2. Coagula4on
and
Liver
• Disturbed
• Elevated
INR
• Low
/
normal
/
elevated
fibrinogen
• Low
platelets
• Elevated
D
Dimer
• APTT
• Percep4on
of
being
at
risk
of
bleeding
– Spontaneous
– Procedure
related
3. • Altera4ons
in
liver
disease
affect
the
whole
spectrum
of
coagula4on
factors
as
compared
to
a
single
deficiency
• Deficiencies
in
procogulant
factors
and
an4coagulant
factors
• At
baseline
likely
in
“balance”
• Haemosta4c
phenotype
is
likely
to
change
with
physiological
varia4on
– Sepsis
– Renal
failure
– Endothelial
ac4va4on
–
inflamma4on
• Rou4ne
coagula4on
tests
do
not
test
or
reflect
these
interac4on
4. disease and progressive liver disease [15]. Patients with NAFLD
may initially present with hemostatic alterations linked to gen- hype
the o
bleed
hemo
existe
iceal
Howe
ally t
[50].
serva
Th
volum
vatio
of pa
plant
[27–2
produ
is thu
Table 1. Alterations in the hemostatic system in patients with liver disease
that contribute to bleeding (left) or counteract bleeding (right).
Changes that impair
hemostasis
Changes that promote hemostasis
Thrombocytopenia Elevated levels of von Willebrand factor
(VWF)
Platelet function defects Decreased levels of ADAMTS-13
Enhanced production of nitric
oxide and prostacyclin
Elevated levels of factor VIII
Low levels of factors II, V, VII,
IX, X, and XI
Decreased levels of protein C, protein S,
antithrombin, a2-macroglobulin, and heparin
cofactor II
Vitamin K deficiency
Dysfibrinogenemia Low levels of plasminogen
Low levels of a2-antiplasmin,
factor XIII, and TAFI
Elevated t-PA levels
Hemostasis and thrombosis in patients with liver disease: The
ups and downs
Ton Lisman1,2,*, Stephen H. Caldwell3
, Andrew K. Burroughs4
, Patrick G. Northup3
, Marco Senzolo5
,
R. Todd Stravitz6
, Armando Tripodi7
, James F. Trotter8
, Dominique-Charles Valla9
, Robert J. Porte1
,
Coagulation in Liver Disease Study Group
1
Section Hepatobiliairy Surgery and Liver Transplantation, The Netherlands; 2
Surgical Research Laboratory, Department of Surgery,
University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; 3
Division of GI/Hepatology,
Department of Internal Medicine, University of Virginia, Charlottesville, VA, USA; 4
The Sheila Sherlock Hepatobiliary-Pancreatic
and Liver Unit, Royal Free Hospital, London, United Kingdom; 5
Gastroenterology, Department of Surgical and Gastroenterological Sciences,
University Hospital of Padua, Italy; 6
Section of Hepatology, Hume-Lee Transplant Center, Virginia Commonwealth University,
Richmond, VA, USA; 7
Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, University Medical School and IRCCS Ospedale Maggiore
Policlinico, Mangiagalli and Regina Elena Foundation, Milan, Italy; 8
Baylor University Medical Center, Dallas, TX, USA; 9
Centre de Référence des
Maladies Vasculaires du Foie, AP-HP, Hôpital Beaujon, Service d’Hépatologie, Clichy, France
Abstract
Patients with chronic or acute liver failure frequently show profound
abnormalities in their hemostatic system. Whereas routine laboratory
tests of hemostasis suggest these hemostatic alterations result in a
bleeding diathesis, accumulating evidence from both clinical and labora-
tory studies suggest that the situation is more complex. The average
patient with liver failure may be in hemostatic balance despite pro-
longed routine coagulation tests, since both pro- and antihemostatic fac-
tors are affected, the latter of which are not well reflected in routine
coagulation testing. However, this balance may easily tip towards a
hypo- or hypercoagulable situation. Indeed, patients with liver disease
may encounter both hemostasis-related bleeding episodes as well as
thrombotic events. During the 3rd International Symposium on Coagu-
lopathy and Liver disease, held in Groningen, The Netherlands (18–19
September 2009), a multidisciplinary panel of experts critically reviewed
the current data concerning pathophysiology and clinical consequences
of hemostatic disorders in patients with liver disease. Highlights of this
symposium are summarized in this review.
