Anticoagulación en la Cirrosis e HTP no cirrótica

Juan Carlos Garcia-PagánBarcelona Hepatic Hemodynamic Laboratory. Liver Unit. IMDIM. Hospital Clinic.

IDIBAPS. Ciberehd. Barcelona

IV Curso para Residentes: “Diagnóstico y Tratamiento de las Enfermedades Hepáticas”

Barcelona, 18-19 Octubre 2013

• Coagulación y Cirrosis: Fundamentos del Tratamiento

• Hay que anticoagular a los cirróticos: ¿Cuándo? ¿hay suficiente evidencia?

• Trombosis portal aguda no cirrótica: anticoagulación y tratamientos locales intervencionistas

Factors contributing to PVT in Cirrhosis

Pro-coagulants• Thrombocytopenia• Reduced procoagulant factors

Anti-coagulant status

Factors contributing to PVT in Cirrhosis

Anti-coagulants

Pro-coagulant status

• Increased vWf• Elevated FVIII• Reduced ATIII, protein C and S

Tripodi Gastroeneterology 2009

Lisman J Hepatol 2002

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

• Prothrombin gen Mut.• Other…

Hereditary or acquired prothrombotic disorders

Amitrano. Hepatol. 2000

Amitrano. J Hepatol. 2004

+

Inc

ide

nc

e o

f P

VT

at

1 y

ea

r

(%)

0

10

20

30

40

50

>15 cm/s<15 cm/s

PBF velocity Zocco. J Hepatol 2009

+

Non-Tumoral PVT in Cirrhosis

•Median 16%

(range: 7.4-19%)

(5 Studies)

1-year incidence

To treat or not to treat?

•Whether PVT causes a further deterioration of the clinical condition (Variceal bleeding, ascites…) or actually appears when liver is already decompensated is not clear

•More clear the impact on Liver Transplantation

PVT in Cirrhosis. OLT

Degree of PVT influences OLT outcome

Yerdel et al. Transplantation 2000

Grade PVT

1. Partially thrombosed PV, thrombus confined <50% of vessel lumen, with or without minimal extension to SMV

2. >50% occlusion PV, including total occlusion, with/without minimal extension SMV

3. Complete thrombosis of PV and proximal SMV. Distal SMW open

4. Complete thrombosis of PV and proximal and distal SMW

Degree of PVT Influences OLT Survival

Yerdel et al. Transplantation 2000

(n=24)

(n=716)

(Grd 2:n=23 ;Grd 3:n=6;Grd 4:n=10))

In patients with cirrhosis and potential OLT candidates preventing the development of severe forms of PVT

(grade 3 and 4) impact outcome

Natural History of PVT in Cirrhosis

What is the evolution of PVT? Is there always progression? Is there spontaneous recanalization?

0

60

5

71

4548

0

10

20

30

40

50

60

70

80

Francoz (2005)(n=10, all partial)

Senzolo (2012)(n=21, 14 partial)

Luca (2012)(n=42, all partial)

Recanalization / *Improvement in Luca’s studyProgression

PVT evolution in patients not receiving anticoagulation

Author/year Sample Size

Type ACO Recanalization % (Complete/partial)

Stable (%) Progression (%)

Francoz/2002 19 LMWH/VKA 42 (42 / 0) 53 5

Amitrano/2010 28 LMWH 84 (75 / 9) 16 0

Senzolo/2012 33 LMWH 63 (36 / 27) 22 15

Delgado/2012 55 LMWH/LMWH/VKA 60 (46 / 14) 40 0

Werner/2013 28 VKA 82 (39 / 43) 18 0

PVT in Cirrhosis. Anticoagulation

•5 Studies (4 retrospective, one prospective)

Delayed initiation of anticoagulation was the only factor associated with no recanalization

Anticoagulation for PVT in Cirrhosis. Complications

No Mortality related to Anticoagulation

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 VB1 Heparin Induced Thrombopenia

Delgado /2012 (n=55) LMWH-LMWH/VKA 5 Non-VB6 VB

Werner /2013 (n=28) VKA 1 Non-VB

What shoud be do if recanalization is achieved?

• Pathophysiological mechanisms leading to the development of thrombosis remain

• Amitrano et al. 2010.

Three of 11 (27%) patients who stopped anticoagulation after achieving recanalization showed rethrombosis at 1, 4, and 24 months

• Delgado et al. 2012.

5 of 13 pts (38.5%) had rethrombosis a median of 1.3 months after stopping anticoagulation.

Long-Term anticoagulation?

