Coagulation Disorders in Liver Disease

Lucio Amitrano, M.D.,1 Maria A. Guardascione, M.D.,1

Vincenzo Brancaccio, M.D.,2 and Antonio Balzano, M.D.1

ABSTRACT

The liver plays a central role in the clotting process, and acute and chronic liver
diseases are invariably associated with coagulation disorders due to multiple causes: de-
creased synthesis of clotting and inhibitor factors, decreased clearance of activated factors,
quantitative and qualitative platelet defects, hyperfibrinolysis, and accelerated intravascu-

Downloaded by: The University of Hong Kong. Copyrighted material.

lar coagulation. The bleeding tendency accounts for increased risk of morbidity and mor-
tality in patients with liver disease undergoing diagnostic or therapeutic invasive proce-
dures. Peculiar coagulation disorders are prevalent in patients with acute fatty liver of
pregnancy or undergoing liver transplantation. Emerging evidence shows that sepsis fur-
ther impairs hemostasis in patients with liver cirrhosis bleeding from esophageal varices.
Thrombotic events, even if rare in cirrhotic patients, occur mainly in the portal and
mesenteric veins. The therapeutic approach to coagulative disorders is also discussed.

KEYWORDS: Liver disease, coagulation, hemostasis, bleeding

Objectives: Upon completion of this article the reader should be able to (1) understand the multiple mechanisms of coagulation dis-
orders in patients with liver disease; (2) recognize peculiar clotting abnormalities occurring in specific clinical settings; and (3) evalu-
ate the risk and the benefit of a specific therapeutic approach to coagulation disorders in liver disease.
Accreditation: Tufts University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to
provide continuing medical education for physicians. TUSM takes full responsibility for the content, quality, and scientific integrity of
this continuing education activity.
Credit: Tufts University School of Medicine designates this education activity for a maximum of 1.0 hour credit toward the AMA
Physicians Recognition Award in category one. Each physician should claim only those hours that he/she actually spent in the edu-
cational activity.

T he liver plays a key role in the blood coagula-
tion process because it is the site of synthesis of all clot-
ting factors and their inhibitors (Table 1). Liver damage
is commonly associated with variable impairment of
hemostasis. Hemostasis is the process of blood clot for-
mation to prevent excessive blood loss due to vessel
injury. Subsequent to endothelial injury, the platelets
adhere to subendothelial matrix through two platelet-
collagen receptors (glycoproteins [GP] Ia, IIa, and VI).1
The activated platelets express the receptor GPIb-IX-V
complex that further strengthens the adhesion by link-
ing to von Willebrand factor (vWF) expressed on the
subendothelial matrix.2 A platelet monolayer covers all
the injured area, and additional activated platelets are
recruited and aggregated to form a platelet plug by the
linking to fibrinogen molecules via another receptor,
GPIIb/IIIa.3 Formation and deposition of fibrin occurs
by activation of the clotting cascade concomitantly with
platelet plug formation. A sequential activation of a se-
ries of inactive precursors leads ultimately to the forma-
tion of thrombin that cleaves fibrinogen to fibrin (Fig.
1). As the hemostatic process starts, a series of in-
hibitory mechanisms is activated to localize and limit
clotting formation to the damaged area (Fig. 2): anti-

Vascular and Coagulation Disorders of the Liver; Editor in Chief, Paul D. Berk, M.D.; Guest Editor, Kunio Okuda, M.D., Ph.D. Seminars in
Liver Disease, volume 22, number 1, 2002. Address for correspondence and reprint requests: Lucio Amitrano, M.D., Via Morghen 92, 80129
Naples, Italy. E-mail: luamitra@tin.it. 1Gastroenterology Unit and 2Coagulation Unit, A. Cardarelli Hospital, Naples, Italy. Copyright © 2002 by
Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662. 0272–8087,p;2002,22,01,
083,096,ftx,en;sld00154x.
83
84 SEMINARS IN LIVER DISEASE/VOLUME 22, NUMBER 1 2002

Table 1 Sites of Synthesis and Functions of Clotting Factors

Factors Synthesis Function

Procoagulants
Factor I or fibrinogen Liver, extrahepatic sites Precursor of fibrin
Factor II or prothrombin Liver Precursor of thrombin
Factor V Liver, endothelium, platelets Cofactor in the prothrombinase complex
Factor VII Liver Linked to TF activates factors X and IX
Factor VIII Liver, extrahepatic sites Cofactor in the intrinsic-X-ase complex
Factor IX (Christmas) Liver Activates factor X
Factor X (Stuart-Prower) Liver Converts prothrombin to thrombin
Factor XI Liver Activates factor IX
Factor XII (Hageman) Liver Activates factor XI
Factor XIII Liver, extrahepatic sites Crosslinks fibrin polymers
Prekallikrein (Fletcher) Liver Activates factor XII
HMWK Liver Activation cofactor for factors XII and factor XI, generates bradikinins
Tissue factor (Factor III) Endothelium, monocytes Cofactor in extrinsic X-ase complex
Anticoagulants

Downloaded by: The University of Hong Kong. Copyrighted material.

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
Heparan 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
Plasminogen Liver Precursor of plasmin
tPA Endothelium Activates plasminogen
Urokinase Kidney Activates plasminogen
Antifibrinolytic
PAI-1 Endothelium, platelets, liver Inhibits tPA
PAI-2 White blood cells Inhibits tPA
2-antiplasmin Liver Inactives plasmin
TAFI Liver Inhibits plasminogen activation
TF, tissue factor; HMWK, high-molecular-weight kininogens; TFPI, tissue factor pathway inhibitor; tPA, tissue plasminogen activator; TAFI,
thrombin activatable fibrinolysis inhibitor.

thrombin III, protein C, protein S synthesised from
the liver, the tissue factor pathway inhibitors 1 and 2
(TFPI-1 and TFPI-2), and platelet inhibitors (prosta-
glandin I2, nitric oxide). Once a clot is formed, fibrino-
lytic mechanisms assure its remodeling and elimination
to restore vessel patency. Plasmin is the key enzyme of
fibrinolysis, which cleaves the polymerized fibrin to fi-
brin degradation products (FDPs). The fibrinolytic
process is regulated by a series of activators and in-
hibitors (Fig. 2).
HEMOSTATIC ABNORMALITIES IN
LIVER DISEASE
Considering the key role of the liver in the coagulation
process, liver disease results in variable impairment of
hemostasis by multiple causes: quantitative and qualita-
tive platelet defects; decreased production of coagulation
and inhibitor factors; vitamin K deficiency; synthesis of
abnormal clotting factors, decreased clearance of acti-
vated factors by the reticuloendothelial system, hyperfib-
rinolysis, and disseminated intravascular coagulation.
Platelet Disorders
A mild thrombocytopenia is seen in 52% and 16% of
cases of acute hepatitis with and without liver failure,
respectively4; rarely a severe thrombocytopenia due to
aplastic anemia complicates the course of acute hepati-
tis.5 Thrombocytopenia is a common feature in chronic
advanced liver disease. It is found in about 30 to 64% of
cirrhotic patients,6,7 but the platelet count is rarely
below 30,000 to 40,000/mm3, and spontaneous bleed-
ing is not common. Splenomegaly due to portal hyper-
tension is considered the main cause of the low platelet
count in cirrhosis. The relationship between portal hy-
pertension and thrombocytopenia is documented by the
association between a low platelet count and the pres-
 COAGULATION DISORDERS/AMITRANO ET AL. 85

Downloaded by: The University of Hong Kong. Copyrighted material.

