Coagulation and Liver Transplantation Yoogoo Kang, MD Paul Audu, MD

Liver transplantation is frequently complicated by hemostatic defects associated with end-stage liver disease, surgical bleeding, and the grafted organ recovering from ischemia and reperfusion injury. Management of hemostatic defects in patients undergoing liver transplantation, therefore, requires a thorough understanding of pathophysiology of coagulation, clinically relevant assessment of coagulation, and the selection of rational treatment modes. ’

Pathophysiology of Coagulation in End-state Liver Disease

Hemostasis, a vital homeostatic function, is the process by which blood in a liquid state is transformed into a solid state, then back to a liquid state. The vascular endothelium, platelets, and coagulation proteins participate, simultaneously and interdependently, in 5 equally important phases, namely the vascular phase, the platelet phase, the fibrin formation phase, the fibrin polymerization phase, and the fibrinolysis phase. Liver disease affects all 5 phases of coagulation.1 The vascular phase of coagulation is impaired by peripheral vasodilation, development of numerous collateral vessels, reduced vascular constrictive response and elasticity, and decreased interaction between vessel walls and platelets, and is seen as prolonged bleeding time.2 The platelet phase is also significantly affected in most patients. Thrombocytopenia is observed in up to 70%,3 and is caused by splenomegaly, shortened platelet survival, platelet consumption, sequestration of platelets in the regenerating liver, the folic acid deficiency in alcoholic liver disease, and toxic effects of alcohol on megakaryocytes. Platelet dysfunction is also revealed by the prolonged bleeding time in the presence of adequate platelet count and diminished clot retraction.4 The coagulation cascade is affected at all levels, because production of most proteins involved in coagulation is 17

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impaired. They are coagulation factors (I, II, V, VII, VIII, IX, X, XI, XII, XIII, Fletcher, Fitzgerald, prekallikrein, plasminogen, and highmolecular-weight kininogen), inhibitors (AT-III and a1-antitrypsin), and regulatory proteins (C1 inhibitor and a2-macroglobulin). The fibrinogen level is generally normal or increased. An excessive sialic acid content in the fibrinogen molecule, however, results in dysfibrinogenemia and prolongs thrombin time (TT) by interfering with polymerization of fibrin.5,6 The level of factor VIII is frequently increased owing to its enhanced production at the enlarged vascular bed and to the increased level of von Willebrand factor (vWF) antigen.7 On the contrary, low levels of proteinases with antithrombin activity (AT-III and a1-antitrypsin) and regulatory proteins (C1 inhibitor and a2macroglobulin) may result in thrombosis. Fibrin polymerization is impaired by low levels of factor XIII and dysfibrinogenemia. The fibrinolytic system is also affected either by reduced levels of proteases involved in fibrinolysis (plasminogen, protein C, protein S, and a2antiplasmin) or by increased level of tissue plasminogen activator (tPA) released from the enlarged vascular bed. Consequently, all forms of coagulopathy may develop depending on the net balance between procoagulants and their inhibitors and prolysins and their inhibitors. The hypocoagulable state is caused by impaired hepatic synthesis of procoagulants and quantitative and qualitative defects of platelets. Fibrinolysis may develop when a large quantity of tPA is produced from the enlarged vascular bed, production of fibrinolysis inhibitors (a2-antiplasmin and histidine glycoprotein) is insufficient, or the hepatic clearance of tPA is reduced.8 On the other hand, decreased activity of coagulation inhibitors or fibrinolysins may cause thrombotic condition. Excessive activation of coagulation or impaired hepatic clearance of activated coagulation factors may lead to thrombosis or disseminated intravascular coagulation.

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Coagulation During Liver Transplantation

The complex, dynamic nature of coagulation during liver transplantation was well described in the early experience of liver transplantation in the 1960s: ‘‘There was an intraoperative bleeding diathesis, and at the same time fibrinolysis and hypofibrinogenemia developed. In 4 of the cases, the hemorrhage was eventually controlled after the administration of e-aminocaproic acid (EACA), fibrinogen, and fresh blood. Subsequently, 3 of 4 survivors formed thrombi at or near femoral venotomy sites which had been used for the insertion of external bypass catheters; in all 3, the eventual result was multiple pulmonary embolization.’’9 They concluded that liver transplantation ‘‘can cause hyperfibrinolysis, thrombocytopenia, and depression of

