la coagulazione nel cirrotico: mito o realtà? - gastrolearning®
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Gastrolearning X lezione La coagulazione nel cirrotico: mito o realtà? - Prof. A. Tripodi (Università di Milano)TRANSCRIPT
A.TRIPODI
La Coagulazione nel Cirrotico: Mito e Realtà
Prof. Armando TripodiAngelo Bianchi Bonomi
Hemophilia and Thrombosis CenterDept. of Clinical Sciences and Community Health
University of Milano
La coagulazione nel cirrotico: mito o realtà?
A.TRIPODI
Alteration of Hemostasis in CirrhosisPotential Implicated Mechanisms
•Primary Hemostasis
• Fibrinolysis
• Coagulation
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Dual Role of Platelets in Hemostasis
•Primary hemostasis Adhesion to the subendothelium
Aggregation one another
•Coagulation Support thrombin generation
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vWF
High levels of VWF in cirrhosis
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Alteration of Hemostasis in CirrhosisPotential Implicated Mechanisms
• Primary Hemostasis
•Fibrinolysis • Coagulation
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Fibrinolysis in CirrhosisBackground
• Cirrhosis is characterized by hyperfibrinolysis (?)
• This complex defect can be documented in plasma through global fibrinolytic tests or through the measurement of individual components
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Cirrhosis and Fibrinolysis
• Decreased levels
Plasminogen
- Anti-plasmin
- FXIII
- TAFI
• Increased levels
- tPA
- PAI-1
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Hyperfibrinolysis and Cirrhosis
• Deficiency of TAFI in cirrhotics is not associated with increased plasma fibrinolysis
Lisman T et al. Gastroenterology 2001; 121: 131
• Deficiency of TAFI in cirrhotics is associated with increased plasma fibrinolysis
Colucci M, et al, Hepatology 2003; 38: 230
A.TRIPODI
Alteration of Hemostasis in CirrhosisPotential Implicated Mechanisms
• Primary Hemostasis
• Fibrinolysis
•Coagulation
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Coagulation in Chronic Liver DiseaseThe Facts….
• Cirrhosis is characterized by an impaired synthesis of all clotting factors (except FVIII and VWF)
• This complex defect has historically been documented through the prolongation of PT & APTT
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Coagulation in Chronic Liver DiseaseThe Dogma…
• The concept of a causal relationship between abnormal coagulation and bleeding is widely accepted
• Common practice of screening patients with hemostasis tests
• Treating patients with abnormal values in order to correct the identified abnormalities prior to liver biopsy
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Te Challenge of the Dogma (1)
• Liver transplantation was initially associated with dramatic transfusion requirements
but…
• The need of transfusion declined dramatically in the last 20 years, despite no major change in medication
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Transplantation 2008; 85: 956
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Te Challenge of the Dogma (2)
Conventional hemostasis tests do correlate poorly with gastrointestinal bleeding or after
biopsy
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Poor Correlation between Global Conventional Hemostasis Tests and Bleeding
Review of the Literature
• Ewe K. Dig Dis Sci 1981; 26; 388• Segal JB & Dzik WH. Transfusion 2005; 45:1413• Boks AL, et al. Hepatology 1986; 6: 79• Diaz LK &Teruya J. New Engl J Med 2001;344:2030• Grabau CM et al. Hepatology 2004;40:484• Terjung B et al. Digestion 2003; 67: 138• Mc Gill DB et al. Gastroenterology 1990; 99: 1396 • Vieira da Rocha E et al.Clin Gastroenterology and
Hepatol 2009; 7: 988
A.TRIPODI Ewe, 1981
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Why Conventional Coagulation Tests do not Correlate with Bleeding in
Cirrhosis ?
