PVT In Patients With Chronic Liver Disease

Dominique-Charles VallaHôpital Beaujon, APHP, Université Paris-7, Inserm CR3B

Cooperation Bilharz-BeaujonCairo - March 16-18, 2008

PVT in Patients with Cirrhosis

Epidemiology

Manifestations

Causal factors

Therapy

Prevalence of Overt PVT in Cirrhosis

Screening for HCC 0.6 %

In-Hospital 7.0 %

Necropsy 8.0 %

Before LTx or PSS 15.0 %

Okuda et al. Gastroenterology 1985;89:279-86. Chang et al. J Pathol Bacteriol 1965;89:473-80.

Incidence of PVT in Patients with Cirrhosis

Amitrano, Endoscopy 2002. Francoz et al. Gut 2005

18% pt/yrListed for liver transplantation

Sclerotherapy 12% pt/yr

Prevalence of Occult PVT in CirrhosisLiver explants

Wanless et al. Hepatology 1995;21:1238-47.

Small mural thrombus 64 %

Large veins (intimal fibrosis) 25 %

Small veins (intimal fibrosis) 36 %

% Veins involved

Prevalence of Overt PVT in Schistosomiasis

Preoperative 5 %

Splenectomy/Devascularization 19 %

Distal splenorenal shunt 50 %

Widman. Hepatogastroenterology 2003

PVT in Patients with Cirrhosis

Epidemiology

Manifestations

Causal factors

Therapy

PVT and Cirrhosis: Associations

• Portal hypertensive bleeding• Failure to control bleeding• Ascites• Hepatic encephalopathy• Hyperdynamic circulation• Intestinal ischemia or infarction

Nonami Hepatology 1992. Orloff J Gastrointest Surg 1997. D’Amico Hepatology 2003. Amitrano J Hepatol 2004.

PVT and Cirrhosis:Associations

Nonami et al. Hepatology 1992;16:1195-8

At LTx N Liver weight

• PVT 63 17 g/Kg

• No PVT 401 21 g/KgP < .02

Thrombosis

Advanced Liver Disease

Decreased Portal Blood Inflow

Blood stasisWall changes (PHT)

Thrombosis

Advanced Liver Disease

PVT in Patients with Cirrhosis

Epidemiology

Manifestations

Causal factors

Therapy

THROMBOSISExternal Factors

Environmental

Local factors

Internal Factors Prothrombotic Disorders

Causes For Venous Thrombosis

Acquired

Inherited

Inherited Prothrombotic Disorders

Loss of function

Inhibitors (PC, PS, AT)

Uncommon (< 0.1%)

High risk

Dg: Plasma level

Gain of function

Factors (FV, FII)

Common (> 2.0%)

Moderate risk

Dg: DNA analysis

Acquired Prothrombotic Disorders

CommonModerate risk

Inflammatory statesMalignancyHyperhomocysteinemia…

UncommonHigh risk

Myeloproliferative dis.APL syndromePNHBehcet’s disease…

Inherited Prothrombotic Disorders

Loss of function

Inhibitors (PC, PS, AT)

Uncommon (< 0.1%)

High risk

Dg: Plasma level

Gain of function

Factors (FV, FII)

Common (> 2.0%)

Moderate risk

Dg: DNA analysis

Coagulation Inhibitors in Cirrhosis

Romero-Gomez. J Clin Gastroenterol 2000

100%

Protein C Protein S Antithrombin

A B C

50%

0%

75%

Child-Pugh

B C A B C A B CA

Acquired Prothrombotic Disorders

CommonModerate risk

Inflammatory statesMalignancyHyperhomocysteinemia…

UncommonHigh risk

Myeloproliferative dis.APL syndromePNHBehcet’s disease…

PVT and Cirrhosis: Antiphospholipid Ab

Mangia, Am J Gastroenterol 1999. Dalekos, Eur J Gastro Hepato 2000.Munoz-Rodriguez, J Hepatol 1999. Prieto, Hepatology 1996.

Quintarelli, J Hepatol 1994. Violi, Hepatology 1997. Romero-Gomez J Clin gastro 2000

• ACL common in chronic liver diseases (20%)

• Usually non specific (low fluctuating titer, no LA)

Risk Factors for Portal Vein Thrombosis.Cirrhosis without HCC

Univariate: Age, Child-Pugh class, Surgery for portal hypertensionEndoscopic sclerotherapyProthrombotic features

Mangia, Am J Gastroenterol 1999. Nonami, Hepatology 1992. Davidson, Transplantation 1994. *Amitrano, J Hepatol 2004.