Ó 2010. Published by Elsevier B.V. All rights reserved.
Introduction
In patients with liver disease, substantial changes in the hemo-
static system are frequently found [1]. These changes include
thrombocytopenia and platelet function defects, decreased circu-
lating levels of coagulation factors and inhibitors, and decreased
levels of proteins involved in fibrinolysis. Consequently, routine
diagnostic tests of hemostasis, such as the platelet count, the pro-
thrombin time (PT), and the activated partial thromboplastin
time (APTT) are frequently abnormal. In patients with isolated
hemostatic defects, such abnormalities in these laboratory tests
often indicate a true bleeding tendency. However, interpretation
of these tests is much less straightforward in the patient with a
complex hemostatic disorder as can be found in patients with
liver disease. In recent years, traditional concepts on the clinical
consequences of the hemostatic disorder in patients with liver
disease have dramatically changed. In particular, it is now estab-
Chronic liver disease – rebalanced hemostasis?
Thrombocytopenia, platelet function defects, and decreased lev-
els of pro- and anticoagulant proteins are frequently observed
in patients with cirrhosis [5]. Although routine hemostatic tests
Journal of Hepatology 2010 vol. 53 j 362–371
D, non-alcoholic fatty liver disease; PAI-1, pl-
SH, non-alcoholic steatohepatitis; INR, inter-
ndoscopic variceal ligation; ALF, acute liver
Ia; ICP, intracranial pressure; PVT, portal vein
hrombosis; AASLD, American society for the
6. Thrombosis
and
Hypercoagulability
• INR
designed
to
measure
warfarin
not
bleeding
risk
• Detects
varia4ons
in
factors
I,II,V,
VII
and
X
• Insensi4ve
to
an4coagulant
factors
–
Protein
C,
S,
ATIII
• Insensi4ve
to
haemosta4c
modulators
on
endothelium
(eg)
thrombomodulin
• Only
assess
5%
of
thrombin
• Assessment
should
consider
ETP,
thromboelastography
and
more
novel
tests
such
as
thrombin
genera4on
tes4ng
(TGT)
7. TEG
R = reaction time
K=kinetics
Alpha = slope between
R and K
MA=mean amplitude
CL= clot lysis
ROTEM
CT=clotting time
CFT = clot formation
time
Alpha = slope of tangent
at 2 mm
MCF= maximal clot
firmness
LY=Lysis
PSC,
PBC
pro-‐coagulant
8. Wilma
Potze
Thrombosis
Research
(2015)
Fibrinogen
levels
strongly
correlated
with
the
clot
density
Endogenous
thombin
genera4on
+
TM
increased
in
CP
–
C
Correla4on
between
APTT
and
clot
density
Con4nuous
monitoring
of
clot
growth
in
non-‐s4rred
plasma
ini4ated
by
a
thin
layer
of
immobilized
4ssue
factor
(TF)
9. Ra4o
of
endogenous
thrombin
poten4al
(ETP-‐Ra4o)
measured
in
the
presence
vs.
absence
of
thrombomodulin.
Armando
Tripodi,
Journal
of
Hepatology
2013
vol.