Figure 1 Clotting cascade. Three macromolecular complexes (demarcated by dashed lines) are identified in the clotting cascade.
They consist of a proteolytic enzyme, ; a cofactor, ; calcium ions; phospholipids (PL); and a substrate . TF, tissue factor; PK,
prekallikrein; HMWK, high-molecular-weight kininogens.

ence of gastroesophageal varices.8,9 Even if the platelet
mass is normal, up to 90% of platelets are pooled in the
spleen. However, these are still able to participate in the
hemostatic process. Direct correlation between spleen
size and platelet count has not been demonstrated,
and decompression of the portal system by surgical or
radiologic shunts does not completely correct the plate-
let count.10 A recent flow cytometric study showed
a reduced number of reticulated platelets, indicating
impaired platelet production11 in cirrhotic patients.
Thrombopoietin (TPO) is a cytokine produced by the
liver responsible for the maturation of megakaryocytes
and the formation of platelets. Serum levels of TPO are
reduced in cirrhotic patients with thrombocytopenia.12
After liver transplantation TPO concentration promptly
increases and reaches a peak on the fifth day, and a sub-
sequent increase in the number of platelets is observed
within 4 to 6 days after the peak of TPO.13 These data
suggest that low levels of TPO due to decreased hepatic
synthesis play a role in the thrombocytopenia of cir-
rhotic patients. Increased destruction of platelets by im-
mune mechanisms has been described: high levels of
immunoglobulin G (IgG), IgM, C3-C4, and platelet-
associated immune complexes have been found in acute
and chronic liver diseases.14 Furthermore, reduction of
the platelet count can be ascribed to the coexistence
86 SEMINARS IN LIVER DISEASE/VOLUME 22, NUMBER 1 2002
Figure 2 Clotting pathway inhibitors and fibrinolytic system.
tide B; tPA, tissue plasminogen activator; PAI-1, plasminogen activator inhibitor 1; PAI-2, plasminogen activator inhibitor 2; TAFI,
thrombin activatable fibrinolysis inhibitor.
of disseminated intravascular coagulation (DIC) during
sepsis, acute hepatic failure, hemolysis elevated liver en-
zyme and low platelet (HELLP) syndrome. Ethanol,15
folate deficiency,16 and drugs may contribute to throm-
bocytopenia by direct suppression of bone marrow
thrombopoiesis.17,18 Stored blood or red blood cells do
not provide viable platelets or Factor V; therefore, the
platelet count decreases when large quantities of blood
are transfused.19 In the absence of any coagulation fac-
tor deficiencies, a prolonged bleeding time with a nor-
mal platelet count is attributed to abnormalities of
platelet functions. Defective interaction among plate-
Downloaded by: The University of Hong Kong. Copyrighted material.
, inhibitors; , activators. FPA, fibrinopeptide A; FPB, fibrinopep-
lets, endothelial surface, and coagulation factors, dem-
onstrated by impaired aggregation to adenosine diphos-
phate, epinephrine, collagen, thrombin, and ristocetin
have been described in patients with liver disease.20,21
As a whole, their clinical implications remain to be
elucidated.
Decreased Synthesis of Coagulation Factors
The liver is the site of the synthesis of all coagulation
factors except for vWF. The degree of impairment of
procoagulants as an expression of decreased liver syn-

Table 2 Coagulation Tests and Their Clinical Usefulness
Hemostatic Tests
First-line tests
Platelet count
Prothrombin time
Activated partial thromboplastin time
Second-line tests
Thrombin time
Bleeding time
Single factor plasmatic activity
Thromboelastography
Tests of clotting activation
Prothrombin fragment F1+2
Thrombin–antithrombin complex
Fibrinopeptides A and B
Fibrin monomers and polymers
Tests of fibrinolysis
Euglobulin lysis time
Fibrin degradation products
D-dimer
Plasmin–2-antiplasmin complexes
thesis is related to the severity of liver damage, bleeding
tendency, and prognosis of liver disease. The clotting
factors measured by the common screening tests are in
the normal range until plasma levels of procoagulants
are reduced below 30 to 40% (Table 2). The measure-
ment of plasma levels of single clotting factors, even if
available for most of them, provides little adjunctive in-
formation. The determination of Factor V, VII, and
VIII activity is useful in specific clinical settings such as
fulminant hepatic failure and DIC. Coagulation disor-
ders are not common features of uncomplicated acute
hepatitis. Impairment of hemostasis implies severe liver
functional derangement and it is related to the severity
of liver damage. Decreased hepatic synthesis and im-
paired clearance of clotting factors and their inhibitors
coexist in patients with acute liver failure (ALF).22 In
these patients prothrombin time (PT) is commonly
used as a prognostic indicator of outcome and the need
for liver transplantation. In the King’s College experi-
ence, PT greater than 100 seconds was predictive of
mortality in 72% and 100% of cases in acetaminophen-
induced and non–acetaminophen-induced ALF.23 Fac-
tors V and VII have the shortest half-lives (12 hours
and 4–6 hours, respectively), and have been evaluated as
prognostic indicators in ALF. In the French-language
literature, a Factor V level below 20% in patients under
30 years of age or a Factor V level below 30% in patients
over 30 years of age were criteria for liver transplanta-
tion in the presence of encephalopathy grade 3 to 4.24
Factor VIII and fibrinogen as well as the other acute
phase reactants are increased, and their progressive re-
duction may indicate the presence of a DIC.
COAGULATION DISORDERS/AMITRANO ET AL. 87
Useful to Diagnose
Quantitative platelet disorders
Extrinsic and common coagulation pathway
Intrinsic and common coagulation pathway
Fibrinogen activity, dysfibrinogenemia
Qualitative platelet disorders
Specific clinical settings
Clotting monitoring during orthotopic liver transplantation
Increased thrombin generation
Increased thrombin generation
Increased thrombin generation
Increased thrombin generation
Downloaded by: The University of Hong Kong. Copyrighted material.
Hyperfibrinolytic activity
Hyperfibrinolytic activity
Hyperfibrinolytic activity
Hyperfibrinolytic activity
Depressed levels of procoagulant factors and
their inhibitors are present in liver cirrhosis. In compen-
sated liver cirrhosis, PT is usually in the normal range
or only moderately prolonged. Depressed synthesis of
extrinsic pathway factors, particularly Factor VII, ac-
counts for these abnormalities.25 Levels of fibrinogen
and Factor V are normal. As liver damage worsens, Fac-
tors XII and XI, high-molecular-weight kininogens,
and prekallikrein (i.e., the intrinsic pathway) are in-
volved in the deficit of protein synthesis, and activated
