Williams Hematology



Hemostatic Defects in Chronic Liver Disease

Bleeding Manifestations


Laboratory Features

Liver Transplantation
Chapter References

Liver diseases are frequently associated with hemostatic derangements that can lead to spontaneous and injury-related bleeding manifestations. The hemostatic abnormalities are complex and can include thrombocytopenia, platelet dysfunction, diminished plasma levels of coagulation factors, enhanced fibrinolysis, dysfibrinogenemia, and/or sometimes disseminated intravascular coagulation. The extent of the hemostatic abnormalities usually correlates with the magnitude of liver dysfunction. Careful laboratory evaluation of the hemostatic systems is essential in patients with liver disease who bleed or in whom surgical procedures are planned. Treatment consists mainly of plasma, cryoprecipitate, and platelet transfusions. Other treatment modalities include infusion of coagulation factor concentrates and administration of antifibrinolytic drugs, but both confer a risk of thrombosis.
Profound hemostatic failure accompanies the different stages of orthotopic liver transplantation and invariably leads to excessive bleeding. The main cause for the hemostatic defect in such patients is accelerated fibrinolysis, and several studies have shown that the use of antifibrinolytic agents, together with replacement therapy by blood components, can ameliorate bleeding.

Acronyms and abbreviations that appear in this chapter include: aPTT, activated partial thromboplastin time; DIC, disseminated intravascular coagulation; FDP, fibrin degradation products; PAI-1, plasminogen activator inhibitor 1; PT, prothrombin time; t-PA, tissue plasminogen activator; TT, thrombin time; vWF, von Willebrand factor.

