CONTROVERSIES IN LIVER TRANSPLANT COAGULATION MANAGEMENT

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1 Clinical Coagulation Monitoring in OLT 655 intraoperative hypothermia, goal-directed transfusion, and routine application of aprotinin the median blood loss in primary transplants in this series was 6Uofpacked red cells (range, U) and 8 U of fresh frozen plasma (range, U). Despite these comparatively low transfusion needs, we still see a negative correlation between blood loss and posttransplantation survival: patients who needed more than 9 U of red blood cells intraoperatively had an actual 1-year survival of 86.1% compared with those who needed up to 9Uofred blood cells (75%) intraoperatively and had a 1-year actual survival of 92% (P.034). Finally, a word of caution: despite the optimism generated by new opportunities with pharmacological intervention, surgical skill and experience are probably still the strongest predictors of blood loss in liver transplantation. References 1. Mor E, Jennings L, Gonwa TA, Holman MJ, Gibbs J, Solomon H, et al. The impact of operative bleeding on outcome in transplantation of the liver. Surg Gynecol Obstet 1993;176: Gerlach H, Slama KJ, Bechstein WO, Lohmann R, Hintz G, Abraham K, et al. Retrospective analysis of coagulation parameters after 250 liver transplantations. Semin Thromb Hemost 1993;19: Ellis AJ, Hughes RD, Wendon JA, Dunne J, Langley PG, Kelly JH, et al. Pilot-controlled trial of the extracorporeal liver assist device in acute liver failure. Hepatology 1996;24: Mammen EF. Coagulopathies of liver disease. Clin Lab Med 1994;14: Porte RJ, Bontempa FA, Knot EAR, Lewis JH, Kang AG, Starzl TE. Systemic effects of tissue plasminogen activator associated fibrinolysis and its relation to thrombin generation on orthotopic liver transplantation. Transplantation 1985;48: Himmelreich G, Jochum M, Bechstein WO, Machleidt W, Neuhaus P, Slama KJ, et al. Mediators of leucocyte activation play a role in disseminated intravascular coagulation during orthotopic liver transplantation. Transplantation 1994;57: Kang Y. Clinical use of synthetic antifibrinolytic agents during liver transplantation. Semin Thromb Hemost 1993;19: Neuhaus P, Bechstein WO, Lefebre B, Blumhardt G, Slama K. Effect of aprotinin on intraoperative bleeding and fibrinolysis in liver transplantation. Lancet 1989;2: Bechstein WO, Riess H, Neuhaus P, Himmelreich G, Steffen R, Slama KJ, et al. The effect of aprotinin on blood product requirements during orthotopic liver transplantation. Clin Transplant 1991;5: Boylan JF, Klinck JR, Sandler AN, Arellano R, Greig PD, Nierenberg H, et al. Tranexamic acid reduces blood loss, transfusion requirements, and coagulation factor use in primary orthtopic liver transplantation. Anesthesiology 1996;85: Douning LK, Ramsay MA, Swygert TH, Hicks KN, Hein HA, Gunning TC, et al. Temperature corrected thromelastography in hypothermic patients. Anesth Analg 1995; 81: Gerlach, Rossaint R, Bechstein WO, Blumhardt G, Neuhaus P, Falke K. Goal-directed transfusion management leads to a distinct reduction of fluid requirement in liver transplantation. Semin Thromb Hemost 1993;19: CONTROVERSIES IN LIVER TRANSPLANT COAGULATION MANAGEMENT Controversy I Does Transfusion That Is Based on Clinical Coagulation Monitors Reduce Hemorrhage During Liver Transplantation? Transfusion Based on Clinical Coagulation Monitoring Does Reduce Hemorrhage During Liver Transplantation Difficulty in management of coagulation and bleeding control has been recognized since the early era of liver transplantation, as described by Sir Roy Calne, Surgeons have long recognized bleeding as a major impediment to successful completion of an operation. In liver transplantation this observation is particularly true. In the last 123 transplants, ten From the Department of Anesthesiology/Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA. Address reprint requests to, M.D., Department of Anesthesiology, Presbyterian-University Hospital (#C-221), Pittsburgh, PA Copyright 1997 by the American Association for the Study of Liver Diseases /97/ $3.00/0

