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The management of coagulopathy and blood loss in liver surgery
The Management of Coagulopathy and Blood Loss in Liver Surgery Michael A. Silva, Vijayaragavan Muralidharan, and Darius F. Mirza Liver surgery has long been associated with massive perioperative blood loss and high rates of postsurgery morbidity and mortality. Recent advances in our knowledge of hepatic segmental anatomy have led to the evolution of liver resection, and a growing awareness of the coagulopathy present in cirrhotic patients has produced a greater understanding of the factors influencing surgical hemostasis. This review will examine the risk factors for perioperative hemorrhage in liver disease patients, and will describe current pharmacological, surgical, and radiological methods available for controlling bleeding and achieving effective hemostasis during liver resection and orthotopic liver transplantation (OLT). The potential role of recombinant factor VIIa (rFVIIa) in providing safe hemostasis during such procedures will also be explored. Today, due to careful monitoring and correction of coagulopathy, improved surgical techniques, and judicious patient selection, liver surgery is no longer a high-risk specialty with an unfavorable risk profile, but a safe and widely practiced procedure. Semin Hematol 41(suppl 1):132-139. © 2004 Elsevier Inc. All rights reserved.
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EPATOBILIARY SURGERY is a growing subspecialty involving operations on the liver, biliary tract, and pancreas, including liver transplantation and procedures undertaken to rectify portal hypertension. Recently, improved understanding of the segmental anatomy of the liver has resulted in the evolution of liver surgery. The development of new surgical approaches to the biliovascular tree, combined with selective inflow occlusion to produce ischemic demarcation, has been important in demonstrating segmental boundaries for resection.10,15,33 Today, in addition to conventional segmentectomy, hemihepatectomy, and extended hepatectomy, more recently developed surgical techniques, including nonanatomical resections for liver tumors, parenchyma-preserving hepatectomies, and central hepatectomy for the treatment of centrally located lesions, are available.10,35,73 Although experience with these newer procedures is limited, liver resection techniques and transplantations have been successfully combined in ex vivo liver resection and autotransplantation for lesions in critical sites that would otherwise have been inaccessible due to the risk of severe hemorrhage.59 Orthotopic liver transplantation (OLT) is the standard procedure for end-stage liver disease.5,56 With the ever-present problem of organ shortage, the improved understanding of resection techniques has From The Liver Unit, University Hospital Birmingham NHS Trust, Queen Elizabeth Hospital, Edgbaston, Birmingham, UK. Address correspondence to Darius F. Mirza, MS, FRCS, 3rd Floor, Nuffield House, University Hospital Birmingham NHS Trust, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, UK. © 2004 Elsevier Inc. All rights reserved. 0037-1963/04/4101-1022$30.00/0 doi:10.1053/j.seminhematol.2003.11.022
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revolutionized OLT by allowing split-liver,2,49,57 reduced size, and living-related transplantation.9,16,17 Many centers report 1-year survival rates in excess of 90% in elective cases,5,56 and an overall 1-year survival rate of 80%5 (Fig 1). Several factors have contributed to this success rate, including: improved organ preservation; careful donor and recipient selection; use of more effective immunosuppressive agents; and improved surgical and anesthetic techniques, which involves better understanding and successful management of coagulopathy.5,56 Coagulopathy is a major issue for cirrhotic patients undergoing any form of liver resection or transplantation. As the liver plays a central role in the maintenance of normal hemostatic function, the effects of liver disease on hemostasis are complex.44,60 The most frequently encountered hematological abnormalities in patients with liver disease include decreased synthesis of clotting factors and inhibitors, reduced clearance of activated factors, quantitative and qualitative platelet defects, hyperfibrinolysis, and accelerated intravascular coagulation.1,60 Cirrhotic patients with low platelet counts and/or a prolonged prothrombin time (PT) do not typically experience spontaneous bleeding, but they do face an increased risk of severe hemorrhage during invasive procedures.48 Liver surgery thus presents a large hemostatic risk to patients with cirrhosis, and the widespread success of such procedures is partly due to increased awareness of the factors influencing perioperative hemostasis. This review examines the process of coagulopathy in cirrhotic patients undergoing surgery and explores the methods currently available for its control, thus making the technically challenging specialty of liver surgery a safe one.
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is well established that patients who receive few or no transfusions of blood and blood products have fewer infectious complications and a higher chance of survival.70 Due to increased knowledge and improved surgical techniques, extreme measures to counter perioperative hemorrhage—such as abdominal packing and the use of abdominal binders—are rarely required during today’s transplants and resections.42
Figure 1. Survival rates of patients transplanted at the Liver Unit, University Hospital Birmingham NHS Trust, Queen Elizabeth Hospital, Birmingham, UK, during the 1980s and 1990s.
