Nuove Acquisizioni in Tema di Trombosi Venose in Sedi Inusuali. Francesco Dentali Dipartimento di Medicina Clinica Università dell Insubria Varese

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1 Nuove Acquisizioni in Tema di Trombosi Venose in Sedi Inusuali Francesco Dentali Dipartimento di Medicina Clinica Università dell Insubria Varese

2 Trombosi Venose in Sedi Inusuali Trombosi venose cerebrali Trombosi venose addominali Occlusioni venose retiniche Trombosi venose profonde degli arti superiori

3 Trombosi Venose in Sedi Inusuali Trombosi venose cerebrali Trombosi venose addominali Occlusioni venose retiniche Trombosi venose profonde degli arti superiori

4 Rarity Why are thrombosis at unusual sites challenging Cerebral vein thrombosis 3-6 cases/1 million adults/year Portal vein thrombosis 4 cases/1 million adults/year Superior mesenteric vein thrombosis 3 cases/100,000/year Budd Chiari syndrome 1 case/2.5 million adults/adults Retinal vein occlusion cases/1,000 adults/year Lack of adequate studies Challenging clinical presentations Different provoking mechanisms Severity of clinical outcomes

5 Why are thrombosis at unusual sites challenging Rarity Lack of adequate studies Nearly no RCTs Mostly observational studies High risk of selection bias Challenging clinical presentations Different provoking mechanisms Severity of clinical outcomes

6 Why are thrombosis at unusual sites challenging Rarity Lack of adequate studies Challenging clinical presentations Intraparenchimal bleeding (approx. 25%) Gastrointestinal bleeding (approx. 25%) Retinal bleeding Heterogeneous clinical pictures Different provoking mechanisms Severity of clinical outcomes

7 Why are thrombosis at unusual sites challenging Rarity Lack of adequate studies Challenging clinical presentations Different provoking mechanisms Gender related risk factors for CVT Myeloproliferative neoplasms for SVT Cardiovascular risk factors for RVO Severity of clinical outcomes

8 Why are thrombosis at unusual sites challenging Rarity Lack of adequate studies Different clinical presentations Different provoking mechanisms Severity of clinical outcomes Residual neurological impairment/epilepsy Liver cirrhosis Portal hypertension Blindness

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10 Trombosi Venose Cerebrali Aspetti Considerati Epidemiologia Fattori di Rischio Diagnosi Terapia Storia Naturale

11 Trombosi Venose Cerebrali Aspetti Considerati Epidemiologia Fattori di Rischio Diagnosi Terapia Storia Naturale

12 Trombofilia e Contraccettivi Orali 17 STUDI SELEZIONATI (da 48 a 2285 Pazienti) OC (8 st, 263 pz 2862 ctr) OR 5.59; 95% CI: FVL (13 st, 469 pz 3023 ctr) OR 3.38; 95% CI: G20210A (9 st, 360 pz 2688 ctr) OR 9.27; 95% CI: 5.85 to HCY (4 st, 222 pz 472 ctr) OR 4.07; 95% CI: 2.54 to 6.52 Dentali, Ageno, Crowther; Blood 2006

13 Accuratezza diagnostica del D-Dimero Meta-Analisi di 14 studi (1134 pts) Bivariate weighted mean sensitivity 93.9%; (95% CI 87.5, 97.1%) Bivariate weighted mean specificity 89.7%; (95% CI 86.5, 92.2%) Sensitivity Study estimate HSROC curve 95% prediction region.6.4 Specificity.2 0 Summary point 95% confidence region Dentali et al, submitted

14 Terapia fase acuta RCT in 20 pazienti (10 UFH, 10 placebo). Al follow up (3 mesi), UFH: 8 recuperi completi e 2 pz con minimi deficit neurologici. Placebo: 1 recupero completo, 6 deficit neurologici, 3 morti (p < 0.01) Einhaulp et al Lancet 1991

15 Terapia fase acuta Death and Other Poor Outcomes After 3 and 12 Weeks De Bruijn et al Stroke 1999

16 Terapia fase acuta La meta-analisi dei due studi ha dimostrato una riduzione del rischio relativo di morte o dipendenza del 13% (CI -30, +3%) con una riduzione del rischio relativo del 50% Stam et al Cochrane 2002

17 Thrombolysis in CVT patients 15 studi (156 pazienti) 12 patients died after thrombolysis (weighted mean 9.2%; 95% CI 4.3, 15.7%) 15 patients had a major bleeding complication (weighted mean 9.8%; 95% CI 5.3, 15.6%). Twelve haemorrhages were intracranial (weighted mean 7.6%; 95% CI 3.5, 13.1%) 7 of these patients died (58.3%; 95% CI 32.0, 80.7%). Dentali et al Thromb Haemost 2010