partial thromboplastin time is prolonged.26,27 PT pro-
longation is related to the severity of liver failure and is
one of the parameters of common prognostic indices
(Child-Pugh, Mayo end-stage liver disease).28,29 The
international normalized ratio (INR) for evaluation of
prothrombin time is commonly used but has not been
validated in patients with liver cirrhosis.30 Factor VIII
levels may remain normal or elevated even in the
presence of severe liver failure, either because of its ex-
trahepatic synthesis or because of a decreased liver
clearance of the vWF–Factor VIII complex. Plasma fi-
brinogen, being an acute-phase reactant, remains nor-
mal or even increases in chronic liver disease. Its de-
creased levels in severe liver insufficiency are attributed
to decreased liver synthesis as well as extravascular loss
(i.e., ascites) or concomitant DIC. Only fibrinogen lev-
els below 100 mg/dL have clinical and prognostic sig-
nificance.31 In obstructive jaundice and primary biliary
cirrhosis, normal or elevated levels of clotting factors are
detectable in the absence of vitamin K deficiency,32 due
to a nonspecific activation of protein synthesis. A hy-
percoagulative state, evaluated by thromboelastography,
88 SEMINARS IN LIVER DISEASE/VOLUME 22, NUMBER 1 2002
may be present in patients with primary biliary cirrhosis
and primary sclerosing cholangitis.33 Natural inhibitors
of coagulation, antithrombin III, protein C, and protein
S are synthesized by the liver as well. Their levels are re-
duced in advanced liver disease.34 Nevertheless, plasma
activity below 50 to 70% is not associated with in-
creased thrombotic events, possibly because of the pro-
portional impairment of clotting activators.35
Vitamin K Deficiency
A further reduction of plasma levels of Factors II ,VII,
IX, and X, and proteins C and S may be due to a con-
comitant vitamin K deficiency. These factors require vi-
tamin K as a cofactor for -carboxylation of glutamic
acid residues in their amino-terminal region. Gamma-
carboxylated residues allow the binding to calcium ions
essential for functional activity of these vitamin K–
dependent clotting factors. Vitamin K deficiency is not
caused by liver injury per se but is frequently associated
with liver disease.Vitamin K is a fat-soluble vitamin re-
quiring biliary salts for its intestinal absorption. The in-
testinal bacteria flora is involved as well, either partici-
pating in the biliary salt metabolism or producing a
small amount of vitamin K. Thus, reduced intestinal ab-
sorption of vitamin K occurs during intra- or extrahep-
atic cholestasis,36 presence of biliary fistulae, and use of
cholestyramine37 and oral antibiotics, especially ceph-
alosporins.38 Moreover, vitamin K deficiency may be
part of the malnutrition state often associated with al-
coholism.39 High levels of decarboxylated precursors of
vitamin K–dependent clotting factors are dosable in
plasma in the presence of vitamin K deficiency. These
precursors (named PIVKA, for precursors induced by
vitamin K absence) are found in small amounts in acute
and chronic liver disease possibly caused by a deficit of
hepatic decarboxylase.40 However, their clinical signifi-
cance does not seem to be relevant. Conversely, high
titers of decarboxylated prothrombin (DCP), antigeni-
cally identical to that induced by warfarin therapy, are
found in patients with hepatocellular carcinoma.41 An
acquired posttranslational defect of -carboxylation in-
duced by the tumoral cells is postulated,42 and a DCP
level greater than 100 ng/mL is considered more spe-
cific than -fetoprotein in the diagnosis of hepatocellu-
lar carcinoma.43
Dysfibrinogenemia
Dysfibrinogenemia is the most common qualitative ab-
normality of clotting factors, found in about 60 to 70% of
acute and chronic liver disease and hepatoma.44 It is char-
acterized by abnormal polymerization of fibrin mono-
mers leading to a disproportionate prolonged thrombin
time despite mild prolonged PT, partial thromboplastin
time (PTT), and normal amount of fibrinogen. An ex-
cessive number of syalic acid residues on the molecule
of fibrinogen interferes with the enzymatic activity of
thrombin. Dysfibrinogenemia induced by liver damage is
a reversible abnormality due to an increased activity of
the enzyme syalil-transferase because of a reexpression of
the fetal gene in hepatic cells.45
Fibrinolysis
Increased fibrinolysis is a common finding in patients
with advanced liver disease. It is revealed by shortened
whole blood euglobin clot lysis time and elevated levels
of plasma D-dimer, fibrin and fibrinogen degradation
products. High levels of plasminogen activators, espe-
cially tissue plasminogen activator (tPA), due to de-
Downloaded by: The University of Hong Kong. Copyrighted material.
creased hepatic clearance, account for hyperfibrinolysis.
Levels of the tPA inhibitor plasminogen activator in-
hibitor-1 are normal or slightly elevated but are insuffi-
cient to counteract the increase of tPA.46 Moreover, low
levels of 2-antiplasmin and thrombin activatable fibri-
nolysis inhibitor, caused by progressive liver damage,
may be an adjunctive cause of accelerated fibrinolysis.47
Controversy still exists over whether fibrinolysis is a
primary phenomenon or induced by clotting activa-
tion.46,48,49 Hyperfibrinolysis is seen in patients with ad-
vanced chronic liver disease but not in patients with
acute liver disease. It is present in 31% of patients with
compensated liver cirrhosis50 and in 93% of patients
with ascites51 and it is related to the severity of the dis-
ease. Elevated levels of D-dimer and FDPs together
with low fibrinogen and plasminogen have been found
in ascitic fluid of cirrhotic patients, suggesting ascitic
hyperfibrinolytic activity. Thus, it is thought that ascites
reabsorption into systemic circulation contributes to the
hyperfibrinolytic state found in cirrhotic patients.51
These data are in accordance with previous observations
of hyperfibrinolysis-like changes in plasma of cirrhotic
patients undergoing ascites reinfusion.52 The clinical
relevance of hyperfibrinolysis in the bleeding tendency
of cirrhotic patients has not been clearly established.
Accelerated fibrinolysis may enhance bleeding from
mucous membranes and increase the incidence of fatal
bleeding.53,54 In a large prospective study, hyperfibrinol-
ysis was found as a main predictive marker of the first
episode of upper gastrointestinal bleeding in cirrhotics
with portal hypertension.55
Disseminated Intravascular Coagulation
Disseminated intravascular coagulation is a widespread
intravascular fibrin deposition due to massive activation
of the clotting cascade. Intravascular fibrin deposition is

