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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
%
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