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various clotting factors; that the extent of these changes are prognostic inasmuch as they are proportional to the magnitude of liver injury; and that the depression of clotting is not necessarily succeeded by hypercoagulability if thrombogenic agents are not administered.’’10 This observation has been confirmed by more recent clinical investigations and summarized in Table 1.3,11,12 During the dissection stage, preexisting coagulopathy is compounded by dilutional coagulopathy as surgical bleeding depletes coagulation proteins and platelets. Bleeding complication is more common and severe in patients with hepatocellular disease, portal hypertension, previous upper abdominal surgery, and chronic steroid therapy. Vascular injury together with impaired clearance of activated coagulation factors caused by decreased hepatic blood flow may result in excessive activation of coagulation and consumptive coagulopathy. Consequently, generalized coagulopathy may be observed, even in the presence of continuous infusion of coagulation factors-rich blood products (Fig. 1). Inadvertent hypothermia and ionized hypocalcemia may also impair coagulation. Fibrinolysis may begin to develop in patients with severe hepatocellular disease or requiring a massive blood transfusion. More significant changes occur during the anhepatic stage. The heparin effect may be observed when heparin solution (2000 to 5000 units of heparin) is used in the venovenous bypass system, and Table 1.

Coagulopathy During Orthotopic Liver Transplantation

Stage

Coagulopathy

Dissection

Preexisting coagulopathy Dilution Fibrinolysis (mild) Ionized hypocalcemia Dilution

Anhepatic

Heparin effect (with venovenous bypass) Fibrinolysis (moderate) Intravascular coagulation Hypothermia Ionized hypocalcemia Fibrinolysis (severe)

Early Neohepatic

Heparin effect Intravascular coagulation Dilution Hypothermia Ionized hypocalcemia

Late Neohepatic

Gradual recovery

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U/mL

1.5

Anhepatic Stage

2.0

1.0 VIII XII 0.5

I VII V

0 Time

Figure 1. Intraoperative changes in coagulation factors. The levels of coagulation factors decrease during the anhepatic stage and reaches nadir immediately reperfusion even with the administration of coagulation factors-rich blood (RBC:FFP:crystalloids = 300:200:250 mL). Normal baseline factor VIII level decreases rapidly during the same period, most likely from activation of fibrinolytic system. Modified with permission from Hepatology. 1989;9:710–714.

dissipates within 30 to 60 minutes. Surgical bleeding and the absence of the hepatic synthetic and clearance function further deplete platelets and coagulation factors. The release of tissue thromboplastin and the absence of the hepatic clearance of activated coagulation factors may cause excessive activation of coagulation, and this is observed by gradual increases in thrombin-antithrombin-III complex (TAT) and fibrin degradation products (FDPs).13 However, clinically significant intravascular coagulation or thrombosis is uncommon during this period. Fibrinolysis, caused by the release of tPA and the absence of its hepatic clearance, is seen in about 20% of patients (Fig. 2). Severe coagulopathy, a component of the postreperfusion syndrome, occurs on reperfusion of the grafted liver, and it is observed as prolonged prothrombin time (PT), activated partial thromboplastin time (aPTT), reptilase time (RT), and TT, thrombocytopenia, a decrease in coagulation factor levels including factors I, V, VII, and VIII, a

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70

tPA activity (IU/mL)

60 50 40

Anhepatic stage

80

30 20 10 0

Minimal fibrinolysis (n=7)

Severe fibrinolysis (n=13)

Figure 2. Intraoperative changes in tPA level of patients with and without fibrinolysis. Intraoperative levels of tPA activity (mean + SEM) is much higher in patients with severe fibrinolysis (solid circles, n = 13) compared to those with minimal fibrinolysis (open circles, n = 7). Modified with permission from Transplantation. 1989;47:978–984.

sudden increase in tPA, a shortened euglobulin lysis time, and a moderate increase in FDP and TAT.13–15 The cause of the postreperfusion coagulopathy is multifactorial. The release of endogenous heparin from the grafted liver results in moderate to severe heparin effect and may last for 60 to 120 minutes. Other coagulation inhibitors or heparin-like substance may also play a role.16 Fibrinolysis occurs in approximately 80% of patients, although clinically significant fibrinolysis and bleeding are observed in about 40% of patients.14 It is caused by the massive release of tPA from the grafted liver, congested viscera and lower extremities together with the reduced plasminogen activator inhibitor activity,17 contact activation of fibrinolysis, and activation of protein C or urokinase-type plasminogen activator.18 Fibrinolysis is most likely primary in origin because of its association with high tPA level, a relatively steady level of AT-III,19 only moderate increases in FDP and D-dimers,14 a selective decrease in factors I, V, and VIII,12 the effectiveness of EACA without complications,14 and no known microembolization. Fibrinolysis is seen as shortened euglobulin lysis time (as short as 0 to 15 min), a very high level of tPA, a prolonged reaction time, and short fibrinolysis time in thromboelastography (TEG). Fibrinolysis dissipates gradually within the next 2 hours if the grafted liver begins to function. Excessive activation of coagulation with secondary fibrinolysis may also contribute to postreperfusion coagulopathy and is observed as high