the result of uncontrolled thrombin generation over-
whelming natural anticoagulant pathways. Thrombin
activation is mediated exclusively by high levels of tis-
sue factor with consequent activation of the extrinsic
pathway.56 Deposition of fibrin in small and medium-
sized vessels leads to arterial or venous thrombosis
and progressive multiorgan failure. The consumption of
clotting factors, platelets, and secondary fibrinolysis
activation are responsible for bleeding manifestations.
Moreover, microangiopathic hemolytic anemia may be
due to enhanced erythrocyte destruction by fibrin
strands. The clinical course of DIC may be extremely
variable from asymptomatic to chronic and acute forms,
depending mostly on the underlying cause, rapidity of
clotting activation, and efficacy of compensatory mech-
anisms.57 The fact that DIC and decompensated cirrho-
sis share similar coagulation abnormalities poses the
question whether a low-grade DIC is present in decom-
pensated liver disease or hepatic coagulopathy mimics a
DIC-like pattern.48,58,59 The issue is still a matter of
debate. More recently, the availability of new sensitive
and specific assays, prothrombin fragment F1+2,
fibrinopeptide A, soluble fibrin, D-dimer, thrombin-
antithrombin (TAT) complexes, and plasmin–2-anti-
plasmin (PAP) complexes, have allowed the recognition
of accelerated intravascular coagulation and fibrinolysis
(AICF) in liver cirrhosis.60 AICF, previously defined as
low-grade DIC, is not a part of stable liver cirrhosis but
is found in about 30% of patients with advanced liver
disease and is related to its severity.61 AICF may be re-
duced by heparin administration, as already suggested
by previous studies.62 Patients with liver cirrhosis and
AICF are prone to develop overt DIC in the presence
of complications such as sepsis, shock, surgery, trauma,
and ascites recirculation. The diagnosis of DIC in cir-
rhotic patients remains difficult and is based on the
presence of a known triggering clinical event; the
progressive worsening of coagulation test results and
platelet counts; a disproportionate reduction of Factor
V; and concomitant decreased level of a previously nor-
mal Factor VIII.
COAGULATION DISORDERS IN SPECIFIC
CLINICAL SITUATIONS
Clinical manifestations of coagulative disorders in pa-
tients with liver disease depend on the degree of hemo-
static impairment. Minor signs of the bleeding ten-
dency are skin hemorrhages such as bruising, petechiae,
purpura, and ecchymosis, or mucosal bleeding such as
epistaxis, gingival bleeding, or metrorrhagia. The bleed-
ing diathesis may have more severe and life-threatening
consequences in cirrhotic patients bleeding from the
gastrointestinal tract or undergoing invasive procedures
or surgery.
COAGULATION DISORDERS/AMITRANO ET AL. 89
Invasive Procedures
Patients with advanced liver disease run an increased
risk of bleeding complications because of underlying
coagulopathy during invasive diagnostic and therapeu-
tic procedures. Patients with liver cirrhosis undergoing
abdominal surgery have increased risks for morbidity
and mortality.63,64 Bleeding accounts for 60% of all
causes of death.65 PT is related both to bleeding risk
and mortality; patients with a PT prolongation of more
than 1.5 seconds and more than 2.5 seconds have mor-
tality rates of 47% and 87% , respectively versus 7% for
patients with normal PT.66 Hence, an accurate preoper-
ative evaluation of cirrhotic patients undergoing surgery
is mandatory. A PT prolonged for more than 3 seconds
and a platelet count of less than 50,000/mm3 are con-
sidered contraindications to elective surgery.64 More-
over, the concomitant presence of portal hypertension
contributes to excessive intra- or postoperative blood
Downloaded by: The University of Hong Kong. Copyrighted material.
loss during liver surgery for trauma, neoplasm, or porto-
caval shunts. Hyperfibrinolysis and clotting activation
occur during resective liver surgery,67 and they are re-
lated to the extension of liver resection and plasma
levels of tPA.68
Liver biopsy is a widespread tool used to diag-
nose diffuse or focal hepatic diseases. Intraperitoneal
hemorrhage is the main complication of liver biopsy.
Significant bleeding, defined as a decrease in hemoglo-
bin level of greater than 20 g/L, occurs in 0.35 to 0.5%
of cases.69,70 A fatal hemorrhage is reported from 0.01
to 0.1%71 and is often associated with advanced cirrho-
sis or malignancy. PT and platelet count are widely ac-
cepted tests used to evaluate the bleeding risk in pa-
tients undergoing liver biopsy. However, no peripheral
coagulative parameters have been found related to liver
bleeding time observed at laparoscopy.72 Several studies
demonstrated no increased bleeding risk associated with
a prolongation of PT until 4 to 7 seconds.69,71,73 On the
other hand, a doubled bleeding risk is reported in pa-
tients with INR greater than 1.5 compared with pa-
tients with INR of 1.3 to 1.5.74 Platelet count values
above which liver biopsy is safely performed range from
56,000 to 80,000 mm3 in different specialized cen-
ters.71,74 The routine use of the bleeding time as a better
indicator of hemorrhagic risk is still debated.75,76 It is
currently used in no more than 30% of liver units before
liver biopsy. Liver biopsy can be safely performed77 if
the platelet count is greater than 60,000 mm3 and PT is
prolonged for less than 4 seconds. If the platelet count is
between 40,000 and 60,000 mm3 and PT is prolonged
for 4 to 6 seconds, platelet and fresh frozen plasma
transfusions have to be given. If the platelet count is
under 40,000 mm3 and PT is prolonged for over 6 sec-
onds, a plugged, transjugular, or laparoscopic biopsy
should be considered.78 Minor invasive procedures such
as paracentesis, thoracentesis, and lumbar puncture do
not usually necessitate platelet or plasma transfusion.
90 SEMINARS IN LIVER DISEASE/VOLUME 22, NUMBER 1 2002
Liver Transplantation
Coagulopathy is one of the main problems in patients
undergoing orthotopic liver transplantation (OLT).
Intra- and postoperative bleeding is frequent and strictly
related to the mortality rate of OLT.79 Different mecha-
nisms are implicated in the bleeding tendency during the
various phases of OLT. In the pre-anhepatic phase the
duration and complexity of the surgical procedure and
the presence of portal hypertension together with preex-
isting impaired hemostasis are the main causes of the
blood loss.80,81 The preoperative hemostatic impairment
is related to transfusion requirements and patient sur-
vival.82 Coagulation tests are less compromised in pa-
tients with primary biliary cirrhosis,83 and a hypercoagu-
lative state may be present.33 In the anhepatic phase,
bleeding is due both to the absence of hepatic clotting
factor production and to hyperfibrinolysis caused by in-
creased levels of tPA not cleared by the liver.84 A brisk
increase in tPA, PAP complexes, and D-dimer levels
after liver graft reperfusion indicate hyperfibrinolysis.85
The release of tPA by graft endothelial cells contributes
to hyperfibrinolysis in this phase.86 Prophylactic admin-
istration of aprotinin, a broad-spectrum serine protease
inhibitor, markedly reduces fibrinolysis and both intra-
and postoperative blood product requirements by at least
30%.87,88 Moreover, tranexamic acid, another antifibri-
nolytic agent, can reduce total packed blood red cell use
during OLT.89 Other mechanisms account for bleeding
tendency during OLT: a nonspecific activation of pha-
gocytic proteases during the reperfusion phase90; an
increased intrinsic heparin-like activity91; a transient
platelet count decrease because of sequestration and acti-
vation of platelets in the graft sinusoids92; and a reduced
platelet aggregation due to adenosine contained in Uni-
versity of Wisconsin fluid.79 Continuous clotting moni-
toring during the different phases of OLT is obtained by
thromboelastography (TEG), which provides rapid in-
formation (within 30 minutes) on coagulation, fibrinoly-
sis, and platelet activity. It has proven to be a valuable
guide for blood product replacement.93
Pregnancy
Two peculiar syndromes, HELLP syndrome and acute
fatty liver of pregnancy, occurring in the third trimester
of pregnancy, are associated with coagulative disorders.
HELLP syndrome, first described in 1982 by Wein-
stein,94 is characterized by elevation of liver enzymes,
hemolysis, and low platelet count. It occurs in 10% of
preeclampsia and eclampsia, and it is caused by diffuse
platelet and fibrin deposition on the damaged sinu-
soidal endothelium. The systemic endothelial dysfunc-
tion is determined by an increased vascular sensitivity to
endogenous pressor agents.95 Fibrin deposition leads to
periportal and portal tract hemorrhages and to ischemic
necrosis that may progress to intrahepatic hematoma
and liver rupture.96 Moreover, hemolysis due to mi-
croangiopathic hemolytic anemia as well as thrombo-
cytopenia97 is generally mild. PT and PTT are normal,
but FDPs, D-dimer, soluble fibrin, and PAP and TAT
complexes increase as markers of secondary fibrinolysis
and clotting activation.98 An overt DIC may be diag-
nosed in only 20% of cases.99 Plasma levels of coagula-
tion and fibrinolysis parameters have prognostic value
in HELLP syndrome. An antithrombin III level of less
than 79%, D-dimer of more than 4 g/mL, and TAT of
more than 26 ng/mL have been proposed as indices for
termination of pregnancy in patients with HELLP syn-
drome.98 Acute fatty liver of pregnancy is an acute dis-
order during pregnancy evolving into fulminant hepatic
failure.100 It is characterized by acute hepatic fatty
microvesicular degeneration, in some cases due to in-
herited mitochondrial fatty acid oxidation enzyme de-
fects.101 It is associated with elevated maternal and in-
Downloaded by: The University of Hong Kong. Copyrighted material.
fant mortality. Thrombocytopenia and a decrease in
clotting factors and their inhibitors are due both to im-
paired hepatic synthesis and accelerated consumption.
DIC is present in almost all patients,102 although bleed-
ing complications ensue in about 25% of cases.103
Sepsis
High rates of bacterial infection have been demon-
strated in cirrhotic patients with gastrointestinal hem-
orrhage.104 It is closely related to mortality and the fail-
ure to control bleeding.105,106 Sepsis is generally thought
to be a complication of bleeding; however, it can cause
bleeding and rebleeding from esophageal varices. This is
because of an increase in portal hypertension and a fur-
ther impairment of hemostasis.107 A hypocoagulable
state has been demonstrated in cirrhotic patients with
sepsis108 and in those with early rebleeding from esoph-
ageal varices.109 Hyperfibrinolysis is associated with the
risk of gastrointestinal bleeding,55,110–112 and bleeding
from esophageal varices overlaps the circadian rhythm
of fibrinolysis in patients with liver cirrhosis.113 In-
fection enhances the production of the cytokines inter-
leukin-1 (IL-1), IL-6, and tumor necrosis factor that
are able to activate clotting and fibrinolysis114 via
stimulation of the extrinsic pathway. Endotoxins, pro-
duced by bacteria, stimulate tissue factor expression on
macrophages and clotting activation via an oxidative
process.115,116 A relationship has been demonstrated be-
tween tissue factor levels and markers of lipid peroxida-
tion, clotting activation, and fibrinolysis in cirrhotic pa-
tients.117 Hyperfibrinolysis delays clotting activation
through clotting factor consumption and inhibition of
fibrin polymerization and reduces platelet adhesion and
aggregation as well.58 Platelet functions are further im-
paired by increased prostacyclin levels, which are in-
duced by endotoxin and endothelin via nitric oxide for-
mation.107 How these phenomena induced by sepsis can

