Review article: coagulation disorders in chronic liver disease

Transcription

1 Alimentary Pharmacology & Therapeutics Review article: coagulation disorders in chronic liver disease M. PECK-RADOSAVLJEVIC Department of Gastroenterology and Hepatology, Medizinische Universität & AKH Wien, Vienna, Austria Correspondence to: Dr M. Peck-Radosavljevic, Department of Gastroenterology and Hepatology, Medizinische Universität & AKH Wien, Währinger Gürtel 18-20, A-1090 Wien, Vienna, Austria. Publication data Accepted 28 August 2007 SUMMARY Background The liver is the site for synthesis of the vast majority of proteins that play a central role in maintaining hemostasis, by participating in the regulation of coagulation and fibrinolysis. Aim To summarize the available data on the impact of coagulation disorders in patients with chronic liver disease. Results Hepatocellular damage in patients with severe liver disease can lead to abnormalities in the production and function of coagulation and fibrinolytic factors, disrupting the balance between coagulation and anticoagulation systems. Conclusions Hemostatic abnormalities (eg. impaired synthesis of clotting factors, heightened fibrinolysis, disseminated intravascular coagulation, thrombocytopenia, and platelet dysfunction) can increase the risk of bleeding in cirrhotic patients. Aliment Pharmacol Ther 26 (Suppl 1), ª 2007 The Author 21 doi: /j x

2 22 M. PECK-RADOSAVLJEVIC INTRODUCTION The liver plays a central role in the maintenance of haemostasis as the site of synthesis for the vast majority of proteins required for regulation of coagulation and fibrinolysis (Table 1). 1 Thus, impairment of liver parenchymal cell function can disturb haemostasis resulting in the development of multiple coagulation abnormalities that, depending on the degree of haemostatic impairment, can predispose the patient to bleeding or thrombosis formation. Minor signs of bleeding tendencies in patients with liver disease include bruising, petechiae, purpura, epistaxis, gingival bleeding, and metrorrhagia. 1 However, patients with advanced liver disease are at increased risk of bleeding during invasive procedures, such as liver biopsy, during which clinically significant bleeding occurs in 0.35% to 0.5% of patients. 1 Bleeding following abdominal surgery causes significant morbidity and mortality in patients with liver cirrhosis; post-operative bleeding accounts for 60% of all deaths in this patient population. 1 Intraoperative and post-operative bleeding are major complications of orthotopic liver transplantation and a major contributing factor in mortality among liver transplant recipients. The pathophysiology of Table 1. Sites of synthesis and function of coagulation, anticoagulation, fibrinolytic and anti-fibrinolytic proteins 1 Proteins Site of synthesis Function Procoagulants Factor I (fibrinogen) Liver, extrahepatic sites Precursor of fibrin Factor II (prothrombin) Liver Precursor of thrombin Factor V Liver, endothelium, platelets Cofactor in prothrombinase complex Factor VII Liver Linked to TF, activates factors X and IX Factor VIII Liver, extrahepatic sites Cofactor in intrinsic-x-ase complex Factor IX Liver Activates factor X Factor X Liver Converts prothrombin to thrombin Factor XI Liver Activates factor IX Factor XII Liver Activates factor XI Factor XIII Liver, extrahepatic sites Crosslinks fibrin polymers Prekallikrein Liver Activates factor XII HMWK Liver Activation cofactor for factors XII and factor XI; Generates bradykinins Tissue factor (Factor III) Endothelium, monocytes Cofactor in extrinsic X-ase complex Anticoagulants Antithrombin III Liver, extrahepatic sites Inactivates thrombin, factors IXa, Xa, XIa, XIIa Heparin cofactor II Liver Inactivates thrombin Protein C Liver, endothelium Inactivates factors Va and VIIIa Protein S Liver, endothelium Enhances protein C activity Heparin sulfate Endothelium Links activating antithrombin III Thrombomodulin Endothelium Thrombin receptor allowing linking to protein C TFPI 1, 2 Endothelium, liver Inhibits TF factors VIIa and Xa Fibrinolytic proteins Plasminogen Liver Precursor of plasmin tpa Endothelium Activates plasminogen Urokinase Kidney Activates plasminogen Antifibrinolytic proteins PAI-1 Endothelium, platelets, liver Inhibits tpa PAI-2 White blood cells Inhibits tpa a2-antiplasmin Liver Inactivates plasmin TAFI Liver Inhibits plasminogen activation Reprinted with permission from Amitrano et al. Semin Liver Dis 2002;22: HMWK, high molecular weight kininogens; TAFI, thrombin activatable fibrinolysis inhibitor; TF, tissue factor; TFPI, tissue factor pathway inhibitor; tpa, tissue plasminogen activator.