18 Natural history of CVT: a systematic review Recurrent CVT: 2.8% (range 0, 11.7%) VTE in other sites: 3.7% (range 0, 8.6%) Total mortality: 9.4% (range 0, 39%) Residual neurologic impairment 1 year: : 9.7% (range 0, 45.8%) Complete recovery 1 year: : 88.3% (range( 54.2, 97.1%) Dentali, Ageno, Gianni, Crowther; Blood 2006

19 Long-term evaluation of recurrent CVT Patients 145 Women 73.1% Age (median) 33 years Follow up (median) 72 months Recurrent CVT (% pts/y) 0.63 ( ) DVT/PE (% pts/y) 1.40 ( ) Predictors of recurrent thrombosis Male gender HR 9.66 ( ) Severe thrombophilia* HR 4.71 ( ) *for DVT/PE only Martinelli et al Circulation 2010

20 Long-term evaluation of CVT Patients 706 Women 73.7% Age (mean) 40 years Follow up (median) 40 months Recurrent thrombosis (% pts/y) 2.38 ( ) Predictors of recurrent thrombosis Previous VTE HR 2.7 ( ) Dentali et al for the CEVETIS study, submitted

21 Long-term evaluation of CVT Total Women Men Patients Age (mean) Mortality (%) mrs 0-1 (%) Disability (mrs 2) Dentali et al for the CEVETIS study, submitted

22 Splanchnic vein thrombosis

23 Trombosi Venose Splancniche Aspetti Considerati Epidemiologia Fattori di Rischio Diagnosi Terapia Storia Naturale

24 Trombosi Venose Splancniche Aspetti Considerati Epidemiologia Fattori di Rischio Diagnosi Terapia Storia Naturale

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26 Prevalence of incidentally detected SVT Retrospective review of abdominal CT scans from September 1st 2009 to March 31st 2010 Total number 2619 CT scan and no suspected SVT 2592 Age (mean) 65 Males (%) 59.2 Incidentally detected SVT 50 (1.93%, ) Indipendent predictors Cancer and liver cirrhosis Ageno et al, submitted

27 Cause di trombosi venosa viscerale Cirrosi Condizioni protrombotiche Neoplasie (epatiche, pancreatiche, MTS epatiche) Sepsi (locale o sistemica) Schistosomiasi/aspergillosi Pancreatiti Post-chirurgiche (trapianto fegato, splenectomia) Contraccettivi orali Gravidanza/puerperio IBD Sindrome di Behçet

28 Trombofilia, mutazione JAK2 e trombosi venosa portale Numero 73 Età media (anni) 42 Maschi 39% Fattori di rischio transitori (traumi, chirurgia) 15.1% Fattore V Leiden 2.7% Protrombina G20210A 20.5% Deficit inibitori 10.0% Anticorpi antifosfolipidi 10.9% Iperomocisteinemia 10.9% JAK2 V617F 35.6% Sindrome mieloproliferativa 53% Primignani M et al Hepatology 2006

29 Inherited Thrombophilic Abnormalities and the Risk of PVT FVL (11 st, 437 pz 2555 ctr) G20210A (10 st, 383 pz 2925 ctr) OR 1.90; 95% CI: 1.25 to 2.90 OR 4.48; 95% CI: 3.10 to 6.48 Dentali et al Thromb Haemost 2008

30 Cause di Trombosi Venosa Mesenterica Dentali et al Thromb Haem 2009

31 JAK2 and splanchnic vein thrombosis 16 studies (831 pts) 280 of 831 SVT patients were JAK2+: mean prevalence 32.7% (95%CI 25.5, 35.9%). Mean prevalence of JAK2 mutation in patients with idiopathic SVT 49.0% (95%CI 32.9, 65.1%) Dentali et al Blood 2009

32 JAK2 and splanchnic vein thrombosis The estimated attributable risk of SVT conferred by JAK2 mutation was % Dentali et al Blood 2009

33 Patients with splanchnic vein thrombosis The mean prevalence of MPD at the time of SVT diagnosis was 59.5% (95%CI 51.3, 67.5%) Five studies evaluated the rate of MPD diagnosis during the follow-up in JAK2+ patients without a diagnosis of MPD at the time of SVT diagnosis: mean rate 52.4% (95%CI 38.0, 66.5%). Dentali et al Blood 2009

