe J, Groenland TN et al. The appearance of donor heparin in the recipient after reperfusion of a liver graft. Transplantation 1993; 56: 327-329.
14 Bayly PJ, Thick M. Reversal of post-reperfusion coagulopathy by protamine sulphate in orthotopic liver transplantation. Br J Anaesth 1994; 73: 840-842.
15 Kettner SC, Gonano C, Seebach F et al. Endogenous heparin-like substances significantly impair coagulation in patients undergoing orthotopic liver transplantation. Anesth Analg 1998; 86: 691-695.
16 Harding SA, Mallett SV, Peachey TD, Cox DJ. Use of heparinase modified thrombelastography in liver transplantation. Br J Anaesth 1997; 78: 175-179.
17 Rohrer MJ, Natale AM. Effect of hypothermia on the coagulation cascade. Crit Care Med 1992; 20: 1402-1405.
18 Bontempo FA, Lewis JH, Van Thiel DH et al. The relation of preoperative coagulation findings to diagnosis, blood usage, and survival in adult liver transplantation. Transplantation 1985; 39: 532-536.
19 Brems JJ, Hiatt JR, Colonna JOII et al. Variables influencing the outcome following orthotopic liver transplantation. Arch Surg 1987; 122: 1109-1111.
20 Borland LM, Roule M. The relation of preoperative coagulation function and diagnosis to blood usage in pediatric liver transplantation. Transplant Proc 1988; 20: 533-535.
21 Ritter DM, Rettke SR, Lunn RJ, Bowie EJ, llstrup D. Preoperative coagulation screen does not predict intraoperative blood product requirements in orthotopic liver transplantation. Transplant Proc 1989; 21: 3533-3534.
22 Carlier M, Van Obbergh LJ, Veyckemans F et al. Hemostasis in children undergoing liver transplantation. Semin Thromb Hemost 1993; 19: 218-222.
23 Gerlach H, Slama KJ, Bechstein WO et al. Retrospective statistical analysis of coagulation parameters after 250 liver transplantations. Semin Thromb Hemost 1993; 19: 223-232.
24 Mor E, Jennings L, Gonwa TA et al. The impact of operative bleeding on outcome in transplantation of the liver. Surg Gynecol Obstet 1993; 176: 219-227.
25 Ozier YM, Le Cam B, Chatellier C et al. Intraoperative blood loss in pediatric liver transplantation: analysis of preoperative risk factors. Anesth Analg 1995; 81: 1142-1147.
26 Hackl W, Zadrobilek E, Mauritz W, Langle F, Hocker P, Sporn P. Preoperative plasma exchange in treatment of plasma-related coagulation disorders before liver transplantation. Anaesthesist 1989; 38: 539-543.
27 Mallett SV, Cox DJ. Thrombelastography. Br J Anaesth 1992; 69: 307-313.
28 Hett DA, Walker D, Pilkington SN, Smith DC. Sonoclot analysis. Br J Anaesth 1995; 75: 771-776.
29 Chapin JW, Becker GL, Hulbert BJ et al. Comparison of Thromboelastograph and Sonoclot coagulation analyzer for assessing coagulation status during orthotopic liver transplantation. Transplant Proc 1989; 21: 3539.
30 Kang Y. Transfusion based on clinical coagulation monitoring does reduce hemorrhage during liver transplantation. Liver Transpl Surg 1997; 3: 655-659.
31 Reyle-Hahn M, Rossaint R. Coagulation techniques are not important in directing blood product transfusion during liver transplantation. Liver Transpl Surg 1997; 3: 659-663, (discussion) 663-665.
32 McNicol PL, Liu G, Harley ID et al. Patterns of coagulopathy during liver transplantation: experience with the first 75 cases using thrombelastography. Anaesth Intensive Care 1994; 22: 659-665.
33 Palareti G, Legnani C, Maccaferri M et al. Coagulation and fibrinolysis in orthotopic liver transplantation: role of the recipient's disease and use of antithrombin III concentrates. S. Orsola Working Group on Liver Transplantation. Haemostasis 1991; 21: 68-76.
34 Garcia-Huete L, Domenech P, Sabate A, Martinez-Brotons F, Jaurrieta E, Figueras J. The prophylactic effect of aprotinin on intraoperative bleeding in liver transplantation: a randomized clinical study. Hepatology 1997; 26: 1143-1148.
