COAGULAZIONE E MALATTIE VASCOLARI DEL FEGATO NELLA DONNA

Transcription

1 COAGULAZIONE E MALATTIE VASCOLARI DEL FEGATO NELLA DONNA Marco Senzolo Multivisceral Transplant Unit Gastroenterology Padua University Hospital

2 What are vascular liver diseases? Disorders of the hepatic vasculature where inflammation or thrombosis lead to the obstruction of blood vessels in the liver. Although rare, collectively represent an important health problem in the field of liver diseases. Affect young patients with an otherwise normal life expectancy that may be markedly shortened if not adequately managed. Senzolo M, Riggio O, Primignani M Vascular disorders of the liver: reccomendations from the AISF ad hoc committee, DLD 2011

3 Budd Chiari syndrome Intrahepatic Nodular regenerative hyperplasia Non-cirrhotic portal hypertension Sinusoidal Obstruction Syndrome Portal vein thrombosis Osler-Weber-Rendu syndrome

4 Epidemiology Portal vein thrombosis The most frequently detected thrombosis among SVT, with a gender-specific incidence of 3.8 cases per 10 5 in males and 1.73 per 10 5 in females Budd-Chiari syndrome Incidence 0.2 x 10 6 per year; prevalence from 1/ in Eastern country up to 1/ in Nepal Non cirrhotic portal hypertension Particularly prevalent in Asia; declining incidence (better socio-economical condiditon) 0.75/10 5 in Japan (1985) to only only an average of 11 new patients in 1992 Sinusoidal Obstruction Syndrome Incidence has declined in HSTT from 50% to 14% Osler-Weber-Rendu 1 2/10 5 in the general population EASL Guidelines 2015 Riva N & Ageno W Thromb Res 2017 Schouten Orphanet Journal of Rare Diseases 2015

5 BCS and PVT according to gender Ageno W Thromb and Haemost 2017

6 Role of age and gender in PVT incidence Ageno W Thromb and Haemost 2017

7 Gender and site of thrombosis Thatipelli MR Clin Gastr and Hep 2010

8 Osler-Weber-Rendu syndrome Donaldson JW Thorax 2014

9 HHT according to gender Relationship among the frequency of arteriovenous malformation (AVM), genotype (ENG vs ALK-1) and gender. Higher prevalence of pulmonary AVM in women compared with men (HHT1). Higher frequency of hepatic AVM in women (HHT1 and HHT2). Genetic counselling can be given more accurately when the familiar mutation is known. Letteboer TGW J Med Genet 2006

10 Non cirrhotic portal hypertension In India more common in males (M:F ratio of 2:1 4:1); average age of years. Sarin SK Journal of Gastroent and Hep 2010 In Japan, middle-aged women are more affected (F:M ratio: 3:1); an average age of 43 years. Ramalingaswamy B Workshop on NCPF 1969 In USA (Mikkelsen series) 19 were females and 17 males with average ages of 49 and 42 years, respectively. Boyer JL Ann Intern Med 1967 In a London series, 16 were females and 42 males with average ages of 46 and 36 years, respectively. Kobayashi Y Report of Res Committee on IPH 1976

11 Sinusoidal occlusive disease and gender Hagglund H Blood 1998

12 Oral contraceptives Hagglund H Blood 1998

13 Effect of sex and oral contraceptive use on TG In the absence ( ) and in the presence of APC ( ) Tchaivkoski SN Thomb Hemost 2007

14 Resistance to APC in women taking IIIgeneration oral contraceptives Gris JC Blood 2004

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16 Gender differences in global coagulation assays in the normal population Thrombin generation test Greater TG in women than in men: ETP: 1390±272 vs 1250±189; p=0.01. Thrombin peak: 236 ± 69 vs 193 ± 50; p= Thromboelastography Greater clot stability (fibrinogen and platelet) in women than in men: Maximum amplitude: 59.4±5.8 vs 54.3±5.6; p=0.01. Prahlad H Throm Res 2017

17 Myeloproliferative diseases Higher incidence in women than in men according to age and geographical distribution: Polycythemia vera: 8-10 vs 6-7: Essential thrombocitosis: 3-4 vs 1-2.5: Predisposing genetic risk factors include female sex. Complex relationship among sex, disease duration and the neutrophil allele burden in patients with JAK2 V617F. Spivak JL NEJM 2017

18 Splanchnic vein thrombosis in MPD according to gender Female (n=164) Male (n=106) p Essential thrombocytosis 2 2 Polycytemia vera 10 1 Idiopathic myelofibrosis 4 1 Total 16 (31.4) 4 (16.7) 0.26 Stein BL Thrombosis 2011