trigger gastroesophageal bleeding remains speculative
and requires further study.
Thrombosis
Coagulation disorders during liver disease mostly re-
sults in an increased bleeding tendency. However, the
balance between the reduced levels of clotting activators
and inhibitors may sometimes lead to hypercoagula-
tion and thrombosis. A hypercoagulable state has been
found in patients with primary biliary cirrhosis, primary
sclerosing cholangitis,83 and advanced cirrhosis, in
which an accelerated intravascular coagulation may be
present. Thrombosis can develop if these patients are
suffering from sepsis or trauma. Spontaneous thrombo-
sis occurs mainly in the portal and mesenteric veins in
patients with liver cirrhosis. The prevalence of non-
neoplastic portal vein thrombosis (PVT) ranges from 8
to 16%,118,119 and it is associated with increased morbid-
ity and mortality during liver transplantation.120 Portal
vein thrombosis, like other venous thrombotic events, is
due to the concomitant presence of congenital or ac-
quired, or local or systemic risk factors.121 The slowing
of the blood flow in the splanchnic venous bed due to
portal hypertension represents the local acquired risk
factor. A prothrombotic state due to inherited disorders
of clotting factors, Factor V Leiden, and prothrombin
G20210A mutation has been found in PVTs of cir-
rhotic patients.122,123 Anticardiolipin antibodies, usually
associated with antiphospholipid syndrome, an acquired
thrombophilic condition, have been advocated in the
pathogenesis of PVT.124 However, the association be-
tween anticardiolipin antibodies and clinical throm-
botic events in patients with chronic hepatitis,125,126
liver cirrhosis,127 or patients receiving a liver transplant
has not been demonstrated.128 Further studies address-
ing this issue are needed.
THERAPY
Spontaneous bleeding is infrequent in patients with ad-
vanced liver disease, and treatment of hemostatic abnor-
malities is not generally required. On the other hand,
correction of coagulation disorders in patients with liver
disease has to be pursued in cases of active persistent
bleeding, before diagnostic or therapeutic invasive pro-
cedures, before major surgery, and in patients with ALF.
Different blood and nonblood products are available as
supportive or repletive treatments.
Fresh frozen plasma (FFP) contains all clotting
and inhibitor factors. Administration of 10 to 20 mL/kg
body weight of FFP may curtail PT prolongation to less
than 3 seconds.27 The correction of coagulation para-
meters is prompt but lasts no more than 12 to 24 hours.
The lack of correction of clotting parameters after ade-
quate FFP transfusion suggests the presence if inhibi-
COAGULATION DISORDERS/AMITRANO ET AL. 91
tors such as FDP or dysfibrinogenemia. Administration
of FFP is indicated in cases of persistent bleeding in
order to gather an INR of under 2129 and to correct a
PT prolongation of more than 4 seconds in patients un-
dergoing liver biopsy.77 However, the large amounts of
FFP (>1,500 mL) required to achieve the hemostatic
effect could be contraindicated in some patients.130 The
risk of transmission of infectious agents by FFP trans-
fusion, as for other blood products should not be under-
estimated.131
The solvent detergent-treated plasma is effective
to lessen the risk of transmission of viral infections, but
it is deficient in Factor VIII, protein C, protein S, and
2-antiplasmin.132
Cryoprecipitate, obtained when FFP is thawed at
4°C, contains Factor VIII, fibrinogen, vWF, fibronectin,
and Factor XIII. One unit of cryoprecipitate (20–30
mL) for every 10 kg body weight increases plasma fi-
Downloaded by: The University of Hong Kong. Copyrighted material.
brinogen by 50 mg/dL.133 Administration of cryopre-
cipitate is indicated in bleeding patients when fibrino-
gen levels are less than 80 to 100 mg/dL because of
DIC or massive blood transfusion.
Prothrombin complex is a concentrate of Factors
II, VII, IX, and X, obtained from the plasma of several
thousand donors. The use of prothrombin complex is
limited by the risk of infectious disease transmission,134
anaphylaxis, and the risk of DIC because of the pres-
ence of activated clotting factors.135,136
Recombinant Factor VIIa is a promising agent to
correct hemostatic impairment in patients with liver fail-
ure.137 In preliminary reports, 80 g/kg dose of recombi-
nant Factor VIIa (Novoseven, Novo Nordisk Pharmaceu-
ticals) normalized PT for more than 12 hours in patients
with Child-Pugh class B and C cirrhosis.138 It has been
successfully used to restore coagulative parameters in a
small number of patients with acute liver failure.139 Lastly,
a single dose of Novoseven seems to reduce blood product
requirements during liver transplantation.140 The overall
potential benefits and risks of recombinant Factor VIIa
need to be confirmed in large controlled studies.
Platelet transfusion is required in patients with
active persistent bleeding when the platelet count is less
than 50,000/mm3.133,141 A platelet count of around
100,000/mm3 needs to be attained.27 Prophylactic use
of platelet concentrates is only indicated in patients
undergoing invasive diagnostic procedures or elective
surgery when the platelet count is less than 60,000/
mm3.77,133 One unit of platelet concentrate increases the
peripheral blood count by about 10,000/mm3, and the
therapeutic dose is 1 U/10 kg body weight.133 Platelets
derived from a single donor by apheresis correspond to
six random platelet concentrates. Repeated platelet
transfusion induces alloimmunization and refractive-
ness to new transfusion.141 This is an important issue in
patients on the waiting list for liver transplantation in
which HLA-matched and cross-matched platelets may
92 SEMINARS IN LIVER DISEASE/VOLUME 22, NUMBER 1 2002
be required.142 The use of recombinant TPO for the
correction of thrombocytopenia of cirrhotic patients is
still under investigation.143
Vitamin K deficiency is not usually present in
patients with liver cirrhosis, whereas it is likely in pa-
tients with cholestatic disease. A trial of 10 mg vitamin
K for 3 days has to be attempted to correct PT prolon-
gation.95 Vitamin K can be administered intravenously
with the advantage of a therapeutic effect within 6 to 8
hours,144 but anaphylaxis can occur. Subcutaneous ad-
ministration has an inconstant rate of absorption,
whereas intramuscular injection has to be avoided be-
cause of the risk of hematoma formation. Menadiol, the
water-soluble formulation of vitamin K, has proved ef-
fective when given orally to correct the INR in patients
with cholestasis.145
Desmopressin, 1-deamino-8-D-arginine vaso-
pressin (DDAVP), a derivative of antidiuretic hormone,
can increase plasma levels of Factor VIII and vWF,146,147
releasing them from storage sites.148 Bleeding time, PT,
and PTT are shortened by DDAVP in patients with
liver cirrhosis despite normal or elevated Factor VIII
and vWF.146,147 However, no clinical benefits have been
demonstrated in cirrhotic patients bleeding from esoph-
ageal varices.149 Its use is proposed in patients with liver
disease and prolonged bleeding time undergoing inva-
sive procedures.148
Antifibrinolytic agents such as aprotinin, epsilon-
aminocaproic acid, and tranexamic acid are the most
commonly used antifibrinolytic agents. They induce in-
hibition of plasminogen activation and plasmin activity.
These drugs have proved useful in the reduction of blood
loss and transfusion requirements during major liver sur-
gery and OLT.85,87–89
Administration of antifibrinolytic agents in pa-
tients with liver cirrhosis is limited by the risk of throm-
bosis when DIC is present.
ABBREVIATIONS
AICF accelerated intravascular coagulation and
fibrinolysis
ALF acute liver failure
DCP decarboxylated prothrombin
DDAVP 1-deamino-8-D-arginine vasopressin
DIC disseminated intravascular coagulation
FDPs fibrin degradation products
FFP fresh frozen plasma
INR international normalized ratio
OLT orthotopic liver transplantation
PAP plasmin–2-antiplasmin complexes
PT prothrombin time
PTT partial thromboplastin time
PVT portal vein thrombosis
TAT thrombin-antithrombin complexes
TFPI tissue factor pathway inhibitor
tPA tissue plasminogen activator
TPO thrombopoietin
vWF von Willebrand factor
REFERENCES
1. Watson SP. Collagen receptor signalling in platelets and
megakaryocytes. Thromb Haemost 1999;82:365–376
2. Berndt MC, Shen Y, Dopheide AM, et al. The vascular
biology of the glycoprotein Ib-IX-V complex. Thromb
Haemost 2001;86:178–188
3. Savage B, Shattil SJ, Ruggeri ZM. Modulation of platelet
function through adhesion receptors: a dual role for glyco-
protein IIb-IIIa (integrin alpha IIb beta 3) mediated by fi-
brinogen and glycoprotein Ib-von Willebrand factor. J Biol
Chem 1992;267:11300–11306
4. Gallus AS, Lucas CR, Hirsh J. Coagulation studies in pa-
tients with acute infectious hepatitis. Br J Haematol 1972;
22:761–771
Downloaded by: The University of Hong Kong. Copyrighted material.
5. Tzakis AG, Arditi M, Whittington PF, et al. Aplastic ane-
mia complicating orthotopic liver transplantation for non-
A, non-B hepatitis. N Engl J Med 1988;319:393–396
6. Lechner K, Niessner H, Thaler E. Coagulation abnormali-
ties in liver disease. Semin Thromb Hemost 1977;4:40–56
7. Bashour FN, Teran JC, Mullen KD. Prevalence of periph-
eral blood cytopenias (hypersplenism) in patients with non-
alcoholic chronic liver disease. Am J Gastroenterol 2000;95:
2936–2939
8. Schepis F, Cammà C, Niceforo D, et al. Which patients
with cirrhosis should undergo endoscopic screening for
esophageal varices detection? Hepatology 2001;33:333–338
9. Zaman A, Hapke R, Flora K, et al. Factors predicting the
presence of esophageal or gastric varices in patients with ad-
vanced liver disease. Am J Gastroenterol 1999;94:3292–3296
10. Karasu Z, Gurakar A, Kerwin B, et al. Effect of transjugular
intrahepatic portosystemic shunt on thrombocytopenia as-
sociated with cirrhosis. Dig Dis Sci 2000;45:1971–1976
11. Koike Y, Yoneyama A, Shirai J, et al. Evaluation of throm-
bopoiesis in thrombocytopenic disorders by simultaneous
measurement of reticulated platelets of whole blood and
serum thrombopoietin concentrations. Thromb Haemost
1998;79:1106–1110
12. Kawasaki T, Takeshita A, Souda K, et al. Serum throm-
bopoietin levels in patients with chronic hepatitis and liver
cirrhosis. Am J Gastroenterol 1999;94:1918–1922
13. Peck-Radosavljevic M, Wichlas M, Zacherl J, et al. Throm-
bopoietin induces rapid resolution of thrombocytopenia
after orthotopic liver transplantation through increased
platelet production. Blood 2000;95:795–801
14. Samuel H, Nardi M, Karpatkin M, et al. Differentiation of
autoiimune thrombocytopenia from thrombocytopenia asso-
ciated with immune complex disease : systemic lupus erythe-
matosus, hepatitis-cirrhosis, and HIV-1 infection by platelet
and serum immunological measurements. Br J Haematol
1999;105:1086–1091
15. Lindenbaum J, Hargrove RL. Thrombocytopenia in alco-
holics. Ann Intern Med 1968;68:526–532
16. Lindenbaum J. Folate and vitamin B12 deficiencies in alco-
holism. Semin Hematol 1980;17:119–129
17. Fattovich G, Giustina G, Favarato S, et al. A survey of ad-
verse events in 11,241 patients with chronic viral hepatitis
treated with alfa interferon. J Hepatol 1996;24:38–47

