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

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

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

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

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

Prothrombotic Disorders in BCS or PVT Myeloproliferative diseases % Hereditary thrombophilias % Antiphospholipid syndrome % PNH % Janssen, Blood Deltenre, Gut, Primignani, Hepatology 2005 BCSPVT

Healthy male patient, 39 year-old. Enlarged spleen (6 cm) at routine examination AST/ALT Normal WBC9 000/fL GGT & ALP1.8 x ULN Platelets /fL Prothrombin72% RBC /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

WBC9 000/fL Platelets /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

How many causal factors have been fully identified ?

WBC9 000/fL Platelets /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

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

WBCC9 000/fL Platelets /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

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

WBCC9 000/fL Platelets /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

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

WBCC9 000/fL Platelets /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

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

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

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

Would you recommend permanent anticoagulation ? YES - NO

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

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 = p = 0.212

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

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

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 Major Bleeding 60% Thrombolysis (in situ, n = 20) 5% Anticoagulation (alone, n = 27) Condat. Hepatology 2000 Holliingshead. J Vasc Interv Radiol 2005 %

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

Anticoagulation for BCS Janssen et al, J Hepatol de Franchis, J Hepatol 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.

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.