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Coagulation in Liver DiseaseConsiderations on the value of PT &
APTT• PT & APTT might be inadequate to reflect the
coagulation balance as it occurs in vivo especially in cirrhosis
- Protein C and antithrombin are reduced in cirrhosis
- Protein C in vitro is activated to a limited extent in the absence of thrombomodulin
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PROTEIN C is activated by THROMBIN
VaVIIIa
ViVIIIi
PSAPC
membraneTM
T PC
PC
T
EPCR
APC
EPCR
PS
It should be noted that plasma and reagents needed to perform PT & APTT do not contain TM
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PT & APTT are responsive only toprocoagulant factors
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…and much less to the anticoagulantfactors
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PT & APTT as Tools to Investigate the Balance of Coagulation
• PT & APTT can tell us whether a patient is deficient in one (or more) pro-coagulants
• ….but not whether this deficiency is counterbalanced by a concomitant deficiency of the anti-coagulants
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0
100
200
300
400
500
600
700T
hro
mb
in G
ener
atio
n E
TP
(F
UX
min
)
withoutthrombomodulin
Controls Cirrhotics
withthrombomodulin
Controls Cirrhotics
Platelet-free PlasmaTripodi et al, Hepatology 2005; 41: 553
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Thrombin Generation in Platelet-free Plasmas
Summary of findings • Plasma coagulation is not abnormal in cirrhosis when
assessed with global tests reflecting the function of both pro- and anti-coagulants
• The findings question
- The usefulness of traditional coagulation tests in assessing hemorrhagic risk in cirrhosis
- And the use of procoagulant agents to correct the coagulopathy
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Poor Efficacy of Activated FVII to Stop Bleeding in Cirrhosis
• Bosch J et al, 2004
• Lodge JP et al, 2005
• Planinsic RM et al, 2005
• Bosch J et al, 2008
Platelets & Thrombin Generation
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0
500
1,000
1,500
2,000
2,500
3,000
3,500
ET
P (
Th
rom
bin
) n
M X
min
Controls Cirrhotics
Without Thrombomodulin
P<0.001
1,965
1,365
Controls Cirrhotics
With Thrombomodulin
N.S.
1,140 1,117
Platelet-Rich Plasma (Plt.s count adjusted to 100,000/L)
Tripodi et al, Hepatology 2006
A. TRIPODI
0
500
1,000
1,500
2,000
2,500
3,000
3,500
ET
P (
Th
rom
bin
) n
M X
min
Without Thrombomodulin
Controls Cirrhotics
P<0.001
1,919
1,280
Controls Cirrhotics
With Thrombomodulin
P<0.001
1,221
929
Platelet-Rich Plasma(Plt.s adjusted to the original patient’s count)
Tripodi et al, Hepatology 2006
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0
500
1000
1500
2000
2500
0 100 200 300
Platelet numbers (X 109/L)
ET
P (
thro
mb
in)
nM
Rho=0.50, p<.001
60
Thrombin Generation and Platelet Numbers
Tripodi et alHepatology, 2006
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Thrombin Generation in Platelet-Rich Plasma
Summary of Findings
• Platelets from cirrhotics are qualitatively suitable to support thrombin generation
• The numbers of platelets in cirrhosis might be the limiting factor for thrombin generation
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Why do Patients with Cirrhosis Occasionally Bleed?
• The “restored” hemostatic balance in cirrhosis may not be as stable as in healthy individuals and, therefore, slight alterations may lead to hemorrhage or thrombosis
• Conditions underlying bleeding
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Conditions Underlying Bleeding in Cirrhosis
• Portal Hypertension
• Endothelial dysfunction
• Bacterial infections
• Renal failure
Therapeutic interventions correcting these abnormalities might be more effective
than correcting coagulopathy
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The Balance of Hemostasis
Healthy subjectExcess pro- &anti-coagulants
CirrhosisRelative deficit pro-
& anti-coagulants
Hemorrhage Thrombosis
A.TRIPODI Am J Gastroenterol 2006;101:1524
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Am J Gastroenterol 2009; 104: 96
These observations suggest a procoagulant imbalance
in plasma from patients with cirrhosis
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Is there any biomarker to identify the procoagulant imbalance in cirrhosis?
