Understanding and Managing the Coagulopathy of Liver Disease

Introduction

The liver plays a pivotal role in thrombosis and hemostasis because it synthesizes many hemostatic proteins. All procoagulant plasma proteins; the anticoagulant plasma proteins except for tissue factor pathway inhibitor; the fibrinolytic plasma proteins plasminogen, α ₂ -antiplasmin, thrombin-activatable fibrinolysis inhibitor, and factor XIII; the von Willebrand factor (VWF)–cleaving protease ADAMTS13 ( a d isintegrin-like a nd m etalloprotease with t hrombo s pondin type 1 repeats, member 13); and thrombopoietin, the hormone involved in platelet production, are synthesized largely or exclusively by the liver. Most of these proteins are synthesized by the hepatocyte, except for factor VIII, which is synthesized by sinusoidal endothelial cells, and ADAMTS13, which is produced by stellate cells. In patients with either chronic or acute liver failure, profound alterations in the hemostatic system may occur, which is due partly to defective protein synthesis but presumably also involves other mechanisms, including defective protein clearance, clotting factor, and platelet consumption by intravascular and intrahepatic activation of coagulation, endothelial cell activation, and defective posttranslational modification of coagulation proteins. Typically the patient with liver disease has thrombocytopenia and/or platelet function defects, decreased levels of procoagulants and anticoagulants, decreased levels of fibrinolytic proteins, and elevated levels of factor VIII, VWF, and the endothelium-derived fibrinolytic proteins tissue-type plasminogen activator and plasminogen activator inhibitor type 1 (PAI-1). However, differences exist in the hemostatic alterations in patients with liver disease of different causes, and these are discussed later. The changes in the hemostatic system are accompanied by abnormal results on routine tests of hemostasis, such as a prolongation of the prothrombin time (PT) and partial thromboplastin time (PTT), as well as a decreased platelet count.

The net effect of all alterations in the hemostatic system has long been considered to favor a bleeding tendency. A hemostasis-related bleeding diathesis in patients with liver disease was thought to be supported by the frequently abnormal results on routine hemostasis tests (i.e., platelet count, PT, PTT). However, recent clinical and laboratory studies have provided solid evidence for a “rebalanced” hemostatic state in patients with chronic liver disease, as a consequence of a concomitant decrease in both prohemostatic and antihemostatic pathways. These novel insights into the hemostatic perturbations of liver disease have a profound impact on the hemostatic management of these patients. This chapter provides an overview of the clinical and laboratory features of hemostasis in patients with liver disease. Guidelines on the management of bleeding and thrombosis are also provided.

Hemostatic Alterations in Different Types of Liver Disease

A characteristic feature of both chronic and acute liver disease is decreased levels of hemostatic proteins, which are likely caused by a combination of decreased synthesis and increased consumption. Clotting factor consumption may be caused by low-grade disseminated intravascular coagulation, but specific intrahepatic activation of coagulation driven by activation of hepatocyte tissue factor may be an important consumptive mechanism as well. Specific types of liver disease may have specific characteristics, and unique features of specific liver diseases are outlined in the following sections.

Difficulty in Interpreting Hemostasis Test Results in Patients With Liver Disease

The interpretation of the results of routine tests of hemostasis is a particular challenge in patients with liver disease due to the multiple simultaneous alterations that occur. Ideally, routine tests of hemostasis would indicate whether a patient is at risk of bleeding, and the ideal routine test of hemostasis would also predict thrombosis risk. However, even in patients without liver disease, the relation between hemostasis test results and bleeding risk are poor, except in the presence of an established disease such as a clotting factor deficiency or an isolated thrombocytopenia. In patients without a diagnosed isolated hemostatic defect, tests such as the bleeding time, PT, and PTT are very poor predictors of spontaneous or procedure-related bleeding. It is important to realize that these tests were never developed to estimate bleeding risk. Rather, the PT and PTT were developed for diagnosing isolated coagulation factor deficiencies and for monitoring oral anticoagulant therapy, and the bleeding time has been used to diagnose platelet function defects (including VWD).

The PT and PTT are frequently prolonged in patients with liver disease, which reflects the decreased levels of procoagulant proteins. However, both the PT and PTT are insensitive for plasma levels of the natural anticoagulants tissue factor pathway inhibitor, protein C and protein S, and antithrombin III. Consequently, the PT and PTT are prolonged in patients with liver disease, despite concomitant changes in both procoagulant and anticoagulant pathways. Furthermore, the PT and PTT detect the formation of a fibrin clot, which occurs early in the process of secondary hemostasis and therefore reflects only part of the coagulation process. In fact, an in vitro fibrin clot is readily formed once only approximately 5% of the total thrombin generation has occurred during coagulation. When the hemostatic status of a patient with liver disease is tested using thrombin generation tests measuring the total amount of thrombin formed during coagulation, lower total thrombin generation is detected in patients than in healthy controls. However, in such an assay, no activation of the protein C system occurs due to the absence of thrombomodulin in plasma. When thrombin generation is studied in the presence of thrombomodulin, no differences are detected between patients with liver disease and healthy controls, and some studies even found increased thrombin generation in patients with cirrhosis. Unfortunately, the thrombin generation test is not yet suitable for use in routine diagnostic care due to the complexity of the assay. Routine diagnostic tests of coagulation also do not take the structure of the fibrin clot into account. Changes in fibrin structure resulting in decreased permeability and resistance to fibrinolysis have been convincingly shown to be present in patients with thrombosis. The structure of the fibrin clot in cirrhosis had thrombogenic features, despite decreased fibrinogen plasma levels. It is thus important to realize that widely used tests of coagulation such as the PT and PTT suggest a defective coagulation system, whereas tests that likely better reflect in vivo coagulation suggest coagulation to be in balance, probably because of a parallel decrease in both procoagulant and anticoagulant drivers.

