1. PVT In Patients With Chronic Liver Disease Dominique-Charles Valla Hôpital Beaujon, APHP, Université Paris-7, Inserm CR3B Cooperation Bilharz-Beaujon Cairo - March 16-18, 2008

2. PVT in Patients with Cirrhosis Epidemiology Manifestations Causal factors Therapy

3. 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.

4. Incidence of PVT in Patients with Cirrhosis Amitrano, Endoscopy 2002. Francoz et al. Gut 2005 18% pt/yr Listed for liver transplantation Sclerotherapy 12% pt/yr

5. Prevalence of Occult PVT in Cirrhosis Liver 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

6. Prevalence of Overt PVT in Schistosomiasis Preoperative 5 % Splenectomy/Devascularization 19 % Distal splenorenal shunt50 % Widman. Hepatogastroenterology 2003

7. PVT in Patients with Cirrhosis Epidemiology Manifestations Causal factors Therapy

8. 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.

9. PVT and Cirrhosis: Associations Nonami et al. Hepatology 1992;16:1195-8 At LTxNLiver weight PVT 6317 g/Kg No PVT40121 g/Kg P <.02

10. Thrombosis Advanced Liver Disease Decreased Portal Blood Inflow Blood stasis Wall changes (PHT) Thrombosis Advanced Liver Disease

11. PVT in Patients with Cirrhosis Epidemiology Manifestations Causal factors Therapy

12. THROMBOSIS External Factors Environmental Local factors Internal Factors Prothrombotic Disorders Causes For Venous Thrombosis Acquired Inherited

13. 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

14. Acquired Prothrombotic Disorders Common Moderate risk Inflammatory states Malignancy Hyperhomocysteinemia … Uncommon High risk Myeloproliferative dis. APL syndrome PNH Behcet’s disease …

15. 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

16. Coagulation Inhibitors in Cirrhosis Romero-Gomez. J Clin Gastroenterol 2000 100% Protein C Protein S Antithrombin A B C 50% 0% 75% Child-Pugh BC A BC A BC A

17. Acquired Prothrombotic Disorders Common Moderate risk Inflammatory states Malignancy Hyperhomocysteinemia … Uncommon High risk Myeloproliferative dis. APL syndrome PNH Behcet’s disease …

18. 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)

19. Risk Factors for Portal Vein Thrombosis. Cirrhosis without HCC Univariate:Age, Child-Pugh class, Surgery for portal hypertension Endoscopic sclerotherapy Prothrombotic features Mangia, Am J Gastroenterol 1999. Nonami, Hepatology 1992. Davidson, Transplantation 1994. *Amitrano, J Hepatol 2004.

20. PVT and Cirrhosis: Prothrombotic Disorders With PVTNo PVT p Amitrano et al. Hepatology 2000;31:345-8. F. V Leiden F. II gene mutation C677T MTHFR At least one Two or more 13 % 35 % 43 % 70 % 22 % NS <.05 <.01 7 % 2 % 5 % 14 % 0

21. Risk Factors for Portal Vein Thrombosis. Cirrhosis without HCC Univariate:Age, Child-Pugh class, Surgery for portal hypertension Endoscopic sclerotherapy Prothrombotic features Mangia, Am J Gastroenterol 1999. Nonami, Hepatology 1992. Davidson, Transplantation 1994. *Amitrano, J Hepatol 2004. Multivariate:G20210A FII (OR 5.94*)

22. PVT in Patients with Cirrhosis Epidemiology Manifestations Causal factors Therapy

23. PVT and Cirrhosis: Why to treat? To prevent aggravation ? To facilitate transplantation

24. Portal Vein Thrombosis Clinical results of anticoagulant therapy In patients without cirrhosis In patients with cirrhosis

25. Acute PVT: Complete Recanalization Pts at risk: 915033191574 0369121518 Time to recanalization (months) 0 20 40 60 Recanalization (%)

26. Chronic Portal Vein Thrombosis Condat et al. Gastroenterology 2001; 120:490 Thrombosis 6.0 yes no yes no Anticoagulation 1.2 Bleeding 7 17 per 100 patients per year p = 0.015 p = 0.212

27. Orr et al. Hepatology 2005; 42: 212A (AASLD San Francisco 2005) Chronic portomesenteric venous thrombosis HR for Death yes no Warfarine 0.10 1.00 p=0.038

28. 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)

29. 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

30. 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

31. 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%

33. 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

34. 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%?

35. Patients on the Waiting List for LTx PVT before transplantation 24 Complete 3 Recanalization 0 Francoz, ILTS 2008 Partial 21 Recanalization* 15 * No post-OLT PVT

36. 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

37. Acute Portal Vein Thrombosis 0 100 Major Bleeding 60% Thrombolysis (in situ, n = 20) 5% Anticoagulation (alone, n = 27) Condat. Hepatology 2000 Holliingshead. J Vasc Interv Radiol 2005 %