19 NCPH and MPD Schouten JNL Orphanet Journal of Rare Diseases 2015

20 Multiple factors contributing to PVT Usually associated with 1/more risk factors which needs to be investigated. Local factors can be identified in up to 40% of patients in acute thrombosis (Valla 2006). 20% of cases remain idiopathic. Liver biopsy is indicated when liver is dismorphic and there is persistent abnormality of LFTs to rule out NCIPH (transient elastography can be used to diagnose cirrhosis). EASL Guidelines 2015

21 Acquired and inherited risk factors Plessier A J Hep 2012

22 Thombophilic screening in PVT Protein C Protein S Anti-thrombin III Leyden FV Prothrombin G20210A JAK2 V617F EASL Guidelines 2015

23 Thombophilic screening in BCS Vasculitis, Sarcoidosis, CMV Protein C Protein S Anti-cardiolipin AB Anti-thrombin III LAC, anti-b2 glycoprotein 1 AB BCS Pro-thrombin G20210A and Leyden V Plasma omocysteine level JAK2V617F PNH Oral contracpetive/ pregnancy EASL Guidelines 2015

24 PVT - investigations Color doppler ultrasonography (CDUS) Echogenic thrombus within portal vein lumen Dilation proximal to the occlusion Absence of an identifiable portal vein Collateral vessels (cavernous transformation) CT scan Diagnosis in the acute phase in 50% of cases Filling defect in (Rajani contrast-enhanced 2010, Condat lumen 2000) Train track appearance when totally occluded MR angiography Portal venography Endoscopic ultrasound EASL Guidelines 2015

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26 BCS - investigations Doppler ultrasound: first line investigation diagnostic sensitivity > 75% MRI/CT (for confirmation) Venography: if the diagnosis remains uncertain. for the characterization of anatomy prior to treatment. Liver biopsy (to assess small hepatic vein thrombosis). EASL Guidelines 2015

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28 Sinusoidal Occlusion Syndrome Non thrombotic obstruction of sinusoids due to toxic injury of the sinusoidal wall. Senzolo M WJG 2007

29 Diagnostic and therapeutic algorithm Senzolo M WJG 2007

30 Non cirrhotic portal hypertension Liver histology remains essential in the diagnosis of INCPH Hystological features: Phlebosclerosis Nodular regeneration Sinusoidal dilatation Paraportal shunt vessels Perisinusoidal fibrosis EASL Guidelines 2015

31 Therapy Specific treatment (i.e.: defibrotide for SOS). Treatment of baseline hematological condition (i.e.: hydroxyurea for MPD). EASL Guidelines 2015

32 Management of complications

33 Varices Esophageal varices in 58% of BCS patients (5% GI bleeding). Darwish Murad S Ann Int Med 2009 Variceal bleeding in 27,5% (19/69) of NCPH patients (16 esophageal and 3 gastric). Siramolpiwat S Hepatology 2014 In EHPVO GI bleeding as a rare mode of presentation; frequent findings of an enlarged spleen, varices or hypertensive gastropathy. EASL Guidelines 2015

34 Ascites Up to 83% of patients with BCS (depending on presentation type). Rare but associated with poor survival in NCPH. Darwish Murad S Ann Int Med % (mild), 6% (moderate) and 48% (severe) of patients who developed SOS after bone marrow transplantation. In 50% of patients in acute PVT. Senzolo M WJG 2007 EASL Guidelines 2015 EASL Guidelines 2015

35 Anticoagulation

36 Portal vein thrombosis Anticoagulant therapy (at least 6 months) should be started immediately. Most patients have good clinical outcome despite not having achieved anticoagulation in case of failure no additional interventions are warranted (ie local thrombolysis). Long term anticoagulation in case of a persistent underlying prothrombotic state. In patients with bloody diarrhea, lactic acidosis and organ failure due to the high risk of bowel infarction surgery should be considered. Baveno VI Consensus Conference

37 604 patients Cirrhosis (27.8%) Anticoagulation in 465 patients (77%), with a mean duration of 13.9 months Median duration of follow-up 2 years (interquartile range 1-2 years) JAMA Intern Med. 2015

38 Incidence of outcome events in subgroup with different risk factors Outcome Liver cirrhosis (n=167) Solid Cancer (n=136) Myeloproliferative neoplasm (n=49) Unprovoked SVT (n=63) Transient risk factors* (n=105) Major bleeding events 22 events 10.0 x 100 pts-years ( ) 7 events 4.4 x 100 pts-years ( ) 3 events 3.6x 100 pts-years ( ) 5 events 1.7 x 100 pts-years ( ) 1 event 0.5x 100 pts-years ( ) Thrombotic events 25 events 11.3x100 pts-years ( ) 12 events 7.6 x 100 pts-years ( ) 5 events 5.9x 100 pts-years ( ) 18 events 6.3x 100 pts-years ( ) 6 events 3.2x 100 pts-years ( ) Mortality 45 events 16.8 x 100 pts-years ( ) 67 events 39.5x 100 pts-years ( ) 3 events 3.4x 100 pts-years ( ) 7 events 2.3x 100 pts-years ( ) 5 events 2.5x 100 pts-years ( ) *Transient risk factors included: recent surgery, intra abdominal infections, hormonal therapy, pregnancy/puerperium, abdominal trauma