• Microthrombosis of small hepatic and portal veins may accelerate disease progression

• Experimental data have shown that hypercoagulability may increase fibrosis progression and this can be reverted by anticoagulation

Are there other beneficial effects of anticoagulation beyond preventing/recanalizing thrombosis?

Enoxaparin did not just prevent thrombosis but also diminished clinical

events during follow-up

Vila et al. Gastroenterology 2012

* *

0

1

2

3

4

5Enoxaparin

Placebo

PVT ClinicalEvents

RCT enoxaparin vs. Placebo 70 pts with cirrhosis (Child B7-C10):

• Enoxaparin 4000UI/day (prophy: n=34)

• No treatment (n=36) for 48 weeks

No differences in bleeding complications were observed between groups

• Microthrombosis of small hepatic and portal veins may accelerate disease progression

• Experimental data have shown that hypercoagulability may increase fibrosis progression and this can be reverted by anticoagulation

Are there other beneficial effects of anticoagulation beyond preventing/recanalizing thrombosis?

Enoxaparin did not just prevent thrombosis but also diminished clinical

events during follow-up

Vila et al. Gastroenterology 2012

* *

0

1

2

3

4

5Enoxaparin

Placebo

PVT ClinicalEvents

RCT enoxaparin vs. Placebo 70 pts with cirrhosis (Child B7-C10):

• Enoxaparin 4000UI/day (prophy: 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

Recent or evident progression of thrombosis

Anticoagulation

Evaluation at 3-6 months with Imaging study

Progression of Thrombosis

Consider TIPS

Stable old thrombus or Portal Cavernoma

Is the spleno-SMV junction patent and is the patient a possible LT candidate?

No

Routine follow-up

Yes

Is there a thrombophilic disorder?

No

Careful Imaging follow-up

Yes

Progression of Thrombosis

Improvement or Stabilization of PVT

Consider Anticoagulation for

life or until LT

PVT in Cirrhosis. Treatment Recommendations

TIPS should also be considered in patients with concomitant severe complications of portal hypertension such as variceal bleeding or refractory ascites

PVT in Healthy Liver

• Abd. Pain/Intestinal Isch.• Infarction

Acute PVT Chronic PVT/Portal Cavernoma

• Variceal Bleeding• Portal Colangiopathy

• Recurrent Thrombosis• Others

xx

• Early Diagnosis• Immediate application of Treatment

Recanalization rate in anticoagulated patients with Portal, Superior Mesenteric, or Splenic Vein Thrombosis

Plessier A et al. Hepatology 2010

61% Mesenteric

54% Splenic

38% Portal trunk or both branches

Portal Venous System completely patent in 20% of patients

Spanish Cohort: 23% Complete recanalization; 23% partial Turnes et al. Clin Gastroenterol Hepatol 2009

Envie Study. Anticoagulation in 95 Acute PVT

• 9 bleeding (5 GI; 3 Severe: No mortality)

• 2 death (1 Late malignancy and 1 sepsis)

• Intestinal Infarction 6 and 12 days after

anticoagulation, limited intestinal resection, both

survived

Low number of adverse events.

Thrombolytic Therapy in Acute thrombosis of the PV System Rate of Recanalization and complications

• Almost 100% success of thrombolytic therapy with a low incidence of complications in reported cases. Potential publication bias.

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60

70

Major complications

Minor complications

No

%Complications

Hollingshead et al. JVIR 2005 (n=20) Smalberg et al. Thromb Haemost 2008 (n=12)

0

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20

30

40

50

Complete Partial No Recanalization

Recanalization%

60

70

In acute SMV thrombosis (n=11): 90.9% restoration flow; 1 hemothorax; 1 deathKim et al. JVIR 2005

Acute PVT. Recommendations for Treatment

•Anticoagulation: First Choice Treatment

•Thrombolysis/Thrombectomy if persistent or worsening symptoms despite anticoagulation (high

risk of Intestinal Infarction!)

Janssen et al. Gut 2001

Patients With Non-Cirrhotic Non-Malignant Chronic Portal Vein Thrombosis had a Good Prognosis

47

Rajani et al. Aliment Pharmacol Ther 2010; 32: 1154-1162

> 85% Survival at 5 y

Barcelona Portal Hypertension Team at Hospital Clinic in Barcelona

Barcelona Portal Hypertension Team at Hospital Clinic in Barcelona

Vascular liver diseases collaborative group

Hepatic hemodynamics laboratory

Anticoagulation in Cirrhosis. Complications

No Mortality related to Anticoagulation

Deep Venous Thrombosis or Pulmonary Embolism)

- Garcia-Fuster (2008) n=17

-14 pts bleeding (85%); 6 Severe (35%); In all but 3, stop anticoag. before 6 m.