Risk Factors for Bleeding in Liver Surgery Even in the noncirrhotic, healthy liver, resection may result in bleeding from the hepatic veins and inferior vena cava during parenchymal transection.10 This hemorrhagic tendency is greatly increased in the presence of cirrhosis, steatosis, steatohepatitis, and in the postchemotherapy liver,10,36 as all of these factors lead to the development of significant coagulopathy. Although primarily a consequence of reduced synthesis of vitamin K– dependent clotting factors, protein C, and protein S, coagulopathy is also exacerbated by hypothermia and acidosis during the surgical procedure.23,62 The situation is worsened further by the presence of thrombocytopenia, which is usually due to hypersplenism, and thrombasthenia, which is common among patients with end-stage liver disease. A greater bleeding tendency may also be induced by both portal hypertension with increased collaterals, and adhesions caused by previous surgery.1,23,60,62 The cause of OLT-associated blood loss is multifactorial, and can be attributed to both technical factors and poor hemostasis.23,62 In addition to those factors of end-stage liver disease that increase the bleeding risk, such as poor synthetic function, the anhepatic phase of OLT is associated with a further decrease in the ability to clear circulating tissue plasminogen activating factor (tPA), and a reduction in the level of plasminogen activator inhibitors. This leads to the upregulation of fibrinolysis. Reperfusion injury also worsens the coagulopathy. The effect of heparinization can be avoided, however, by utilizing heparin-coated or heparin-free veno-venous bypass circuits.72 During the early period of OLT evolution from an experimental procedure to a routine, safe one, uncontrolled bleeding leading to massive transfusion requirements was a major problem.23,72,74 The excessive transfusions often needed were associated with an increased 30-day mortality rate post-OLT,27 and it
Identification of Coagulopathy and Subsequent Risk of Perioperative Hemorrhage Neither the cause and severity of liver disease, nor basic tests of coagulation, can help to predict excessive intraoperative bleeding.11,64,69 The preoperative identification of patients with a potential hemorrhagic tendency could theoretically be achieved using a comprehensive coagulation screen including full blood count, assays for proteins C and S, PT test, partial thromboplastin time (PTT) test, and thrombin time (TT) test, along with evaluation of fibrinogen levels, fibrin degradation products, and antithrombin III (ATIII). Levels of hemoglobin and fibrin degradation products, as well as a history of previous upper abdominal surgery, have been shown to predict a risk for perioperative blood loss, but they lack sensitivity.75 Other studies have also identified low platelet count and high serum urea levels as being potential predictive factors.23 Despite efforts to identify predictive risk factors for bleeding during OLT, however, no clear indicators have yet been found, even among homogeneous populations.75 In the absence of definitive risk factors, it is recommended that centers should assess their practice individually to identify patients at high risk of perioperative hemorrhage.75
Thrombelastography The coagulopathy present during liver transplantation is dynamic, and varies in severity. The routine coagulation profile does not provide an accurate overview of the interaction between stimulators, inhibitors, and available procoagulants that eventually leads to solid clot formation. Each phase of the operation is therefore associated with unexpected and unpredictable changes in coagulation dynamics. Thrombelastography is a “near-patient” test of coagulation, and has played an integral part in the growth and success of liver transplantation.28,71,82 First developed by Hartert in 1948, it allows global evaluation of hemostatic function from a singe sample of whole blood.4,39 Because this assay is performed using whole blood, the physiological importance of platelet and leukocyte function during coagulation and fibrinolysis are represented, in contrast to plasma-based assays (PT, PTT). The
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tracings generated can provide vital information on clotting factor activity, platelet function, and clinically significant fibrinolytic processes within 20 to 30 minutes.4,39 The thromboelastograph is a small instrument that can be easily set up in the operating theatre, anesthetic room, or ward. The presence of two separate channels allows the performance of serial blood coagulation profiles, allowing coagulation to be monitored directly at regular intervals, thus enabling the effects of therapeutic interventions to be rapidly assessed.4,39 This unique, gross test of clot strength is perfectly suited to monitor the changes that occur during OLT,28,71,82 and initial pioneering work undertaken with thrombelastography in this indication has inspired its assessment in related surgical fields.
Management of Coagulation and Bleeding in Patients With Liver Disease Undergoing Surgery Surgical Treatment of Bleeding There are a number of techniques to help reduce bleeding in the liver surgeon’s armamentarium. Good operative technique and tissue handling, the judicious use of diathermy for dissection, and meticulous suture ligation of vessels not controlled by diathermy all contribute towards a “dry” operative field. Ordinary diathermy is ineffective, however, in the face of generalized oozing from a raw surface.67 An alternative option is the argon-beam coagulator, which delivers a coagulating diathermy current along a spray of inert argon gas. This spray blows away the blood from the operative field, allowing good contact between the diathermy current and the raw tissue, thus facilitating hemostasis.23,67 The harmonic scalpel causes vascular occlusion while dividing structures, and is another useful device in maintaining hemostasis.76 Other devices such as high-intensity focused ultrasound may be of use in controlling oozing from the raw surface of a resected liver,81 and local hemostatic foams and fibrin glues also help to promote coagulation on such surfaces.19,58,78 Very few controlled clinical trials investigating the use of topical agents have been performed, however, and scientific evidence supporting their use is still limited.65 In liver resection, the portal and arterial inflows to the segments undergoing resection are identified and ligated early in the procedure. Deliberate retrohepatic dissection of minor and major hepatic veins to control hepatic venous outflow is performed before commencing parenchymal transection,22 which is usually carried out using a cavitron ultrasonic aspirator (CUSA) or harmonic scalpel.22,76 Hepatic vascular exclusion, or the Pringle maneu-
ver, is an effective way to limit blood loss in hepatic resection without causing severe liver injury. This procedure, however, causes a rise in interleukin-6 production and hence a higher morbidity rate. Paradoxically, periodic release of pedicular clamping increases the blood loss but does not reduce liver cell injury or interleukin-6 production.41 The use of the Pringle maneuver should therefore be restricted to exceptional cases, such as those with infiltration of the inferior vena cava by a tumor that demands substitution of the involved vessel.79 The liver dysfunction associated with the Pringle maneuver is associated with clamp times exceeding 1 hour, particularly if the remaining parenchyma is abnormal or small.25
Pharmacological Control of Bleeding In general, pharmacological therapies and surgical hemostasis can be complementary in controlling blood loss. Whereas adequate surgical hemostasis may suffice in most patients, prohemostatic pharmacological agents may be of additional benefit in those with diffuse surgical bleeding or those with a specific underlying hemostatic defect, such as that commonly encountered in liver surgery.65 Antifibrinolytic agents. The use of antifibrinolytic agents—such as aprotinin, tranexamic acid, and aminocaproic acid—in liver surgery and OLT is supported by highly favorable evidence.65 Meta-analyses of randomized, controlled trials have suggested a slight advantage of aprotinin over the other antifibrinolytics.65 Through its inhibitory effects on kallikrein, aprotinin reduces FXIIa formation and thus indirectly inhibits the release of tPA.21 Aprotinin has been shown to reduce intra-operative blood transfusion in OLT,47 and its efficacy in both this indication and other types of liver surgery is perhaps best demonstrated by thrombelastography during the surgical procedure.66 Some studies, however, have also shown that aprotinin exerts an anticoagulant, rather than a procoagulant, effect. Its blood-sparing (prohemostatic) efficacy appears to be the overall result of a strong antifibrinolytic and a weaker anticoagulant effect.50 High-dose tranexamic acid has also been shown to significantly decrease intraoperative blood loss during OLT, and to reduce requirements for platelets and cryoprecipitate in randomized controlled clinical trials.14,65,66 Blood and blood products. Bleeding in patients undergoing liver resection or OLT may be also controlled using vitamin K, fresh-frozen plasma, fibrinogen concentrates, and platelet concentrates.14,63 In addition, packed cells can be transfused to replace lost red blood cells (RBCs). The use of autologous transfusion of cell-saver blood has also reduced the need for transfusions.32 This procedure, however, is only useful for those
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patients requiring massive transfusions due to blood loss. Most patients undergoing liver surgery do not require autologous transfusion, and it has proven difficult to accurately predict which patients would benefit from its use.