18. Schirren CA, Berghaus TM, Sackmann M. Thrombotic
thrombocitopenic purpura after Ecstasy-induced acute liver
failure. Ann Intern Med 1999;130:163
19. Ratnoff OD. Hemostatic defects in liver and biliary tract
disease and disorders of vitamin k metabolism. In: Ratnoff
OD, Forbes CD, eds. Disorders of Hemostasis. Philadel-
phia: WB Saunders; 1991:459–479
20. Rubin MH, Weston MJ, Langley MH, et al. Platelet func-
tion in chronic liver disease: relationship to disease severity.
Dig Dis Sci 1979;24:197–202
21. Ingeberg S, Jacobsen P, Fischer E, et al. Platelet aggregation
release of ATP in patients with hepatic cirrhosis. Scand J
Gastroenterol 1985;20:285–288
22. Pereira SP, Langley PG, Williams R. The management of
abnormalities of hemostasis in acute liver failure. Semin
Liver Dis 1996;16:403–414
23. O’Grady JG, Alexander GJM, Hayllat KM, et al. Early indi-
cators of prognosis in fulminant hepatic failure. Gastroen-
terology 1989;97:439–445
24. Bismuth H, Samuel D, Castaing D, et al. Orthotopic liver
transplantation and subfulminant hepatitis. The Paul
Brousse experience. Ann Surg 1995;222:109–119
25. Green G, Poller L, Thomsen JM, et al. Factor VII as a
marker of hepatocellular synthetic function in liver disease. J
Clin Pathol 1976;29:971–97
26. Paramo JA, Rocha E. Hemostasis in advanced liver disease.
Semin Thromb Hemost 1993;19:184–190
27. Brophy MT, Fiore LD, Deykin D. Hemostasis. In: Zakim
D, Boyer TD, eds. Hepatology, a Textbook of Liver Disease.
Philadelphia: WB Saunders; 1996:691–719
28. Pugh RNH, Murray-Lyon IM, Dawson JL, et al. Transec-
tion of the oesophagus for bleeding oesophageal varices. Br J
Surg 1973;60:646–649
29. Forman LM, Lucey MR. Predicting the prognosis of
chronic liver disease: an evolution from child to MELD.
Mayo end-stage liver disease. Hepatology 2001;33:473–475
30. Rovert A, Chazouilleres O. Prothrombin time in liver fail-
ure: time, ratio, activity percentage, or international normal-
ized ratio? Hepatology 1996;24:1392–1394
31. Dymock IW, Tucker JS, Woolf IL, et al. Coagulation studies
as a prognostic index in acute liver failure. Br J Haematol
1975;29:385–395
32. Cederblad G, Korsan-Bengsten K, Olsson R. Observation
of increased levels of blood coagulation factors and other
plasmaproteins in cholestatic liver disease. Scand J Gas-
troenterol 1976;11:391–396
33. Ben-Ari Z, Panagou M, Patch D, et al. Hypercoagulability
in patients with primary biliary cirrhosis and primary scle-
rosing cholangitis evaluated by thromboelastography. J He-
patol 1997;26:554–559
34. Dumontier I, Alhenc-Gelas M, Chatellier G, et al. Modifi-
cations des taux des inhibiteurs plasmatiques de la coagula-
tion au cours de la cirrhose. Gastroenterol Clin Biol 1992;
16:120–125
35. Denninger MH. Maladies du foie et hemostase. Path Biol
1999;47:1006–1015.
36. Sherlock S. Nutritional complications of biliary cirrhosis.
Chronic colestasis. Am J Clin Nutr 1970;23:640–644
37. Gross L, Brotman M. Hypoprothrombinemia and hemor-
rhage associated with cholestyramine therapy. Ann Intern
Med 1970;72:95–96
38. Andrassy K, Bechtold H, Ritz E. Hypoprothrombinemia
caused by cephalosporins. J Antimicrob Chemother 1985;
15:133–136
COAGULATION DISORDERS/AMITRANO ET AL. 93
39. Iber FL, Shamszad M, Miller PA, et al. Vitamin K defi-
ciency in chronic alcoholic males. Alcohol Clin Exp Res
1986;10:679–681
40. Blanchard RA, Furie BC, Jorgensen M, et al. Acquired vita-
min K dependent carboxylation deficiency in liver disease. N
Engl J Med 1981;305:242–248
41. Weitz IC, Liebman HA. Des-(-carboxy (abnormal) pro-
thrombin and hepatocellular carcinoma: a critical review.
Hepatology 1993;18:990–997
42. Liebman HA, Furie B, Tong M, et al. Des-gamma-carboxy
(abnormal) prothrombin as a serum marker of primary he-
patocellular carcinoma. N Engl J Med 1984;310:1427–1431
43. Nakao A, Virji A, Karr B, et al. Abnormal prothrombin
(des--carboxy prothrombin) in hepatocellular carcinoma.
Hepatogastroenterology 1991;38:450–453
44. Drin FG, Thomson JM, Dymock IW, et al. Abnormal fibrin
polymerisation in liver disease. Br J Haematol 1976;34:
427–437
45. Barr RD, et al. Dysfibrinogenemia and liver cell growth. J
Clin Pathol 1978;31:89–92
46. Violi F, Ferro D, Basili S, et al. Hyperfibrinolysis resulting
Downloaded by: The University of Hong Kong. Copyrighted material.
from clotting activation in patients with different degree of
cirrhosis. Hepatology 1993;17:78–83
47. Van Thiel DH, George M, Fareed J. Low levels of thrombin
activatable fibrinolysis inhibitor (TAFI) in patients with
chronic liver disease. Thromb Haemost 2001;85:667–670
48. Car JM. Disseminated intravascular coagulation in cirrhosis.
Hepatology 1989;10:103–110
49. Hersch SL, Kunelis T, Francis RB. The pathogenesis of ac-
celerated fibrinolysis in liver cirrhosis: a critical role for plas-
minogen activator inhibitor. Blood 1987;69:1315–1319
50. Hu KQ, Yu AS, Tiyygura L, et al. Hyperfibrinolytic activity
in hospitalized cirrhotic patients in a referral liver unit. Am J
Gastroenterol 2001;96:1581–1586
51. Agarwal S, Joyner KA, Swaim MW. Ascites as a possible
origin for hyperfibrinolysis in advanced liver disease. Am J
Gastroenterol 2000;95:3218–3224
52. Patrassi GM, Martinelli S, Sturniolo GC, et al. Fibrinolytic
study in plasma and ascitic fluid of cirrhotic patients before
and after ascites concentration reinfusion technique. Eur J
Clin Invest 1985;15:161–165
53. Francis RB, Feinstein DI. Clinical significance of accelerated
fibrinolysis in liver disease. Haemostasis 1984;14: 460–465
54. Violi F, Alessandro C, Ferro D, et al. Interrelation between
factor VII, prekallikrein and hyperfibrinolysis in advanced
cirrhosis. J Clin Pathol 1989;42:1246–1249
55. Violi F, Basili S, Ferro D, et al. Association between high
values of D-dimer and tissue-plasminogen activator activity
and first gastrointestinal bleeding in cirrhotic patients.
Thromb Hemost 1996;76:177–183
56. Levi M, Ten Cate H. Disseminated intravascular coagula-
tion. N Engl J Med 1999;341:586–592
57. Okajima K, Sakamoto Y, Uchiba M. Heterogeneity in the
incidence and clinical manifestations of disseminated in-
travascular coagulation: a study of 204 cases. Am J Hematol
2000;65:215–222
58. Violi F, Ferro D, Basili S, et al. Association between low-
grade disseminated intravascular coagulation and endotox-
emia in patients with liver cirrhosis. Gastroenterology 1995;
109:531–539.
59. Kemkes-Matthes B, Bleyl H, Matthes KJ. Coagulation acti-
vation in liver diseases. Thromb Res 1991;64:253–261
60. Joist JH. AICF and DIC in liver cirrhosis: Expressions of a hy-
