Haematological and vascular complications affecting the liver
Dominique-Charles Valla
Hôpital Beaujon, Clichy, France
BSG Postgraduate CourseBirmingham 2006
Blood disorders affecting the liver
• Lymphoproliferative or myeloproliferative diseases
• Activated Macrophages
• Lymphoproliferative diseases
• Prothombotic disorders
Infiltration
InfiltrationCytokine 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
AtrophyHypertrophy
Fibrosis
Prothrombotic disorders affecting hepatic vessels
• Extrahepatic portal vein thrombosisPylephlebitis and Portal cavernoma
• Hepatic vein/IVC thrombosisBudd-Chiari syndrome
• Intrahepatic vascular obstructionHepatic 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 %
60 30
35 35
15 15
5 0
Janssen, Blood 2000. Deltenre, Gut, 2001. Primignani, Hepatology 2005
BCS PVT
• Healthy male patient, 39 year-old.Enlarged spleen (6 cm) at routine examination
• AST/ALT Normal WBC 9 000/fL GGT & ALP 1.8xULN Platelets 250 000/fL Prothrombin 72% RBC4.2 106/fLFactor 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
WBC 9 000/fLPlatelets 250 000/fLHematocrit 39%Prothrombin 72%Factor V 70%
Antithrombin N > 75% 70%Protein C N > 65% 55%Protein S N > 65% 62%Factor V Leiden AbsentFactor II mutation PresentAPL Ab/LA Absent
How many causal factors have been fully identified ?
WBC 9 000/fLPlatelets 250 000/fLHematocrit 39%Prothrombin 72%Factor V 70%
Antithrombin N > 75% 70%Protein C N > 65% 55%Protein S N > 65% 62%Factor V Leiden AbsentFactor II mutation PresentAPL Ab/LA Absent
123
• F II gene mutation
• X
How many causal factors have been fully identified ?
WBCC 9 000/fLPlatelets 250 000/fLHematocrit 39%Prothrombin 72%Factor V 70%
Antithrombin N > 75% 70%Protein C N > 65% 55%Protein S N > 65% 62%Factor V Leiden AbsentFactor II mutation PresentAPL Ab/LA Absent
PVT - Coagulation inhibitors
Fisher. Gut 2000; 46:534
WBCC 9 000/fLPlatelets 250 000/fLHematocrit 39%Prothrombin 72%Factor V 70%
Antithrombin N > 75% 70%Protein C N > 65% 55%Protein S N > 65% 62%Factor V Leiden AbsentFactor II mutation PresentAPL Ab/LA Absent
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
WBCC 9 000/fLPlatelets 250 000/fLHematocrit 39%Prothrombin 72%Factor V 70%
Antithrombin N > 75% 70%Protein C N > 65% 55%Protein S N > 65% 62%Factor V Leiden AbsentFactor II mutation PresentAPL Ab/LA Absent
BCS or PVTFeatures of Myeloproliferative Disease
PPV
100%
Chait et al. Br J Haematol 2005
Δ Spleen > 5 cm
Platelets > 200 000/fL
Myeloproliferative diseases
• Classical criteria (PVSG) % 10 0• Endogenous erythroid colonies % 60 30• Bone marrow biopsy % 60 30• V617F JAK2 mutation % 60 30
Diagnostic criteria BCS PVT
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
• 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 1995. Landolfi NEJM 2004. Eliott Br J Haematol 2004. Crother Thromb Res 2004. Harrisson NEJM 2005
Data still unclear for venous thromboses
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
Chronic PVT – GI Bleeding
Condat et al. Gastroenterology 2001;120:490-497
1724
Moderate/large-sized varices
yesnoProphylaxis
per
100
pat
ien
tsp
er y
ear
Orr et al. Hepatology 2005; 42: 212A (AASLD San Francisco 2005)
Chronic portomesenteric venous thrombosis
Hazard Ratio for Death
Beta-blockersyesno
0.28
1.00p=0.030
yesnoWarfarine
0.10
1.00p=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
0
100Major 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 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.
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.