Pharmacological, Radiological, and Surgical Control of Portal Hypertension Portal hypertension is common in end-stage liver disease, and is frequently complicated by upper gastrointestinal bleeding and ascites.20 It results in the opening up of portosystemic collateral shunts, which are a major cause for bleeding during hepatectomy when they occur around the liver and in the posterior abdominal wall. When not contraindicated, betablockers have proven to be of benefit, and are the pharmacological treatment of choice in reducing portal pressure and thus the risk of variceal rebleeding in these patients.18 Transjugular intrahepatic portosystemic shunt (TIPS) was developed in the 1980s for the treatment of complications associated with portal hypertension.13 Once shown that the shunt could be placed with relative ease, TIPS was widely used for complications such as variceal rebleeding, control of refractory ascites, hepatic hydrothorax, treatment of hepato-renal syndrome, and hepatopulmonary syndrome.13 The procedure has also been used for the treatment of Budd-Chiari syndrome and veno-occlusive disease.13 Although TIPS has provided more effective control of variceal rebleeding and refractory cirrhotic ascites than other available methods, it has not achieved an improvement in long-term survival rates, and is associated with a high incidence of encephalopathy.13 The availability of TIPS, however, has decreased the number of patients requiring surgical portocaval shunts for reduction of perioperative bleeding risk or prevention of portal hypertensionassociated complications.12 The relative advantages of TIPS over surgical decompression of portal hypertension in patients with liver cirrhosis relate to the ability of TIPP to bridge the patient successfully to ultimate OLT, if subsequently indicated, without impacting post-OLT survival. Preservation of the vena cava during OLT and use of the piggyback technique for the donor/recipient cavo-caval anastomosis have gained wide acceptance.26,80 These procedures have eliminated the requirement for extra corporeal veno-venous bypass during the anhepatic phase of OLT. The hemodynamic instability and subsequent increase in portal hypertension that may occur following division of the portal vein upon recipient liver explantation is overcome by the addition of a temporary internal portocaval shunt.26,51 Temporary internal porto-caval
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shunting during OLT is technically easy to perform, and improves hemodynamic status by reducing portal hypertension and gut engorgement. Randomized controlled trials have shown that it also reduces intraoperative transfusion requirements, and preserves renal function both during and after the procedure.26
Anesthesia in Liver Surgery: Methods for Reducing Blood Loss Hemorrhage during hepatic resection usually arises from major hepatic veins or the vena cava. To reduce blood loss, resections are routinely carried out with a controlled central venous pressure that is maintained at ⱕ5 mm Hg using a combination of anesthetic techniques and intraoperative fluid restriction. An intraoperative urine output of 25 mL/h is considered to be the minimum accepted level.22 Should vascular isolation of the liver be necessary, the anesthetic requirements change to incorporate the need to maintain cardiac output during caval cross clamping.22 In the pre-anhepatic stage of OLT, surgical entry into the abdominal cavity may be associated with drainage of large amounts of ascitic fluid, necessitating anticipation and correction of any volume shifts.54 Blood transfusion and manipulation may cause marked defects of coagulation. Tests of coagulation and hematological function are performed frequently during this stage, and any hemostatic deficiencies are corrected. Due to a continued fall in ionized calcium, it may also become necessary to correct calcium levels to maintain the normal range.54 Factors inducing metabolic alterations during the anhepatic phase include progressive academia, base deficit, continued fall in ionized calcium, and hypothermia. The post-anhepatic phase may be complicated by continued bleeding, which is exacerbated by a reperfusion coagulopathy that can be partly attributed to a heparin-like action. This reperfusion coagulopathy can be reversed using protamine sulfate, the use and efficacy of which can be monitored and guided using thrombelastography.3 Perioperative hypothermia is common, and can have a profound physiological effect on the body by worsening pre-existent coagulopathies.23,62 In the anesthetized patient, normal protective reflexes such as shivering are absent, particularly when muscle relaxants are used.8 Maintaining constant ambient temperatures in the operating theatre, infusing warm intravenous fluids, transfusing warm blood and blood products, and the use of warm irrigation and liver flush fluids all help to prevent inadvertent hypothermia. Heat is lost through radiation, convection, and conduction, with conduction having the greatest effect.8 Forced air warmers such as the Bair
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Hugger (Augustine Medical Inc, Eden Prairie, MN) are the most effective means of preventing and treating heat loss, and are used routinely in liver surgery.8 It should also be remembered that the liver is an important source of heat generation, and that a cooled organ is implanted into the recipient at transplantation since the liver is maintained at 4°C during transport and storage.
Recombinant Factor VIIa: A Novel Method to Control Hemostatic Defects in Liver Surgery Recombinant factor VIIa (rFVIIa; NovoSeven威, Novo Nordisk, Bagsvaerd, Denmark) was first developed for the treatment of bleeding in hemophilia patients with inhibitors, and has shown considerable efficacy in this indication.29,37,40 Pharmacological doses of rFVIIa have been found to enhance thrombin generation on activated platelets, and are therefore of further benefit in improving hemostasis in nonhemophilia patients experiencing profuse bleeding and impaired thrombin generation.29 Clinical experience has also shown that treatment with rFVIIa can significantly enhance the hemostatic effect in patients with thrombocytopenia and functional platelet defects.43,61 In addition, rFVIIa has been shown to normalize a prolonged PT in both stable cirrhotic patients7 and in patients with alcoholic cirrhosis and bleeding from esophageal varices.24 The agent has also been used to successfully induce hemostasis during invasive procedures in patients with advanced liver disease,6 and has reduced the need for transfusion of RBCs and plasma during OLT.31
Mechanism of Action of rFVIIa Recombinant FVIIa is thought to exert its prohemostatic effect via enhancement of the extrinsic coagulation pathway in a tissue factor (TF)-dependent manner.77 Approximately 1% of total FVII protein mass is normally present in the circulation in an activated form.53,83 Hemostasis is initiated by the formation of a complex between FVII and TF,68 which is not normally exposed to circulating blood, as it is found on various cells in the deeper layers of the vessel wall. Following injury, TF is exposed to the circulation and forms a complex with FVII or FVIIa.29 Therefore, this mechanism of action of rFVIIa suggests that the induced enhancement of hemostasis is limited to the injury site, without systemic activation of the coagulation cascade.55 An additional mode of action of rFVIIa has also been proposed. Full thrombin generation is necessary for full and effective hemostasis, and this requires the presence of activated platelets that are provided by the initial thrombin formation. In a
recently developed cell-based model, the addition of exogenous rFVIIa in doses of ⱖ50 nmol/L enhances the rate of thrombin generation on activated platelet surfaces independently of TF.34 This produces the full thrombin burst necessary to induce a fully stabilized fibrin plug with a tight structure that demonstrates increased resistance to premature lysis.29 Premature fibrinolysis is also prevented by the formation of thrombinactivatable fibrinolysis inhibitor (TAFI),52 and by the fibrin-stabilizing actions of the coagulation proteins fibrinogen, FXIII, and perhaps other factors important in regulating fibrinolysis.29 These findings imply that rFVIIa has a dual mode of action: a TF-dependent mechanism that “drives” the extrinsic pathway, and a TF-independent binding to activated platelets to induce a substantial burst of thrombin generation. Both mechanisms of action serve to localize rFVIIa activity to the injury site without inducing widespread coagulation. Current evidence, however, indicates that rFVIIa does not possess an additional antifibrinolytic action,45 although this has been disputed.