percoagulable state. Am J Gastroenterol 1999;94:2801–2803
94 SEMINARS IN LIVER DISEASE/VOLUME 22, NUMBER 1 2002
61. Ben-Ari Z, Osman E, Hutton RA, et al. Disseminated in-
travascular coagulation in liver cirrhosis: fact or fiction? Am
J Gastroenterol 1999;94:2977–2982
62. Cordova C, Musa A, Violi F, et al. Improvement of some co-
agulation factors in cirrhotic patients treated with low dose
of heparin. Scand J Hematol 1982;29:235–240
63. Patel T. Surgery in the patient with liver disease. Mayo Clin
Proc 1999;74:593–599
64. Friedman LS. The risk of surgery in patients with liver dis-
ease. Hepatology 1999;29:1617–1623
65. Aranha GV. Cholecystectomy in cirrhotic patients: a formi-
dable operation. Am J Surg 1982;143:55–60
66. Garrison RN, et al. Clarification of risk factor for abdominal
operations in patients with hepatic cirrhosis. Ann Surg
1984;199:648–655
67. Tsuji K, Eguchi Y, Kodama M. Postoperative hypercoagula-
ble state followed by hyperfibrinolysis is related to wound
healing after hepatic resection. J Am Coll Surg 1996;183:
230–238
68. Meijer C, Wiezer MJ, Hack CE, et al. Coagulopathy fol-
lowing major liver resection: the effect of rBPI21 and the
role of decreased synthesis of regulating proteins by the liver.
Shock 2001;15:261–271
69. McGill DB, Rakela J, Zinsmeister AR, et al. A 21-year ex-
perience with major haemorrhage after percutaneous liver
biopsy. Gastroenterology 1990;99:1396–1400
70. Forssell PL, Bronkowsky HL, Anderson PB, et al. Intrahep-
atic haematoma after aspiration liver biopsy: a prospective
randomised controlled trial using two different needles. Dig
Dis Sci 1981;26:631–635
71. Piccinino F, Sagnelli E, Pasquale G, et al. Complications
following percutaneous liver biopsy. J Hepatol 1986;2:
165–173
72. Ewe K. Bleeding after liver biopsy does not correlate with
indices of peripheral coagulation. Dig Dis Sci 1981;26:
388–393
73. Dillon JF, Simpson KJ, Hayes PC. Liver biopsy bleeding
time-an unpredictable event. J Gastroenterol Hepatol 1994;
9:269–271
74. Gilmore IT, Burroughs A, Murray-Lyon IM, et al. Indica-
tions, methods, and outcomes of percutaneous liver biopsy
in England and Wales: an audit by the British Society of
Gastroenterology and the Royal College of Physicians of
London. Gut 1995;36:437–441.
75. Bonnard P, Vitte R-L, Barbare JC, et al. Is bleeding time
measurement useful for choosing the liver biopsy route? The
results of a pragmatic, prospective multicentric study in 219
patients. J Clin Gastroenterol 1999;29:347–349
76. Boberg KM, Brosstad F, Egeland T, et al. Is a prolonged
bleeding time associated with an increased risk of hem-
orrhage after liver biopsy? Thromb Haemost 1999;81:
378–381
77. Grant A, Neuberger J. Guidelines on the use of liver biopsy
in clinical practice. Gut 1999;45(suppl IV):1–11.
78. Papatheodoridis GV, Patch D, Watkinson A, et al. Trans-
jugular liver biopsy in the 1990s: a 2-year audit. Aliment
Pharmacol Ther 1999;13:603–608
79. Ozier Y, Steib A, Ickx B, et al. Haemostatic disorders during
liver transplantation. Eur J Anaesthesiol 2001;18:208–218
80. Haagsma EB, Gips CH, Wesenhagen H, et al. Liver disease
and its effect on haemostasis during liver transplantation.
Liver 1985;5:123–128
81. Bechstein WO, Neuhaus P. Bleeding problems in liver sur-
gery and liver transplantation. Chirurgie 2000;71:363–368
82. Bontempo FA, Lewis JH, Van Thiel DH, et al. The relation
of preoperative coagulation findings to diagnosis, blood
usage, and survival in adult liver transplantation. Transplan-
tation 1985;39:532–536
83. Segal H, Cottam S, Potter D, et al. Coagulation and fibrino-
lysis in primary biliary cirrhosis compared with other liver
disease and during orthotopic liver transplantation. Hepa-
tology 1997;25:683–688
84. Dzik WH, Arkin CF, Jenkins RL, et al. Fibrinolysis during
liver transplantation in humans: role of tissue-type plas-
minogen activator. Blood 1988;71:1090–1096
85. Kang Y, Lewis JH, Navalgund A, et al. Epsilon-
aminocaproic for treatment of fibrinolysis during liver trans-
plantation. Anesthesiology 1987;66:766–773
86. 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 trans-
plantation. Transplantation 1989;47:978–984
87. Porte RJ, Molenaar IQ, Begliomini B, et al. Aprotinin and
transfusion requirements in orthotopic liver transplantation:
a multicentre randomized double-blind study. EMSALT
Downloaded by: The University of Hong Kong. Copyrighted material.
Study Group. Lancet 2000;355:1303–1309
88. Marcel RJ, Stegall WC, Suit CT, et al. Continuous small-
dose aprotinin controls fibrinolysis during orthotopic liver
transplantation. Anesth Analg 1996;82:1122–1125
89. Dalmau A, Sabate A, Acosta F, et al. Tranexamic acid re-
duces red cell transfusion better than epsilon-aminocaproic
acid or placebo in liver transplantation. Anesth Analg 2000;
91:29–34
90. Riess H, Jochum M, Machleidt W, et al. Possible role of ex-
tracellularly released phagocyte proteinase coagulation dis-
order during liver transplantation. Transplantation 1991;52:
482–484
91. Kettner SC, Gonano C, Seebach F, et al. Endogenous hepa-
rin-like substances significantly impair coagulation in pa-
tients undergoing orthotopic liver transplantation. Anesth
Analg 1998;86:691–695.
92. Porte RJ, Blauw E, Knot EA, et al. Role of the donor liver in
the origin of platelet disorders and hyperfibrinolysis in liver
transplantation. J Hepatol 1994;21:592–600
93. Gillies BS. Thromboelastography and liver transplantation.
Semin Thromb Hemost 1995;21(suppl 4):45–49
94. Weinstein L. Syndrome of hemolysis, elevated liver en-
zymes, and low platelet count: a severe consequence of hy-
pertension in pregnancy. Am J Obstet Gynecol 1982;142:
159–167
95. Sherlock S, Dooley J. Diseases of the Liver and Biliary Sys-
tem, 10th ed. Oxford, UK: Blackwell Science; 1987:475–483
96. Sheikh RA, Yasmeen S, Pauly MP, et al. Spontaneous intra-
hepatic hemorrhage and hepatic rupture in the HELLP syn-
drome: four cases and a review. J Clin Gastroenterol 1999;
28:323–328
97. Audibert F, Coffineau A, Edouard D, et al. Prise en charge
du HELLP syndrome avant 32 semaines d’amenorrhee.
Presse Med 1996;25:235–239
98. Kobayashi T, Tokunaga N, Sugimura M, et al. Predictive val-
ues of coagulation/fibrinolysis parameters for the determi-
nation of pregnancy complicated by severe preeclampsia.
Semin Thromb Hemost 2001;27:137–141
99. Kox TA, Olans LB. Liver disease in pregnancy. N Engl J
Med 1996;335:569–576
100. Pereira SP, O’Donohue J, Wendon J, et al. Maternal and
perinatal outcome in severe pregnancy-related liver disease.
Hepatology 1997;26:1258–1262