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levels of TAT complex, FDP, and fibrin monomers, and low levels of AT-III and plasminogen activator inhibitor. This phenomenon seems to be caused by tPA-induced platelet activation20 or the release of lysosomal proteinases from macrophages (cathepsin B) and granulocytes (elastase),21 and may induce consumption coagulopathy, venous thrombosis, or pulmonary thromboembolism.22 In a clinical study, transesophageal echocardiography revealed a significant pulmonary thromboembolism (>0.5 cm in diameter) within 60 seconds of reperfusion in 59% of patients without venovenous bypass and 11% of patients with venovenous bypass.23 Gologorsky et al24 reported 6 patients who developed clinical signs or echocardiographically visible intracardiac thrombi or pulmonary embolism and speculated that the complication could have been associated with ischemic damage of endothelium, release of lysosomal proteinases from activated macrophages and platelets, or low AT-III level. Fortunately, fatal pulmonary embolism occurs rarely, possibly due to the simultaneous activation of fibrinolysis. Platelet defects may play a significant role in most patients. The transhepatic gradient of platelet count is as much as 55%, and may be caused by extravasation of platelets into Disse spaces in the perisinusoidal region or phagocytosis by Kupffer cells.25 Platelet function can be impaired by the loss of granulation and impaired platelet aggregation. Reperfusion hypothermia (by 1to 21C), dilutional coagulopathy, unknown coagulation inhibitors released from the grafted liver, and ionic hypocalcemia may also interfere with coagulation. Coagulopathy improves gradually as the grafted liver begins to function. Fibrinolysis and the heparin effect dissipate gradually within 2 hours, and the levels of coagulation factors and platelet count increase toward baseline levels at the end of surgery.3 However, bleeding or oozing may persist in some patients. Bleeding with persistent coagulopathy may be caused by either insufficient replacement therapy or poorly functioning graft liver.22,26 Bleeding with persistent low levels of factors I, V, and VIII is a complication of fibrinolysis as plasminogen and plasmin selectively destroys these factors.12 Delayed bleeding or oozing in the presence of an acceptable coagulation profile and TEG may occur approximately 1 to 2 hours after reperfusion. This is frequently caused by the loss of defective clots formed in the presence of dilutional coagulopathy or gradual digestion of clots containing fibrin-plasmin complex. No specific treatment is effective, and bleeding complication dissipates within 60 to 90 minutes once new clots are formed at the injured vessels. Postoperatively, levels of coagulation factors and platelet count increase steadily toward normal values. In patients with a poorfunctioning graft, however, severe coagulopathy may persist.

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Assessment and Monitoring of Coagulation

Although a variety of conventional laboratory tests are performed to identify the type and severity of the coagulation disorder, most tests have limited application during liver transplantation. PT measures the time to form the initial clot after tissue thromboplastin is added to the recalcified, citrated blood specimen, and is an expression of the extrinsic pathway. Clinical use of PT is limited during liver transplantation, because it, being the most sensitive hepatic synthetic function test, is prolonged in most patients during surgery. aPTT measures the time to form the initial clot after phospholipid, calcium, and a contact activator (kaolin or silica) are added to the recalcified, citrated specimen and reflects the activity of the intrinsic and common pathways. Although it is sensitive in monitoring heparin activity, its clinical application in liver transplantation is limited as its intraoperative changes are similar to those of PT. TT measures the time to form the initial clot after thrombin is added to the recalcified, citrated specimen. It is prolonged in hypofibrinogenemia, dysfibrinogenemia, and in the presence of thrombin inhibitors, such as heparin and FDPs. The RT is a modification of the TT. Reptilase, like thrombin, cleaves fibrinogen, but the cleavage fragments can spontaneously polymerize even in the presence of FDPs. Additionally, reptilase is unaffected by AT-III and heparin. An abnormal TT with a normal RT suggests the presence of a thrombin inhibitor. The Bleeding Time is a sensitive test of platelet dysfunction as long as platelet count is greater than 100,000/mm3. Therefore, simultaneous determination of platelet count is important in interpretation of bleeding time. It is also prolonged in patients with anemia, severe hypofibrinogenemia, and vascular defects. It is labor intensive, and results may vary depending on the test site, technical expertise, and age and sex of the patient. Platelet Aggregometry measures platelet aggregation induced by adenosine diphosphate, thrombin, and collagen. Flow Cytometry uses monoclonal antibodies to determine platelet surface receptor density. The Platelet Function Analyzer evaluates primary hemostasis by measuring the time required for whole blood to occlude an aperture in the test cartridge membrane that is coated with platelet agonist. It is reported to be a simple, reliable, and reproducible platelet function test.27 The Activated Clotting Time measures the time to form the initial clot after an activator (kaolin or diatomaceous earth) is added to whole blood at 371C. It monitors clot formation by the intrinsic pathway and is reliable, even when a large dose of heparin is given during cardiopulmonary bypass. The conventional coagulation profile described above, however, has several drawbacks to be used for clinical coagulation monitoring. It does not assess blood coagulability, has poor correlation with clinical bleeding, and requires laboratory facility. Common perioperative coagulation tests