35 Scherer R, Kabatnik M, Erhard J, Peters J. The influence of antithrombin III (AT III) substitution to supranormal activities on systemic procoagulant turnover in patients with end-stage chronic liver disease. Intensive Care Med 1997; 23: 1150-1158.
36 Kang YG, Martin DJ, Marquez J et al. Intraoperative changes in blood coagulation and thrombelastographic monitoring in liver transplantation. Anesth Analg 1985; 64: 888-896.
37 Dupont J, Messiant F, Declerck N et al. Liver transplantation without the use of fresh frozen plasma. Anesth Analg 1996; 83: 681-686.
38 Marcel RJ, Stegall WC, Suit CT et al. Continuous smalldose aprotinin controls fibrinolysis during orthotopic liver transplantation. Anesth Analg 1996; 82: 1122-1125.
39 Gerlach H, Rossaint R, Bechstein WO, Blumhardt G, Neuhaus P, Falke K. ‘Goal-directed’ transfusion management leads to distinct reduction of fluid requirement in liver transplantation. Semin Thromb Hemost 1993; 19: 282-285.
40 Christophe JL, Rouget C, Roullier M et al. Use of AT-III concentrate during liver transplantation. Transplant Proc 1991; 23: 1942-1943.
41 Baudo F, DeGasperi A, deCataldo F et al. Antithrombin III supplementation during orthotopic liver transplantation in cirrhotic patients: a randomized trial. Thromb Res 1992; 68: 409-416.
42 Grosse H, Lobbes W, Frambach M, von Broen O, Ringe B, Barthels M. The use of high-dose aprotinin in liver transplantation: the influence on fibrinolysis and blood loss. Thromb Res 1991; 63: 287-297.
43 Himmelreich G, Muser M, Neuhaus P et al. Different aprotinin applications influencing hemostatic changes in orthotopic liver transplantation. Transplantation 1992; 53: 132-136.
44 Segal HC, Hunt BJ, Cottam S et al. Fibrinolytic activity during orthotopic liver transplantation with and without aprotinin. Transplantation 1994; 58: 1356-1360.
45 Porte RJ, Molenaar IQ, Begliomini B et al. Aprotinin and transfusion requirements in orthotopic liver transplantation: a multicentre randomised double-blind study. EMSALT Study Group. Lancet 2000; 355: 1303-1309.
46 Ickx B, Pradier O, DeGroote F et al. Effect of two different dosages of aprotonin on perioperative blood loss during liver transplantation. Semin Thromb Hemost 1993; 19: 300-301.
47 Soilleux H, Gillon MC, Mirand A, Daibes M, Leballe F, Ecoffey C. Comparative effects of small and large aprotinin doses on bleeding during orthotopic liver transplantation. Anesth Analg 1995; 80: 349-352.
48 Boylan JF, Klinck JR, Sandler AN et al. Tranexamic acid reduces blood loss, transfusion requirements, and coagulation factor use in primary orthotopic liver transplantation. Anesthesiology 1996; 85: 1043-1048, (discussion) 30A-31A.
49 Kaspar M, Ramsay MA, Nguyen AT, Cogswell M, Hurst G, Ramsay KJ. Continuous small-dose tranexamic acid reduces fibrinolysis but not transfusion requirements during orthotopic liver transplantation. Anesth Analg 1997; 85: 281-285.
50 Dalmau A, Sabate A, Acosta F et al. Tranexamic acid reduces red cell transfusion better than epsilon- aminocaproic acid or placebo in liver transplantation. Anesth Analg 2000; 91: 29-34.
51 Baubillier E, Cherqui D, Dominique C et al. A fatal thrombotic complication during liver transplantation after aprotinin administration. Transplantation 1994; 57: 1664-1666.
52 Sopher M, Braunfeld M, Shackleton C, Busuttil RW, Sangwan S, Csete M. Fatal pulmonary embolism during liver transplantation. Anesthesiology 1997; 87: 429-432.
53 Bontempo FA. Monitoring of coagulation during liver transplantation - how much is enough? Mayo Clin Proc 1987; 62: 848-849.
Keywords:

LIVER TRANSPLANTATION; HAEMOSTASIS; blood coagulation; fibrinolysis; ANTIFIBRINOLYTIC AGENTS; BLOOD COAGULATION TESTS; BLOOD TRANSFUSION

© 2001 European Society of Anaesthesiology