The bleeding time, which has been widely used as a measure of platelet function but is becoming obsolete, is also frequently abnormal in patients with liver disease, as are results of platelet aggregation tests, including the classic suspension aggregometry and more contemporary platelet function analyses. The prolongation of the bleeding time is only partially explained by thrombocytopenia, and abnormal aggregation test results suggest that the prolonged bleeding time may also be related to platelet dysfunction. However, the prolonged bleeding time in liver disease is likely also related to changes in vasoreactivity or anemia. The predictive value of the bleeding time and results of aggregation tests for bleeding complications is limited. Furthermore, shortening of the bleeding time (e.g., by administration of 1-desamino-8- d -arginine vasopressin [DDAVP]) does not necessarily correlate with reduced bleeding risk. Also, platelet function defects as detected by suspension aggregometry are not found in some studies in which platelet function is studied under physiologic flow conditions. Like the changes in the coagulation system, the changes in primary hemostasis in patients with liver disease are complex and are not fully reflected by the available diagnostic tests. Importantly, the substantially increased levels of VWF and the decreased levels of the VWF-cleaving protease ADAMTS13 may compensate (in part) for the decreased platelet count and platelet function defects. The VWF-ADAMTS13 interplay is not reflected by routine tests of platelet function.

In vivo activation of platelets, coagulation, or fibrinolysis can be assessed by markers in plasma such as platelet factor 4/β-thromboglobulin (platelets), prothrombin fragment 1 + 2 or fibrinopeptide A (coagulation), and D-dimer or plasmin-antiplasmin complexes (fibrinolysis). Most of these assays, with the exception of D-dimer levels, are used only for research purposes. Elevated levels of these markers are frequently found in plasma from patients with liver disease, which may suggest that platelets, the coagulation system, and the fibrinolytic system are in an activated status in these patients. However, a more likely explanation is that levels of all these markers are elevated by accumulation due to decreased clearance rather than increased production, because all these markers are presumably largely or exclusively cleared by the liver.

(Mis)Use of the International Normalized Ratio in Liver Disease

The normalized PT, or INR, has been widely adopted by the hepatology community, although this test was specifically developed for monitoring long-term stable oral anticoagulant therapy in the general population. The INR is considered by hepatologists to be an important tool in stratifying severity of liver disease. The INR is used to define acute liver failure, with an INR of more than 1.5 required for the diagnosis, and is part of prognostic models such as the Kings College criteria. In chronic liver failure, the INR is an important determinant of the Model for End-Stage Liver Disease (MELD) score, which is used to prioritize liver transplant candidates. Furthermore, the INR is still frequently used to estimate bleeding risk in patients with liver disease, despite accumulating evidence that no relation exists between the INR and risk of bleeding in these patients.

Although the INR may be a reasonable marker of liver synthetic capacity, and thus may be useful in determining the severity of disease, there are major issues with the standardization of the INR in patients with liver disease, often with profound clinical consequences. The INR normalizes the PT to correct for differences in reagent and equipment according to the following equation: INR = (patient PT/control PT) ^ISI , in which the control PT is derived from the geometric mean of the PT for 20 or more healthy subjects and the ISI is the International Sensitivity Index, which takes into account both the PT reagent and the specific apparatus used. The ISI is calculated using samples from patients receiving oral anticoagulant therapy. It has been clearly demonstrated by multiple independent studies that interlaboratory variation in measuring the INR of patients with liver disease is unacceptably high, which is a direct consequence of the way the ISI is calibrated. The INR calculated for a single patient sample varies to such an extent when assayed in different laboratories that significant differences in the MELD score (a mean of 3 to 5 points) are obtained. The largest variations in the INR have been observed when reagents with higher ISI values are used, and the interlaboratory variability becomes larger with increasing INR. For a given patient with a high MELD score, these interlaboratory differences may substantially, yet artificially, alter the patient's position on the transplant waiting list, and thereby alter the chance of receiving a liver transplant. Because patients with the highest MELD scores are those with the highest risk of mortality, those with a MELD score assessed in a laboratory that produces a relatively lower INR test result may have an increased risk of dying while on the waiting list. Multiple solutions for this large interlaboratory variability in INR and MELD score have been proposed, including an alternative calibration of the ISI using plasmas from patients with liver disease instead of patients receiving oral anticoagulant treatment, but none of these solutions has been translated into clinical practice.