PVT and Cirrhosis: Prothrombotic Disorders

With PVT No PVT p

Amitrano et al. Hepatology 2000;31:345-8.

F. V LeidenF. II gene mutationC677T MTHFRAt least oneTwo or more

13 %35 %43 %70 %22 %

NS< .05< .05< .01

7 %2 %5 %

14 %0

Risk Factors for Portal Vein Thrombosis.Cirrhosis without HCC

Univariate: Age, Child-Pugh class, Surgery for portal hypertensionEndoscopic sclerotherapyProthrombotic features

Mangia, Am J Gastroenterol 1999. Nonami, Hepatology 1992. Davidson, Transplantation 1994. *Amitrano, J Hepatol 2004.

Multivariate: G20210A FII (OR 5.94*)

PVT in Patients with Cirrhosis

Epidemiology

Manifestations

Causal factors

Therapy

PVT and Cirrhosis: Why to treat?

• To prevent aggravation ?

• To facilitate transplantation

Portal Vein Thrombosis Clinical results of anticoagulant therapy

• In patients without cirrhosis

• In patients with cirrhosis

Acute PVT: Complete Recanalization

Pts at risk: 91 50 33 19 15 7 4

0 3 6 9 12 15 18

Time to recanalization (months)

0

20

40

60

Rec

anal

izat

ion

(%)

Chronic Portal Vein Thrombosis

Condat et al. Gastroenterology 2001; 120:490

Thrombosis

6.0

yesno yesnoAnticoagulation Anticoagulation

1.2

Bleeding

7

17

per

100

pat

ien

tsp

er y

ear

p = 0.015

p = 0.212

Orr et al. Hepatology 2005; 42: 212A (AASLD San Francisco 2005)

Chronic portomesenteric venous thrombosis

HR for Death

yesno

Warfarine

0.10

1.00p=0.038

Patients on the Waiting List for LTx

PVT before transplantation(n = 29)

Anticoagulation(n = 19)

Recanalization(n = 8)

Francoz, Gut 2005

No anticoagulation(n = 10)

Recanalization(n = 0)

TIPS for PVT in Cirrhosis

• Limited data• Feasible and safe• Risk of obstruction unclear • Risk of encephalopathy unclear• Benefit unclear

Senzolo Alim Pharmacol Therap 2006. Van Ha Cardiovasc Intervent Radiol 2006. Bauer Liver Transplant 2006

PVT and Cirrhosis: Summary

• Common in end-stage cirrhosis

• Uncommon in well-compensated cirrhosis

• Causal factors: surgery, stasis, thrombophilias

• A marker for severity: certainly

• A cause for aggravation: uncertain

• A limitation for liver transplantation: certainly

PVT and Cirrhosis: What we do in Beaujon

Objectives: Recanalization (recent thrombus)Prevention of thrombus extension

Indications: → Child A with thrombophilia→ Patients listed for LTx

Monitoring: Anti-Xa 0.5 U/ml Factor II 25% to 35%

Hemostasis in Cirrhosis

• Normal thrombin generation in platelet-poor plasma.

• Decreased thrombin generation in severely thrombocytopenic blood.

• Elevated levels of vWF support platelet adhesion despite reduced functional capacities.

Caldwell. Hepatology 2006

INR in Patients with Cirrhosis

• Not related to prothrombin levels along the same regression line as for Vitamin K antagonists.

• Due to uncarboxylated metabolites of coagulation factors

• Interlaboratory variability.

→ Adjustment based on Factor II level 25-35%?

Patients on the Waiting List for LTx

PVT before transplantation24

Complete3

Recanalization0

Francoz, ILTS 2008

Partial21

Recanalization*15

* No post-OLT PVT

Recanalisation

83 %

Anticoagulation (alone, n = 27)

Condat. Hepatology 2000

Thrombolysis (in situ, n = 20)

75 %

Acute Portal Vein Thrombosis

Holliingshead. J Vasc Interv Radiol 2005

Acute Portal Vein Thrombosis

0

100Major Bleeding

60%

Thrombolysis (in situ, n = 20)

5%

Anticoagulation (alone, n = 27)

Condat. Hepatology 2000

Holliingshead. J Vasc Interv Radiol 2005

%