Use of rFVIIa in Liver Surgery A multinational, randomized, double blind, placebocontrolled trial recently evaluated the hemostatic efficacy and safety of rFVIIa in noncirrhotic patients scheduled to undergo partial hepatectomy due to liver cancer/metastasis and/or benign tumors.46 In total, 204 patients were equally randomized to receive an injection of either 20 or 80 g/kg rFVIIa or placebo. A second dose of rFVIIa was given 5 hours after the start of the operation if the anticipated surgery time exceeded 6 hours. Dosage was based on the drug pharmacokinetics and knowledge of duration of action (Fig 2). Key efficacy parameters included transfusion requirements and blood loss postsurgery.46 The results of this liver resection study suggested that 80 g/kg rFVIIa improved hemostasis, as mea-
Figure 2. rFVIIa titers over time during and after liver resection. Reprinted from Lodge et al46 by permission of Wiley-Liss, Inc, a subsidiary of John Wiley & Sons, Inc. Copyright © 2002, Wiley-Liss, Inc.
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sured by RBC transfusion requirements and blood loss during surgery. Single or repeated administration of rFVIIa at doses up to 80 g/kg did not appear to cause any adverse effects.46 Additional trials are currently being initiated to further investigate the safety and hemostatic effects of rFVIIa in liver resection. Preliminary reports also indicate that rFVIIa significantly reduces transfusion requirements in OLT.30,31,38 A multinational, placebo-controlled, double-blind, randomized study is currently investigating the role of rFVIIa in this indication. The results of this trial, which shares considerable similarity with the liver resection study reported by Lodge et al,46 are eagerly awaited.
Conclusions Liver surgery has evolved from being a high-risk specialty associated with massive perioperative blood loss and high morbidity and mortality, to a safe and widely practiced field. Much of its success can be attributed to a greater knowledge of the anatomy of the biliovascular tree and its common variations. With this improved understanding, more effective and relatively bloodless parenchymal dissection techniques have been developed. Additionally, better understanding of end-stage liver disease and associated coagulopathy has resulted in more successful methods of achieving hemostasis during surgery. Patient optimization and specialist anesthetic management during surgery have also helped to reach this goal. The pre-existing coagulation defects in patients with liver disease are further exacerbated during the operative procedure by factors such as hypothermia, acidosis, increased fibrinolysis, and alterations of factors that enhance and inhibit clotting. This results in significant defects of the clotting mechanism that can be both unexpected and unpredictable. Dynamic methods of monitoring the status of clotting, such as thrombelastography, have thus proved invaluable in patients undergoing liver surgery. Techniques developed for liver resection have also been applied in the field of OLT, facilitating such procedures as split-liver grafts and live-donor transplantations. Increasingly effective management of coagulopathy in OLT has contributed towards its establishment as a routine procedure in the management of end-stage liver disease. Early results from trials using rFVIIa in the management of bleeding during liver surgery are encouraging, suggesting that the potential role of this agent in the management of patients with end-stage liver disease is highly promising for the future of liver surgery. Results from large, ongoing, multicenter trials of rFVIIa use in liver resection and OLT are therefore awaited with great interest.
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with recombinant factor VIIa in patients with thrombocytopenia. Haemostasis 26:159-164, 1996 (suppl) Lisman T, Leebeek FW, de Groot PG: Haemostatic abnormalities in patients with liver disease. J Hepatol 37:280-287, 2002 Lisman T, Mosnier LO, Lambert T, et al: Inhibition of fibrinolysis by recombinant factor VIIa in plasma from patients with severe hemophilia A. Blood 99:175-179, 2002 Lodge P, Jonas S, Jaeck D, et al: Recombinant factor VIIa (NovoSeven威) in partial hepatectomy: A randomized, placebocontrolled, double-blind clinical trial. Presented at the American Association for the Study of Liver Diseases Annual Meeting, Boston, MA, Nov 2002 (abstr 177) Mallett S, Rolles K, Cox D, et al: Intraoperative use of aprotinin (Trasylol) in orthotopic liver transplantation. Transplant Proc 23:1931-1932, 1991 Mammen EF: Coagulation defects in liver disease. Med Clin North Am 78:545-554, 1994 Mirza DF, Achilleos O, Pirenne J, et al: Encouraging results of split-liver transplantation. Br J Surg 85:494-497, 1998 Molenaar IQ, Legnani C, Groenland TH, et al: Aprotinin in orthotopic liver transplantation: Evidence for a prohemostatic, but not a prothrombotic, effect. Liver Transplant 7:896-903, 2001 Molmenti EP, Marsh JW, Fung JJ, et al: Rapid temporary portosystemic bypass. Dig Dis Sci 47:448-449, 2002 Monroe DM, Hoffman M, Oliver JA, et al: Platelet activity of high-dose factor VIIa is independent of tissue factor. Br J Haematol 99:542-545, 1997 Morrissey JH, Macik BG, Neuenschwander PF, et al: Quantitation of activated factor VII levels in plasma using a tissue factor mutant selectively deficient in promoting factor VII activation. Blood 81:734-744, 1993 Moysey J, Freeman JW: Liver transplantation: Anesthesia, perioperative management and postoperative intensive care, in Blumgart LH, Fong Y (eds): Surgery of the Liver and Biliary Tract. London, UK, Saunders, 2000, pp 2035-2054 Murkin JM: A novel hemostatic agent: The potential role of recombinant activated factor VII (rFVIIa) in anesthetic practice. Can J Anaesth 49:S21-26, 2002 Neuberger J, McMaster P: Liver transplantation: Indications, in Blumgart LH, Fong Y (eds): Surgery of the Liver and Biliary Tract. London, UK, Saunders, 2000, pp 2055-2069 Noujaim HM, Gunson B, Mirza DF, et al: Ex-situ preparation of left split-liver grafts with left vascular pedicle only: Is it safe? A comparative single-center study. Transplantation 74: 1386-1390, 2002 Noun R, Elias D, Balladur P, et al: Fibrin glue effectiveness and tolerance after elective liver resection: A randomized trial. Hepatogastroenterology 43:221-224, 1996 Oldhafer KJ, Lang H, Schlitt HJ, et al: Long-term experience after ex situ liver surgery. Surgery 127:520-527, 2000 Papatheodoridis GV, Burroughs AK: Hemostasis in hepatic and biliary disorders, in Blumgart LH, Fong Y (eds): Surgery of the Liver and Biliary Tract. London, UK, Saunders, 2000, pp 199-216 Poon MC, Demers C, Jobin F, et al: Recombinant factor VIIa is effective for bleeding and surgery in patients with Glanzmann thrombasthenia. Blood 94:3951-3953, 1999 Porte RJ: Coagulation and fibrinolysis in orthotopic liver transplantation: Current views and insights. Semin Thromb Hemost 19:191-196, 1993 Porte RJ, Bontempo FA, Knot EA, et al: Systemic effects of tissue plasminogen activator associated fibrinolysis and its relation to thrombin generation in orthotopic liver transplantation. Transplantation 47:978-984, 1989