3 REVIEW: COAGULATION DISORDERS IN CHRONIC LIVER DISEASE 23 coagulation disorders in chronic liver disease is reviewed in this paper. NORMAL HAEMOSTASIS The maintenance of normal haemostasis requires a balance between stimulation and inhibition of coagulation. Following endothelial injury, platelets adhere to the exposed subendothelial surface through platelet adhesion receptors, glycoprotein (GP) Ib-IX-V and GP VI. Respectively, these platelet receptors bind von Willebrand factor and collagen, expressed on the subendothelial matrix. 2 Adhesion triggers transmembrane signalling events that lead to platelet activation, and eventually to activation of the platelet integrin, aiibb3 (GP IIb-IIIa), which mediates platelet adhesion and aggregation at the injury site to form a platelet plug. 2 Activation of the coagulation cascade occurs simultaneously, which leads to formation and deposition of fibrin, thus stabilizing the clot (Figure 1). 1 To limit clot formation to the injured area, and to eliminate it later, pathways are activated that inhibit clot formation, and initiate fibrinolysis (Figure 2). ABNORMALITIES IN HAEMOSTASIS ASSOCIATED WITH CHRONIC LIVER DISEASE Liver disease is associated with a variety of haemostatic abnormalities that disrupt the delicate balance between clotting and fibrinolysis (Table 2). 3, 4 Reduced synthesis of coagulation factors As the liver is the primary source for most of the coagulation factors, circulating levels of these factors can be significantly reduced in patients with chronic liver disease who have extensive hepatocellular damage, and hence, substantial loss of hepatic parenchymal cell function. In this clinical setting, factor VII is the first coagulation factor that decreases, probably because of its short half-life (4 6 h). 1 The hepatic production of factor VII decreases as disease severity increases (Figure 3) and liver function decreases. 5, 6 Up to 60% of patients with chronic active liver disease have reduced levels of factor VII 7 that probably contribute to the prolonged prothrombin time typically observed in patients with advanced liver disease. 8, 9 Also, low factor VII activity has been shown to be an independent prognostic indicator for reduced survival Figure 1. Simplified schematic of the coagulation cascade. tpa, tissue plasminogen activator; upa, urokinasetype plasminogen activator. Reprinted with permission from Rosenberg et al. NEJM 1999;340: in patients with advanced cirrhosis across Child-Pugh grades A, B, and C. 10 Reductions in synthesis of factors II, V, IX, X, and XI also correlate with the extent of cirrhosis and the loss of liver parenchymal cells. The magnitude of the deficiencies of these coagulation factors varies considerably among patients. 6, 9, 11 Factor VIII levels remain normal or elevated, even 11, 12 in cirrhotic patients, because of either extrahepatic synthesis (e.g., endothelial cells) 13 or reduced clearance of the factor VIII-von Willebrand factor 12, 14 complex in the liver. Factor XIII activity remains within the normal range in the majority of patients with chronic liver disease of various aetiologies and at various stages (no

4 24 M. PECK-RADOSAVLJEVIC Figure 2. Clotting pathway inhibitors and fibrinolytic system. PAI-1, plasminogen activator inhibitor 1; PAI-2, plasminogen activator inhibitor 2; TAFI, thrombin activatable fibrinolysis inhibitor; tpa, tissue plasminogen activator. Reprinted with permission from Amitrano et al. Semin Liver Dis 2002;22: cirrhosis, or Child-Pugh grades A to C); however, factor XIII deficiency (<50% of normal activity) can be detected, albeit infrequently, in patients with advanced liver cirrhosis (Child-Pugh grade C). 6 Plasma fibrinogen levels generally remain normal or elevated in patients with chronic liver disease, 5, 6 although the presence of severe fibrosis (Child-Pugh grade C) may be associated with depressed levels. 6 The circulating fibrinogen levels typically include a high percentage of non-functional fibrinogen (up to 78% in patients with chronic liver disease), 15 because of abnormal polymerization of fibrin monomers, leading to prolonged plasma thrombin times. 