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0
100
200
300
400
500
600
700
ET
P (
FU
Xm
in)
58% Difference
32% Difference
A.Tripodi et al, Hepatology 2005
Controls
No TM
450
TM
200
Cirrhotics
No TM
300
TM
210
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0
100
200
300
400
500
600
700
ET
P (
FU
Xm
in)
200/450 = 0.44 210/300 = 0.70
A.Tripodi et al, Hepatology 2005
Controls
No TM
450
TM
200
Cirrhotics
No TM
300
TM
210
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Study on the Procoagulant Imbalance in Cirrhosis
•Aim of the Study- To detect biochemical signs of
procoagulant imbalance
•Laboratory tools- Measurement of pro- and anti-coagulants
- Measurement of thrombin generation assessed as ratio of values with/without thrombomodulin
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Case Material
•Patients- 134 patients with cirrhosis with graded
severity according to the Child-Pugh score
•Controls - 131 healthy subjects matched for age
and gender to the patients
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Results
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Pro-coagulants Anti-coagulants
Pro-coagulant Drivers in Cirrhosis
A.TRIPODI et al, Gastroenterology 2009
Healthysubjects
CHILDA
CHILDB
CHILDC
0
100
150
Fac
tor
II (
%)
50
p < 0.001
p < 0.001
Factor II
A.TRIPODI et al, Gastroenterology 2009
p < 0.001
Healthysubjects
CHILDA
CHILDB
CHILDC
0
300
Fac
tor
VII
I (%
)
200
100
p = 0.02
Factor VIII
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Pro-coagulantsAnti-
coagula
nts
Anti-coagulant Drivers in Cirrhosis
A.TRIPODI et al, Gastroenterology 2009
Healthysubjects
CHILDA
CHILDB
CHILDC
Protein Cdeficiency
0
50
150
Pro
tein
C (
%)
100
p < 0.001
p < 0.001
p = 0.03
Protein C
A.TRIPODI et al, Gastroenterology 2009
Healthysubjects
CHILDA
CHILDB
CHILDC
0
40
100
120
An
tith
rom
bin
(%
)
60
80
20
p < 0.001
p < 0.001
Antithrombin
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Pro-coagulants Anti-co
agulants
Balance of Pro- vs Anti-coagulant Drivers in Cirrhosis
Assessed as ratio of thrombin generation
with/without thrombomodulin
A.TRIPODI et al, Gastroenterology 2009
0.0
0.4
1.0
1.2
Rat
io E
TP
(w
ith/w
ithou
t th
rom
bom
odul
in)
0.6
0.8
0.2
Healthysubjects
CHILDA
CHILDB
CHILDC
Protein Cdeficiency
p < 0.001
p = 0.03
Ratio of thrombin generation (with/without TM)
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Summary of Findings
• Cirrhotics present with significantly higher ratios of thrombin generation with/without thrombomodulin than controls
• These ratios increase progressively from Child A to Child C
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….how can this procoagulant imbalance be explained?
A.TRIPODI et al, Gastroenterology 2009
Healthysubjects
CHILDA
CHILDB
CHILDC
0
5
15
10R
atio
(F
acto
r V
III/
Pro
tein
C)
p < 0.001
p < 0.001Ratio FVIII/protein C
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Summary of findings
• Cirrhotics present with
- High factor VIII (pro-coagulant driver)- Low protein C (anti-coagulant driver)• The ratio of pro- vs anti-coagulant drivers is much
higher than the unity and increases progressively from Child A to C
The increased ratios are consistent with the procoagulant imbalance detected
by thrombin generation
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Procoagulant Imbalance in Patients with Chronic Liver Disease
• Tripodi et al, Hepatology 2010
• Lisman et al, J Hepatol 2010
• Gatt et al, J Thromb Haemost 2010
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Overall Conclusions
• The re-assessment of hemostasis in cirrhosis questions consolidated therapeutic strategies
• “Correcting” abnormal traditional hemostasis tests prior to invasive procedure should be reconsidered
• While platelet transfusion may be useful, plasma, anti-fibrinolytics, or pro-coagulants should be used on individual basis
• Patients with cirrhosis are not auto-anticoagulated• Hyper- rather than hypo-coagulability might be the
distinctive feature of cirrhosis
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Practical Implications of the Procoagulant Imbalance in Chronic Liver Disease
• Secondary prevention of VTE (VKA or LMWH) should be more extensively used in cirrhosis
• Primary PVT prevention should be considered in patients awaiting liver transplantation
- Villa E. et al, Gastroenterology 2012
• Other (non coagulation) thrombin effect should be considered in patients with cirrhosis
- Tripodi et al, J Thromb Haemost 2010
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Acknowledgements
• M. Primignani• A. Dell’Era• V. Chantarangkul• M. Clerici• P.M. Mannucci• F. Salerno• M. Colombo• R. de Franchis
• Patients Care
• Data management
• Testing• Advice