1. Haematological and vascular complications affecting the liver Dominique-Charles Valla Hôpital Beaujon, Clichy, France BSG Postgraduate Course Birmingham 2006

2. Blood disorders affecting the liver Lymphoproliferative or myeloproliferative diseases Activated Macrophages Lymphoproliferative diseases Prothombotic disorders Infiltration Cytokine release Light chain deposition Thrombosis

3. Prothrombotic Disorders Involvement of hepatic vessels Portal venous thrombosis large- or small-sized veins Hepatic venous thrombosis large- or small-sized veins Any combination thereof

4. Secondary architectural changes portal central sinusoidal macronodules micronodules Vascular obstruction Sinusoidal dilatation central random Atrophy Hypertrophy Fibrosis

5. Prothrombotic disorders affecting hepatic vessels Extrahepatic portal vein thrombosis Pylephlebitis and Portal cavernoma Hepatic vein/IVC thrombosis Budd-Chiari syndrome Intrahepatic vascular obstruction Hepatic veins or Portal veins Non-cirrhotic architectural changes Portal hypertension or Abnormal liver tests

6. Prothrombotic Disorders in BCS or PVT Myeloproliferative diseases % Hereditary thrombophilias % Antiphospholipid syndrome % PNH % 60 30 353515 50 Janssen, Blood 2000. Deltenre, Gut, 2001. Primignani, Hepatology 2005 BCSPVT

7. Healthy male patient, 39 year-old. Enlarged spleen (6 cm) at routine examination AST/ALT Normal WBC9 000/fL GGT & ALP1.8 x ULN Platelets250 000/fL Prothrombin72% RBC4.2 10 6 /fL Factor V 70% Hematocrit 39% No cause for chronic liver disease CT / US : Portal cavernoma. Grade III esophageal varices with red signs Needle biopsy: Normal liver Case history

8. WBC9 000/fL Platelets250 000/fL Hematocrit 39% Prothrombin72% Factor V 70% Antithrombin N > 75% 70% Protein C N > 65% 55% Protein S N > 65% 62% Factor V Leiden Absent Factor II mutationPresent APL Ab/LAAbsent

9. How many causal factors have been fully identified ?

10. WBC9 000/fL Platelets250 000/fL Hematocrit 39% Prothrombin72% Factor V 70% Antithrombin N > 75% 70% Protein C N > 65% 55% Protein S N > 65% 62% Factor V Leiden Absent Factor II mutationPresent APL Ab/LAAbsent

11. 1 2 3 F II gene mutation X How many causal factors have been fully identified ?

12. WBCC9 000/fL Platelets250 000/fL Hematocrit 39% Prothrombin72% Factor V 70% Antithrombin N > 75% 70% Protein C N > 65% 55% Protein S N > 65% 62% Factor V Leiden Absent Factor II mutationPresent APL Ab/LAAbsent

13. PVT - Coagulation inhibitors Fisher. Gut 2000; 46:534

14. WBCC9 000/fL Platelets250 000/fL Hematocrit 39% Prothrombin72% Factor V 70% Antithrombin N > 75% 70% Protein C N > 65% 55% Protein S N > 65% 62% Factor V Leiden Absent Factor II mutationPresent APL Ab/LAAbsent

15. Combination of prothrombotic disorders At least 2 disorders (%) 25-35%10-20% BCS PVT Denninger. Hepatology 2000. Janssen Blood 2000. Primignani Hepatology 2005 Myeloproliferative disease in 20-60% of patients with hereditary thrombophilias

16. WBCC9 000/fL Platelets250 000/fL Hematocrit 39% Prothrombin72% Factor V 70% Antithrombin N > 75% 70% Protein C N > 65% 55% Protein S N > 65% 62% Factor V Leiden Absent Factor II mutationPresent APL Ab/LAAbsent

17. BCS or PVT Features of Myeloproliferative Disease PPV 100% Chait et al. Br J Haematol 2005 Δ Spleen > 5 cm Platelets > 200 000/fL

18. Myeloproliferative diseases Classical criteria (PVSG) % 100 Endog enous erythroid colonies % 6030 Bone marrow biopsy % 6030 V617F JAK2 mutation % 6030 Diagnostic criteriaBCSPVT James Nature 2005. Kralovics NEJM 2005. Baxter Lancet 2005. Levine Cancer Cell 2005. Patel RK et al. ASH Dec 2005. Fabris FH et al. EASL 2006

19. F II gene mutation Myeloproliferative disease Portal vein thrombosis Large oesophageal varices with red signs

20. Would you recommend permanent anticoagulation ? YES - NO

21. Disease-specific Antithrombotic Therapies Myeloproliferative diseases  Hydroxyurea  Low dose aspirin  Anagrelide Other acquired or inherited conditions  Little or no data Cortelazzo NEJM 1995. Landolfi NEJM 2004. Eliott Br J Haematol 2004. Crother Thromb Res 2004. Harrisson NEJM 2005 Data still unclear for venous thromboses

22. 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

23. Chronic PVT – GI Bleeding Condat et al. Gastroenterology 2001;120:490-497 17 24 Moderate/large-sized varices yes no Prophylaxis per 100 patients per year

24. Orr et al. Hepatology 2005; 42: 212A (AASLD San Francisco 2005) Chronic portomesenteric venous thrombosis Hazard Ratio for Death Beta-blockers yes no 0.28 1.00 p=0.030 yes no Warfarine 0.10 1.00 p=0.038

25. 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

26. 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 %

27. Portal Vein Thrombosis Current guidelines in Beaujon → Permanent anticoagulation No contraindication Prophylaxis for PHT-related bleeding Permanent prothrombotic disorder

28. Anticoagulation for BCS Janssen et al, J Hepatol 2003. de Franchis, J Hepatol 2005. Anticoagulation recommended to all patients, in the absence of major contraindication. Previous bleeding from portal hypertension is not considered a major contraindication, provided appropriate prophylaxis for recurrent bleeding is initiated.

29. Conclusions Blood disorders are major causes of vascular liver diseases. Atypical myeloproliferative diseases most commonly implicated. Frequent combination of several causes. Permanent anticoagulation is generally recommended once prophylaxis for portal hypertensive bleeding has been instituted.