The liver plays a central role in hemostasis. Liver parenchymal cells are the site of synthesis of many coagulation factors as well as many of the physiological inhibitors of coagulation (e.g., protein C, protein S, and antithrombin III) and essential components of the fibrinolytic system (e.g., plasminogen and a2-antiplasmin). The liver also regulates hemostasis and fibrinolysis by clearing activated coagulation factors from the circulation and plasminogen activators. When significant liver dysfunction occurs, the supervening outcome is usually a bleeding tendency that is related to the decreased levels of procoagulants and enhanced fibrinolysis. Thrombosis due to decreased synthesis of inhibitors of coagulation, although a theoretical possibility, is in fact uncommon. The bleeding tendency can also stem from thrombocytopenia, platelet dysfunction, decreased vitamin K availability, dysfibrinogenemia, and disseminated intravascular coagulation (DIC) associated with secondary fibrinolysis.
Patients with acute viral or toxic hepatitis usually do not present with a bleeding tendency unless the disorder is fulminant. In contrast, patients with chronic liver disease frequently present with spontaneous bleeding or with injury-related hemorrhage. This chapter reviews the hemostatic abnormalities that occur in patients with chronic liver disease and in patients undergoing orthotopic liver transplantation.
Patients with chronic liver disease may present with purpura, epistaxis, gingival bleeding, and/or menorrhagia. Minor or major surgical procedures at sites where there is a high level of local fibrinolysis (e.g., oral mucosa, urogenital tract) are particularly prone to excessive bleeding. Bleeding can also follow head trauma and soft-tissue trauma.
The progressive loss of liver parenchymal cells is associated with diminished synthesis of all coagulation factors except for von Willebrand factor (vWF), which is produced by endothelial cells and megakaryocytes (see Chap. 135), and factor VIII, whose levels in plasma are increased for an unknown reason.1 The vitamin K–dependent factors, particularly factor VII, are sensitive to liver dysfunction. Thus, decreased plasma activity of factors II, VII, X, and, to lesser extent, factor IX2 can result not only from the decreased synthetic capacity of the liver cells but also from diminished g-carboxylation due to reduced vitamin K availability. Common causes for a limited supply of vitamin K in patients with liver disease include diminished intestinal absorption due to cholestasis, malnutrition, prolonged gut sterilization by antibiotics, and intestinal malabsorption. Plasma factor V is frequently decreased, and the extent of the deficiency correlates well with the magnitude of liver dysfunction.3 Plasma fibrinogen concentrations are usually in the normal range unless liver dysfunction is advanced4 or the patient has DIC.
The leading cause of thrombocytopenia in patients with chronic liver disease is congestive splenomegaly or “hypersplenism.” Up to 90 percent of the total platelet mass may be in the massively enlarged spleen, compared with about 33 percent in a normal spleen.5,6 Patients with cirrhosis have shortened platelet survival, which may contribute to the thrombocytopenia.5,7 Thrombocytopenia can also be related to an autoimmune mechanism. Thus, patients with primary biliary cirrhosis, but not patients with alcoholic cirrhosis, were shown to have antibodies against the glycoprotein (GP)Ib/IX complex and against GPIIb/IIIa.8 Additional potential causes for thrombocytopenia are DIC, folic acid deficiency, and decreased megakaryopoiesis.9
In a study of 60 patients with severe, but stable, cirrhosis, mean values of bleeding time, platelet adhesion, and platelet aggregation induced by collagen, epinephrine, or ADP were in the normal range.5 In contrast, other studies have demonstrated a platelet storage pool defect,10 reduced thromboxane A2 synthesis,11 impaired signal transduction,12 and diminished adhesion under flow conditions.13 Studies of the interaction of platelet GPIb/IX complex vWF in patients with cirrhosis have yielded different results. Thus, one group of investigators observed a diminished number of GPIb/IX complexes on platelets, decreased platelet binding of vWF, and reduced ristocetin–induced platelet agglutination.14 In sharp contrast, another group showed an increased number of GPIb molecules and enhanced botrocetin-induced platelet agglutination.15 Increased plasma levels of vWF antigen and activity have been described,15,16 albeit with a reduction of the high-molecular-weight vWF multimers which are hemostatically most active.15,17 The decrease in the large vWF multimers, which has been attributed to enhanced proteolysis, has been proposed to give rise to excessive bleeding during orthotopic liver transplantation17 (see Liver Transplantation, below). Thus, when judged in its entirety, it is unclear whether platelet dysfunction contributes significantly to the hemostatic diathesis in chronic liver disease.
The enhanced fibrinolysis observed in patients with chronic liver disease is thought to be caused by impaired control of the fibrinolytic system. Thus, the synthesis of a2-antiplasmin is decreased,18 there is diminished clearance of tissue plasminogen activator (t-PA),19 and for unknown reasons there are reduced plasma levels of plasminogen activator inhibitor 1 (PAI-1), which is synthesized by endothelial cells.20 These defects lead to increased plasma levels of t-PA and urokinase21 and to a decreased half-life of plasminogen.5,22 Enhanced fibrinolysis was also shown to be secondary to low-grade DIC in patients with cirrhosis due to endotoxemia23 and was implicated in another group of patients in whom a shortened half-life of plasminogen was corrected by administration of heparin.22
Dysfibrinogenemia characterized by impaired fibrin polymerization and a prolonged thrombin time is commonly observed in patients with chronic liver disease.24,25 The dysfibrinogenemia is due to an increased content of sialic acid in fibrinogen synthesized by the affected liver.26 Removal of the excess sialic acid from the aberrant fibrinogen by neuraminidase results in correction of the thrombin time and normalization of fibrin monomer aggregation.27 It is unknown, however, whether the dysfibrinogenemia contributes to the bleeding tendency exhibited by patients with chronic liver disease.
Patients with chronic liver disease are prone to develop DIC, and when it occurs they have a diminished capacity to contain the process. These defects stem from: (1) reduced plasma levels of the physiological inhibitors of coagulation, protein C, protein S, and antithrombin III; (2) diminished capacity of the liver to clear activated coagulation factors; and (3) impaired capacity to replenish coagulation factors that have been consumed by DIC. In addition, the secondary fibrinolysis that is associated with DIC may be particularly excessive due to the defective control mechanisms of fibrinolysis displayed by patients with chronic liver disease (see Chap. 126).
Patients with chronic liver disease who present with bleeding or are candidates for surgical intervention need to undergo laboratory evaluation for hemostatic abnormalities. The changes in hemostatic parameters that can be observed are summarized in Table 125-1. Frequently, the degree of the changes is related to the extent of liver dysfunction.1