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64. Porte RJ, Knot EA, Bontempo FA: Hemostasis in liver transplantation. Gastroenterology 97:488-501, 1989 65. Porte RJ, Leebeek FW: Pharmacological strategies to decrease transfusion requirements in patients undergoing surgery. Drugs 62:2193-2211, 2002 66. 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 355:1303-1309, 2000 67. Postema RR, Plaisier PW, ten Kate FJ, et al: Haemostasis after partial hepatectomy using argon beam coagulation. Br J Surg 80:1563-1565, 1993 68. Rapaport SI, Rao LV: Initiation and regulation of tissue factordependent blood coagulation. Arterioscler Thromb 12:11111121, 1992 69. Ritter DM, Rettke SR, Lunn RJ, et al: Preoperative coagulation screen does not predict intraoperative blood product requirements in orthotopic liver transplantation. Transplant Proc 21:3533-3534, 1989 70. Rouch DA, Thistlethwaite JR, Lichtor L, et al: Effect of massive transfusion during liver transplantation on rejection and infection. Transplant Proc 20:1135-1137, 1988 71. Salooja N, Perry DJ: Thrombelastography. Blood Coagul Fibrinolysis 12:327-337, 2001 72. Scholz T, Solberg R, Okkenhaug C, et al: The significance of heparin-coated veno-venous bypass circuits in liver transplantation. Perfusion 17:45-50, 2002 73. Shimada H, Endo I, Sugita M, et al: Is parenchyma-preserving hepatectomy a noble option in the surgical treatment for
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high-risk patients with hilar bile duct cancer? Langenbecks Arch Surg 388:33-41, 2003 Starzl TE, Marchioro TL, Porter KA, et al: Homotransplantation of the liver. Transplantation 5:790-803, 1967 (suppl) Steib A, Freys G, Lehmann C, et al: Intraoperative blood losses and transfusion requirements during adult liver transplantation remain difficult to predict. Can J Anaesth 48:10751079, 2001 Sugo H, Mikami Y, Matsumoto F, et al: Hepatic resection using the harmonic scalpel. Surg Today 30:959-962, 2000 ten Cate H, Bauer KA, Levi M, et al: The activation of factor X and prothrombin by recombinant factor VIIa in vivo is mediated by tissue factor. J Clin Invest 92:1207-1212, 1993 Tokunaga Y, Tanaka K, Uemoto S, et al: Fibrin sealant of the cut surface of partial liver grafts from living donors. J Invest Surg 8:243-251, 1995 Torzilli G, Makuuchi M, Inoue K: The vascular control in liver resection: Revisitation of a controversial issue. Hepatogastroenterology 49:28-31, 2002 Tzakis A, Todo S, Starzl TE: Orthotopic liver transplantation with preservation of the inferior vena cava. Ann Surg 210: 649-652, 1989 Vaezy S, Martin R, Schmiedl U, et al: Liver hemostasis using high-intensity focused ultrasound. Ultrasound Med Biol 23: 1413-1420, 1997 Whitten CW, Greilich PE: Thromboelastography: past, present, and future. Anesthesiology 92:1223-1225, 2000 Wildgoose P, Nemerson Y, Hansen LL, et al: Measurement of basal levels of factor VIIa in hemophilia A and B patients. Blood 80:25-28, 1992
H
EPATOBILIARY SURGERY is a growing subspecialty involving operations on the liver, biliary tract, and pancreas, including liver transplantation and procedures undertaken to rectify portal hypertension. Recently, improved understanding of the segmental anatomy of the liver has resulted in the evolution of liver surgery. The development of new surgical approaches to the biliovascular tree, combined with selective inflow occlusion to produce ischemic demarcation, has been important in demonstrating segmental boundaries for resection.10,15,33 Today, in addition to conventional segmentectomy, hemihepatectomy, and extended hepatectomy, more recently developed surgical techniques, including nonanatomical resections for liver tumors, parenchyma-preserving hepatectomies, and central hepatectomy for the treatment of centrally located lesions, are available.10,35,73 Although experience with these newer procedures is limited, liver resection techniques and transplantations have been successfully combined in ex vivo liver resection and autotransplantation for lesions in critical sites that would otherwise have been inaccessible due to the risk of severe hemorrhage.59 Orthotopic liver transplantation (OLT) is the standard procedure for end-stage liver disease.5,56 With the ever-present problem of organ shortage, the improved understanding of resection techniques has From The Liver Unit, University Hospital Birmingham NHS Trust, Queen Elizabeth Hospital, Edgbaston, Birmingham, UK. Address correspondence to Darius F. Mirza, MS, FRCS, 3rd Floor, Nuffield House, University Hospital Birmingham NHS Trust, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, UK. © 2004 Elsevier Inc. All rights reserved. 0037-1963/04/4101-1022$30.00/0 doi:10.1053/j.seminhematol.2003.11.022
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revolutionized OLT by allowing split-liver,2,49,57 reduced size, and living-related transplantation.9,16,17 Many centers report 1-year survival rates in excess of 90% in elective cases,5,56 and an overall 1-year survival rate of 80%5 (Fig 1). Several factors have contributed to this success rate, including: improved organ preservation; careful donor and recipient selection; use of more effective immunosuppressive agents; and improved surgical and anesthetic techniques, which involves better understanding and successful management of coagulopathy.5,56 Coagulopathy is a major issue for cirrhotic patients undergoing any form of liver resection or transplantation. As the liver plays a central role in the maintenance of normal hemostatic function, the effects of liver disease on hemostasis are complex.44,60 The most frequently encountered hematological abnormalities in patients with liver disease include decreased synthesis of clotting factors and inhibitors, reduced clearance of activated factors, quantitative and qualitative platelet defects, hyperfibrinolysis, and accelerated intravascular coagulation.1,60 Cirrhotic patients with low platelet counts and/or a prolonged prothrombin time (PT) do not typically experience spontaneous bleeding, but they do face an increased risk of severe hemorrhage during invasive procedures.48 Liver surgery thus presents a large hemostatic risk to patients with cirrhosis, and the widespread success of such procedures is partly due to increased awareness of the factors influencing perioperative hemostasis. This review examines the process of coagulopathy in cirrhotic patients undergoing surgery and explores the methods currently available for its control, thus making the technically challenging specialty of liver surgery a safe one.