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(PT, aPTT, fibrinogen level, and platelet count) are poor screening tools for surgical population and do not per se predict the risk of bleeding.28,29 In patients undergoing liver transplantation, PT does not have significant relationship with the fresh frozen plasma (FFP) use, and aPTT does not predict the perioperative RBC requirement.30 TEG

TEG, developed in the 1950s, was introduced to the clinical arena only recently.3 It continuously measures the shear elasticity of fibrins formed in the fresh whole blood, including the interaction of all cellular and noncellular elements involved in coagulation, and has been shown to be effective in monitoring clinical coagulation during liver transplantation,3 cardiac surgery, and other major surgical procedures.31 Its technical aspects have been extensively reviewed.32,33 Briefly, a small quantity of fresh whole blood (0.36 mL) is placed into a cuvette (371C) and a central pin suspended by a torsion wire is lowered into the blood specimen (Fig. 3). The cuvette rotates with a 4.5 angle in either direction at every 4.5 seconds with a 1 second midcycle oscillatory pause. When the blood remains in a fluid state, the pin is stationary. As clot begins to form, elastic force of fibrin strands attached to the pin and the cuvette couples them, and oscillatory movement of the cuvette is subsequently transmitted to the pin. The torque applied to the pin is plotted against time and displayed graphically or, digitally on a computer screen (Hemoscope, Skokie, IL). Most commonly, the recording should begin

4.5o

37oC

Figure 3. Schematic diagram of thromboelastography.

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α

r

MA

A60

20 min 60 min

r+k 4 min

T

F

Figure 4. Typical thromboelastographic variables and normal values. r indicates reaction time —6 to 8 minutes; r + k, coagulation time —10 to 12 minutes; a, clot formation rate —>50 degrees; MA, maximum amplitude —50 to 70 mm; A60, amplitude at 60 minutes after MA; A60/MA100, fibrinolysis index —>85%; F, fibrinolysis time —>300 minutes. With permission from Hepatic Transplantation: Anesthetic and Perioperative Management. New York: Praeger; 1986:154.

exactly 4 minutes after blood sampling when done at the bedside, or 4 minutes after recalcification when the sample is collected in a citrated tube for TEG testing in a remote laboratory facility. The reaction time (r) is the latency period between the initiation of the recording and measurable fibrin formation (amplitude of 2 mm) (Fig. 4). The clot formation time (k) begins from the initiation of clot formation (amplitude of 2 mm) to the point where shear elasticity reaches the amplitude of 20 mm. r and k are prolonged in patients with coagulation factor deficiency, in the presence of anticoagulants, hypothermia and hypocalcemia. The alpha angle (a) measures the rate of clot formation and is a function of coagulation proteins and/or platelets. Maximum amplitude (MA) is affected by platelet function and fibrinogen concentration. The time interval between the MA and subsequent zero amplitude is the fibrinolysis time (F). The amplitude 60 minutes after MA (A60) is used to determine the fibrinolysis index (A60/MA. 100). A fibrinolysis index of less than 85% indicates fibrinolysis. Attempts have been made to compare TEG variables with conventional coagulation tests.34 r and k times correlate with aPTT, and amplitude (A) with the clot strength or shear elastic modulus, G [G (dynes/cm – 2) = (5000A)/ (100 – A)]. A positive relation between MA and platelets and fibrinogen has been demonstrated.35 However, a strong positive relation between conventional coagulation tests and TEG variables is unlikely, because TEG variables are determined by combined effects of proteases, cellular components, and other chemical elements. TEGs of various clinical conditions are shown in Figure 5.36 A normal TEG pattern is characterized by an initial latency period, followed by a gradual increase in fibrin shear elasticity or amplitude that reaches MA within 30 to 60 minutes. The fibrinolysis index remains above 85%. Deficiency of coagulation factors (eg, hemophilia),

