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.