Terapia anticoagulante nelle trombosi splancniche Walter Ageno Dipartimento di Medicina Clinica e Sperimentale Università dell Insubria Varese
Considerazioni preliminari Eterogeneità di fattori predisponenti Eterogeneità di presentazioni cliniche
Cause di trombosi venosa viscerale Cirrosi Trombofilia Neoplasie solide (epatiche, pancreatiche) Neoplasie mieloproliferative Sepsi (locale o sistemica) Pancreatiti Post-chirurgiche (trapianto fegato, splenectomia) Contraccettivi orali Gravidanza/puerperio IBD Sindrome di Behçet
Causes of splanchnic vein thrombosis in a multicenter, prospective cohort Number 613 Unprovoked events 27.6% Liver cirrhosis 27.8% Solid cancer 22.3% Abdominal infection/inflammation 11.5% Hematologic malignancies 9.0% JAK 2 mutation 42/204 (20.6%) Surgery 8.9% Hormonal therapy 4.1% Pregnancy or puerperium 1.1% Ageno W et al Semin Thromb Haemost 2014
Non cirrhotic non-malignant Cirrhotic patients Malignancy
Clinical presentations and treatment of SVT in non-cirrhotic patients Incidental diagnosis 28.1% (medical therapy or no therapy) Abdominal infarction 28.1% (surgical therapy) Bowel ischemia 32.2% (medical therapy) Bleeding from portal hypertension 11.6% Amitrano L et al Am J Gastroenterol 2007
Trombosi venose splancniche diagnosticate incidentalmente Prevalenza in TC addominali eseguite senza il sospetto di trombosi: 1.1% 1-1.7% 2 Cancro (OR 3.17, 95% CI 1.5-6.7) e cirrosi (14.7, 95% CI 7.6-28.6) fattori predittivi indipendenti 2 Prevalenza di diagnosi incidentali nei pazienti con trombosi spancnica: 18.0% 3-29.8% 4 1 Douma Thromb Res 2010 2 Ageno JTH 2012 3 Thatipelli Clin Gastroenterol Hepatol 2010 4 Ageno Semin Thromb Hemost 2014
Emorragie digestive concomitanti alla diagnosi di trombosi venosa portale Prevalenza di emorragie riportata tra l 11.6% 1 e il 28% 2 Prevalenza di varici gastroesofagee note riportata fino nel 35% dei pazienti 2 Incidenza di ipertensione portale secondaria a trombosi venosa portale non definita 1 Amitrano Am J Gastroenterol 2007 2 Thatipelli Clin Gastroenterol Hepatol 2010
Le linee guida sulla terapia anticoagulante
Symptomatic splanchnic vein thrombosis: anticoagulation over no anticoagulation (Grade 1B) Incidentally detected splanchnic vein thrombosis (portal, mesenteric, hepatic, and/or splenic vein thromboses): no anticoagulation over anticoagulation (Grade 2C)
ISTH Guidance statements In patients with incidental splanchnic vein thrombosis (AND CANCER), we suggest anticoagulant therapy in patients with thrombosis that appears to be acute, shows progression or extension over time, and in those who are not actively bleeding nor have a very high risk of bleeding. Di Nisio M. J Thromb Haemost 2015
Minimum duration of treatment 3 months Discontinue when secondary to surgery or infections Indefinite treatment duration when secondary to cirrhosis, cancer (including MPN), autoimmune disorders, thrombus extension into the mesenteric veins (?)
LMWH may be preferred over VKA if there is active malignancy, liver disease, or thrombocytopenia.