16 Significantly reduced levels of coagulation factors (factor II, V, VII, XIII), prolonged prothrombin times (PTs), and activated partial thromboplastin times (apt- Ts) have been observed in patients with chronic liver disease exhibiting current systemic bleeding tendency unrelated to portal hypertension. 6 This observation suggests a contribution of insufficient coagulation factor activity in the aetiology of bleeding complications in this population. The ability of routine coagulation tests to evaluate haemostasis in liver disease has been questioned recently. It was shown in elegant studies that routine coagulation tests (PTs, aptts) often overestimate Table 2. Hemostatic abnormalities and pathogenetic mechanisms 3, 4 Hemostatic abnormality Abnormalities that predispose to bleeding Impaired coagulation Excessive fibrinolysis Low platelet count (thrombocytopenia) Impaired platelet function Disseminated intravascular coagulation Abnormalities that predispose to thrombosis Hypercoagulable state Pathogenic mechanisms Reduced synthesis of coagulation factors Vitamin K deficiency Fibrinogen abnormalities (dysfibrinogenemia) Impaired clearance of tpa and fibrinolytic enzymes Reduced synthesis of a2-antiplasmin and TAFI Platelet sequestration due to splenomegaly Impaired hepatic synthesis of thrombopoietin Immune-mediated platelet destruction Bone marrow suppression by virus or interferon treatment Defect in signal transduction Deficiency of glycoprotein Ib receptors on platelet surface Reduced thromboxane A2 synthesis Platelet storage pool defect Increased consumption of coagulation proteins and platelets Reduced clearance of activated clotting factors Reduced synthesis of coagulation inhibitors Release of procoagulants from damaged hepatocytes High levels of factor VIII and von Willebrand factor Low levels of protein C, protein S, antithrombin Adapted with permission from Kujovich JL. Crit Care Clin 2005;21: TAFI, thrombin activatable fibrinolysis inhibitor; tpa, tissue plasminogen activator.

5 REVIEW: COAGULATION DISORDERS IN CHRONIC LIVER DISEASE 25 Figure 3. Percentage of hepatocytes expressing factor VII in subsets of patients with different stages of liver disease. * P < for Stage 4 vs. Stages 0, 1, 2, or 3. Reprinted with permission from Rodriguez-Inigo et al. Blood Coagul Fibrinolysis. 2001;12: coagulopathy in liver disease. Because these routine tests do not adequately measure activation of the anticoagulant protein C, the reduced anticoagulant activity in liver disease is not detected. 17 Excessive fibrinolysis Patients with cirrhotic liver disease have an increased bleeding tendency because of increased fibrinolysis causing premature disintegration of the haemostatic clot at the injured site. 1 Hyperfibrinolysis results from an imbalance between activators and inhibitors of fibrinolysis. The levels of tissue plasminogen activator (tpa) are elevated because of reduced hepatic clearance, whereas the levels of plasminogen activator inhibitor-1 (PAI-1) do not respond appropriately to the changes in tpa level, thus skewing the balance between tpa and PAI-1 activity levels towards excessive tpa activity in patients with severe cirrhosis. 18, 19 Also, activity levels of the anti-fibrinolytic proteins, a2-antiplasmin 19 and thrombin activatable fibrinolysis 18, 20 inhibitor, are reduced as a result of substantial liver damage, causing a further shift towards increased fibrinolysis. Hyperfibrinolysis is correlated with other coagulation abnormalities, including thrombocytopenia, reduced fibrinogen levels, and abnormally prolonged PT and PTT values. 21 The elevated levels of tpa on platelets lead to inhibition of platelet aggregation, degradation of platelet receptors (GP Ib and GP IIb IIIa), 22 and induction of platelet disaggregation. 23 Hyperfibrinolysis occurs in approximately 30% of patients with compensated cirrhotic liver disease and is positively correlated with the severity of liver disease as assessed by Child-Pugh grade. 