1 / 31

Fisiopatologia, diagnosi e classificazione delle trombocitemie

Fisiopatologia, diagnosi e classificazione delle trombocitemie. Alessandro M. Vannucchi UF di Ematologia Università degli Studi, Firenze. Kaushansky K. N Engl J Med 2006;354:2034-2045. Classification of Thrombocytosis. Primary Thrombocytosis Inherited, familial

trents
Download Presentation

Fisiopatologia, diagnosi e classificazione delle trombocitemie

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Fisiopatologia, diagnosi e classificazione delle trombocitemie Alessandro M. Vannucchi UF di Ematologia Università degli Studi, Firenze

  2. Kaushansky K. N Engl J Med 2006;354:2034-2045

  3. Classification of Thrombocytosis • Primary Thrombocytosis • Inherited, familial • Acquired, clonal thrombocytosis • Chronic myeloproliferative neoplasms • Chronic myelogenous leukemia • Myelodysplastic syndromes (5q- and RARS-T) • Secondary (Reactive) Thrombocytosis Schafer AJ, NEJM 2004

  4. Fisiopatologia, diagnosi e classificazione delle trombocitosi primarie • Fisiopatologia della trombosi nella ET

  5. Fisiopatologia, diagnosi e classificazione delle trombocitosi primarie • Fisiopatologia della trombosi nella ET

  6. EPOR MPL G/GM-CSFR IL3R IL5R GP130 W515L/K Mpl V617F Exon12 JAK2 JAK2 JAK2 JAK2 JAK2 JAK2 P P P P Ras SOCS3 PI3K SOCS1 P SOCS3 Stat5 Raf SOCS1 P P Stat5 Stat5 P AKT MEK P P mTOR FOXO P ERK ERK Activation of genes (proliferation/survival/differentiation) Meccanismi molecolari: mutazioni di JAK2 e MPL

  7. Only the MPL W515 mutations promote a G(1)/S-phase transition Chaligne, R. Leukemia 2008

  8. Chronic Ph1-neg myeloproliferative neoplasms * Referred to V617F-negative

  9. A PV, rather than an ET phenotype, is reproduced in JAK2 V617F mice James C, Nature 2005;Wernig G, Blood 2006; Lacout C, Blood 2006; Zaleskas V, PLoS ONE 2006

  10. Ratio of mutant JAK2-V617F to wild-type Jak2 determines the MPD phenotypes in transgenic mice • Transgenic line (FF1-Vav)with an expression of JAK2-V617F lower than the endogenous wild-type JAK2 developed a phenotype resembling ETwith strongly elevated platelet counts and moderate neutrophilia. • Transgenic JAK2-V617F/MxCre mice had expression of JAK2-V617F approximately equal to wild-type JAK2 and developed a PV-like phenotype with increased hemoglobin, thrombocytosis, and neutrophilia. • Higher levels of JAK2-V617F in mouse bone marrow by retroviral transduction caused a PV-like phenotype without thrombocytosis. Tiedt, R. et al. Blood 2008;111:3931-3940

  11. JAK2 V617F allele burden in MPNs 100 80 60 allele burden (%) 40 20 V617F 0 JAK2 PV ET PMF postPV / ET MF Antonioli E, Haematologica 2007

  12. Identification of disease subtypes in ET based on JAK2 V617F mutation JAK2V617F pos ETresembles PV: - increased erythropoiesis - higher leukocyte count - more venous thromboses - more frequent PV “transformation” - lower ferritin (p < 0.01) - lower MCV (p < 0.0001) - lower serum Epo (p < 0.0001) JAK2V617F neg ET - higher platelet counts Campbell et al Lancet 2005& Blood 2005; Antonioli et al Leukemia 2005;

  13. Induction of thrombocytosis and myelofibrosis by MPLW515L MPLWT MPLW515L

  14. Clinical correlates of MPL W515 mutations in ET 994 ET pts 3.0% 418 V617Fneg 8.1% 12 (40%) W515K 18 (60%) W515L In 8 pts both MPLW515 and JAK2V617F AM Vannucchi et al., Blood, 2008

  15. WHO 2008 DIAGNOSTIC CRITERIA *, Tefferi A, 2007

  16. ST 100% ET 60% 1- 4% 40% PMF 60% 5- 8% 40% PV 95% RARS-T 50% 50% 5q-  5% 95% CML 100% Vannucchi AM, ASH2007

  17. Fisiopatologia, diagnosi e classificazione delle trombocitosi primarie • Fisiopatologia della trombosi nella ET

  18. A GIMEMA retrospective study on 1,224 patients Crude-analysis Probability Years Years 1 2 3 4 5 6 7 8 9 10 Pts at risk PV 397 339 275 235 206 168 139 120 95 82 67 ET 637 549 479 421 365 316 262 220 191 169 140 MF 190 123 94 78 68 60 48 40 36 30 28 Thrombosis-free survival in MPN Vannucchi AM, Blood 2007 & unpubl.

  19. 5.6%pt-yr 49.9% Cumulative probability (%) 3.4%pt-yr 2.2%pt-yr Time after first thrombosis (months) Recurrent Thrombosis in PV or ET  n=494 De Stefano V, Haematologica 2007

  20. Risk Stratification in ET (*) Hyperthension, Hypercholesterolemia, Diabetes, Smoking; Familial thrombophilia. Their contribution to thrombotic risk is controversial

  21. Thrombocytosis and Thrombosis: an Uneven Relationship - 1 Schafer AJ, NEJM 2004

  22. ECLAP cohort Thrombocytosis and Thrombosis: an Uneven Relationship - 2 • In a series of 99 young (16-59) ET pts, receiving or not prophylactic cyroreductive therapy, no difference in thrombosis (nor hemorrhages) was noted Berk PD et al, 1995; Di Nisio M et al, BJH 2006; Tefferi A et al, Blood 2006

  23. Thrombocytosis and Thrombosis: an Uneven Relationship - 3 Carobbio A, Blood 2008

  24. Thrombocytosis and Thrombosis: an Uneven Relationship - 4 MRC PT-1 Trial Harrison C et al, NEJM 2005

  25. Leukocytosis and Thrombosis in ET Wolanskyi A, Mayo Clin Proc, 2006 Carobbio A, Blood 2007 (*) Multivariable analysis

  26. Leukocytosis and “conventional” risk factors in ET High-risk Low-risk P=.003 Carobbio A et al, Blood 2007; JCO 2008

  27. Interaction of leukocytosis and thrombocytosis on thrombotic risk in ET Carobbio A, Blood 2008

  28. Venous thrombosis 2.09 [1.44, 3.05] Arterial thrombosis 1.96 [1.43, 2.67] Thrombosis at presentation 1.88 [1.38, 2.56] V617F Status and Thrombosis in ET Ziakas PD et al, Haematologica 2008

  29. V617F Burden and Thrombosis in ET * adjusted for age, sex, previous thrombosis and leukocytosis Vannucchi AM et al, Blood 2007

  30. Interactions between JAK2 V617F genotype and inherited thrombophilia • 132 ET pts, 45 pts (34%) with major thrombosis. • 83 pts (62.8%) V617F+, 8 pts (6%) were Homo De Stefano V, EHA 2008

  31. Acknowledgments • Tiziano Barbui Chairman of the GIMEMA-MPD WP and all the colleagues of the WP • Paola Guglielmelli, Elisabetta Antonioli, Lisa Pieri, Alberto Bosi Dip. Ematologia, Firenze

More Related