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