101. Sherlock S. Acute fatty liver of pregnancy. In: Reyes HB,
Leuschner U, Arias IM, eds. Pregnancy, sex hormones and
liver. Dordrecht, The Netherlands: Kluwer Academic, 1996:
202–208
102. Castro MA, Fassett MJ, Reynolds TB, et al. Reversible peri-
partum liver failure: a new perspective on the diagnosis,
treatment, and cause of acute fatty liver of pregnancy, based
on 28 consecutive cases. Am J Gynecol 1999;181:389–395
103. Castro MA, Goodwin TM, Shaw KJ, et al. Disseminated
intravascular coagulation and antithrombin III depression in
acute fatty liver of pregnancy. Am J Obstet Gynecol 1996;
174:211–216
104. Bernard B, Grange JD, Khac EN, et al. Antibiotic prophy-
laxis for the prevention of bacterial infections in cirrhotic
patients with gastrointestinal bleeding: a meta-analysis. He-
patology 1999;29:1655–1661
105. Goulis J, Armonis A, Patch D, et al. Bacterial infection is in-
dependently associated with failure to control bleeding in
cirrhotic patients with gastrointestinal hemorrhage. Hepa-
tology 1998;27:1207–1212
106. Bernard B, Cadranel JF, Valla D, et al. Prognostic signifi-
cance of bacterial infection in bleeding cirrhotic patients: a
prospective study. Gastroenterology 1995;108:1828–1834
107. Goulis J, Patch D, Burroughs AK. Bacterial infection in the
pathogenesis of variceal bleeding. Lancet 1999;353:139–142
108. Papatheodoridis GV, Patch D, Webster JM. Infection and he-
mostasis in decompensed cirrhosis: a prospective study using
thromboelastography. Hepatology 1999;29:1085–1090
109. Chau TN, Chan YW, Patch D, et al. Thromboelastographic
changes and early rebleeding in cirrhotic patients with
variceal bleeding. Gut 1998;43:267–271
110. Oka K, Tanaka K. Local fibrinolysis of esophagus and stom-
ach as the cause of hemorrhage in liver cirrhosis. Thrombo-
sis Res 1979;14:837–844
111. Francis RJ, Feinstein DI. Clinical significance of accelerated
fibrinolysis in liver disease. Haemostasis 1984;14:460–465
112. Boks AL, Brommer EJ, Schalm SW, et al. Hemostasis and
fibrinolysis in severe liver failure and their relation to hem-
orrhage. Hepatology 1986;6:79–86
113. Piscaglia F, Siringo S, Hermida RC, et al. Diurnal changes
of fibrinolysis in patients with liver cirrhosis and esophageal
varices. Hepatology 2000;31:349–357
114. Grignani G, Maiolo A. Cytokines and hemostasis. Haema-
tologica 2000;85:967–972
115. Basili S, Ferro D, Violi F. Endotoxaemia, hyperfibrinolysis
and bleeding in cirrhosis. Lancet 1999;353:1102
116. Saliola M, Lorenzet R, Ferro D, et al. Enhanced expression
of monocyte tissue factor in patients with liver cirrhosis. Gut
1998;43:428–432
117. Ferro D, Basili S, Pratico D, et al. Vitamin E reduces mono-
cyte tissue factor expression in cirrhotic patients. Blood
1999;93:2945–2950
118. Yerdel MA, Gunson B, Mirza D, et al. Portal vein throm-
bosis in adults undergoing liver transplantation: risk fac-
tors, screening, management, and outcome. Transplantation
2000;69:1873–1881
119. Okuda K, Ohnishi K, Kimura K, et al. Incidence of portal
vein thrombosis in liver cirrhosis: an angiographic study of
708 patients. Gastroenterology 1985;89:279–286
120. Manzanet G, Sanjuan F, Orbis P, et al. Liver transplantation
in patients with portal vein thrombosis. Liver Transplant
2001;7:125–131
121. Denninger MH, Chait Y, Casadevall N, et al. Cause of por-
tal and hepatic venous thrombosis in adults: the role of mul-
tiple concurrent factors. Hepatology 2000;31:587–591
COAGULATION DISORDERS/AMITRANO ET AL. 95
122. Valla DC, Condat B. Portal vein thrombosis in adults:
pathophysiology, pathogenesis and management. J Hepatol
2000;32:865–871
123. Amitrano L, Brancaccio V, Guardascione MA, et al. Inher-
ited coagulation disorders in cirrhotic patients with portal
vein thrombosis. Hepatology 2000;31:345–348
124. Romero Gomez M, Garcia ES, Lacomba DL, et al. An-
tiphospholipid antibodies are related to portal vein throm-
bosis in patients with liver cirrhosis. J Clin Gastroenterol
2000;31:237–240
125. Dalekos GN, Kistis KG, Boumba DS, et al. Increased inci-
dence of anti-cardiolipin antibodies in patients with hepati-
tis C is not associated with aetiopathogenetic link to anti-
phospholipid syndrome. Eur J Gastroenterol Hepatol 2000;
12:67–74
126. Ordi-Ros J, Villarreal J, Monegal F, et al. Anticardiolipin
antibodies in patients with chronic hepatitis C virus infec-
tion: characterization in relation to antiphospholipid syn-
drome. Clin Diagn Lab Immunol 2000;7:241–244
127. Mangia A, Margaglione M, Cascavilla I, et al. Anticardi-
olipin antibodies in patients with liver disease. Am J Gas-
Downloaded by: The University of Hong Kong. Copyrighted material.
troenterol 1999;94:2983–2987
128. Collier JD, Sale J, Friend PJ, et al. Graft loss and the an-
tiphospholipid syndrome following liver transplantation. J
Hepatol 1998;29:999–1003
129. Everson GT. A hepatologist’s perspective on the manage-
ment of coagulation disorders before liver transplantation.
Liver Transplant Surg 1997;3:646–652
130. Spector I, Corn M, Ticktin HE. Effect of plasma transfu-
sions on the prothrombin time and clotting factors in liver
disease. N Engl J Med 1966;275:1032–1037
131. Holland PV. Post-transfusion hepatitis: current risks and
causes. Vox Sang 1998;74(Suppl 2):135–141
132. Williamson LM, Llewelyn CA, Fisher NC, et al. A ran-
domized trial of solvent/detergent-treated and standard
fresh-frozen plasma in the coagulopathy of liver disease and
liver transplantation. Transfusion 1999;39:1227–1234
133. Practice guidelines for blood component therapy. Anesthesi-
ology 1996;84:732–747
134. Seitz R, Dodt J. Virus safety of prothrombin complex con-
centrates and factor IX concentrates. Thromb Res 1999;
95(Suppl):19–23
135. Kohler M. Thrombogenicity of prothrombin complex con-
centrates. Thromb Res 1999;95(Suppl 1):13–17
136. Hellstern P, Halbmayer WM, Kohler M, et al. Prothrombin
complex concentrates: indications, contraindications, and
risks: a task force summary. Thromb Res 1999;95(Suppl):
3–6
137. Hedner U. Novoseven as a universal haemostatic agent.
Blood Coagul Fibrinolysis 2000;11(suppl 1):107–111
138. Bernstein D. Effectiveness of the recombinant factor VIIa in
patients with the coagulopathy of advanced child’s B and C
cirrhosis. Semin Thromb Hemost 2000;26:437–438
139. Chaunsumrit A, Chantarojanasiri T, Isarangkura P, et al.
Recombinant activated factor VII in children with acute
bleeding resulting from liver failure and disseminated in-
travascular coagulation. Blood Coagul Fibrinolysis 2000;
11(Suppl 1):101–105
140. Hendriks HG, Meijer K, de Wolf JT, et al. Reduced transfu-
sion requirements by recombinant factor VIIa in orthotopic
liver transplantation: a pilot study. Transplantation 2001;71:
402–405
141. Murphy MF. State of the art in platelet transfusion therapy.
Transfus Sci 1996;17:575–584
96 SEMINARS IN LIVER DISEASE/VOLUME 22, NUMBER 1 2002
142. Weber T, Marino IR, Kang YG, et al. Intraoperative blood
transfusions in highly alloimmunized patients undergoing
orthotopic liver transplantation. Transplantation 1989;47:
797–801
143. Kaul VV, Munoz SJ. Coagulopathy of liver disease. Curr
Treat Options Gastroenterol 2000;3:433–438
144. Carr JM. Hemostatic disorders in liver disease. In: Schiff L,
Schiff ER, eds. Diseases of the Liver. Philadelphia: JB Lip-
pincott; 1993:1061–1076
145. Green B, Cairns S, Harvey R, et al. Phytomenadione or
menadiol in the management of an elevated international
normalized ratio (prothrombin time). Aliment Pharmacol
Ther 2000;14:1685–1689
146. Burroughs AK, Matthews K, Qadiri M, et al. Desmopressin
and bleeding time in patients with cirrhosis: Br J Med
1985;291:1377–1381
147. Mannucci PM, Vicente V, Vianello L, et al. Controlled trial
of desmopressin (DDAVP) in liver cirrhosis and other con-
ditions associated with a prolonged bleeding time. Blood
1986;67:1148–1153
148. Mannucci PM. Desmopressin (DDAVP) in the treatment
of bleeding disorders: the first 20 years. Blood 1997;90:
2515–2521
149. de Franchis R, Arcidiacono PG, Carpinelli PG, et al. Ran-
domized controlled trial of desmopressin plus terlipressin
and terlipressin alone for the treatment of acute variceal
hemorrhage in cirrhotic patients: a multicenter, double blind
study. Hepatology 1993;18:1102–1107
Downloaded by: The University of Hong Kong. Copyrighted material.