ipertensione polmonare nelle malattie ematologiche

1. L’Ipertensione Polmonare nelle Malattie Ematologiche Corso di aggiornamento sull’ipertensione polmonare. Pavia 21 maggio 2011 Giovanni Barosi Laboratorio di Epidemiologia Clinica/Centro per lo Studio della Mielofibrosi. IRCCS Policlinico S. Matteo Foundation, Pavia, Italy

3. Pathogenesis of PH in hemolytic anemias

6. Myeloproliferative Neoplasms (MPNs) CML CNL/MCD PV ET PMF

7. 1. Clonal proliferation of hematopoietic stem cell (mutational events like JAK2V617F) Current Biological Pradigm of MMM

8. 2. Clonal cells (CD34+, megakaryocytes, monocytes) excessively produce hematopoietic, fibrogenic and angiogenic growth factors Current Biological Pradigm of MMM MO fibroblast endothelium M-CSF SCF IL-6 TGF-  MYELOPROLIFERATION MYELOFIBROSIS NEOANGIOGENESIS TGF-  PDGF MK CD34+ TGF-  VEGF Castro-Malaspina, 1984; Le Bousse Kardiles et al, 2001; Rameshwar et al, 2000

9. Primary myelofibrosis

10. Barosi et al. Blood 2001 Barosi et al, BJH 2003 3. CD34+ hemopoietic stem cells constitutionally migrate from bone marrow to blood and to extramedullary organs Current Biological Paradigm of MMM CD34 + in PB CD34 + in Spleen

11. PERIPHERAL BLOOD HEMATOPOIESIS FIBROSIS BONE MARROW A Biological Model of MMM CD34+ CELLS HEMATOPOIESIS Anemia, thrombocytopenia SPLEEN Splenomegaly Blast transformation ANGIOGENESIS ANGIOGENESIS?

13. PH in PMF (and MPNs) 36% TTE PMF or post ET/Post PV MF =36 Cortelezzi et al. (Leukemia, 2008) 48% TTE ET=9 PV=15 CML=3 Gupta et al. (J Natl Med Ass 2006) ET= 47.8% Reactive thrombocytosis=0% TTE ET=46 Reactive thrombocytosis=40 Altintas et al. (Leukemia & Lymphoma, 2007) Transthoracic Echo (TTE) Diagnosis of PH 41.7% PV =2 ET=14 PMF=6 CML=2 Garypidou et al. (Haematologica 2004) Incidence Disorders Author

17. Thrombocytosis Secretion of vasoactive cytokines Circulating TPO levels PDGF secretion Smooth muscle cells hyperplasia Pulmonary hypertension

18. Non-hepatosplenic extramedullary hematopoiesis Pulmonary myeloid infiltration Growth factors and cytokine secretion Pulmonary hypertension

20. Circulating megakaryocytes Megakaryocyte embolism Pulmonary capillary obstruction Pulmonary hypertension

21. Enhanced angiogenesis High serum VEGF levels, low number of circulating EPCs Pulmonary hypertension

24. Pulmonary vascular disease and myeloid abnormalities in PAH. Farha S et al. Blood 2011;117:3485-3493 ©2011 by American Society of Hematology