59
j
265–270
10. Table 1. Demographic, clinical and laboratory characteristics on hospital admission for ALI/ALF and subgroups according to outcome. (Mean ± SD or median [range])
Feature Normal Range Entire Group
(n = 51)
Spontaneous Survivors
(n = 29)
Death or OLT
(n = 22)
Demographics:
Age (years) 43.1 ± 14.7 40.3 ± 15.0 46.7 ± 13.8
Female Gender (%) 61 59 64
Caucasian Race (%) 65 66 64
BMI (Kg/m2
) 28.2 ± 6.6 26.7 ± 5.1 30.3 ± 8.0
Clinical Characteristics:
Etiology of ALI/ALF (N [%]):
Acetaminophen
Autoimmune hepatitis
Hepatitis B
Idiosyncratic drug
Indeterminate
Hepatic ischemia
Mushroom poisoning
Heat stroke
22 [43]
7 [14]
7 [14]
6 [12]
4 [8]
2 [4]
1 [2]
1 [2]
1 [2]
17 [59] 5 [23]**
Hepatic encephalopathy (ALF) (%) 73 55 96**
Number of SIRS 1.6 ± 1.2 1.2 ± 1.0 2.1 ± 1.3**
Pulse (beats/min) 95 ± 21 93 ± 21 97 ± 22
Mean arterial pressure (mmHg) 86 ± 14 87 ± 13 85 ± 16
Respiratory rate (breaths/min) 20 ± 6 18 ± 4 22 ± 8*
Temperature (°C) 36.7 ± 0.7 37.0 ± 0.7 36.3 ± 0.6***
Laboratory Data:
White blood cell count (x 109
/L) 3.9-11.7 11.8 ± 7.2 11.1 ± 6.7 12.5 ± 7.8
Creatinine (mg/dl) 0.5-1.0 1.0 [0.4-8.1] 0.9 [0.4-7.5] 1.5 [0.5-8.1]
Total bilirubin (mg/dl) 0.0-1.3 6.5 [0.3-44.2] 4.7 [0.9-29.4] 21.0 [0.3-44.2]**
Albumin (g/dl) 3.7-5.2 2.9 ± 0.5 3.0 ± 0.5 2.7 ± 0.4*
Venous ammonia (µmol/L) 0-35 80 ± 38 71 ± 36 91 ± 38
Lactate (mmol/L) 0.5-2.2 3.4 [0.4-21.4] 2.5 [0.4-6.6] 5.6 [0.7-21.4]**
Phosphate (mg/dl) 2.5-4.6 3.6 ± 2.4 2.8 ± 1.3 4.8 ± 3.1**
Malignant infiltration
JOURNAL OF HEPATOLOGY
hepatitis and hepatitis B in 7 patients (14%) each, idiosyncratic
drug reactions in 6 (12%), indeterminate etiology in 4 patients
(8%), ischemia in 2 patients (4%), and malignant infiltration of
the liver, heat stroke, and mushroom (Amanita) poisoning in 1
(2%) case each. Hepatic encephalopathy of some degree (ALF)
was present in 37 (73%) of patients. At the time of TEG measure-
ment, the mean number of SIRS components was 1.6; 8 patients
had a mean arterial pressure (MAP) of 670 mm Hg. Fourteen
patients (28%) died and 8 (16%) underwent orthotopic liver trans-
plantation (OLT), yielding a transplant-free survival (TFS) of 29
patients (57%). Clinical features and laboratories predictive of
poor outcome (death or OLT) included non-APAP etiology, the
presence of hepatic encephalopathy, lower body temperature,
albumin, and fibrinogen, and higher number of SIRS, respiratory
rate, bilirubin, lactate, phosphate, aPTT, INR, and MELD score
(Table 1).
