Portal vein thrombosis: when to anticoagulate?

Transcription

1 Portal vein thrombosis: when to anticoagulate? Dr Aurélie Plessier Centre National de Référence, Maladies Vasculaires du Foie, Service d Hépatologie, Université Paris-Diderot, CRB3 INSERM U773 Hôpital Beaujon (APHP), Clichy, France

2 Epidemiology of portal vein thrombosis Country Sweden Sweden Registries Autopsy Inpatients Outpatients Period Prevalence per Ogren. WJG ,796 autopsies. Rajani, APT 2010

3 Portal vein obstruction Causal factors Malignancy diverse* 1/3 Cirrhosis thrombosis 1/3 Others thrombosis 1/3 *Invasion or encasement or thrombosis Janssen Blood Ogren WJG Rajani APT 2010

4 Portal Vein Thrombosis In patients without cirrhosis In patients with cirrhosis

5 Portal Vein Thrombosis In patients without cirrhosis In patients with cirrhosis

6 Non-cirrhotic, non-malignant PVT A manifestation of underlying blood disorders. Complications of portal venous obstruction generally controlled. Place of anticoagulation debated.

7 Prothrombotic disorders in PVT Myeloproliferative neoplasms % Inherited disorders % Antiphospholipid syndrome % Others (IBD, ) % Any of the above % Any combination % From Janssen, HLA Blood Denninger, MH Hepatology Primignani, Hepatology Plessier, Hepatology 2010

8 Non-cirrhotic, non-malignant PVT Risk factors for venous thrombosis At least one 67% Multiple 18% Local factor 21% Plessier. Hepatology N = 102

9 Non-cirrhotic, non-malignant PVT Risk factors for venous thrombosis At least one 67% Multiple 18% Local factor 21% General factor in 36% of patients with local factors Plessier. Hepatology N = 102

10 Non-cirrhotic, non-malignant PVT Local factors Inflammation: Cancer: Venous injury: Venous stasis: Splanchnic organs Gastrointestinal Splenectomy Obliterative portal venopathy Plessier Hepatology 2010

11 Non-cirrhotic, non-malignant PVT A manifestation of underlying blood disorders. Complications of portal venous obstruction generally controlled. Place of anticoagulation debated.

12 Portal Vein Thrombosis Intestinal Ischemia Uncomplicated Acute PVT Chronic PVT Bleeding Ascites MOF Abdo minal Pain SIRS Bleeding Encephalopathy Cholangiopathy

13 Portal Vein Thrombosis Intestinal Ischemia Uncomplicated Acute PVT Chronic PVT Bleeding Ascites MOF Abdo minal Pain SIRS Bleeding Encephalopathy Cholangiopathy

14 Acute PVT. Anticoagulation in 95 Patients 100 Intestinal Infarction* Death** N Plessier. Hepatology 2010 * Limited intestinal resection. Both survived. ** Late malignancy in 1. Sepsis in 1

15 Risk factors for mesenteric infarction Resection n =18 No resection n =36 p Diabetes % Metabolic syndrome % Choc % 44 0 <0.001 Ascites % Renal failure mic mol/l Hematochezia % Delay of anticoagulation initiation was not different E l

16 Acute Portal Vein Thrombosis EN-Vie Cohort: 95 anticoagulated patients Sup. mesenteric Splenic Portal Plessier. Hepatology 2010

17 Acute PVT: EN-Vie Cohort Predictive Factors for Portal Vein Recanalization EN-Vie Cohort Recanalization rate (%)100 Splenic vein patent, no ascites Splenic vein obstructed, no ascites Splenic vein patent, ascites Splenic vein obstructed, ascites Time to follow-up (months) Plessier. Hepatology 2010

18 Portal Vein Thrombosis Intestinal Ischemia Uncomplicated Acute PVT Chronic PVT Ascites MOF Abdo minal Pain SIRS Bleeding Encephalopathy Cholangiopahy

19 Chronic Portal Vein Thrombosis - Complications % Pt-yr Bleeding Thrombosis Biliary Condat. Gastroenterology 2001 & Hepatology Chait Br J Haematol 2005

20 Chronic Portal Vein Thrombosis - Complications % Pt-yr 30 Recurrent Thrombosis GI Bleeding p = 0.04, 0.07 and Prothrombotic Disorder - + Large Varices - + Previous Bleed Condat, Gastroenterology 2001