21, 24 It is not observed in patients with non-cirrhotic liver disease. 21 Patients with ascites appear to be at increased risk for hyperfibrinolysis. Evidence of increased fibrinolytic activity (elevated levels of D-dimer and fibrinogen degradation products together with low fibrinogen and plasminogen levels) has been detected in ascitic fluid, and it has been proposed that reabsorption of ascites into the systemic circulation contributes to hyperfibrinolysis in patients with advanced liver disease. 25 In a group of 112 patients with liver cirrhosis and oesophageal varices, hyperfibrinolysis (defined as concomitant high values of D-dimer and tpa activity) was identified as an independent predictor of gastrointestinal bleeding. 24 This study also demonstrated a higher risk of gastrointestinal bleeding in patients with ascites and hyperfibrinolysis than in those with ascites who did not have hyperfibrinolysis. Thrombocytopenia Abnormalities in both platelet number and platelet function are common in chronic liver disease. Thrombocytopenia is observed in 15% to 70% of patients with cirrhosis, depending on the stage of the disease and the definition of thrombocytopenia, and is usually mild to moderate in severity. 26 Thrombocytopenia does not appear to increase the risk of bleeding from oesophageal varices or other sites in patients with stable liver disease. However, thrombocytopenia is associated with other coagulation abnormalities (including decreased fibrinogen level, decreased activity of coagulation factors, and increased fibrinolytic activity), and together, these abnormalities may synergistically increase the risk of bleeding in patients with 6, 21 cirrhotic liver disease. The pathophysiology of thrombocytopenia in chronic liver disease is reviewed elsewhere in this supplement and is thus discussed briefly in this paper. Multiple pathogenic mechanisms contribute to the decreased numbers of circulating platelets (Table 2). These include splenomegaly secondary to portal hypertension and subsequent sequestration of platelets in the spleen, 27 reduced hepatic production of the thrombopoietin (thrombopoietic growth factor), 28, 29 bone marrow suppression by hepatitis C virus 30 or interferon antiviral treatment, 26 and increased platelet destruction

6 26 M. PECK-RADOSAVLJEVIC mediated by immune mechanisms involving anti-platelet autoantibodies and platelet-associated immune 31, 32 complexes. Platelet function defects Platelet aggregation in response to standard agonists is impaired in patients with cirrhosis, probably because of a variety of intrinsic platelet defects. These include a defective signal transduction mechanism, 37 reduced thromboxane A2 synthesis (which may contribute to impaired platelet signalling), 35 a platelet storage pool defect, 34 and deficiency of GPIb receptors on the platelet surface (which negatively affects platelet aggregation and activation, and platelet-endothelial cell adhesion). 38, 39 The adhesion of platelets with vascular subendothelial components is also impaired in patients with Child-Pugh grade A and higher cirrhosis 36 ; deficiency of platelet GPIb receptors may contribute to this abnormality. 39 Disseminated intravascular coagulation Disseminated intravascular coagulation (DIC), also referred to as consumption coagulopathy, is characterized by activation of the clotting cascade by a magnitude overpowering the anticoagulation pathway, resulting in widespread intravascular fibrin deposition and ultimately, arterial or venous thrombosis and multiorgan failure. 40 The increased consumption of clotting factors and platelets can also lead to severe bleeding. Common laboratory features of DIC include low platelet count, prolonged PT, prolonged thrombin time, decreased fibrinogen concentration, and elevation of fibrinogen degradation products. 4 Disseminated intravascular coagulation in patients with liver disease involves multiple triggering mechanisms (Table 2), many of which are related to liver damage, including increased release of procoagulants, impaired removal of activated coagulation proteins and endotoxins produced by gut bacteria, and reduced synthesis of coagulation inhibitors. 