The essential tests that need to be performed are: prothrombin time (PT), activated partial thromboplastin time (aPTT), thrombin time (TT), platelet count, fibrinogen, whole blood or euglobulin clot lysis time, D-dimer and fibrin degradation products (FDP). Results of these tests should allow one to establish whether thrombocytopenia, fibrinolysis, DIC, or deficiency of coagulation factors is present. More subtle interpretation may also be possible. For example, a prolonged TT in the presence of normal plasma fibrinogen and normal FDP suggests the presence of a dysfibrinogenemia.
Assays of factors V, VII, and VIII can be helpful in further evaluation of the hemostatic abnormalities. Thus, decreased levels of factors V and VII with a normal or increased level of factor VIII is consistent with liver dysfunction; decreased levels of factor VII with normal levels of factors V and VIII is consistent with vitamin K deficiency, and decreased levels of factors V, VII, VIII, and fibrinogen suggest the presence of DIC.
The various hemostatic defects associated with chronic liver disease may constitute the main cause of spontaneous and injury-related bleeding. Alternatively, they can enhance bleeding from esophageal varices, erosive gastritis, or hemorrhoids. The treatment strategy should be based on careful clinical evaluation of the causes of bleeding and assessment of the major hemostatic abnormalities involved. Thus, in patients with esophageal varices, sclerotherapy or therapy to decrease the pressure in the portal system are the primary targets, whereas attempts to correct the hemostatic defects are secondary. In patients who bleed spontaneously, in patients who bleed following trauma, or in patients predicted to bleed following surgery, the primary goal of treatment would be correction of the hemostatic defects.
Transfusion of fresh-frozen plasma replenishes all the deficient coagulation factors and physiological inhibitors of the coagulation and fibrinolytic systems. The correction of the levels of these components, however, is brief for factors like factor VII that have a short half-life so that repeated transfusion of relatively large volumes of fresh-frozen plasma is necessary for maintenance of adequate levels of these coagulation factors. As a consequence, volume overload can become a serious limiting factor. In extreme circumstances, plasma exchange can be employed. Another drawback of plasma replacement therapy is the risk of transmission of viral diseases, although the risk of transmitting HIV and hepatitis B and C can be diminished by using solvent-detergent-treated plasma.
Prothrombin complex concentrates provide all the vitamin K–dependent factors, which are frequently diminished in the plasma of patients with chronic liver disease. The use of these concentrates, however, does not correct the level of factor V, and since the deficiency of this factor may significantly enhance bleeding, concomitant transfusion of fresh-frozen plasma may be necessary. Administration of prothrombin complex concentrates can result in thrombosis, since activated coagulation factors present in the concentrates are not adequately cleared by the affected liver (see Chap. 122, Chap. 123, Chap. 126). In addition, the use of prothrombin complex concentrates may be associated with a risk of transmitting viruses like hepatitis A virus or parvovirus (see Chap. 122 and Chap. 123).
When decreased vitamin K availability is suggested, as in patients with intra- or extrahepatic cholestasis, patients who have received antibiotics for a long time, or patients whose factor VII level is markedly decreased but factor V level is normal, administration of vitamin K1 (10 mg) is warranted. Vitamin K1 given intravenously can correct or improve the PT and aPTT within 8 to 24 h. The dose can be repeated daily until correction is complete and then as maintenance doses if the cause of the deficiency is ongoing.
When serious or life-threatening bleeding occurs in patients with chronic liver disease or when it is anticipated during surgical procedures, platelet transfusion should be used with the aim of increasing their number to 75,000/µL or more. In patients with severe splenomegaly this may not be possible to attain. The number of platelet units to be used depends on the platelet count prior to transfusion but is difficult to assess accurately, since the extent of sequestration of platelets by the spleen is unpredictable. Performing a platelet count 1 h after transfusion provides valuable information on the degree of sequestration.
Since fibrinogen levels are usually not decreased to levels likely to cause bleeding, it is usually unnecessary to use cryoprecipitate in patients with chronic liver disease who bleed. The plasma level of fibrinogen may be decreased when DIC occurs, and in such conditions administration of cryoprecipitate may be warranted (see Chap. 126).
Tranexamic acid or e-aminocaproic acid have been successfully used in patients with chronic liver disease who underwent dental extractions.28 Since hyperfibrinolysis is one of the significant causes for the hemostatic abnormalities in liver disease, the use of these agents can be beneficial for achieving hemostasis in other circumstances as well. However, if DIC is associated with liver disease, the use of antifibrinolytic agents can induce thromboembolism. Consequently, before using an antifibrinolytic agent, DIC has to be excluded.
Orthotopic liver transplantation is associated with profound disturbances in hemostasis that lead to excessive bleeding during the procedure.29,30 The patient is initially always hemostatically compromised, surgical trauma is extensive, there is an obligatory anhepatic phase during which coagulation factors are not produced, and there is excessive fibrinolysis during both the anhepatic phase and early reperfusion phase.
During the anhepatic phase, t-PA released from the endothelial cells of the recipient is not cleared from the circulation, resulting in a profound increase in plasma t-PA level. Since PAI-1 levels are low, the t-PA produces marked conversion of plasminogen to plasmin31; moreover, since a2-antiplasmin levels are low, the plasmin can act relatively unopposed.18,20
During the reperfusion phase there is a second fibrinolytic “burst” due to massive t-PA release from the stored organ.32,33 This is accompanied by generation of other proteolytic enzymes, such as elastases, trypsin, and cathepsin B,34 that may also contribute to the overall proteolytic state and the associated bleeding.35 Proteolytic breakdown of vWF also appears to contribute to the severe bleeding during this phase of transplantation.17
Thromboelastography has been used during transplantation to monitor the hemostatic status of the patient during the various phases of surgery, including ex vivo clot formation, clot strength, and fibrinolysis.36 The availability of these data in the operating room allows the anaesthesiologists and surgeons to evaluate and follow the effects of replacement therapy and antifibrinolytic treatment.33 The excessive bleeding during liver transplantation has been ameliorated by the use of aprotinin, a broad-spectrum serine protease inhibitor, in several37,38 but not all studies.39 Thus, in some studies, administration of aprotinin reduced the need for transfusion of blood components37,38 and was associated with decreased plasma levels of t-PA and D-dimer and increased levels of a2-antiplasmin.38 In another study, however, the use of aprotinin failed to reduce the requirement for blood component replacement.39 Large doses of tranexamic acid have also been reported to reduce blood loss and transfusion requirement.40

