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2192 Part XII: Hemostasis and Thrombosis Chapter 128: Hemostatic Alterations in Liver Disease and Liver Transplantation 2193

SECONDARY HEMOSTASIS: COAGULATION pro- and antifibrinolytic, are synthesized by the liver. Therefore,
36
AND ANTICOAGULATION chronic liver disease leads to decreased plasma levels of plasminogen,
α -antiplasmin, TAFI, and factor XIII. Plasma levels of t-PA are elevated
2
The liver is the site of synthesis of most procoagulant proteins. As as a result of increased secretion from endothelial cells and/or reduced
a result, decreased levels of coagulation factors II, V, VII, IX, X, and clearance by the diseased liver. Plasma levels of PAI-1 also are increased
21
XI are commonly observed in patients with liver failure. In contrast, but not to the same extent as t-PA, which may lead to a shift in balance
factor VIII levels are increased, which may be related to the elevated in the fibrinolytic system. It has long been assumed that most patients
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level of its carrier protein VWF and to decreased clearance of factor VIII with chronic liver disease had accelerated fibrinolysis. This was based
from the circulation by the liver low-density lipoprotein-related recep- on in vitro assays, including various clot lysis assays and on measure-
tor. Factor VIII is synthesized primarily in hepatic sinusoidal endo- ments of increased fibrin(ogen) degradation products, D-dimer and
14
thelial cells, whose function is preserved in liver disease. 14,22 Acquired plasmin–antiplasmin complexes (reviewed in Ref. 36). However, more
vitamin K–dependent carboxylation deficiency may lead qualitative recent studies found no evidence of hyperfibrinolysis in the majority
defects in coagulation factors. Because of vitamin K deficiency or of patients with cirrhosis despite decreased levels of TAFI and ele-
decreased production of gamma-glutamyl carboxylase, circulating vita- vated D-dimer levels. 38,39 This conclusion was recently challenged by a
min K–dependent coagulation factors II, VII, IX, and X may be deficient study that used two assays to detect fibrinolysis in patients with various
in γ-carboxylated glutamic acid residues in their GLA domains, giving degrees of severity of cirrhosis. In both tests approximately 40 percent
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rise to impaired function of these factors. On the other hand, levels of patients had evidence of hyperfibrinolysis, and in 60 percent of the
of anticoagulant protein C, protein S, antithrombin, heparin cofactor patients, one of the tests revealed an increased fibrinolytic capacity,
II, and α -macroglobulin are also decreased in patients with liver dis- especially in those with severe liver dysfunction. Hyperfibrinolysis in
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2
ease. Fibrinogen levels are frequently in the normal range in patients patients with cirrhosis may also occur secondary to low-grade dissem-
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with chronic liver disease, but may be decreased in patients with dec- inated intravascular coagulation (DIC) induced by endotoxemia and is
ompensated cirrhosis or acute liver failure. A qualitative defect in manifested by concomitant increased levels of prothrombin fragment
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fibrinogen may be found in patients with liver disease. Screening tests 1+2, fibrinopeptide A, D-dimer, thrombin–antithrombin complex, and
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of coagulation, such as the prothrombin time (PT) or activated partial plasmin–antiplasmin complex. However, it has been argued that the
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thromboplastin time (aPTT), are frequently prolonged in patients with increased levels of these markers may result from their decreased clear-
chronic liver disease. These results have been traditionally interpreted to ance by the liver rather than from DIC. In patients with liver disease who
reflect a hypocoagulable state. The PT and aPTT are sensitive to levels of presented with gastrointestinal bleeding or soft-tissue bleeding after
procoagulant proteins in plasma, but not to the natural anticoagulants, trauma, in vitro signs of increased fibrinolysis have been reported. 42,43
proteins C, protein S, and antithrombin. The use of a more sophisti-
cated test of coagulation, such as total thrombin generation test, illus-
trates the limitation of the PT and aPTT. In a thrombin-generation test A REBALANCED HEMOSTATIC SYSTEM
measuring the total amount of thrombin generated during coagulation,
decreased total thrombin generation is measured in patients with cir- IN CHRONIC LIVER DISEASE
rhosis compared to controls. 11,27,28 Yet, when measured in the presence It has been a longstanding dogma that patients with liver disease are
of thrombomodulin to enable protein C activation and thereby also tak- at a high risk of bleeding due to reduction of synthesis of coagulation
ing into account the contribution of the main inhibitor of coagulation factors and other changes in hemostasis. More recent studies using
protein C, thrombin generation was indistinguishable from controls, more sophisticated coagulation tests have shown that thrombin gener-
despite abnormal conventional coagulation tests. Others found normal ation is normal in patients with chronic liver failure and that some may
thrombin generation without addition of thrombomodulin and even even have a prothrombotic phenotype. 24,27,44 Because both procoagulant
increased thrombin generation with addition of thrombomodulin. 29,30 and anticoagulant proteins decline in patients with chronic liver dis-
These results suggest that thrombin generation in vivo can be normal eases, it has been postulated that the hemostatic system is rebalanced
in patients with liver failure, and that a prolonged PT does not per se (Table 128–1). 24,31,45 In addition reductions of platelet number and
indicate a bleeding risk. These findings indicate that a concomitant impairment of platelet function is counteracted by high levels of VWF
decrease of pro-and anticoagulant factors result in a rebalanced hemo- and in many patients the decline in profibrinolytic factors is balanced
static system. 31 by the reduction of inhibitors of fibrinolysis. 13,38 This led to the model
Despite the limitations of the use of the PT in patients with liver of a rebalanced hemostatic system in these patients, which has impor-
disease the international normalized ratio (INR), which is a derivative tant implications for treatment. 24,31 This model also explains why most
of the PT, is still used in prognostic scores for patients with acute or patients with liver disease usually do not exhibit severe bleeding mani-
chronic liver disease. The model of end-stage liver disease (MELD) festations—neither during minor invasive procedures, such as biopsies
score is used to prioritize patients for liver transplantation. The INR and paracentesis, nor during major surgeries, including liver trans-
was originally developed and validated only to monitor anticoagulant plantation. 46,47 Furthermore, patients with liver disease may even have
therapy with vitamin K antagonists. The interlaboratory variation of the increased risk of venous thromboembolism, not only liver-specific
INR in patients with liver disease is substantial, and its use results in thrombosis, but also deep vein thrombosis. 48–50 The hemostatic balance
significant differences in MELD scores when a single patient sample is in patients with liver disease is, however, quite delicate and vulnerable
tested in different laboratories using various PT reagents. 32,33 The use to be tipped toward bleeding or thrombosis. So far it is impossible to
of alternative international sensitivity index (ISI) values obtained by identify which patients are more prone to bleeding or to thrombosis
calibration against plasma samples from patients with liver disease was based on current laboratory assays. The complex changes in hemostasis
shown to decrease this variability. 34,35
encountered in patients with liver disease are depicted in Table 128-1.
FIBRINOLYSIS The delicate hemostatic balance in patients with liver disease may be
changed by comorbidities, such as bacterial infections and renal failure
Except for tissue-type plasminogen activator (t-PA) and plasminogen- frequently observed in these patients. It is of major importance to treat
activator inhibitor (PAI)-1, all proteins involved in fibrinolysis, both these comorbidities so as to reduce the risk of bleeding and thrombosis. 51

Kaushansky_chapter 128_p2191-2198.indd 2192 9/18/15 10:38 AM