21 Extrahepatic PHT : Anticoagulation Thrombosis Bleeding p = % Pt-yr p = Anticoagulation Anticoagulation Condat et al. Gastroenterology 2001; 120:490

22 Chronic Portal Vein Thrombosis Severity of GI Bleeding Anticoagulation No Yes p Hemoglobin (g/dl) NS Hospital stay (days) NS Blood units (n) NS Condat et al. Gastroenterology 2001;120:

23 PVT, bleeding and anticoagulation PVT & VKA PVT no VKA Hospitalisation 75 % 69 % Days in hospital 7,4 11 Days in USI 2,3 0,6 Blood units 3,2 ± 1,9 4,2 ± 2,2 Christol. EASL 2012

24 Anticoagulation and non-selective B-blockers Chronic portomesenteric venous thrombosis Orr DW et al. Clin Gastroenterol Hepatol 2007

25 Extrahepatic Portal Hypertension - Warfarin Thrombosis Bleeding n/yr n = Anticoagulation Anticoagulation Kitchens, J Thromb Thrombolysis 2007

26 Acute PVT Recanalization rate (%)100 EN-Vie Alternative Cohort therapy? Thrombolysis: NO TIPS: Uncertain Splenic vein patent, no ascites Splenic vein obstructed, no ascites Splenic vein patent, ascites Splenic vein obstructed, ascites Time to follow-up (months)

27 Acute Portal Vein Thrombosis Recanalization 100 in situ Thrombolysis 75 % % Incomplete 60 % 0 Complete 15 % Hollingshead. J Vasc Interv Radiol 2005

28 Acute Portal Vein Thrombosis 100 Major Complications % 0 3 % Anticoagulation alone, n = 95 Plessier. Hepatology % Thrombolysis in situ, n = 20 Holliingshead. J Vasc Interv Radiol 2005

29 Prophylaxis for bleeding in adults with PVT Beta blockers Endoscopic therapy

30 Secondary prophylaxis for PHT Bleeding Propranolol Variceal Ligation ~ 20% at 2 yr P = NCIPHT Anticoagulation=0 Sarin. Gastro 2010

31 Portal Vein Thrombosis Consider local and general risk factors Treat PHT as recommended for cirrhosis Consider anticoagulation Acute PVT: 6 months Chronic PVT - After prophylaxis for GI bleeding - Underlying prothrombotic disorders

32 Chronic non-cirrhotic, non-malignant PVT N of Patients 23 to 136 Period 1980 to 2005 Median follow-up 3-5 years Mortality 7-20% Prognosis SMV involvement Associated conditions Consecutive patients, most without cirrhosis or cancer Merkel, J Hepatol Condat, Gastroenterology Janssen, Gut Orr, Hepatology Sogaard, BMC Gastro Amitrano AJG 2007

33 PVT Management in Beaujon Acute and chronic PVT Permanent anticoagulation when One at least of the following Permanent prothrombotic disorder Personal history of thrombosis Familial history >1 thrombosis episode Past history suggestive of intestinal ischemia Superior mesenteric vein involvement No contraindication beside PHT

34 Portal Vein Thrombosis In patients without cirrhosis In patients with cirrhosis

35 Thrombotic Liver Disease in Cirrhosis 1. Cirrhosis is a prothrombotic state 2. PVT & HVT associated with cirrhosis severity 3. A strengthening rationale for anticoagulation HVT, hepatic vein thrombosis. PVT, Portal vein thrombosis

36 Cirrhosis as a prothrombotic state Maintained thrombin generation potential in plasma when tested in appropriate conditions Resistance to the anticoagulant action of thrombomodulin ( factor VIII, protein C) Increased risk for deep vein thrombosis Tripodi, NEJM 2011

37 Thrombin generation in cirrhosis Controls Child A Child B Child C Tipodi Tripodi INR < > 2.0 Gatt Cirrhosis Senzolo

38 Cirrhosis as a Prothrombotic State Maintained thrombin generation potential in plasma when tested in appropriate conditions Resistance to the anticoagulant action of thrombomodulin ( factor VIII, protein C) Increased risk for deep vein thrombosis Tripodi, NEJM 2011

39 Advanced Cirrhosis Portal Vein Thrombosis Decreased Portal Flow Prothrombotic Mutations

40 Advanced Cirrhosis Portal Vein Thrombosis Decreased Portal Flow Independent predictor Portal flow velocity < 15 cm/sec 47% p < % Zocco. J Hepatol 2009 < 15 > 15