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is well established that patients who receive few or no transfusions of blood and blood products have fewer infectious complications and a higher chance of survival.70 Due to increased knowledge and improved surgical techniques, extreme measures to counter perioperative hemorrhage—such as abdominal packing and the use of abdominal binders—are rarely required during today’s transplants and resections.42
Figure 1. Survival rates of patients transplanted at the Liver Unit, University Hospital Birmingham NHS Trust, Queen Elizabeth Hospital, Birmingham, UK, during the 1980s and 1990s.
Risk Factors for Bleeding in Liver Surgery Even in the noncirrhotic, healthy liver, resection may result in bleeding from the hepatic veins and inferior vena cava during parenchymal transection.10 This hemorrhagic tendency is greatly increased in the presence of cirrhosis, steatosis, steatohepatitis, and in the postchemotherapy liver,10,36 as all of these factors lead to the development of significant coagulopathy. Although primarily a consequence of reduced synthesis of vitamin K– dependent clotting factors, protein C, and protein S, coagulopathy is also exacerbated by hypothermia and acidosis during the surgical procedure.23,62 The situation is worsened further by the presence of thrombocytopenia, which is usually due to hypersplenism, and thrombasthenia, which is common among patients with end-stage liver disease. A greater bleeding tendency may also be induced by both portal hypertension with increased collaterals, and adhesions caused by previous surgery.1,23,60,62 The cause of OLT-associated blood loss is multifactorial, and can be attributed to both technical factors and poor hemostasis.23,62 In addition to those factors of end-stage liver disease that increase the bleeding risk, such as poor synthetic function, the anhepatic phase of OLT is associated with a further decrease in the ability to clear circulating tissue plasminogen activating factor (tPA), and a reduction in the level of plasminogen activator inhibitors. This leads to the upregulation of fibrinolysis. Reperfusion injury also worsens the coagulopathy. The effect of heparinization can be avoided, however, by utilizing heparin-coated or heparin-free veno-venous bypass circuits.72 During the early period of OLT evolution from an experimental procedure to a routine, safe one, uncontrolled bleeding leading to massive transfusion requirements was a major problem.23,72,74 The excessive transfusions often needed were associated with an increased 30-day mortality rate post-OLT,27 and it
Identification of Coagulopathy and Subsequent Risk of Perioperative Hemorrhage Neither the cause and severity of liver disease, nor basic tests of coagulation, can help to predict excessive intraoperative bleeding.11,64,69 The preoperative identification of patients with a potential hemorrhagic tendency could theoretically be achieved using a comprehensive coagulation screen including full blood count, assays for proteins C and S, PT test, partial thromboplastin time (PTT) test, and thrombin time (TT) test, along with evaluation of fibrinogen levels, fibrin degradation products, and antithrombin III (ATIII). Levels of hemoglobin and fibrin degradation products, as well as a history of previous upper abdominal surgery, have been shown to predict a risk for perioperative blood loss, but they lack sensitivity.75 Other studies have also identified low platelet count and high serum urea levels as being potential predictive factors.23 Despite efforts to identify predictive risk factors for bleeding during OLT, however, no clear indicators have yet been found, even among homogeneous populations.75 In the absence of definitive risk factors, it is recommended that centers should assess their practice individually to identify patients at high risk of perioperative hemorrhage.75
Thrombelastography The coagulopathy present during liver transplantation is dynamic, and varies in severity. The routine coagulation profile does not provide an accurate overview of the interaction between stimulators, inhibitors, and available procoagulants that eventually leads to solid clot formation. Each phase of the operation is therefore associated with unexpected and unpredictable changes in coagulation dynamics. Thrombelastography is a “near-patient” test of coagulation, and has played an integral part in the growth and success of liver transplantation.28,71,82 First developed by Hartert in 1948, it allows global evaluation of hemostatic function from a singe sample of whole blood.4,39 Because this assay is performed using whole blood, the physiological importance of platelet and leukocyte function during coagulation and fibrinolysis are represented, in contrast to plasma-based assays (PT, PTT). The
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tracings generated can provide vital information on clotting factor activity, platelet function, and clinically significant fibrinolytic processes within 20 to 30 minutes.4,39 The thromboelastograph is a small instrument that can be easily set up in the operating theatre, anesthetic room, or ward. The presence of two separate channels allows the performance of serial blood coagulation profiles, allowing coagulation to be monitored directly at regular intervals, thus enabling the effects of therapeutic interventions to be rapidly assessed.4,39 This unique, gross test of clot strength is perfectly suited to monitor the changes that occur during OLT,28,71,82 and initial pioneering work undertaken with thrombelastography in this indication has inspired its assessment in related surgical fields.
