Post on 25-Jul-2020
Juan Carlos Garcia-Pagán
Barcelona Hepatic Hemodynamic Laboratory. Liver Unit. IMDIM.
Hospital Clinic. IDIBAPS. Ciberehd. Barcelona
EQUILIBRIO HEMOSTÁTICO EN PACIENTES CON
CIRROSIS HEPÁTICA
XI Curso de Formación Continuada. Trombosis y Hemostasia.
Alicante 26 Noviembre 2016
Recent change in paradigm
From cirrhosis being associated with a “coagulopathy” to cirrhosis
being a prothrombotic disorder
N Engl J Med 2011
Coagulation and Cirrhosis
Pro-coagulants • Thrombocytopenia
• Reduced procoagulant factors
Anti-coagulant status
Anti-coagulants
Pro-coagulant status
• Increased vWf
• Elevated FVIII
• Reduced ATIII, protein C and S
Tripodi Gastroeneterology 2009
Lisman J Hepatol 2002
Coagulation and Cirrhosis
The fragile new re-balance of Hemostasis in Cirrhosis
A. TRIPODI, Modified from Monroe & Hoffman, 2009
• Thrombocytopenia
• Reduced procoagulant factors
Anti-coagulant status Pro-coagulant status
• Increased vWf
• Elevated FVIII
• Reduced ATIII, protein C and S
The fragile new re-balance of Hemostasis in Cirrhosis
Hemorrhage
A. TRIPODI, Modified from Monroe & Hoffman, 2009
Anti-coagulant status Pro-coagulant status
Thrombosis
Bleeding risk Thrombotic risk
PT/APTT Insensitive to
anticoagulants
Fibrinogen, Protein C,…
Only association
Platelet count
Detects risk of bleeding at
extreme low levels
Thrombophilic studies
No currently used
Platelet function test Thrombopenia
Bleeding time Do not predict the bleeding
risk
Fibrinolysis Euglobulin lysis time no
widely available
Global test:
-Thrombin generation
- Viscoelastic tests:
Thromboelastometry/gra
phy
The best but too complex
Better reflect the whole coagulation system but thresholds have not been validated yet
How to assess the bleeding & thrombotic risk?
Annual Incidence of Venous thromboembolism (VTE: Deep venous
thrombosis/Pulmonary embolism)
- General Population (0.1-0.3%)
- Hospitalized patients with cirrhosis (0.5-6.3%). Increased risk
but probably lower than in other comorbidities (cancer
Studies assessing benefit/risk of thromboprophylaxis in
hospitalized patients excluded patients with severe liver disorders
Patients with cirrhosis are at risk of developing
thrombotic complications
Is there Indication for Thromboprophylaxis in Hospitalized
Patients with Cirrhosis (immobile; severe ascites, HE …)?
Thromboprophylaxis with heparins did not increase the
risk of bleeding but did not reduce the risk of VTE either
Gomez Cuervo et al. Thrombosis Research 2013
Pooled risk of bleeding
Thromboprophylaxis with heparins did not increase the
risk of bleeding but did not reduce the risk of VTE either
Gomez Cuervo et al. Thrombosis Research 2013
Pooled risk of VTE
Pooled risk of bleeding
No formal recommendations. RCTs needed.
Fragile new re-balance of Coagulation in Cirrhosis
• Thrombocytopenia
• Reduced procoagulant factors
Anti-coagulant status
Pro-coagulants
Pro-coagulant status
• Increased vWf
• Elevated FVIII
• Reduced ATIII, protein C and S
Inc
ide
nc
e o
f P
VT a
t 1
ye
ar
(%
)
0
10
20
30
40
50
>15 cm/s <15 cm/s
PBF velocity Zocco. J Hepatol 2009
+
Non-Tumoral PVT in Cirrhosis
• Evaluated in 5 studies.
Median 16% (range: 7.4-19%)
1-year incidence
PVT in Cirrhosis.
To treat or not to treat?
• Natural History of PVT
(Spontaneous Resolution?, Progression?, No change)
• Potential Impact of PVT on Liver Disease
• Efficacy and Safety of Treatment
We do not Know!!!!