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Hemophilia Normal

Thrombocytopenia

Fibrinolysis Hypercoagulation

Figure 5. Thromboelastographic patterns of normal and disease states. With permission from Hepatic Transplantation: Anesthetic and Perioperative Management. New York: Praeger; 1986:155–173.

hypocalcemia, hypothermia, and heparin effect are seen as a prolonged reaction time and slow clot formation rate. MA, however, is within the normal range, because normal clot formation occurs once greater than the critical level of factor X is activated. Thrombocytopenia is seen as small MA. In addition, reaction time is prolonged and clot formation rate is reduced because platelet surface receptors are essential to the progression of the coagulation cascade. In patients with fibrinolysis, amplitude decreases gradually to zero amplitude. More importantly, active digestion of fibrin decreases the number of fibrin strands as the clot is being formed and results in prolonged reaction time and reduced clot formation rate and amplitude. Excessive activation of coagulation is seen as a very short reaction time and rapid clot formation rate. Once disseminated intravascular coagulation develops, all TEG variables deteriorate, and a straight line is observed. TEG has several advantages over standard methods in clinical coagulation monitoring. Results can be obtained fairly quickly; the onset of clot formation within a few minutes and platelet function within 45 minutes. Although most conventional coagulation tests end their observation when clots begin to form, TEG assesses dynamic changes of the complete coagulation process, from the onset of coagulation to complete clot formation, and to fibrinolysis. Further, definitive differential diagnosis of coagulopathy can be made by comparing multiple channels of TEG, allowing a selective replacement or pharmacologic therapy. For example, a comparison between TEG of untreated blood (0.36 mL) and that of blood treated with FFP (0.03 mL of FFP in

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5 min before reperfusion 5 min after reperfusion Untreated blood

EACA-treated blood

Protamine-treated blood Figure 6. Fibrinolysis and the heparin effect on reperfusion. The first TEG is taken 5 minutes before reperfusion. The next 3 TEGs are taken 5 minutes after reperfusion with untreated blood, blood treated with EACA (0.3 mg), and blood treated with protamine sulfate (3 mg). Fibrinolysis and potential heparin effect are seen in the untreated blood, and their presence is confirmed by inhibition of fibrinolysis in the blood treated with EACA and shortened reaction time in the blood treated with protamine sulfate, respectively. With permission from Hepatic Transplantation: Anesthetic and Perioperative Management. New York: Praeger; 1986:151–173.

0.33 mL of whole blood) identifies the presence of coagulation factor deficiency and beneficial effects of FFP administration. Other types of coagulation defects can be diagnosed by comparing TEGs with blood treated with other blood products (platelets and cryoprecipitate) or pharmacologic agents (EACA, protamine sulfate, aprotinin, and DDAVP).14,36,37,38 Differential diagnosis of pathologic coagulation during liver transplantation is shown in Figure 6. A dramatic reperfusion coagulopathy is shown as a prolonged reaction time, small amplitude, and severe fibrinolysis. A blood specimen treated with EACA improved coagulation by a shortened reaction time, increased amplitude and disappearance of fibrinolysis, suggesting active fibrinolysis. The same blood specimen treated with protamine sulfate normalized the reaction time and increased amplitude with persistent fibrinolysis, indicating the heparin effect. The most important contribution of TEG to the clinical coagulation, however, may be that it helps clinicians understand the global coagulation process. Some clinicians may implicate several drawbacks in TEG monitoring. The test results may not be reliable at times, but most of them are operator-related quality control issue. The test is best performed using fresh whole blood sample, not with citrated blood sample, which may be inconvenient in the laboratory setting. It cannot differentiate coagulopathy associated with a specific coagulation factor deficiency (eg, factor VIII vs. IX). This difficulty, however, is not a drawback of TEG, because

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it is a global monitoring tool, not a diagnostic test for an individual coagulation defect. TEG results may not correlate with surgical bleeding or field. Unfortunately, TEG, like all other tests, does not measure vascular phase of coagulation including the severity of vascular injury. ’