Management of Coagulation and Bleeding in Patients With Liver Disease Undergoing Surgery Surgical Treatment of Bleeding There are a number of techniques to help reduce bleeding in the liver surgeon’s armamentarium. Good operative technique and tissue handling, the judicious use of diathermy for dissection, and meticulous suture ligation of vessels not controlled by diathermy all contribute towards a “dry” operative field. Ordinary diathermy is ineffective, however, in the face of generalized oozing from a raw surface.67 An alternative option is the argon-beam coagulator, which delivers a coagulating diathermy current along a spray of inert argon gas. This spray blows away the blood from the operative field, allowing good contact between the diathermy current and the raw tissue, thus facilitating hemostasis.23,67 The harmonic scalpel causes vascular occlusion while dividing structures, and is another useful device in maintaining hemostasis.76 Other devices such as high-intensity focused ultrasound may be of use in controlling oozing from the raw surface of a resected liver,81 and local hemostatic foams and fibrin glues also help to promote coagulation on such surfaces.19,58,78 Very few controlled clinical trials investigating the use of topical agents have been performed, however, and scientific evidence supporting their use is still limited.65 In liver resection, the portal and arterial inflows to the segments undergoing resection are identified and ligated early in the procedure. Deliberate retrohepatic dissection of minor and major hepatic veins to control hepatic venous outflow is performed before commencing parenchymal transection,22 which is usually carried out using a cavitron ultrasonic aspirator (CUSA) or harmonic scalpel.22,76 Hepatic vascular exclusion, or the Pringle maneu-
ver, is an effective way to limit blood loss in hepatic resection without causing severe liver injury. This procedure, however, causes a rise in interleukin-6 production and hence a higher morbidity rate. Paradoxically, periodic release of pedicular clamping increases the blood loss but does not reduce liver cell injury or interleukin-6 production.41 The use of the Pringle maneuver should therefore be restricted to exceptional cases, such as those with infiltration of the inferior vena cava by a tumor that demands substitution of the involved vessel.79 The liver dysfunction associated with the Pringle maneuver is associated with clamp times exceeding 1 hour, particularly if the remaining parenchyma is abnormal or small.25
Pharmacological Control of Bleeding In general, pharmacological therapies and surgical hemostasis can be complementary in controlling blood loss. Whereas adequate surgical hemostasis may suffice in most patients, prohemostatic pharmacological agents may be of additional benefit in those with diffuse surgical bleeding or those with a specific underlying hemostatic defect, such as that commonly encountered in liver surgery.65 Antifibrinolytic agents. The use of antifibrinolytic agents—such as aprotinin, tranexamic acid, and aminocaproic acid—in liver surgery and OLT is supported by highly favorable evidence.65 Meta-analyses of randomized, controlled trials have suggested a slight advantage of aprotinin over the other antifibrinolytics.65 Through its inhibitory effects on kallikrein, aprotinin reduces FXIIa formation and thus indirectly inhibits the release of tPA.21 Aprotinin has been shown to reduce intra-operative blood transfusion in OLT,47 and its efficacy in both this indication and other types of liver surgery is perhaps best demonstrated by thrombelastography during the surgical procedure.66 Some studies, however, have also shown that aprotinin exerts an anticoagulant, rather than a procoagulant, effect. Its blood-sparing (prohemostatic) efficacy appears to be the overall result of a strong antifibrinolytic and a weaker anticoagulant effect.50 High-dose tranexamic acid has also been shown to significantly decrease intraoperative blood loss during OLT, and to reduce requirements for platelets and cryoprecipitate in randomized controlled clinical trials.14,65,66 Blood and blood products. Bleeding in patients undergoing liver resection or OLT may be also controlled using vitamin K, fresh-frozen plasma, fibrinogen concentrates, and platelet concentrates.14,63 In addition, packed cells can be transfused to replace lost red blood cells (RBCs). The use of autologous transfusion of cell-saver blood has also reduced the need for transfusions.32 This procedure, however, is only useful for those
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patients requiring massive transfusions due to blood loss. Most patients undergoing liver surgery do not require autologous transfusion, and it has proven difficult to accurately predict which patients would benefit from its use.
Pharmacological, Radiological, and Surgical Control of Portal Hypertension Portal hypertension is common in end-stage liver disease, and is frequently complicated by upper gastrointestinal bleeding and ascites.20 It results in the opening up of portosystemic collateral shunts, which are a major cause for bleeding during hepatectomy when they occur around the liver and in the posterior abdominal wall. When not contraindicated, betablockers have proven to be of benefit, and are the pharmacological treatment of choice in reducing portal pressure and thus the risk of variceal rebleeding in these patients.18 Transjugular intrahepatic portosystemic shunt (TIPS) was developed in the 1980s for the treatment of complications associated with portal hypertension.13 Once shown that the shunt could be placed with relative ease, TIPS was widely used for complications such as variceal rebleeding, control of refractory ascites, hepatic hydrothorax, treatment of hepato-renal syndrome, and hepatopulmonary syndrome.13 The procedure has also been used for the treatment of Budd-Chiari syndrome and veno-occlusive disease.13 Although TIPS has provided more effective control of variceal rebleeding and refractory cirrhotic ascites than other available methods, it has not achieved an improvement in long-term survival rates, and is associated with a high incidence of encephalopathy.13 The availability of TIPS, however, has decreased the number of patients requiring surgical portocaval shunts for reduction of perioperative bleeding risk or prevention of portal hypertensionassociated complications.12 The relative advantages of TIPS over surgical decompression of portal hypertension in patients with liver cirrhosis relate to the ability of TIPP to bridge the patient successfully to ultimate OLT, if subsequently indicated, without impacting post-OLT survival. Preservation of the vena cava during OLT and use of the piggyback technique for the donor/recipient cavo-caval anastomosis have gained wide acceptance.26,80 These procedures have eliminated the requirement for extra corporeal veno-venous bypass during the anhepatic phase of OLT. The hemodynamic instability and subsequent increase in portal hypertension that may occur following division of the portal vein upon recipient liver explantation is overcome by the addition of a temporary internal portocaval shunt.26,51 Temporary internal porto-caval
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shunting during OLT is technically easy to perform, and improves hemodynamic status by reducing portal hypertension and gut engorgement. Randomized controlled trials have shown that it also reduces intraoperative transfusion requirements, and preserves renal function both during and after the procedure.26
Anesthesia in Liver Surgery: Methods for Reducing Blood Loss Hemorrhage during hepatic resection usually arises from major hepatic veins or the vena cava. To reduce blood loss, resections are routinely carried out with a controlled central venous pressure that is maintained at ⱕ5 mm Hg using a combination of anesthetic techniques and intraoperative fluid restriction. An intraoperative urine output of 25 mL/h is considered to be the minimum accepted level.22 Should vascular isolation of the liver be necessary, the anesthetic requirements change to incorporate the need to maintain cardiac output during caval cross clamping.22 In the pre-anhepatic stage of OLT, surgical entry into the abdominal cavity may be associated with drainage of large amounts of ascitic fluid, necessitating anticipation and correction of any volume shifts.54 Blood transfusion and manipulation may cause marked defects of coagulation. Tests of coagulation and hematological function are performed frequently during this stage, and any hemostatic deficiencies are corrected. Due to a continued fall in ionized calcium, it may also become necessary to correct calcium levels to maintain the normal range.54 Factors inducing metabolic alterations during the anhepatic phase include progressive academia, base deficit, continued fall in ionized calcium, and hypothermia. The post-anhepatic phase may be complicated by continued bleeding, which is exacerbated by a reperfusion coagulopathy that can be partly attributed to a heparin-like action. This reperfusion coagulopathy can be reversed using protamine sulfate, the use and efficacy of which can be monitored and guided using thrombelastography.3 Perioperative hypothermia is common, and can have a profound physiological effect on the body by worsening pre-existent coagulopathies.23,62 In the anesthetized patient, normal protective reflexes such as shivering are absent, particularly when muscle relaxants are used.8 Maintaining constant ambient temperatures in the operating theatre, infusing warm intravenous fluids, transfusing warm blood and blood products, and the use of warm irrigation and liver flush fluids all help to prevent inadvertent hypothermia. Heat is lost through radiation, convection, and conduction, with conduction having the greatest effect.8 Forced air warmers such as the Bair
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Hugger (Augustine Medical Inc, Eden Prairie, MN) are the most effective means of preventing and treating heat loss, and are used routinely in liver surgery.8 It should also be remembered that the liver is an important source of heat generation, and that a cooled organ is implanted into the recipient at transplantation since the liver is maintained at 4°C during transport and storage.