Mean/median TEG parameter values were within normal
limits for the entire study population (Table 1; mean R-time
Creatinine (mg/dl) 0.5-1.0 1.0 [0.4-8.1] 0.9 [0.4-7.5] 1.5 [0.5-8.1]
Total bilirubin (mg/dl) 0.0-1.3 6.5 [0.3-44.2] 4.7 [0.9-29.4] 21.0 [0.3-44.2]**
Albumin (g/dl) 3.7-5.2 2.9 ± 0.5 3.0 ± 0.5 2.7 ± 0.4*
Venous ammonia (µmol/L) 0-35 80 ± 38 71 ± 36 91 ± 38
Lactate (mmol/L) 0.5-2.2 3.4 [0.4-21.4] 2.5 [0.4-6.6] 5.6 [0.7-21.4]**
Phosphate (mg/dl) 2.5-4.6 3.6 ± 2.4 2.8 ± 1.3 4.8 ± 3.1**
Fibrinogen (mg/dl) 200-450 195 ± 84 223 ± 55 154 ± 102**
PTT (sec) 25-36 49 ± 17 41 ± 10 59 ± 19****
INR 3.4 ± 1.7 3.0 ± 1.3 4.0 ± 1.9*
MELD score 31.3 ± 8.6 27.7 ± 7.1 36.2 ± 8.3***
TEG Parameters:
R-time (min) 2.5-7.5 4.7 ± 1.9 4.1 ± 1.5 5.5 ± 2.2**
K-time (min) 0.8-2.8 1.7 [0.8-20.0] 1.9 [0.8-20.0] 1.7 [0.9-10.5]
α-Angle (degrees) 55.2-78.4 63.7 ± 12.2 63.6 ± 12.7 63.7 ± 11.8
Maximum Amplitude (mm) 50.6-69.4 55.0 ± 10.9 55.0 ± 11.2 55.1 ± 10.6
Lysis 30 (%) 0.0-7.5 0.0 [0.0-2.1] 0.0 [0.0-1.8] 0.0 [0.0-2.1]
⁄
p <0.05, ⁄⁄
p 60.01, ⁄⁄⁄
p <0.001, ⁄⁄⁄⁄
p 60.0001 indicates significant difference between spontaneous survivors and those who died or underwent OLT.
TEG parameters in patients with ALI/ALF reflect specific
phases of blood clot formation and are associated with specific
aspects of the clinical syndrome. The R-time mirrors activation
of the coagulation cascades and procoagulant factor levels. Con-
sistent with the well-recognized importance of the INR and factor
V in predicting outcome in patients with ALF [21,22], the R-time
directly correlated with the SIRS, specific laboratories which pre-
dict poor outcome (lactate and phosphate), complications of the
ALI/ALF syndrome other than hepatic encephalopathy, and poor
outcome. R-time was significantly higher in patients with infec-
tion, those requiring CVVH, and in those with bleeding complica-
tions. The TEG was, in fact, more sensitive than the INR for
predicting bleeding, since the INR was not significantly different
in those who bled and those who did not (p = 0.14). This observa-
Factor VIII -0.27 -0.31* 0.38** 0.33*
Protein C Activity -0.19 0.02 -0.14 -0.04
Protein S Activity -0.14 0.11 -0.20 -0.14
Antithrombin Activity -0.14 -0.02 -0.06 0.17
SIRS Components:
Pulse 0.18 -0.43** 0.29* 0.44**
Respirations 0.46*** -0.34* 0.15 0.31*
Temperature -0.20 0.03 0.02 -0.06
WBC 0.29* -0.13 0.19 0.30*
Chemistries:
Lactate 0.58**** 0.16 -0.23 0.01
Ammonia (venous) 0.13 -0.37** 0.38** 0.38**
Phosphate 0.47*** -0.04 0.00 0.25
Creatinine 0.11 -0.05 0.13 0.23
Total Bilirubin -0.14 -0.16 0.22 0.10
⁄
p <0.05, ⁄⁄
p <0.01, ⁄⁄⁄
p <0.001, ⁄⁄⁄⁄
p 60.0001 indicates significant correlation.