Perioperative Management of Coagulation Preoperative Management

Preoperative optimization of coagulation determined by the conventional coagulation profile is frequently unsuccessful owing to insufficient hepatic synthesis of coagulation factors and ongoing excessive activation of coagulation. Preoperative management of coagulation, therefore, should be tailored to meet specific clinical needs based on the type and severity of coagulation defects, the type of invasive procedure, and the nature and location of bleeding. Vitamin K, absorbed directly from the GI tract with the assistance of bile salts or produced by intestinal flora, is required for hepatic synthesis of coagulation factors II, VII, IX, and X. For mild vitamin K deficiency, oral administration of vitamin K together with bile salts, or injection of vitamin K1 (IM or IV, 5 mg/d) is effective in correcting PTwithin 24 to 48 hours. Repeated administration of vitamin K1 and coagulation factors may be necessary to treat bleeding tendency. Vitamin K, however, may not be effective in patients with severe hepatocellular disease.39 FFP, containing most coagulation elements and their inhibitors, is commonly administered to correct coagulopathy. It is generally accepted that FFP is given to patients with a prolonged PT (>1.5 INR) before liver needle biopsy. Improvement of coagulation, however, is only transient, and a large volume of FFP required to treat coagulopathy may cause fluid overloading. Platelet transfusion is used to treat severe thrombocytopenia. Its therapeutic effect is short lived, as platelets are removed by splenic sequestration and ongoing activation of coagulation. Clinical bleeding is rare with platelet count of greater than 75,000/mm3, although satisfactory hemostasis can be obtained with lesser platelet counts (>40,000/mm3). Cryoprecipitate, containing fibrinogen and factors VIII and XIII, is indicated, when hypofibrinogenemia or fibrinolysis is present. One unit of cryoprecipitate contains 300 mg of fibrinogen and the transfusion of 1 unit of cryoprecipitate increases the fibrinogen level approximately 10 mg/dL in a patient weighing 60 kg. The half-life of the fibrinogen is about 3 to 4 days and repeated transfusion of cryoprecipitate is necessary to supplement the loss. Anticoagulation therapy is rarely indicated in liver disease, although a subcutaneous injection of a small dose of heparin (<5000 units) seems to be acceptable in patients with thrombotic tendency. Oral anticoagulant therapy requires a close monitoring owing to unpredictable response. Antifibrinolytic agents may

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reduce bleeding even without signs of fibrinolysis by stabilizing fragile hemostatic plugs formed at the gastric mucosal ulcer or esophageal varices. However, EACA has been shown not to improve coagulation in patients with liver disease.40 Plasmapheresis (30 to 40 mL/kg), in combination with replacement therapy, may improve coagulation by removing filterable coagulation inhibitors, particularly in patients with fulminant hepatic failure. Plasmapheresis is shown to decrease PT from 28.3 to 17.7 seconds and aPTT from 64.8 to 43.3 seconds in liver transplantation candidates.39 Intraoperative Management

The goal of medical coagulation therapy is to maintain close to normal blood coagulability by frequent monitoring and specific replacement and/or pharmacologic therapy while avoiding thrombosis. It consists of physiologic therapy, replacement therapy, and pharmacologic Therapy. Physiologic Therapy Hypothermia inhibits coagulation by interfering with the activity of proteases involved in coagulation, and is shown to prolong reaction time and decrease clot formation rate on TEG operated on patient’s temperature. Hypothermia-induced delayed coagulation, however, may be beneficial to patients with hypothermiainduced venous stasis by preventing thrombosis. A similar delayed coagulation is observed in patients with ionized hypocalcemia, because calcium ion is a cofactor in the coagulation cascade. Acidosis and altered electrolyte balance may alter coagulation, directly by triggering inflammatory process or indirectly by impairing tissue perfusion.41 Therefore, body temperature, tissue perfusion, gas exchange, acid-base state, and fluid-electrolyte balance should be optimized to maintain normal blood coagulability. Replacement Therapy Replacement therapy is guided by the conventional coagulation profile or TEG variables. Replacement guidelines based on conventional coagulation vary widely from institution to institution, ranging from specific guideline [PT (INR) <1.5, hematocrit >30%, platelet count >30,000/mm3, and AT-III level >70%)]42 to general guideline (hemoglobin >9 g%, FFP to correct coagulopathy, and platelet count >100,000/mm3).43 Most transplantation centers administer coagulation factors-rich blood (RBC:FFP = 1:1) to maintain the sufficient coagulation factor level above 30% of normal value and/or PT (INR) <1.5 to 2.0. The critical level of platelet count is considered to be in the range of 40,000 to 50,000/mm3. At the Thomas Jefferson University Hospital, coagulation therapy is guided by TEG variables and platelet count. In general, continuous

