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.
E-mail: markus.peck@meduniwien.ac.at
Publication data
Accepted 28 August 2007
ª 2007 The Author
Journal compilation ª 2007 Blackwell Publishing Ltd
doi:10.1111/j.1365-2036.2007.03509.x
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 fibri-
nolytic factors, disrupting the balance between coagulation and anti-
coagulation systems.
Conclusions
Hemostatic abnormalities (eg. impaired synthesis of clotting factors,
heightened fibrinolysis, disseminated intravascular coagulation, thrombo-
cytopenia, and platelet dysfunction) can increase the risk of bleeding in
cirrhotic patients.
Aliment Pharmacol Ther 26 (Suppl 1), 21–28
21
22 M . P E C K - R A D O S A V L J E V I C

epistaxis, gingival bleeding, and metrorrhagia.1 How-

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 coag-
ulation and fibrinolysis (Table 1).1 Thus, impairment
of liver parenchymal cell function can disturb hae-
mostasis 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,
ever, patients with advanced liver disease are at
increased risk of bleeding during invasive proce-
dures, 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 proteins1

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
TFPI1, 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;22:83–96.
HMWK, high molecular weight kininogens; TAFI, thrombin activatable fibrinolysis inhibitor; TF, tissue factor; TFPI, tissue fac-
tor pathway inhibitor; tPA, tissue plasminogen activator.

ª 2007 The Author, Aliment Pharmacol Ther 26 (Suppl 1), 21–28

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 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 coagu-
lation. Following endothelial injury, platelets adhere
to the exposed subendothelial surface through plate-
let 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 transmem-
brane signalling events that lead to platelet activa-
tion, 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 haemo-
static abnormalities that disrupt the delicate balance
between clotting and fibrinolysis (Table 2).3, 4 Figure 1. Simplified schematic of the coagulation cas-
cade. tPA, tissue plasminogen activator; uPA, urokinase-
type plasminogen activator. Reprinted with permission
Reduced synthesis of coagulation factors from Rosenberg et al. NEJM 1999;340:1555–1564.

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 dam-
age, and hence, substantial loss of hepatic parenchy-
mal 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 pro-
duction 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 VII7 that probably con-
tribute 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
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 consid-
erably among patients.6, 9, 11
Factor VIII levels remain normal or elevated, even
in cirrhotic patients,11, 12 because of either extrahe-
patic synthesis (e.g., endothelial cells)13 or reduced
clearance of the factor VIII-von Willebrand factor
complex in the liver.12, 14
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