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Schmidt KG, Rasmussen J, Bekker C, Madsen PE: Kinetics and in vivo distribution of indium-111 labeled autologous platelets in chronic hepatic disease: Mechanisms of thrombocytopenia. Scand J Haematol 34:39, 1985.

Aoki Y, Hirai K, Tanikawa K: Mechanisms of thrombocytopenia in liver cirrhosis: Kinetics of indium-111 tropolone labelled platelets. Eur J Nucl Med 20:123, 1993

Feistauer SM, Penner E, Mayr WR, Panzer S: Target platelet antigens of autoantibodies in patients with primary biliary cirrhosis. Hepatology 25:1343, 1997.

Cowan DH: Effect of alcoholism on hemostasis. Semin Hematol 17:137, 1980.

Laffi G, Marra F, Gresele P, et al: Evidence for a storage pool defect in platelets from cirrhotic patients with defective aggregation. Gastroenterology 103:641, 1992.

Laffi G, Cominelli F, Ruggiero M, et al: Altered platelet function in cirrhosis of the liver. Impairment of inositol lipid and arachidonic acid metabolism in response to agonists. Hepatology 8:1620, 1988.

Laffi G, Marra F, Ruggiero M, et al: Defective signal transduction in platelets from cirrhotics is associated with increased cyclic nucleotides. Gastroenterology 105:148, 1993.

Ordinas A, Escolar G, Cirera I, et al: Existence of a platelet-adhesion defect in patients with cirrhosis independent of hematocrit: studies under flow conditions. Hepatology 24:1137, 1996.

Sanchez-Roig MJ, Rivera J, Moraleda JM, Garcia UV: Quantitative defects of glycoprotein Ib in severe cirrhotic patients. Am J Hematol 45:10, 1994.

Beer JH, Clerici N, Baillod P, von Felten A, Schlappritzi E, Büchi L: Quantitative and qualitative analysis of platelet GPIb and von Willebrand factor in liver cirrhosis. Thromb Haemost 73:601, 1995.

Green AJ, Ratnoff OD: Elevated antihemophilic factor (AHF, factor VIII) procoagulant activity and AHF-like antigen in alcoholic cirrhosis of the liver. J Lab Clin Med 83:189, 1974.