41 Advanced Cirrhosis Portal Vein Thrombosis Decreased Portal Flow Prothrombotic Mutations Independent predictor G20210A FII Amitrano, J Hepatol 2004

42 Factor II Leiden and Portal Vein Trombosis in Cirrhosis Factor II Leiden Cirrhosis with PVT Cirrhosis No PVT N tested N positive % positive 17% 4% Amitrano, J Hepatol Erkan, EJGH Jaswinder, Hepatology 2010:A. Mangia, EJGH 2005

43 Thrombotic Liver Disease in Cirrhosis 1. Cirrhosis is a prothrombotic state 2. PVT & HVT associated with cirrhosis severity 3. A strengthening rationale for anticoagulation PVT, portal vein thrombosis. HVT, hepatic vein thrombosis.

44 Extrahepatic PVT in cirrhosis Author Year N PVT Partial/ Occlusive Yerdel % - Manzanet % 12% / 4% Francoz % Dumortier % 7% / 1% Englesbe % - Ravaioli % 6% / 4%

45 Extrahepatic PVT in Cirrhosis Prevalence Screening for HCC 0.6 % In-Hospital 7.0 % Necropsy 8.0 % Before LTx or PSS % Okuda, Gastroenterology Chang, J Pathol Bacteriol Tsochatzis, APT 2010

46 PVT and Cirrhosis Severity Atrophy (and regeneration) in explanted liver with advanced clinical disease Smaller liver weight PVT associated with Portal hypertensive bleeding, failure to control bleeding, ascites, hepatic encephalopathy Wanless, Hepatology Shimamatsu, Hepatology 1997 Nonami, Hepatology Orloff, J Gastrointest Surg D Amico, Hepatology Amitrano, J Hepatol 2004.

47 Embolization or Ligation of a portal vein branch Portal venous obstruction induces Atrophy of the obstructed lobe Hypertrophy of non obstructed lobe(s) Bilodeau, J HEP Lambotte, J HEP Farges, Ann Surg 2003

48 Advanced Cirrhosis Portal Vein Thrombosis Decreased Portal Flow

49 Thrombotic Liver Disease in Cirrhosis 1. Cirrhosis is a prothrombotic state 2. PVT & HVT associated with cirrhosis severity 3. A strengthening rationale for anticoagulation PVT, portal vein thrombosis. HVT, hepatic vein thrombosis.

50 Anticoagulation in Patients with Cirrhosis Recanalization of thrombosed portal vein Preventing PVT in high risk patients Preventing decompensation

51 Anticoagulation for PVT recanalization 200 patients reported Various anticoagulation protocols Partial occlusion in 80-88% of patients Recanalization 60-80% (3-12 months). More likely when occlusion is partial and anticoagulation therapy is prolonged Bleeding apparently not a problem Romero-Gomez Gastroenterology Amitrano J Clin Gastro Francoz Gut Francoz ILTS Pellicelli EASL Senzolo Intern Emerg Med Senzolo Liver Int Seijo Clin Gastroenterol Hepatol 2012

52 Anticoagulation in cirrhosis Author N of patients Treatment Complete /partial response (%) Related mortality Francoz (2005) Amitrano (2010) Senzolo (2012) Seijo (2012) 19 LMWH-VKA 42/5 0% 28 LMWH 75/8 0% 33 LMWH 36/27 0% 55 LMWH-VKA 45/15 0%

53 Anticoagulation in Patients with Cirrhosis Recanalization of thrombosed portal vein Preventing PVT in high risk patients Preventing decompensation

54 PVT Prophylaxis in Child B7-C10 Cirrhosis Enoxaparin Placebo Number of Pt Partial PVT 0 3 Complete PVT 0 3 Decompensation 4 19 Villa. The Liver Meeting 2011, #120. Enoxaparin UI/d, for 12 mo.

55 Cirrhotic portal vein thrombosis 1.PVT is related to cirrhosis-associated prothrombotic state, to underlying thrombophilia, and to blood stasis. 2.PVT is caused by advanced liver disease. In turn, occlusive PVT aggravates liver disease. 3.The benefit of anticoagulation could be much broader than the prevention of PVT. Further studies needed. 4.Bleeding on anticoagulation apparently not a problem. Further studies needed.

56 PVT and Cirrhosis: Management 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%