ª 2007 The Author, Aliment Pharmacol Ther 26 (Suppl 1), 21–28

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24 M . P E C K - R A D O S A V L J E V I C
Figure 2. Clotting pathway inhibitors and fibrinolytic
system. PAI-1, plasminogen activator inhibitor 1; PAI-2,
plasminogen activator inhibitor 2; TAFI, thrombin acti-
vatable fibrinolysis inhibitor; tPA, tissue plasminogen
activator. Reprinted with permission from Amitrano et al.
Semin Liver Dis 2002;22:83–96.
cirrhosis, or Child-Pugh grades A to C); however,
factor XIII deficiency (<50% of normal activity) can
be detected, albeit infrequently, in patients with
Table 2. Hemostatic abnormalities and pathogenetic mechanisms
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
Adapted with permission from Kujovich JL. Crit Care Clin 2005;21:563–587.
TAFI, thrombin activatable fibrinolysis inhibitor; tPA, tissue plasminogen activator.
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 pro-
longed 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 fac-
tor 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
3, 4
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
ª 2007 The Author, Aliment Pharmacol Ther 26 (Suppl 1), 21–28
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 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 dis-
ease. * P < 0.001 for Stage 4 vs. Stages 0, 1, 2, or 3. Re-
printed with permission from Rodriguez-Inigo et al. Blood
Coagul Fibrinolysis. 2001;12:193–199.
coagulopathy in liver disease. Because these routine
tests do not adequately measure activation of the anti-
coagulant 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 clear-
ance, 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 exces-
sive tPA activity in patients with severe cirrhosis.18, 19
Also, activity levels of the anti-fibrinolytic proteins,
a2-antiplasmin19 and thrombin activatable fibrinolysis
inhibitor,18, 20 are reduced as a result of substantial
liver damage, causing a further shift towards increased
fibrinolysis. Hyperfibrinolysis is correlated with other
coagulation abnormalities, including thrombocyto-
penia, reduced fibrinogen levels, and abnormally pro-
longed PT and PTT values.21 The elevated levels of
tPA on platelets lead to inhibition of platelet aggrega-
tion, degradation of platelet receptors (GP Ib and GP
IIb ⁄ IIIa),22 and induction of platelet disaggregation.23
ª 2007 The Author, Aliment Pharmacol Ther 26 (Suppl 1), 21–28
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Hyperfibrinolysis occurs in approximately 30% of
patients with compensated cirrhotic liver disease and
is positively correlated with the severity of liver dis-
ease 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 hyper-
fibrinolysis in patients with advanced liver disease.25
In a group of 112 patients with liver cirrhosis and
oesophageal varices, hyperfibrinolysis (defined as con-
comitant high values of D-dimer and tPA activity) was
identified as an independent predictor of gastrointesti-
nal 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 Thrombocyto-
penia 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 activ-
ity of coagulation factors, and increased fibrinolytic
activity), and together, these abnormalities may syner-
gistically increase the risk of bleeding in patients with
cirrhotic liver disease.6, 21
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 virus30 or interferon anti-
viral treatment,26 and increased platelet destruction
26 M . P E C K - R A D O S A V L J E V I C
mediated by immune mechanisms involving anti-plate-
let autoantibodies and platelet-associated immune
complexes.31, 32
Platelet function defects
Platelet aggregation in response to standard agonists is
impaired in patients with cirrhosis,33–36 probably
because of a variety of intrinsic platelet defects. These
include a defective signal transduction mechanism,37
reduced thromboxane A2 synthesis (which may con-
tribute to impaired platelet signalling),35 a platelet
storage pool defect,34 and deficiency of GPIb receptors
on the platelet surface (which negatively affects plate-
let aggregation and activation, and platelet-endothelial
cell adhesion).38, 39 The adhesion of platelets with vas-
cular subendothelial components is also impaired in
patients with Child-Pugh grade A and higher cirrho-
sis36; deficiency of platelet GPIb receptors may con-
tribute to this abnormality.39
Disseminated intravascular coagulation
Disseminated intravascular coagulation (DIC), also
referred to as ‘consumption coagulopathy,’ is charac-
terized by activation of the clotting cascade by a mag-
nitude 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 eleva-
tion of fibrinogen degradation products.4
Disseminated intravascular coagulation in patients
with liver disease involves multiple triggering mecha-
nisms (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 simi-
lar haemostatic abnormalities, (i.e., elevated prothrom-
bin, 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 proteo-
lytic cleavage products of coagulation reactions
(including fibrinopeptide A, prothrombin fragment F1
+ 2, thrombin-antithrombin and plasmin-a2-antiplas-
min complexes, soluble fibrin, and D-dimer), acceler-
ated 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 cirrho-
sis 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, pro-
gressive 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 inhibi-
tors 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 cir-
rhotic 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., anti-
thrombin 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 cir-
rhotic patients with thrombophilic disorders, including
the 20210 prothrombin gene mutation (which
increases the risk of PVT by more than 5-fold),44 and
antiphospholiplid antibodies.45
ª 2007 The Author, Aliment Pharmacol Ther 26 (Suppl 1), 21–28
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 REVIEW: COAGULATION DISORDERS IN CHRONIC LIVER DISEASE 27

abnormalities that increase the risk of thrombosis can

CONCLUSIONS
In summary, progressive liver damage in patients with
chronic liver disease of various aetiologies is associ-
ated with the development of coagulopathies. Hepato-
cellular damage adversely affects the hepatic
production of proteins that play critical roles in coag-
ulation 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, thrombo-
cytopenia, and platelet dysfunction. All of these
defects increase the risk of bleeding. Haemostatic
also occur including mutations in procoagulant pro-
teins together with decreased levels of anticoagulants
(Protein C and Protein S).
ACKNOWLEDGEMENT
Declaration of personal interests: MPR was an investi-
gator in a study funded by Novo Nordisk and has
acted as a consultant. This article appeared in a sup-
plement whose development was supported by Glaxo-
SmithKline.

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