2 656 patients returned to theater for management. 1 The bleeding complication is caused by the difficult dissection through the fragile and dilated collateral vessels in the presence of portal hypertension and coagulopathy associated with impaired production of coagulation factors and excessive activation of coagulation and fibrinolysis. 2,3 Therefore, most clinicians in the liver transplantation field agree that some form of coagulation monitoring is necessary to identify the presence of coagulopathy and to select the proper therapeutic mode. In this presentation, the concept and significance of monitoring clinical coagulation are described. Figure 1. Hypothetical relationship between blood coagulability and coagulation profiles. Figure 2. Blood coagulability and coagulation profiles during liver transplantation. Solid circles represent a hypothetical patient without coagulation monitoring and therapy, and open circles represent a patient with monitoring of coagulability and treatment. Monitoring of Clinical Coagulation The goals of coagulation monitoring, identical to those of other organ systems, are identification of clinically significant pathological states, guiding of appropriate therapy, and confirmation of the effectiveness of the therapy. In addition, coagulation monitoring should help achieve the goal of coagulation therapy: maintenance of blood coagulability with minimal blood products and pharmacological agents to avoid bleeding diathesis and thrombosis. Traditionally, coagulation has been monitored by analytical quantitative coagulation studies, and normalization of coagulation profiles has been considered the goal of coagulation therapy. In the clinical setting, however, assessment of blood coagulability, defined as the formation of solid blood clots within a reasonable time followed by a natural fibrinolytic process, is more important than determination of coagulation profiles. The hypothetical relationship between blood coagulability and coagulation profiles is shown in Figure 1. Normal blood coagulability is expected in patients with normal coagulation profiles and is well maintained until coagulation profiles or coagulation factors gradually decrease to the critical level. This is indirectly observed in hemophiliac patients in whom normal hemostasis occurs unless factor VIII levels fall below 30% of normal. 4 However, blood coagulability is impaired rapidly and becomes a clinical concern once coagulation factor levels decrease below this critical level. If this relationship exists, normal blood coagulability can be achieved by specific coagulation therapy, allowing the coagulation profiles to remain above the critical level. Therefore, normal blood coagulability does not necessarily indicate normal quantity or activity of coagulation factors, and the reverse is true: hypothermia and hypocalcemia impair clotting even with normal coagulation profiles. This concept can be extended to patients undergoing liver transplantation (Fig. 2). Coagulability and coagulation profiles of untreated patients deteriorate rapidly by dilution, heparin effect, fibrinolysis, excessive coagulation, hypocalcemia, and hypothermia and recover gradually once the grafted liver begins to function. Open circle indicates those of monitored and treated patients: decreased coagulability is improved to above the critical level by selective administration of minimal amount of blood products and pharmacologic agents, and by normalization of physical and chemical environment. Mode of Clinical Coagulation Monitoring Unfortunately, determination of blood coagulability is not an easy task: all coagulation tests except for bleeding time is performed in vitro, and differentiation between medical and surgical bleeding can be very difficult. Conventional coagulation profiles, including

3 Clinical Coagulation Monitoring in OLT 657 simple coagulation profiles (prothrombin time [PT], activated partial thromboplastin time [aptt], platelet count, fibrinogen level, and euglobulin lysis time) and complete coagulation profiles with assays of coagulation factors and specific proteins of coagulation, play an important role in characterization of the pathophysiology of coagulation. However, conventional coagulation profiles have drawbacks when used for clinical coagulation monitoring. PT is the most sensitive test for hepatic synthetic function, and aptt is useful for identification of the heparin effect that occurs on reperfusion. PT and aptt are frequently prolonged during liver transplantation, and their reversal to normal values by use of large volumes of fresh-frozen plasma (FFP) may not be feasible or desirable. Platelet count is an important test, but platelet dysfunction cannot be identified. Fibrinogen levels are usually high in patients with liver disease, although they can reach a very low level in the presence of active fibrinolysis or consumption coagulopathy. However, dysfibrinogenemia that occurs in patients with liver disease cannot be identified. Factor assays and specific coagulation tests were used in the past, but their clinical value does not appear to be significant. For example, an increase in the thrombin-antithrombin complex level was considered to be an indicator of excessive activation of coagulation, but administration of antithrombin III neither decreases the thrombinantithrombin complex level nor reduces transfusion requirements. 