Trombosi in sedi atipiche: il ruolo delle nuove mutazioni Walter Ageno Dipartimento di Medicina Clinica Università dell Insubria Varese
Trombosi venose in sedi atipiche Trombosi venose in sedi diverse dagli arti inferiori e dal circolo polmonare In genere più rare o molto più rare Diversa età di insorgenza e prevalenza di genere Fattori di rischio differenti Presentazione clinica spesso complessa
Fattori di rischio prevalenti nelle trombosi venose in sedi atipiche Trombosi venose cerebrali Estroprogestinici/gravidanza/puerperio Trombofilia Trombosi venose retiniche Fattori di rischio cardiovascolari Trombosi venose splancniche Neoplasie solide e mieloproliferative Cirrosi epatica
Trombosi in sedi atipiche e mutazione JAK2V617F
Twenty-four studies (6 case-controls, 18 retrospective cohorts) were included Studies ranged in size from 11 to 560 patients for a total of 3508 patients
Prevalence of JAK2 mutation in patients with splanchnic vein thrombosis Sixteen studies (831 patients) assessed the prevalence of JAK2 mutation in SVT patients JAK2+ mean prevalence: 32.7% (95%CI 25.5-35.9%) Mean prevalence in patients with idiopathic SVT 49.0% (95%CI 32.9-65.1%) Dentali et al Blood 2009
Prevalence of JAK2 mutation in patients with cerebral vein thrombosis Six studies (248 pts) JAK2+ mean prevalence 2.57% (95%CI 0.97-4.91%) Dentali et al Blood 2009
Prevalence of JAK2 mutation in patients with retinal vein occlusion Six studies (153 patients) JAK2+ mean prevalence: 0.99% (95%CI 0.05-3.20%) Dentali et al Blood 2009
Prevalence of JAK2 mutation in patients with DVT of the lower limbs or PE Eight studies (1293 pts) JAK2+ mean prevalence 0.88% (95%CI 0.44-1.45%) Dentali et al Blood 2009
Association between JAK2 mutation and splanchnic vein thrombosis Four case-control studies (297 cases and 363 controls) The JAK2 mutation was found significantly more often in patients with SVT than in those without (OR, 53.98; 95% CI, 13.10-222.45; I² = 0%) The estimated attributable risk for SVT conferred by JAK2 mutation was 12.74% Dentali et al Blood 2009
MPN diagnosis in JAK2 positive patients with splanchnic vein thrombosis The rate mean of MPN diagnosis during follow-up in JAK2+ patients without a MPN diagnosis at the time of SVT diagnosis: 52.4% (95%CI 38.0-66.5%) Dentali et al Blood 2009
JAK2 status and thrombotic risk 23 studies: Patients with essential thrombocythaemia (ET) or idiopathic myelofibrosis (IM) - ET: OR 1.92 (95% CI 1.45-2.53; I2:47%) - IM: OR 1.76 (95% CI, 0.91-3.42; I2:0%) Lussana et al Thromb Res 2009
JAK2 status and thrombotic risk ET patients Venous Thrombosis (9 studies, 2124 patients): OR 2.49 (95%CI 1.71-3.61) Arterial thrombosis (9 studies, 2124 patients): OR 1.77 (95% CI 1.29-2.43) Lussana et al Thromb Res 2009
Potential Confounding Factors Different in the two groups Age Hemoglobin levels White cell (or neutrophil) count
JAK2 status and thrombotic risk Potential role on haemostasis JAK2 may modify red cell adhesion molecules and promote increased adhesiveness JAK2 may affect platelet activation by modifying cmpl cell surface localisation and stability P-selectin and trombomodulin levels are higher in JAK2+ patients in comparison to JAK2- patients Royer et al JBC 2005 Robertson et al JTH 2007 Falanga et al Experim Hematol 2005
Overall survival Budd Chiari Syndrome Event free survival
Screening of MPL515 exon 10 mutations (n: 212) JAK2 exon 12 mutations (n: 123) Negative in all patients
The CC genotype may independently predispose either to MPN or SVT A significant increase in the occurrence of SVT in CC carriers, as compared to non CC carriers, was found in idiopathic SVT patients as well as in secondary SVT patients
46/1 is associated with JAK2V617F positive SVT There is an association between 46/1 and SVT in JAK2 negative patients with MPNs, but not in patients without MPNs Potential role for 46/1 as a diagnostic tool in SVT in addition to JAK2V617F
TET2 mutations have been identified in a high proportion of patients with JAK2 positive and JAK2 negative MPNs The TET2 gene locus was investigated for mutations in 23 SVT patients with JAK2 mutation Independently of the JAK2 V617F mutation, screening for TET2 mutations may be useful for identifying patients who should be carefully monitored for the subsequent development of MPNs
Conclusioni La mutazione JAK2 V617F è presente in circa un terzo dei pazienti con SVT, molto più rara in pazienti con trombosi venose in altre sedi La ricerca della mutazione nei pazienti con SVT ha un importante ruolo diagnostico per MPN occulte Ulteriori valutazioni genetiche potrebbero migliorare il processo diagnostico La mutazione JAK2 potrebbe essere un fattore di rischio indipendente per SVT, al momento non sembra avere un valore prognostico indipendente