Recombinant Factor VIIa: A Novel Method to Control Hemostatic Defects in Liver Surgery Recombinant factor VIIa (rFVIIa; NovoSeven威, Novo Nordisk, Bagsvaerd, Denmark) was first developed for the treatment of bleeding in hemophilia patients with inhibitors, and has shown considerable efficacy in this indication.29,37,40 Pharmacological doses of rFVIIa have been found to enhance thrombin generation on activated platelets, and are therefore of further benefit in improving hemostasis in nonhemophilia patients experiencing profuse bleeding and impaired thrombin generation.29 Clinical experience has also shown that treatment with rFVIIa can significantly enhance the hemostatic effect in patients with thrombocytopenia and functional platelet defects.43,61 In addition, rFVIIa has been shown to normalize a prolonged PT in both stable cirrhotic patients7 and in patients with alcoholic cirrhosis and bleeding from esophageal varices.24 The agent has also been used to successfully induce hemostasis during invasive procedures in patients with advanced liver disease,6 and has reduced the need for transfusion of RBCs and plasma during OLT.31
Mechanism of Action of rFVIIa Recombinant FVIIa is thought to exert its prohemostatic effect via enhancement of the extrinsic coagulation pathway in a tissue factor (TF)-dependent manner.77 Approximately 1% of total FVII protein mass is normally present in the circulation in an activated form.53,83 Hemostasis is initiated by the formation of a complex between FVII and TF,68 which is not normally exposed to circulating blood, as it is found on various cells in the deeper layers of the vessel wall. Following injury, TF is exposed to the circulation and forms a complex with FVII or FVIIa.29 Therefore, this mechanism of action of rFVIIa suggests that the induced enhancement of hemostasis is limited to the injury site, without systemic activation of the coagulation cascade.55 An additional mode of action of rFVIIa has also been proposed. Full thrombin generation is necessary for full and effective hemostasis, and this requires the presence of activated platelets that are provided by the initial thrombin formation. In a
recently developed cell-based model, the addition of exogenous rFVIIa in doses of ⱖ50 nmol/L enhances the rate of thrombin generation on activated platelet surfaces independently of TF.34 This produces the full thrombin burst necessary to induce a fully stabilized fibrin plug with a tight structure that demonstrates increased resistance to premature lysis.29 Premature fibrinolysis is also prevented by the formation of thrombinactivatable fibrinolysis inhibitor (TAFI),52 and by the fibrin-stabilizing actions of the coagulation proteins fibrinogen, FXIII, and perhaps other factors important in regulating fibrinolysis.29 These findings imply that rFVIIa has a dual mode of action: a TF-dependent mechanism that “drives” the extrinsic pathway, and a TF-independent binding to activated platelets to induce a substantial burst of thrombin generation. Both mechanisms of action serve to localize rFVIIa activity to the injury site without inducing widespread coagulation. Current evidence, however, indicates that rFVIIa does not possess an additional antifibrinolytic action,45 although this has been disputed.
Use of rFVIIa in Liver Surgery A multinational, randomized, double blind, placebocontrolled trial recently evaluated the hemostatic efficacy and safety of rFVIIa in noncirrhotic patients scheduled to undergo partial hepatectomy due to liver cancer/metastasis and/or benign tumors.46 In total, 204 patients were equally randomized to receive an injection of either 20 or 80 g/kg rFVIIa or placebo. A second dose of rFVIIa was given 5 hours after the start of the operation if the anticipated surgery time exceeded 6 hours. Dosage was based on the drug pharmacokinetics and knowledge of duration of action (Fig 2). Key efficacy parameters included transfusion requirements and blood loss postsurgery.46 The results of this liver resection study suggested that 80 g/kg rFVIIa improved hemostasis, as mea-
Figure 2. rFVIIa titers over time during and after liver resection. Reprinted from Lodge et al46 by permission of Wiley-Liss, Inc, a subsidiary of John Wiley & Sons, Inc. Copyright © 2002, Wiley-Liss, Inc.
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sured by RBC transfusion requirements and blood loss during surgery. Single or repeated administration of rFVIIa at doses up to 80 g/kg did not appear to cause any adverse effects.46 Additional trials are currently being initiated to further investigate the safety and hemostatic effects of rFVIIa in liver resection. Preliminary reports also indicate that rFVIIa significantly reduces transfusion requirements in OLT.30,31,38 A multinational, placebo-controlled, double-blind, randomized study is currently investigating the role of rFVIIa in this indication. The results of this trial, which shares considerable similarity with the liver resection study reported by Lodge et al,46 are eagerly awaited.
Conclusions Liver surgery has evolved from being a high-risk specialty associated with massive perioperative blood loss and high morbidity and mortality, to a safe and widely practiced field. Much of its success can be attributed to a greater knowledge of the anatomy of the biliovascular tree and its common variations. With this improved understanding, more effective and relatively bloodless parenchymal dissection techniques have been developed. Additionally, better understanding of end-stage liver disease and associated coagulopathy has resulted in more successful methods of achieving hemostasis during surgery. Patient optimization and specialist anesthetic management during surgery have also helped to reach this goal. The pre-existing coagulation defects in patients with liver disease are further exacerbated during the operative procedure by factors such as hypothermia, acidosis, increased fibrinolysis, and alterations of factors that enhance and inhibit clotting. This results in significant defects of the clotting mechanism that can be both unexpected and unpredictable. Dynamic methods of monitoring the status of clotting, such as thrombelastography, have thus proved invaluable in patients undergoing liver surgery. Techniques developed for liver resection have also been applied in the field of OLT, facilitating such procedures as split-liver grafts and live-donor transplantations. Increasingly effective management of coagulopathy in OLT has contributed towards its establishment as a routine procedure in the management of end-stage liver disease. Early results from trials using rFVIIa in the management of bleeding during liver surgery are encouraging, suggesting that the potential role of this agent in the management of patients with end-stage liver disease is highly promising for the future of liver surgery. Results from large, ongoing, multicenter trials of rFVIIa use in liver resection and OLT are therefore awaited with great interest.
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