Portal Vein Thrombosis

Francoz/2005

n=19

Amitrano/2010

n=28

Senzolo/2012

n=33

Delgado/2012

n=55

1 Post-EBL bleeding 2 PHG anemia 1 VB; 1 Cereb Hemorrh; 1 heparin ind thrombop

In 10 pts: 6 VB; 5 Non-VB

Platelet < 50.000 Bleed predictive factor

PVT in Cirrhosis. Anticoagulation

Delayed initiation of anticoagulation was the only factor associated with no recanalization

• 5 Studies (4 retrospective, one prospective)

• 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%)

Francoz 2002; Amitrano 2010; Senzolo 2012; Delgado 2012; Werner 2013

Anticoagulation in Chronic PVT

Condat et al. Gastroenterology 2001

Aim: To prevent further episodes of thrombosis

Indication:

• Existence of an underlying prothrombotic disorder• Previous thrombosis of other vascular territories• Rethrombosis/thrombosis progression

Results:

• Prevents recurrent thrombosis (reduced by half) • Without more risk or severity of gastrointestinal

bleeding

Anticoagulation can always be delayed until treatment to prevent variceal bleeding has been initiated

Recurrent Thrombosis in pts with NCNT-PVT

- More common than suspected, but frequently asymptomatic

and only recognized if intentionally investigated

- Rethrombosis may deteriorate outcome (EV, Colangiopathy)

- Different risk according with underlying etiology.

Anticoagulation in Chronic PVT if:

• Existence of an underlying prothrombotic disordes• Previous thrombosis of other vascular territories• Rethrombosis/thrombosis progression

Prevents recurrent thrombosis without * or with **more risk of GI bleeding but without increasing the severity of bleeding when it occurs

*Condat et al. Gastroenterology 2001;**Spaander et al. J Thromb Haem 2013

Anecdotic reports of systemic or local administration of different thrombolytic agents.

Thrombolytic therapy may be useful but severe complications may occur

Thrombolysis in Patients with Cirrhosis and PVT

A pilot study in 9 patients with cirrhosis and PVT, suggests that systemic thrombolysis with low dose r-tPA could be effective in obtaining recanalization (45% partial and 45% complete recanalization) with no major side effects

De Santis. Dig Liv Dis 2010

TIPS in Patients with Cirrhosis and PVT

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60

70

80

90

100 TIPS Feasibility (%)

Senzolo 200625 pts

Van Ha 200615 pts

Perarnau 201034 pts

Han 201157 pts

Luca 201170 pts

• The number of patients in whom TIPS was not considered because of the presence of PVT is unknown. Therefore, It is difficult to estimate the real applicability of TIPS in the management of PVT in cirrhosis

• In most cases, TIPS was indicated to treat severe complications of portal hypertension and not PVT itself

PVT Recanalization after TIPS Placement in Cirrhosis

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50

60

57%

CompleteRec

30%

PartialRec

13%

No change

Luca et al. 2011

Predictors of complete recanalization were a less extensive PVT, de novo PVT and absence of gastroesophageal varices

52%

70%97%

0 6 12 18 24 m

100

80

60

40

20

0

No anticoagulation after TIPS. Increased Portal flow?

A Long Way to go…

Predictors for Absence of Recanalization. Envie Study

Multivariate analysis: Ascites (HR 3.2, 95% CI 1.3-8) Splenic vein obst. (HR 3.2, 95% CI 1.3-7.6)

Other factors that have been shown to be associated with a lower rate or recanalization under anticoagulation:

- Extension of thrombosis- Presence of 2 or more prothrombotic causes

TIPS in Non-Cirrhotic patients with Portal Cavernoma - Anecdotic Cases

- 2 recent retrospective cohorts

•10/13 pts (77%) successful TIPS

•6 (47%) alive and free of PH complications

PTFE-covered stents (Fanelli et al: Dig Liv Dis 2011)

Bare stents (Qi et al. Dig Dis Sci 2012)

•7/20 pts (35%) successful TIPS (only 1 through the Transj. approach)

•No different significant survival in successful (71%) vs failure TIPS

group (85%)

TIPS could be a therapeutic alternative in a small and very selected group of patients

Derivative surgery. Failures of medical Rx.

No patent vessel suitable for derivation in 37% of our pts.