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replacement of coagulation factors is required to compensate for their loss from dilution, excessive coagulation, and fibrinolysis. This is achieved by the administration of a mixture of blood products (RBC:FFP:crystalloids = 300:200:250 mL) containing 30% to 50% of normal levels of coagulation factors. Additional blood products may be administered based on TEG variables and platelet count. Platelets (10 units) are administered when MA is less than 40 mm to improve MA as well as reaction time. Cryoprecipitate (6 units) may be given when clot formation rate is persistently less than 40 degrees even after platelet transfusion, particularly in patients with fibrinolysis-induced hypofibrinogenemia. Additional FFP (2 units) may be administered when reaction time is persistently longer than 15 minutes even after the administration of platelets and cryoprecipitate.44 During the anhepatic stage, administration of platelets and cryoprecipitate is discouraged to prevent potential thromboembolism. An aggressive replacement therapy may be needed during the neohepatic stage when surgical bleeding persists, or fibrinolysis or the heparin effect remains untreated. Untreated fibrinolysis may require replacement of a large quantity of factors I, V, and VIII by administration of FFP and cryoprecipitate. Additional platelet transfusion may be required in patients with poorly functioning graft livers. In addition, alloimmunization to specific class-1 human lymphocyte antigens in highly sensitized patients may result in refractoriness to platelet transfusion, and they may benefit from transfusion of typespecific single-donor platelets.45 Administration of AT-III was suggested to minimize excessive activation of coagulation during the anhepatic and early neohepatic stages. However, its level remains above 30% to 50% of normal with FFP administration alone,19 and additional AT-III preparation neither improved the coagulation profile nor reduced blood loss and fibrinolytic activity.46 Therefore, AT-III is reserved for patients with excessively low AT-III levels. The TEG patterns and coagulation profile of a patient with fulminant hepatic failure are shown in Figure 7.3,46 The baseline TEG pattern (I+ 5) showed a prolonged reaction time and decreased MA and clot formation rate indicating a generalized decrease in coagulation factors and platelets. Administration of 2 units of FFP (I+ 30) improved reaction time. The administration of 10 units of platelets (I+ 120) improved MA, but mild fibrinolysis began to develop. Transfusion of 6 units of cryoprecipitate (I+ 180) did not improve clot formation rate owing to continuous deterioration of coagulation and worsening fibrinolysis. Severe fibrinolysis was observed during the anhepatic stage (II+ 30). On reperfusion (III+ 5), severe coagulopathy was noted with a prolonged reaction time, decreased clot formation rate and MA, and signs of fibrinolysis, and improved gradually in the following 2 hours.

Cryo 6u

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End

Plat 10u

III + 120’

III + 30’

III + 5’

II + 30’

Cryo 6u

I + 180’

Plat 10u I + 120’

Baseline FFP 2 U I + 30’

Coagulation and Liver Transplantation

Figure 7. Thromboelastographic patterns and coagulation profile of a patient with fulminant hepatic failure during liver transplantation. I = dissection phase; II = anhepatic phase; III = reperfusion to end of surgery phase. Numbers refer to number of minutes after start of phase. Modified with permission from Anesth Analg. 1985;64:888–896.

The administration of platelets and cryoprecipitate normalized the TEG by the end of surgery. The majority of coagulation tests were moderately or severely abnormal at the beginning of surgery. The coagulation profile gradually improved at the end of surgery, although it was still in the moderately abnormal range. Pharmacologic Therapy Although any pharmacologic intervention that promotes hemostasis and reduces the need for blood transfusion is of obvious benefit, the benefit should be weighted against the potential thrombotic complications. Synthetic antifibrinolytic therapy uses lysine analogs, EACA, and tranexamic acid, They accelerate the conversion of plasminogen to plasmin by inducing conformational changes, but inhibit fibrinolysis by blocking the lysine-binding site of plasmin. EACA was used in the 1960s to treat generalized oozing caused by fibrinolysis, but all 3 patients developed fatal bleeding or pulmonary embolism.9 Although this unfortunate experience discouraged the use of the antifibrinolytic therapy, recent clinical studies have shown positive results. In a study of 79 patients, EACA (1 g) was administered to 20 patients who developed severe fibrinolysis (fibrinolysis time <120 min), and fibrinolysis was corrected in all without thrombotic, hemorrhagic, or renal complications.14 The use of a small dose of EACA was one of the important findings of this study compared to the conventional priming dose of 4 to 5 g followed by 1 g/h to achieve a plasma level of 13 mg/dL.47 It seems that a single, small dose of EACA is sufficient to treat severe, but