5 Most of all, conventional coagulation profiles are time consuming and expensive, and test results are difficult to relate to blood coagulability. Sonoclot evaluates the physical properties of blood clots in a real-time fashion. Its drawbacks are that it measures changes in blood viscosity instead of strength of fibrins and does not allow observation of the progress of clot formation as blood begins to evaporate during the test. Thrombelastography (TEG) measures the elastic property of fibrins from its formation to complete dissolution and, together with platelet count, has been used to monitor coagulation at the University of Pittsburgh Medical Center with a reasonable degree of satisfaction for the past 15 years. Monitoring of Clinical Coagulation by TEG TEG appears to be nearly the ideal coagulation monitoring system, indicating blood coagulability on the surgical field. Deficiency of coagulation factors, hypocalcemia, hypothermia, and heparin effect are seen as a prolonged reaction time and slow clot-formation rate. 6 Thrombocytopenia is seen as a small maximum amplitude and prolonged reaction time and slow clot formation rate, because platelet function is essential to the progress of coagulation cascade. Hypofibrinogenemia is recorded as a relatively normal reaction time with a slow clot-formation rate. In patients with fibrinolysis, a prolonged reaction time, slow clot-formation rate, and small maximum amplitude are accompanied by a gradual decrease in amplitude to zero because the net amount of fibrin is reduced in the presence of active digestion of fibrins. Excessive activation of coagulation is seen as a very short reaction time and rapid clot-formation rate followed by generalized deterioration of all variables of the subsequent TEGs as consumption coagulopathy develops. Further definitive diagnosis of coagulopathy is made by comparison of multiple channels of TEG. For example, comparison between TEG of untreated blood (0.36 ml) and that of blood treated with FFP (0.03 ml of FFP in 0.33 ml of whole blood) elucidates the presence of coagulation factor deficiency and beneficial effects of FFP administration. A similar comparison can be made by comparing TEG results for blood treated with blood products (platelets and cryoprecipitate) and pharmacological agents ( -aminocaproic acid, protamine sulfate, aprotinin, DDAVP, etc.). 7,8 In addition, the effects of physical (hypothermia) and chemical properties (hypocalcemia) on coagulation can be demonstrated clearly by TEG. 9 Response to Clinical Coagulation Monitoring Most liver transplantation centers institute coagulation therapy based on coagulation monitoring of one type or another. It is noteworthy most centers administer close to one-to-one ratio of red blood cells (RBCs) and FFP, regardless of the type of monitoring, because continuous infusion of FFP is necessary to compensate for the rapid decrease in coagulation factors in the presence of excessive activation of coagulation and fibrinolysis. Coagulation therapy based on conventional techniques is somewhat vague and varies from institution to institution: RBCs to maintain hematocrit above 27 to 30 vol%, FFP to maintain PT less than 1.2 to 1.5 international normalized ratio, and platelets to keep the count above 50,000 to 100,000/ mm 3, -aminocaproic acid for oozing or prophylaxis of fibrinolysis, and aprotinin for prophylaxis