0 1 2 3 4
30
40
50
60
70
80
Maximum
amplitude(mm)
SIRS (N)
Fig. 2. Maximum amplitude of clot formation according to the number of
SIRS concurrently determined in patients with acute liver injury/failure on
admission to study. Data represent mean values with lower/higher 95%; width of
R time higher in infection
and those requiring RRT
and appeared to predict
bleeding risk whilst INR
did not
Minimal effects of acute liver injury/acute liver failure on
hemostasis as assessed by thromboelastography
R. Todd Stravitz1,⇑
, Ton Lisman3
, Velimir A. Luketic1
, Richard K. Sterling1
, Puneet Puri1
,
Michael Fuchs1
, Ashraf Ibrahim2
, William M. Lee4
, Arun J. Sanyal1
1
Section of Hepatology and Hume-Lee Transplant Center, Virginia Commonwealth University, Richmond, VA, USA; 2
Department of
Anesthesiology, Virginia Commonwealth University, Richmond, VA, USA; 3
Department of Surgery, University Medical Center Groningen,
University of Groningen, Groningen, The Netherlands; 4
Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center,
Dallas, TX, USA
Background & Aims: Patients with acute liver injury/failure (ALI/
ALF) are assumed to have a bleeding diathesis on the basis of ele-
vated INR; however, clinically significant bleeding is rare. We
hypothesized that patients with ALI/ALF have normal hemostasis
despite elevated INR.
Methods: Fifty-one patients with ALI/ALF were studied prospec-
tively using thromboelastography (TEG), which measures the
dynamics and physical properties of clot formation in whole
blood. ALI was defined as an INR P1.5 in a patient with no pre-
vious liver disease, and ALF as ALI with hepatic encephalopathy.
Results: Thirty-seven of 51 patients (73%) had ALF and 22
patients (43%) underwent liver transplantation or died. Despite
a mean INR of 3.4 ± 1.7 (range 1.5–9.6), mean TEG parameters
were normal, and 5 individual TEG parameters were normal in
32 (63%). Low maximum amplitude, the measure of ultimate clot
strength, was confined to patients with platelet counts
<126 Â 109
/L. Maximum amplitude was higher in patients with
ALF than ALI and correlated directly with venous ammonia con-
centrations and with increasing severity of liver injury assessed
by elements of the systemic inflammatory response syndrome.
All patients had markedly decreased procoagulant factor V and
VII levels, which were proportional to decreases in anticoagulant
proteins and inversely proportional to elevated factor VIII levels.
Conclusions: Despite elevated INR, most patients with ALI/ALF
maintain normal hemostasis by TEG, the mechanisms of which
include an increase in clot strength with increasing severity of
liver injury, increased factor VIII levels, and a commensurate
decline in pro- and anticoagulant proteins.
Ó 2011 European Association for the Study of the Liver. Published
by Elsevier B.V. All rights reserved.
Introduction
Acute liver injury and acute liver failure (ALI/ALF) are syndromes
defined by ‘‘coagulopathy’’ on the basis of increased prothrombin
time (PT)/INR; ALF represents a more severe liver injury resulting
in hepatic encephalopathy [1]. Thrombocytopenia frequently
accompanies ALI/ALF, although its pathogenesis remains poorly
defined [2]. Consequently, patients with ALI/ALF have been
assumed to have a bleeding diathesis [3], even though most ser-
ies report a low incidence of spontaneous, clinically significant
bleeding [4]. Although invasive procedures such as intracranial
pressure (ICP) monitor placement are also rarely associated with
bleeding complications (<5% [5]), coagulation factor and platelet
transfusion remain a routine practice despite potential adverse
effects [6].
In patients with cirrhosis, who also have thrombocytopenia
and elevated INR, a concept of ‘‘re-balanced hemostasis’’ has been
proposed to explain the fact that patients rarely bleed outside of
the consequences of portal hypertension [7]. As shown by Tripodi
[8], thrombin generation is normal in patients with cirrhosis pro-
vided that thrombomodulin is added to the reaction mixture to
activate the anticoagulant protein C system. These and other
Keywords: Acute liver failure; Coagulopathy; Hepatic encephalopathy; Hemos-
tasis; Thromboelastography.