Le evidenze
1847 anni paziente di follow up Incidenza emorragie maggiori 6.9/100 pazienti anno Predittori indipendenti Varici esofagee HR 2.63 (95% CI 1.72-4.03) Warfarin HR 1.91 (95% CI 1.25-2.92) Incidenza recidive 3.5/100 pazienti anno Predittori indipendenti Terapia estroprogestinica HR 2.2 (95% CI 1.09-4.45)
Prognosi Recurrence free survival (Vs DVT) Mallikarjun et al CGH 2010
Efficacy and safety of VKA therapy after portal vein thrombosis in non-cirrhotics 136 patients, median follow-up 46 months (84 on VKA), retrospective cohort study GI bleeding 12.5 (95% CI 10-15) 100 pt/y Recurrent venous thrombosis 5.5 (95% CI 3.8-7.2) 100 pt/y Condat et al Gastroenterology 2001
ISTH International registry on SVT: results of 2-year follow up 0.25 Major bleeding events Non-malignant non-cirrhotic Liver cirrhosis 0.25 Vascular thrombotic events Non-malignant non-cirrhotic Liver cirrhosis Cumulative incidence 0.20 0.15 0.10 0.05 Liver cirrhosis 10.0/100pt-y Non-malignant non-cirrhotic 1.8/100pt-y Cumulative incidence 0.20 0.15 0.10 0.05 11.3/100pt-y 5.6/100pt-y 0.00 0.00 0.5 1 1.5 2 Follow-up (years) 0.5 1 1.5 2 Follow-up (years) Ageno et al JAMA Intern Med 2015
ISTH International registry on SVT: results of 2-year follow up Liver cirrhosis Solid cancer MPN Unprovoked Transient risk factors N 167 136 49 163 105 Major bleeding 10.0% pt-yrs (6.6-15.1) 4.4% pt-yrs (2.1-9.3) 3.6% pt-yrs (1.1-11.1) 1.7% pt-yrs (0.7-4.2) 0.5% pt-yrs (0.1-3.7) Thrombosis 11.3% pt-yrs (7.7-16.8) 7.6% pt-yrs (4.3-13.3) 5.9% pt-yrs (2.5-14.3) 6.3% pt-yrs (4.0-10.0) 3.2% pt-yrs (1.4-7.0) Ageno et al, JAMA Intern Med 2015
Anticoagulation for the management of portal vein thrombosis in cirrhosis Design prospective cohort Number 35 patients Mean MELD score n.a. LMWH alone, n 33 Bleeding 1 patient* All patients underwent endoscopic screening for varices at inclusion Endoscopic ligation in case of: previous variceal bleed, grade II varices with red signs or grade III varices *Variceal bleeding Senzolo et al Liver Int 2012
Safety of VKAs for SVT: multicenter retrospective cohort study Demographic characteristics Patients with SVT Number 375 Age (years), median (IQR) 53 (43-63) Males 54.7% Unprovoked SVT 37.1% Haematologic cancer 21.6% Cirrhosis 15.2% Solid cancer 10.7% Recent surgery 8.0% Inflammation/infection 6.7% Esophageal varices: 23.2% Riva N et al J Thromb Haemost 2015
Safety of VKAs for SVT: multicenter Time-point retrospective cohort study Cumulative number of events Incidence rate of major bleeding (95% CI) 6 months 5 2.85 per 100 pt-y (1.18-6.84) 1 year 7 2.18 per 100 pt-y (1.04-4.56) 2 years 10 1.83 per 100 pt-y (0.99-3.41) 5 years 13 1.41 per 100 pt-y (0.82-2.44) End of follow 15 1.24 per 100 pt-y (0.75-2.06) Predictors of bleeding: esophageal varices (HR 4.9, 1.4-17.1), IBD (HR 15.2, 0.99-233.1) Riva N et al J Thromb Haemost 2015
Clinical history of incidentally detected SVT in the ISTH registry Number 177 Median follow-up 2 years Major bleeding 3.3/100 pt-yrs (95% CI 1.7-6.3) Thrombotic events 8.0/100 pt-yrs (95% CI 5.2-12.1) Major bleeding on treatment 3.2/100 pt-yrs (95% CI 1.2-8.4) Thrombosis off-treatment 11.9/100 pt-yrs (95% CI 5.0-28.7) Riva et al submitted
Clinical history of incidentally detected SVT in the ISTH registry Liver cirrhosis (n:82) Solid cancer (n:62) Non-malignant non-cirrhotic SVT (n:57) Major bleeding 6.1/100 pt-yrs (95% CI 2.9-12.8) 1.2/100 pt-yrs (95% CI 0.2-8.2) 1.8/100 pt-yrs (95% CI 0.5-7.4) Thrombotic events 14.8/100 pt-yrs (95% CI 9.2-23.8) 8.1/100 pt-yrs (95% CI 3.9-17.0) 2.8/100 pt-yrs (95% CI 0.9-8.6) Mortality 9.9/100 pt-yrs (95% CI 5.9-16.7) 21.7/100 pt-yrs (95% CI 14.0-33.6) 0 events Riva et al submitted
Treatment of splanchnic vein thrombosis - summary Anticoagulant therapy to be always considered if no absolute contraindications Careful assessment of underlying risk factors Careful assessment of esophageal varices in cirrhotic patients LMWH alone as initial strategy for higher risk patients (cirrhosis, cancer, low platelet count)
The direct oral anticoagulants for the treatment of splanchnic vein thrombosis Treatment of portal, mesenteric, and splenic vein thrombosis with rivaroxaban. A pilot, prospective cohort study The study is ongoing at Italian, German and Canadian centers