4 658 of fibrinolysis. TEG-based coagulation therapy at the University of Pittsburgh is administration of a fluid mixture of RBC, FFP, and crystalloids (300: 200:250 ml) for volume replacement, platelets for maximum amplitude of 40 mm, cryoprecipitate for persistent poor clot-formation rate even after the correction of thrombocytopenia particularly in the presence of fibrinolysis, and additional FFP for persistent prolonged reaction time ( 12 minutes) even after the administration of platelets and cryoprecipitate. In addition, protamine sulfate (25 to 50 mg) or -aminocaproic acid (250 to 500 mg) is administered when heparin effect or fibrinolysis is present by observation of improved coagulability in blood treated with protamine sulfate or -aminocaproic acid, respectively. 7,10 Timely antifibrinolytic therapy appears critical in coagulation therapy; it reduces blood loss without thrombotic complications and avoids selective destruction of factors I and VIII by plasmin. Does Coagulation Monitoring Reduce Bleeding? Does coagulation monitoring reduce bleeding and improve coagulation during liver transplantation? This is a very difficult question because no literature has compared blood loss based on the presence or the type of coagulation monitoring in a double-blind fashion. Furthermore, comparison of blood loss may not have scientific merit in liver transplantation because blood loss can depend largely on the type and severity of liver disease, surgical technique, technical skill of surgeons, and graft function, to name a few. However, indirect evidence suggests that coagulation monitoring is clinically beneficial. Kang et al 10 claim that blood transfusion requirements decreased significantly in patients monitored by TEG compared with historic controls. However, reduction in blood loss in their patients could have been attributable to improved surgical technique and intraoperative patient care. Other indirect evidence is found in the progressive reduction of blood loss in all liver transplantation centers to approximately 10 units of RBCs and FFP. Again, improved surgical technique, anesthetic management, and organ preservation could have played an equally important role. Does coagulation monitoring reduce bleeding during liver transplantation? I believe it does. It is similar to the invasive hemodynamic monitoring that clearly helps detect and treat pathological rhythm, preload, contractility, wall motion, and afterload of critically ill patients, although its clinical benefit has not been shown in a scientific manner. Monitoring of clinical coagulation, not laboratory coagulation, should be an essential tool in treatment of patients with severe liver disease because (1) it helps differentiate medical bleeding from surgical bleeding, (2) timely administration of blood products together with appropriate pharmacological agents should maintain acceptable blood coagulability, (3) maintenance of blood coagulability minimizes surgical hemostasis time to improve graft perfusion, (4) excessive administration of blood products based on clinical impression can be avoided to minimize transfusion-related complications and health care costs, and (5) prophylactic administration of a large dose of pharmacological agents can be avoided to prevent thrombotic or other complications. This view is supported by the most experienced surgeons in this field: Although this (coagulation) information was available, it was not acted upon systematically for therapeutic correction of until the anesthesiologists at the University of Pittsburgh did so in the early 1980s....Nowcautious correction of coagulation defects is an integral part of liver transplantation, greatly diminishing the hemorrhage of nightmare proportions that were common, according to Thomas Starzl, 11 and Control of bleeding... not only brought down the need for blood products... but also had a positive influence on the rates of surgical, immunologic, and infectious complications. A new understanding of coagulation disorders in cirrhosis, the anhepatic stage, and reperfusion have allowed more specific therapy of these conditions. Blind substitution and replacement policies have been exchanged for very specific measures according to intraoperative clotting analysis. An important step forward was made with the use of pharmacologic agent to prevent fibrinolysis, according to Peter Neuhaus. 12 References 1. Calne RY. Management of bleeding. In: Calne RY, ed. Liver transplantation: The Cambridge/King s College Hospital experience. Grune & Stratton, 1983: Groth CG, Pechet L, Starzl TE. Coagulation during and after orthotopic transplantation of the human liver. Arch Surg 1969;98: Lewis JH, Bontempo FA, Awad SA, Kang YG, Kiss JE, Ragni MV, et al. Liver Transplantation: Intraoperative changes in coagulation factors in 100 first transplants. Hepatology 1989;9: Kasper CK, Dietrich SC. Comprehensive management of hemophilia. Clin Hematol 1985;14: Coccheri S, Palareti G. Antithrombin III replacement in