Lattuade A, Mannucci PM, Chen C, Legnani C, Palaretti G: Transfusion requirements are correlated with the degree of proteolysis of von Willebrand factor during orthotopic liver transplantation. Thromb Haemost 78:813, 1997.

Aoki NM, Yamanaka T: The a2-plasmin inhibitor levels in liver disease. Clin Chim Acta 84:99, 1978.

Tytgat G, Collen D, De Vreker RR, Verstraete M: Investigations on the fibrinolytic system in liver cirrhosis. Acta Haematol (Basel) 40:265, 1968.

Hersch SL, Kunelis T, Francis RB: The pathogenesis of accelerated fibrinolysis in liver cirrhosis: a critical role for tissue plasminogen activator inhibitor. Blood 69:1315, 1987.

Booth NA, Anderson JA, Bennett B: Plasminogen activators in alcoholic cirrhosis: demonstration of increased tissue type and urokinase type activator. J Clin Pathol 37:777, 1984.

Collen D, Bouvier J, Chamone DAF, Verstraete M: Turnover of radiolabelled plasminogen and prothrombin in cirrhosis of the liver. Eur J Clin Invest 8:185, 1978.

Violi F, Ferro D, Basili S, et al: Association between low-grade disseminated intravascular coagulation and endotoxemia in patients with liver cirrhosis. Gastroenterology 109:531, 1995.

Green G, Thomson JM, Dymock IW, Poller L: Abnormal fibrin polymerization in liver disease. Br J Haematol 34:427, 1976.

Palascak JE, Martinez J: Dysfibrinogenemia associated with liver disease. J Clin Invest 60:89, 1977.

Martinez J, Palascak JE, Kwasniak D: Abnormal sialic acid content of the dysfibrinogenemia associated with liver disease. J Clin Invest 61:535, 1978.

Martinez J, MacDonald KA, Palascak JE: The role of sialic acid in the dysfibrinogenemia associated with liver disease: distribution of sialic acid on the constituent chains. Blood 61:1196, 1983.

Francis RB, Feinstein DI: Clinical significance of accelerated fibrinolysis in liver disease. Haemostasis 14:460, 1984.

Neuhaus P: Hemostasis in liver transplantation. The surgeon’s view. Semin Thromb Hemost 19:183, 1993.

Porte RJ: Coagulation and fibrinolysis in orthotopic liver transplantation. Current views and insights. Semin Thromb Hemost 19:191, 1993.

Lewis JH, Bontempo FA, Awad SA, et al: Liver transplantation: intraoperative changes in coagulation factors in 100 first transplants. Hepatology 9:710, 1989.

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 47:478, 1989.

McNicol PL, Liu G, Harely ID, et al: Patterns of coagulopathy during liver transplantation: experience with the first 75 cases using thromboelastography. Anaesth Intensive Care 22:659, 1994.

Legnani C, Palareti G, Rodorigo G, et al: Protease activities, as well as plasminogen activators, contribute to the “lytic” state during orthotopic liver transplantation. Transplantation 56:568, 1993.

Ries H, Jochum M, Machleidt W, et al: Possible role of the phagocytic proteinases, cathepsin B and elastase in orthotopic liver transplantation. Transplant Proc 23:1947, 1991.

Kang YG, Martin DJ, Marquez J, et al: Intraoperative changes in blood coagulation and thromboelastographic monitoring in liver transplantation. Anesth Analg 64:888, 1985.

Scudamore CH, Randall TE, Jewesson PJ, et al: Aprotinin reduces the need for blood products during liver transplantation. Am J Surg 169:546, 1995.

Llamas P, Cabrera R, Gomez-Arnau J, Fernandez MN: Hemostasis and blood requirements in orthotopic liver transplantation with and without high-dose aprotinin. Haematologica 83:338, 1998.

Garcia-Huete L, Domenech P, Sabate A, Martinez-Brotons F, Jaurrieta E, Figueras J: The prophylactic effect of aprotinin on intraoperative bleeding in liver transplantation: a randomized clinical study. Hepatology 26:1143, 1997.

Boylan JF, Klinck JR, Sandler AN, et al: Tranexamic acid reduces blood loss, transfusion requirements, and coagulation factor use in primary orthotopic liver transplantation. Anesthesiology 85:1043, 1996.
Copyright © 2001 McGraw-Hill
Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn
Williams Hematology



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