34 Prevalenza di cloni con fenotipo di emoglobinuria parossistica notturna in pazienti con trombosi splancniche Previsto l arruolamento di 250 pazienti in circa 20 centri: Ospedale di Circolo di Varese Walter Ageno Ospedale di Reggio Emilia Angelo Ghirarduzzi Ospedale Maggiore di Milano Ida Martinelli Ospedale di Vicenza Alberto Tosetto Ospedale di Udine Giovanni Barillari Clinica Humanitas di Torino Mario Bazzan Ospedale di Catanzaro Rita Santoro Ospedale Galliera di Genova Renzo Poggio Ospedale S. Martino di Genova Ugo Armani Ospedale di Sassari Gianpaolo Vidili Ospedale S. Paolo di Milano Marco Cattaneo, Federico Lussana Ospedale di Cremona Sophie Testa Ospedale di Bergamo Anna Falanga Policlinico Gemelli Valerio De Stefano Policlinico di Palermo Sergio Siragusa, Alessandra Malato Ospedale di Perugia Cecilia Becattini Ospedale di Faenza Eugenio Bucherini Ospedale Careggi Firenze Daniela Poli Policlinico S. Matteo Franco Piovella Ospedale S. Gerardo di Monza Monica Carpenedo Studio spontaneo supportato da Alexion, USA

35 Recurrence free survival SVT vs DVT Only 28% of patients received secondary prevention with oral anticoagulants Mallikarjun et al CGH 2010

36 1847 patient years of follow up Major bleeding events 6.9/100 patient years Independent predictors Gastroesophageal varices HR 2.63 (95% CI ) Warfarin HR 1.91 (95% CI ) Recurrent VTE 3.5/100 patient years Independent predictors Estrogen/progesteron therapy HR 2.2 (95% CI )

37 Natural history of MVT 77 pts, median follow up 36 months 7 had VTE recurrence (5 SVT, 2 PE) (IR 23.4 events /1,000 year pts) 2 during OAT (IR 10.5 events /1,000 year pts) 5 when OAT was suspended (IR 45.9 events /1,000 year pts). 2 pts (2.6%) had a major bleeding event. 97.3% of pts were alive at 1 year, and 7 pts (9.1%) died during follow up. Dentali et al Thromb Haemost 2009

38 International registry on splanchnic vein thrombosis 25 centers 7 countries (Europe, Asia, North America) 530 patients (as of March 31st 2011) 40.5% portal vein thrombosis 11.9% mesenteric vein thrombosis 7.5% Budd Chiari Syndrome 36.4% multiple segments 56.9% treated with UFH/LMWH OAT 30.8% treated with UFH/LMWH only

39 ISTH registry on splanchnic vein thrombosis Total Women Men Patients (37.7%) 264 Age (mean) PVT 40.5% MVT 11.9% BCS 7.5% Multiple 36.4% Cancer 24.1% 23.6% 24.4% MPN 15.4% 17.1% 14.3% Cirrhosis 23.1% 17.7% 26.5% OC/HRT 10.5% Pregnancy 1.2%

40 RVO: Arterial or venous pathology? A V

41 Occlusioni Venose Retiniche Aspetti Considerati Epidemiologia Fattori di Rischio Diagnosi Terapia Storia Naturale

42 Occlusioni Venose Retiniche Aspetti Considerati Epidemiologia Fattori di Rischio Diagnosi Terapia Storia Naturale

43 Fattori di rischio cardiovascolari ed occlusione venosa retinica OR (95% CI)* Età 1.10 ( ) Aterosclerosi carotidea 5.20 ( ) Ipertensione diastolica 1.47 ( ) Incrocio arterovenoso 4.44 ( ) *Analisi multivariata Wong et al Ophthalmology 2005

44 Antithrombotic and fibrinolytic drugs for RVO: a systematic review of RCTs 3 studies: LMWH vs ASA 1 study: ticlopidine vs placebo 1 study: fibrinolytics vs hemodilution 1 study: fibrinolytics vs no treatment Squizzato et al Thromb Haemost 2009

45 RCT: LMWH vs ASA Ageno et al Thromb Research 2010

46 RCT: LMWH vs ASA Ageno et al Thromb Research 2010

47 LMWH for the treatment of RVO: a systematic review and meta-analysis of randomized trials Lazo-Langner, Ageno et al Haematologica 2010

48 Kaplan-Meier survival curves for development of second episode of RVO (same or fellow eye) Cumulative probability of developing 0.20 = episode of RVO in the FELLOW eye = 2nd episode of RVO in the SAME eye Number of years from onset of first episode of RVO Hayreh SS et al, Am J Opthalm 1994

49 Conclusioni La diagnosi, il trattamento e la definizione della prognosi delle trombosi venose in sedi inusuali sono un problema frequente nella pratica clinica Ulteriori informazioni su queste patologie sono sicuramente necessarie Studi collaborativi multicentrici e revisioni sistematiche/meta-analisi della letteratura possono contribuire ad aumentare la nostra conoscenza su queste patologie