3, 4 Other triggers include shock, surgery, or trauma. 41 Because DIC and decompensated cirrhosis share similar haemostatic abnormalities, (i.e., elevated prothrombin, decreased fibrinogen, increased D-dimers, elevated fibrin degradation products, and thrombocytopenia), the diagnosis of DIC is difficult, and there is some debate about whether DIC is a coagulation disorder in cirrhosis. 42 However, with the recent availability of assays that allow quantitative determination of proteolytic cleavage products of coagulation reactions (including fibrinopeptide A, prothrombin fragment F1 + 2, thrombin-antithrombin and plasmin-a2-antiplasmin complexes, soluble fibrin, and D-dimer), accelerated intravascular coagulation and fibrinolysis (AICF) can now be detected in patients with liver cirrhosis. 41 The term DIC is used predominantly for decompensated AICF. 41 Studies have detected AICF in less than 30% of patients with cirrhosis, 41 and the extent of AICF appears to correlate with the severity of cirrhosis (Child-Pugh grade). 43 However, AICF does not appear to be common in patients with stable, uncomplicated, non-advanced liver cirrhosis. 42 In patients with cirrhosis and AICF, the coexistence of sepsis, shock, surgery, trauma, or ascites may cause the progression of AICF to overt DIC. 1 Amitrano et al. (2002) suggest that the diagnosis of DIC can be made on the basis of: the occurrence of a known triggering clinical event, progressive worsening of coagulation test results and platelet counts, a disproportionate reduction in Factor V, and a concomitant decrease in previously normal levels of Factor VIII. 1 Thrombosis An imbalance between clotting activators and inhibitors can occasionally lead to hypercoagulation and thrombosis in patients with liver cirrhosis. As the increased risk of thrombosis is almost exclusively restricted to the portal and mesenteric veins, several other factors like portal hypertension and related abnormalities (not just coagulation factor deficiency) seem to play a dominant role. 1 Portal vein thrombosis (PVT) has been documented in 9% to 20% of patients with cirrhosis, 3 with higher rates occurring in patients with more severe liver disease. 44 Of a group of 79 cirrhotic patients with PVT, Amitrano et al. (2004) found that only 10% had Child-Pugh grade A disease, whereas 52% had Child-Pugh grade B, and 39% had Child-Pugh grade C disease. 44 In patients with severe liver disease, predisposing factors for thrombosis include decreases in anticoagulant proteins (e.g., antithrombin III, protein C, and protein S) 43, 45 and high levels of factor VIII and von Willebrand factor. 12 Also, the risk of thrombosis is substantially increased in cirrhotic patients with thrombophilic disorders, including the prothrombin gene mutation (which increases the risk of PVT by more than 5-fold), 44 and antiphospholiplid antibodies. 45

7 REVIEW: COAGULATION DISORDERS IN CHRONIC LIVER DISEASE 27 CONCLUSIONS In summary, progressive liver damage in patients with chronic liver disease of various aetiologies is associated with the development of coagulopathies. Hepatocellular damage adversely affects the hepatic production of proteins that play critical roles in coagulation and fibrinolytic systems. Thus, a variety of haemostatic abnormalities can occur in patients with severe liver disease, including impaired synthesis of clotting factors, excessive fibrinolysis, DIC, thrombocytopenia, and platelet dysfunction. All of these defects increase the risk of bleeding. Haemostatic abnormalities that increase the risk of thrombosis can also occur including mutations in procoagulant proteins together with decreased levels of anticoagulants (Protein C and Protein S). ACKNOWLEDGEMENT Declaration of personal interests: MPR was an investigator in a study funded by Novo Nordisk and has acted as a consultant. 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