39 Thrombotic events 25 patients 11.3 ( ) per 100 pt-y 23 splanchnic vein thrombosis 1 acute coronary syndrome 1 vascular death (not treated) On-treatment (n=8) 8.2 ( ) per 100 pt-y Off-treatment - after discontinuation 16.8 ( ) per 100 pt-y - never treated 14.1 ( ) per 100 pt-y

40 Budd Chiari syndrome Patients should receive anticoagulant therapy as soon as possible for an indefinite period of time (also after LT, when performed). To reduce the risk of clot extension and new thrombotic episodes. Target: INR>2.5. Stabilizes 20% of the patients. Senzolo M Nature Clinical Pactice Gastro 2005

41 Senzolo M Nature Clinical Pactice Gastro 2005

42 Transjugular Intra hepatic porto-systemic shunt Vascular Liver Disease VOD PVT BCS Indications Not indicated in BMT; can be considered in Solid Organ Recipients as stand alone treatment or as bridge to LT in a setting of multidisciplinary evaluation. Feasible in PVT patients with and without cirrhosis (higher failure and complications rate when portal cavernoma or intrahepatic branches thrombosis are present); it can be considered to treat PVT in case of progression despite adequate anticoagulation treatment, with special attention to LT candidates. Indicated when there is failure of anticoagulation; in case of acute liver failure (not delaying listing for LT). NCPH It can be considered with common indications for the management of portal hypertensive complications (caution in those patients with refractory ascites). AISF Consensus conference on TIPS DLD 2017

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44 Liver transplantation for BCS Zanetto A & Senzolo M Management of thrombosis in LT candidate in Bezinover/Saner Critical Care for Potential LT, Springer 2018

45 Liver transplantation for SOS LT has been reported anedoctically as a rescue therapy in patients with VOD after SCT not responding to medical therapy. The presence of malignancies and multiple organ failure (if VOD is advanced) contraindicates LT. When VOD develops after LT itself, re-lt can be performed as a rescue therapy as the liver is the only organ damaged. Previous placement of TIPS allows more time to the clinician to re-list the patients for LT and it does not jeopardize subsequent LT. Senzolo M WJG 2007

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47 Outcomes of pregnancies in women with previously diagnosed BCS or PVT BCS (24 pregnancies) PVT (104 pregnancies) Miscarriages (%) Stillbirths (%) 6 2 Premature births (%) Cesarean section (%) Variceal hemorrhages (%) 0 5 Non-variceal hemorrhages (%) 35 6 Thrombotic events (%) 15 3 Rautou P-E J Hep 2009 Hoekstra J J Hep 2012 Mandal D Singapore Med J 2012

48 Fetal outcome in pregnancies with known and treated PVT or BCS Bissonette J J of Clin and Exp Hep 2015

49 Factors associated with unfourable pregnancy outcome in PVT Hoekstra J J Hep 2012

50 Anticoagulation and pregnancy * Before conception screen for oesophageal varices and apply proper prophylaxis Bissonette J J of Clin and Exp Hep 2015

51 Pregnancy in PVT: maternal outcome * *Cesarean section Hoekstra J J Hep 2012

52 LMWH from the first trimester is safe for mother and fetus Deruelle P Eur J of Obs and Gin 2006

53 NCPH and pregnancy 10 pregnancies in 8 women (4 received LMWH; 1 ASA + LMWH). Fetal outcome: 8 term deliveries (5 caesarean and 3 vaginal); all infants healthy. 1 miscarriage and 1 ectopic pregnancy. Maternal outcome: 1 GI bleeding due to gastric varices (history of gastric varices bleeding before pregnancy, was receiving BB and LMWH) endoscopic treatment and then TIPS. 2 Genital bleeding postpartum (both receiving LMWH and having had caesarean section). No thrombotic event, no change in liver function and no ascites following deliveries. Fetal and maternal outcomes are favourable but careful in case of LMWH and cesarean section. Andrade F, ILC 2017, abs

54 Conclusions - Vascular liver disorders are a rare, but cumulatively important aetiology of liver disease - Often they are seen in your individuals and in some disease with prevalence in female population - Female population has specific risk factors that needs to be screened - Management comprehends medical and radiological/surgical interventions - Specific knowledge for counseling and management of women with vascular liver disorders before and during pregnancy is essential