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transient fibrinolysis, although its short half-life may necessitate a second dose in patients with an extremely high tPA level or massive transfusion. Recently, even a smaller dose of EACA (250 to 500 mg) was found to be effective in treating most types of fibrinolysis.48,49 Early diagnosis and treatment of fibrinolysis seems to be beneficial, It reduces bleeding and blood transfusion, conserves factors I, V, and VIII by inhibiting plasmin, and minimizes warm ischemia by reducing surgical hemostasis time. Fibrinolysis can be diagnosed in its early stage by observing a significant improvement in TEG variables (reaction time and clot formation rate) in blood treated with EACA compared with untreated blood in the first 10 to 15 minutes of recordings. The prophylactic use of EACA is not recommended, however, to avoid any potential thrombotic complications.24,50 Carlier et al50 reported that the use of tranexamic acid was safe in pediatric patients undergoing liver transplantation, and similar positive results were reported in prospective randomized clinical trials of tranexamic acid.51,52 Aprotinin is a nonspecific inhibitor of serine protease and inactivates a large number of serine proteases including trypsin, chymotrypsin, plasmin, kallikrein, Hageman factor, and most coagulation factors. It also prevents platelet activation during cardiopulmonary bypass and has been shown to preserve platelet GPIb receptors. The beneficial effects of aprotinin seem to be related to reduced production of tPA and plasmin through inhibition of kallikrein and fibrinolysis.53 This antifibrinolytic effect is observed indirectly by the similar blood product requirement between patients receiving aprotinin and tranexamic acid.54 Interestingly, aprotinin also inhibits coagulation cascade, and this has been well demonstrated in the TEG of blood treated with aprotinin.37 Therefore, the clinical benefit of aprotinin may be associated with the inhibition of excessive activation of coagulation and fibrinolysis. The dosage of aprotinin ranges from a high dose (2 million KIU followed by 0.5 million KIU/h) to a continuous infusion of low dose (0.2 to 0.4 million KIU/h). Early clinical trials showed that aprotinin decreased blood loss, operative time, and length of stay in the intensive care unit in patients undergoing liver transplantation.53,55,56 However, recent literature questions the clinical benefit of aprotinin,57–59 and its use has been reduced in many centers. Aprotinin is not without potential complications, and anaphylactic reaction, renal injury, and fatal pulmonary embolism have been reported.60 Protamine sulfate (25 to 50 mg) is used to reverse the heparin effect during the anhepatic or neohepatic stage. In clinical trials, the administration of protamine sulfate or heparinase has shown to shorten the reaction time of TEG and aPTT. Desmopressin acetate (DDAVP, 1-deamino 8-D-arginine vasopressin) is a synthetic analog of the naturally occurring posterior pituitary hormone, vasopressin (antidiuretic hormone). It stimulates endothelial

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cells to release factor VIII and subtypes of vWF within 1 hour. Desmopressin improves hemostasis in patients with hemophilia A and von Willebrand disease61 and shortens bleeding time in patients with uremia,62 congenital platelet defects, end-stage liver disease,63 and possibly those undergoing cardiac surgery.64 The recommended dosage of desmopressin is 0.3 mg/kg intravenously or subcutaneously; or 300 mg (150 mg in children) intranasally, and it may be repeated 12 to 24 hours after the initial dose. DDAVP improves blood coagulability of patients undergoing liver transplantation in vitro, possibly by activating coagulation factors and platelets.38 However, its benefit in clinical liver transplantation has not been established. Recombinant factor VIIa (rVIIa) is the most recently introduced pharmacologic agent in liver transplantation. Factor VII, in high concentrations, binds to the surface of activated platelets and directly activates factor X, resulting in platelet surface thrombin generation without factors VIIIa and IXa.65 It has been shown to improve coagulation in factor VII deficiency, factor X deficiency, factor XI deficiency, von Willebrand disease with inhibitors to vWF, platelet function defects, and thrombocytopenia. It has been shown to reduce PT in patients with liver disease and reduce blood loss during liver transplantation. However, further clinical studies are required to identify its benefit and potential complications. Fully borrowed (permission necessary) with permission from Am J Gastroenterol 1989;28:475–480. Modified or adapted (permission necessary) adapted with permission from Blood. 1990;125:615–623. Created using data from other sources (no permission is necessary). Data from Arch Surg 1988;89:339–345. Hepatic Transplantation: Anesthetic and Perioperative Management. New York: Praeger; 1986:135–141.

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