- Deep venous thrombosis/Pulmonary embolism

- Portal Vein Thrombosis

Risk of DVT/PE has been shown to range from 0.5 to 1.87%

Studies assessing benefit/risk of thromboprophylaxis in hospitalized patients systemically excluded patients with severe liver disorders

Patients with cirrhosis are at risk of developing thrombotic complications

Is there Indication for Thrombophrophylaxis in Hospitalized Patients with Cirrhosis (immobile; severe ascites, HE …)?

Anstee et al. Gastroenterol Clin Biol. 2008

InflammationLiver injury

Antagonistas PAR-1 Ratones knock-out PAR-1• Fibrosis en modelos CBDL y

CCl4Rullier. Am J Physiol. 2008

Fiorucci. Hepatol. 2004

2) Papel de la trombina en la fibrogénesis a través de PAR-1

Antagonista sintético de la

trombina Heparina• Fibrosis en modelos CBDL y

CCl4

Duplantier. Gut. 2004Abe W. et al. Journal of Hepatology 2007

Abdel-Salam et al. Pharm Res 2005

Agonistas PAR-1• Proliferación de CEH• Fibrosis

Gaca. J Hep. 2002

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 !!!)

• Current guidelines do not make formal recommendations on thromboprophylaxis in hospitalized patients with cirrhosis

• RCTs needed.

Intagliata et al. (Liver International 2013 in press); Cerini & Garcia-Pagan (editorial)

• 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.New antithrombotic agents. Direct action on antithrombin or in Factor Xa. Better option?

Anticoagulation agent in cirrhosis. LMWH or VKA?

2.5% (7.2 x100pts year)

(1.3 x100pts year)

0.22% (1.1 x100pts year)0.1% mortality

37 fatal 11 fatal

Anstee et al. Gastroenterol Clin Biol. 2008

InflammationLiver injury

1) Microtrombosis

Wanless IR Hepatology 1995 Anstee et al. Clin Liver Dis. 2009

Coagulación y fibrosis hepática :Mecanismos patogénicos TROMBINA

Anecdotic reports of systemic or local administration of different thrombolytic agents.

Thrombolytic therapy may be useful but severe complications may occur

Thrombolysis in Patients with Cirrhosis and PVT

A pilot study in 9 patients with cirrhosis and PVT, suggests that systemic thrombolysis with low dose r-tPA could be effective in obtaining recanalization (45% partial and 45% complete recanalization) with no major side effects

De Santis. Dig Liv Dis 2010

Thus, the experience of thrombolysis in patients with cirrhosis and PVT is very limited and complication of thrombolysis may be severe.

Zocco. J Hepatol 2009

Procoagulant and Anticoagulant Factors in Cirrhosis. Relation with Severity of the Disease

Tripodi. Gastroenterology. 2009

Delgado et al. Clin Gastroenterol Hepatol 2012

0

5

10

15

20

25

30

8/22

27%

5/33

15%

RecanalizationPartial/complete

No Recanalization

p=0.1

Clinical Events During Anticoagulation Therapy

13 patients had 23 liver-related clinical events

• Variceal Bleeding n=6• Ascites n=8• Hepatic Encephalopathy n=5• SBP n=2• HCC n=2

Enoxaparin prevents development of 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

5Enoxaparin

No Rx

PVT ClinicalEvents

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

Enoxaparin prevents development of 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

5Enoxaparin

No Rx

PVT ClinicalEvents

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

Han G et al. J Hepatol 2011

TIPS for PVT in Patients with Cirrhosis

Trans-splenicTrans-hepatic

Always Balance Risk-Benefit of interventions

PVT in Cirrhosis

• The natural history of PVT in cirrhosis (rate of progression, stability or possible regression, impact on the course of the disease) as well as the clinical impact of achieving recanalization is poorly known.

• PVT could increase morbidity and mortality associated with OLT and it may even contraindicate it, especially if the thrombus extends to the splenic-SMV junction

• Optimal Management unknown

Points to take into consideration

11

No anticoagulación

2727

SíSí

38 pts con T. Portal Aguda

Turnes et al. Clin Gastroenterol Hepatol 2009

Anticoagulación precoz y Trombosis Portal Aguda

No repermeab.No repermeab.

1515 66

Parcial

66

Completa(23% of Rx)

62% de los que iniciaron anticoagulación en la primera

semana

Englesbe MJ et al. Liver Transplant 2010

Impact of PVT on Liver Transplantation

Waiting list:

No PVT (n=45,573) Yes PVT (n=957) (2,1%)

Patients with cirrhosis and PVT no higher mortality while in the waiting-list,

Transplant Recipients

No PVT (n=21,394) Yes PVT (n=897) (4%)

but higher post-transplant mortality