5 Coagulation Techniques During OLT 659 orthotopic liver transplantation. Semin Thromb Hemost 1993;19: Kang YG. Monitoring and treatment of coagulation. In: Winter PM, Kang YG, eds. Hepatic transplantation anesthetic and perioperative management. Philadelphia: Praeger, 1986: Kang YG, Lewis JH, Navalgund A, Russell MW, Bontempo FA, Niren LS, et al. Epsilon-aminocaproic acid for treatment of fibrinolysis during liver transplantation. Anesthesiology 1987;66: Kang Y, Scott V, DeWolf A, Roskoph J, Aggarwal S. In vitro effects of DDAVP during liver transplantation. Transplant Proc 1993;25: Douning LK, Ramsay MAE, Swygert TH, Hicks KN, Hein HAT, Gunning TC, et al. Temperature corrected thrombelastography in hypothermic patients. Anesth Analg 1995;81: Kang YG, Martin DJ, Marquez J, Lewis JH, Bontempo FA, Shaw BW Jr, et al. Intraoperative changes in blood coagulation and thrombelastographic monitoring in liver transplantation. Anesth Analg 1985;64: Starzl TE. Human trials. In: Starzl TE, Groth CG, Makowka L, eds. Clio. Chirurgica. Liver transplantation. Austin: Silvergirl, 1988: Neuhaus P. Hemostasis in liver transplantation: The surgeon s view. Semin Thromb Hemost 1993;19:183. Controversy I (continued): Coagulation Techniques Are Not Important In Directing Blood Product Transfusion During Liver Transplantation Matthias Reyle-Hahn and Rolf Rossaint Preoperative acquired clotting parameters such as prothrombin time, activated partial thromboplastin time, antithrombin III, platelet concentration, and fibrinogen show coagulopathy caused by insufficiency of the diseased liver. Intraoperative determination of clotting factors or parameters is not helpful to direct intraoperative transfusion of blood, blood components, or platelets because transfusions performed solely for correction of clotting data do not correlate with the real intraoperative requirements and increase the costs of orthotopic liver transplantation. However, the use of antihyperfibrinolytic drugs seems to reduce intraoperative blood loss. Patients with cirrhotic disorders caused by portalvenous hypertension show extensive collaterals and increased intravascular blood volume. Thus it is plausible that especially overcorrection of blood loss during the surgical preparation in the preanhepatic phase of the operation results in extensive blood loss. Therefore, to avoid blood loss we attempt to keep volume substitution to a minimum during the preanhepatic phase of the operation. In contrast, during the anhepatic and postanhepatic phases we attempt to reestablish normovolemia by transfusing red packed blood cells and fresh-frozen plasma. Strictly confined use of blood products in the preanhepatic phase, followed by later correction of intravascular blood volume, may reduce intraoperative blood loss; it also seems to ensure adequate substitution of clotting factors. Copyright 1997 by the American Association for the Study of Liver Diseases Atypical requirement of orthotopic liver transplantation (OLT) is the need for extensive transfusion of blood components such as packed red blood cells (RBC), fresh-frozen plasma (FFP), random donor platelets (RDP), cryoprecipitates and/or purified clotting factors (antithrombin III [AT III], fibrinogen, prothrombine complex), and albumin. The role of routine preoperative screening in OLT is the subject of much debate. Most patients with acute or chronic liver insufficiency have a reduced capacity to produce clotting factors and commonly demonstrate thrombopenia. 1 It is common sense that prothrombin time (PT), activated partial thromboplastin time (aptt), AT III, platelets, and fibrinogen should be measured before the start of the surgical procedure to quantify the degree of coagulopathy. In addition, some authors advocate preoperative determination of platelet function by thromboelastography (TEG). 2-5 However, no study shows that knowledge or even preoperative correction of preexisting coagulopathies is associated with a reduced intraoperative blood transfusion requirement. In contrast, our own group was able to show that there was a significant correlation between the cause of liver disease and preoperative clotting parameters but From the Klinik für Anaesthesiologie und operative Intensivmedizin Virchow-Klinikum der Humboldt-Universität, Berlin, Germany. Address reprint requests to Matthias Reyle-Hahn, M.D., Clinic for Anaesthesiology and Intensive Care Medicine, Virchow University Clinic, Humboldt University of Berlin, Augustenburger Platz 1, Berlin, Germany. Copyright 1997 by the American Association for the Study of Liver Diseases /97/ $3.00/0