PVT in Cirrhosis. Anticoagulation Efficacy
• Most studies retrospective
• Small Sample Size (19-55 patients)
• Different Anticoagulants (2 LMWH; 2 LMWH then VKA; 1 VKA)
• Improvement (42-84%)
•Complete renacalization (36-75%)
•Partial recanalization (0-43%)
• Stable (17-40%)
• Progression despite ACO (0-15%)
Anticoagulation in Cirrhosis. Complications
Venous Thromboembolism
- Garcia-Fuster (2008) n=17
-14 pts bleeding (85%); 6 Severe (35%); In all but 3, stop anticoag. before 6 m.
Francoz /2005 (n=19) LMWH/VKA 1 post-EBL Bleeding
Amitrano /2010 (n=28) LMWH 2 PHG anemia
Senzolo /2012 (n=33) LMWH 3 Non-VB (1 non fatal cerebral)
1 VB
1 Heparin Induced Thrombopenia
Delgado /2012 (n=55) LMWH-LMWH/VKA 5 Non-VB
6 VB
Werner /2013 (n=28) VKA 1 Non-VB
Portal Vein Thrombosis
No Mortality related to Anticoagulation
More data needed!
• No RCTs
• LMWH:
• Requires antithrombin; reduced in cirrhosis.
• 1-2 daily injections.
• Do not need monitoring (anti-FXa assay is not reliable in
patients with cirrhosis to measure anticoagulant effect).
• Safer than VKA?
• VKA:
• Also decrease the anticoagulants protein C and S already
reduced in cirrhosis
• INR aimed at interval 2.0-3.0 but suboptimal monitoring
using INR. Value of Modified INR (INR-Liver) unknown.
Anticoagulation agent in cirrhosis. LMWH or VKA?
New antithrombotic agents. Direct action on
antithrombin or in Factor Xa. Better option?
Intagliata et al. Dig Dis Sci 2016
Retrospective Cohort
Similar data: European Survey on the use of Direct Oral
Anticoagulants in a cohort of 36 patients with cirrhosis
De Gottardi and VALDIG members. Liv Intern 2016 (in press)
Incidence of DILI <1%. No differences were found between different DOACS
(Rivaroxaban, Dabigatran, Apixaban)
29 fase III RCTs including >150.000 Pts. Mean follow-up 16 months.
No patients with liver disorders included!!
• Microthrombosis of small hepatic
and portal veins by promoting
hepatic parenchyma extinction
may accelerate disease
progression
Are there other beneficial effects of anticoagulation
beyond preventing/recanalizing thrombosis?
Thrombin
Fibrin Clot
Formation
Parenchymal
extinction
Fibrosis
Factor Xa
Hepatic Stellate Cell
PAR1
Activated HSC
• Thrombin and activated Factor X
by activating PAR1 receptor of
HSC may further increase fibrosis
Enoxaparin on CCl4 cirrhotic rats with PH
1 week Enoxaparin/
vehicle
Cirrhosis induction
and
stop CCl4
1 week
Wash-out
Hepatic
hemodynamic
study
8,00
11,00
14,00
17,00
mm
Hg
Portal Pressure
p= 0.02
Cerini et al. J Hepatology 2016
Vehicle Enoxaparin
Sirius Red
Similar Results with Rivaroxaban
Is there indication for anticoagulation to prevent PVT
in patients with Cirrhosis?
Vila et al. Gastroenterology 2012
Enoxaparin did not just prevent
thrombosis but also diminished clinical
events and mortality during follow-up
* *
0
1
2
3
4
5 Enoxaparin
No Rx
PVT Clinical
Events
RCT enoxaparin vs. No Rx
70 pts with cirrhosis (Child B7-C10) randomized:
• Enoxaparin 4000UI/day (prophylactic dose) (n=34)
• No treatment (n=36) for 48 weeks
No differences in bleeding complications
were observed between groups
Is there indication for anticoagulation to prevent PVT
in patients with Cirrhosis?
Vila et al. Gastroenterology 2012
Enoxaparin did not just prevent
thrombosis but also diminished clinical
events and mortality during follow-up
* *
0
1
2
3
4
5 Enoxaparin
No Rx
PVT Clinical
Events
RCT enoxaparin vs. No Rx
70 pts with cirrhosis (Child B7-C10) randomized:
• Enoxaparin 4000UI/day (prophylactic dose) (n=34)
• No treatment (n=36) for 48 weeks
No differences in bleeding complications
were observed between groups
Not Double Blind; Small Sample Size; Significant
number of patients lost to follow-up; most benefits
lost early after enoxaparin discontinuation.