Received 26 January 2011; received in revised form 29 March 2011; accepted 6 April
2011; available online 19 May 2011
⇑ Corresponding author. Address: Section of Hepatology, P.O. Box 980341,
Virginia Commonwealth University, Richmond, VA 23298-0341, USA. Tel.: +1
804 828 4060; fax: +1 804 828 4945.
effects of procoagulant and antic
platelets, and red blood cells. Com
Journal of Hepatology 2012 vol. 56 j 129–136
disease score; ADAMTS13, a disintegrin and metalloprotease with thrombospon-
din type-1 motifs 13; vWF, von Willebrand factor.
13. ETP
endogenous
thrombin
poten4al
ra4o
sugges4ng
hypercoagulability.
Habib
et
al
Liver
Int
2013
T.
Lisman
et
al
Journal
of
Thrombosis
and
Haemostasis,
2013
10:
1312–1319
14. T.
Lisman
et
al
Journal
of
Thrombosis
and
Haemostasis,
10:
1312–1319
16. Heparinase
effect
HEPATOLOGY
1999;29:1085-‐1090
Resolu4on
of
infec4on
resulted
in
Improved
r
and
alpha
angle
Montalto
et
al
J
Hepatology
2002
37(4):463
17. Philipp
A.
Reuken
Liver
Int.
2015;
35:
37–45
Prothrombo4c
state
correlated
with
OF
19. Retrospective chart study in patients undergoing RRT without initial anticoagulation
Anticoagulation added to a sub group and filter life increased from 5.6 to 19 hours
Citrate well tolerated in liver failure
Coagulation data
Circuit life
20. Kidney
Interna4onal
(2013)
84,
158–163;
AKI
stage
3
associated
with
low
platelets
,
factor
V,
Protein
C
and
AT
III
Tissue
factor
levels
increased,
along
with
Von
Willibrand
factor
Increased
micropar4cles
No
increased
bleeding
Increased
circuit
clolng
21. Statistical decrease in platelets and fibrinogen and other TEG functions
but no evidence of clot lysis / fibrinolysis however
Doria et al
Clinical Transplantation
2004;18:365
Significant worsening of
PT, all TEG variables,
factor VIII, von WB,
DDimers
24. Nicolas
M.
Intagliata
Liver
Int.
2014:
34:
26–32
9
gastrointes4nal
bleeding
events
(2.5%
of
admissions)
5
venous
thromboembolisms
(1.4%
of
admissions)
2
cases
of
HIT
(0.5%
of
admissions)
and
14
deaths
overall
(3.9%
of
admissions)
DVT
prophylaxis
25%
CLD
admissions
Monitoring
Low
ATIII
levels
in
cirrhosis
results
in
falsely
elevated
APTT
levels
and
falsely
Decreased
an4Xa
levels
-‐
Lau
Clin
Med
2015
Potze
Drug
Monit
2015
37;2,
BJH
2013;163:666
25.
26. Treat
Ac4ve
Bleeding
:
Prevent
thrombosis
Ensure
appropriate
monitoring
• Overt
ooze
/
bleed
– low
fibrinogen
and
platelets
<
30
and
elevated
INR
/APTR
/
fibrinolysis
– Avoid
procedures
if
possible
– Isolated
eleva4on
of
INR
:
ignore
– Platelets
>
30-‐
50
:
no
Rx
• Ac4ve
bleeding
/varices
Rx
as
per
standard
bleed
• Rx
bleeding
– Fresh
frozen
plasma
(10-‐15
ml/kg)
or
concentrate
– Cryoprecipitate
–
if
bleeding
and
fibrinogen
<
0.8
mg/dl
– Concentrates
:
balance
of
pro
and
an4coagulant
factors
– Platelets
– Tranexamic
acid
–
watch
for
overt
thrombosis
and
early
Rx
(CRASH)
An4coagula4on
DVT
prophylaxis
Avoid
/
Rx
PVT
Full
an4coagula4on
monitoring
complex
be
aware
of
APTR
/
an4Xa
issues
HIT
high
screen
rate
If
concern
Rx
with
Agatroban