Mores studies needed before recommending
prophylactic enoxaparin in the treatment of
patients with cirrhosis without PVT
The Barcelona Portal Hypertension Team
Vascular liver diseases collaborative group
Barcelona Hepatic Hemodynamics Laboratory
1. El INR es un buen predictor del riesgo de sangrado.
2. La cirrosis sólo altera los niveles de factores anticoagulantes.
3. Las plaquetas en la cirrosis pueden estar disminuidas, no obstante su adherencia al endotelio dañado es normal o mayor que en los no cirróticos.
4. La cirrosis se considera como un estado de anticoagulación adquirido.
¿Cuál de las siguientes aseveraciones es correcta acerca del equilibrio hemostático en el cirrótico?
1. El INR es un buen predictor del riesgo de sangrado.
2. La cirrosis sólo altera los niveles de factores anticoagulantes.
3. Las plaquetas en la cirrosis pueden estar disminuidas, no obstante su adherencia al endotelio dañado es normal o mayor que en los no cirróticos.
4. La cirrosis se considera como un estado de anticoagulación adquirido.
¿Cuál de las siguientes aseveraciones es correcta acerca del equilibrio hemostático en el cirrótico?
1. Tiempo de protrombina prolongado.
2. Trombocitopenia moderada.
3. El grado de hipertensión portal.
4. El uso de anticoagulantes por cualquier indicación.
¿Cuál de los siguientes factores se asocia a un mayor riesgo de sangrado en pacientes con cirrosis hepática?
1. Tiempo de protrombina prolongado.
2. Trombocitopenia moderada.
3. El grado de hipertensión portal.
4. El uso de anticoagulantes por cualquier indicación.
¿Cuál de los siguientes factores se asocia a un mayor riesgo de sangrado en pacientes con cirrosis hepática?
1. Heparinas de bajo peso molecular
2. Inhibidores directos de la trombina
3. Antagonistas de la vitamina K
4. No existe evidencia clínica que permita realizar una
recomendación al respecto.
¿Qué grupo de anticoagulantes son de elección en la tromboprofilaxis en pacientes hospitalizados con
cirrosis hepática?
1. Heparinas de bajo peso molecular
2. Inhibidores directos de la trombina
3. Antagonistas de la vitamina K
4. No existe evidencia clínica que permita realizar una
recomendación al respecto.
¿Qué grupo de anticoagulantes son de elección en la tromboprofilaxis en pacientes hospitalizados con
cirrosis hepática?
Zocco. J Hepatol 2009
Procoagulant and Anticoagulant Factors in
Cirrhosis. Relation with Severity of the Disease
Tripodi. Gastroenterology. 2009
Retrospective study in 235 pts with cirrhosis (355 hospitalizations)
submitted for at least 2 days to thromboprophylaxis with heparin
• No control group: Then, no possible assessment of efficacy
• Complications: Almost 4% of pts. and 2.5% of
hospitalizations had GI bleeding during hospitalization
(spontaneous GI bleeding is frequent in hospitalized patients
with cirrhosis !!!)
Intagliata et al. (Liver International 2014)
Prophylactic anticoagulation for venous
thromboembolism in hospitalized cirrhosis patients is not
associated with high rates of gastrointestinal bleeding.
(7.2 x100pts year)
(1.3 x100pts year)
(1.1 x100pts year)
0.1% mortality
Cirrhotic patients usually excluded!!
0
4
8
12
16
20
ml·
min
-1
PBF
0
4
8
12
16
mm
Hg
PP
0,0
0,2
0,4
0,6
0,8
1,0
1,2
1,4
mm
Hg/
ml·
min
-1
IHR
Rivaroxaban (RVXB) 20mg/kg/day or Vehicle (2 weeks)
P<0.05
p=0.13 p=0.49
CCl4 cirrhosis
0
4
8
12
16
20
mm
Hg
PP
*
0
5
10
15
20
25
ml·
min
-1
PBF
p=0.59
0,0
0,4
0,8
1,2
1,6
2,0
mm
Hg/
ml·
min
-1
IHR
p=0.21
TAA cirrhosis
Rivaroxaban reduces Portal Pressure in 2
experimental models of cirrhosis