L’Ipertensione Polmonare nelle Malattie Ematologiche Corso di aggiornamento sull’ipertensione polmonare. Pavia 21 maggio 2...
Malattie ematologiche con ipertensione polmonare <ul><li>Hemolytic anemias </li></ul><ul><li>Thalassemia intermedia </li><...
Pathogenesis  of PH in hemolytic anemias
<ul><li>Perspectives </li></ul><ul><li>Primary myelofibrosis –associated PH </li></ul><ul><li>PH-associated myelofibrosis ...
WHO Classification of tumours of hematopoietic and lymphoid tissues (2008) MYELOPROLIFERATIVE NEOPLASMS  <ul><li>Chronic m...
Myeloproliferative   Neoplasms (MPNs) CML CNL/MCD PV ET PMF
1. Clonal proliferation of hematopoietic stem cell (mutational events like JAK2V617F) Current Biological Pradigm of MMM
2. Clonal cells (CD34+, megakaryocytes, monocytes) excessively produce hematopoietic, fibrogenic and angiogenic growth fac...
Primary myelofibrosis
Barosi et al. Blood 2001 Barosi et al, BJH 2003  3. CD34+ hemopoietic stem cells constitutionally migrate from bone marrow...
PERIPHERAL BLOOD HEMATOPOIESIS FIBROSIS BONE MARROW A Biological Model of MMM CD34+ CELLS HEMATOPOIESIS Anemia, thrombocyt...
<ul><li>Relief of fatigue and constitutional symptoms </li></ul><ul><li>Relief of pruritus </li></ul><ul><li>Relief of sev...
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 Gup...
Limitations of epidemiological studies in MPNs <ul><li>Diagnosis of PH was not established as recommended by guidelines (O...
Clinical forms of PH in MPNs <ul><li>Chronic thromboembolic PH (CTEPH) </li></ul><ul><li>Precapillary PH, mimicking Primar...
Mechanisms for the development of PAH–like disease in primary myelofibrosis <ul><li>Thrombocythosis </li></ul><ul><li>Non-...
Thrombocytosis Secretion of vasoactive cytokines Circulating TPO levels PDGF secretion Smooth muscle cells hyperplasia Pul...
Non-hepatosplenic extramedullary hematopoiesis Pulmonary myeloid infiltration Growth factors and cytokine secretion Pulmon...
 
Circulating megakaryocytes Megakaryocyte embolism Pulmonary capillary obstruction Pulmonary hypertension
Enhanced angiogenesis High serum VEGF levels, low number of  circulating EPCs Pulmonary   hypertension
The current recommendations for how to manage PH in PMF Tefferi, Mayo Clinic, 2011 <ul><li>MF-associated PH is suspected i...
PH-associated myelofibrosis <ul><li>Myelofibrosis is present in patients with PH. It is not a primary neoplastic hematopoi...
Pulmonary vascular disease and myeloid abnormalities in PAH. Farha S et al. Blood 2011;117:3485-3493 ©2011 by American Soc...
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Ipertensione Polmonare nelle malattie ematologiche

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Ipertensione Polmonare nelle malattie ematologiche

  1. 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
  2. 2. Malattie ematologiche con ipertensione polmonare <ul><li>Hemolytic anemias </li></ul><ul><li>Thalassemia intermedia </li></ul><ul><li>Sickle cell anemia </li></ul><ul><li>Hereditary spherocytosis </li></ul><ul><li>PK deficiency </li></ul><ul><li>Unstable hemoglobin </li></ul><ul><li>Paroxysmal nocturnal hemoglobinuria </li></ul><ul><li>Microangiopathic hemolytic anemia </li></ul><ul><li>Myeloproliferative neoplasms </li></ul><ul><li>Essential thrombocythemia </li></ul><ul><li>Polycythemia vera </li></ul><ul><li>Primary myelofibrosis </li></ul><ul><li>Eosinophilic leukemia </li></ul><ul><li>Lymphoproliferative disorders </li></ul><ul><li>Castelman disease </li></ul><ul><li>POEMS </li></ul>
  3. 3. Pathogenesis of PH in hemolytic anemias
  4. 4. <ul><li>Perspectives </li></ul><ul><li>Primary myelofibrosis –associated PH </li></ul><ul><li>PH-associated myelofibrosis </li></ul>Myelofibrosis and Pulmonary Arterial Hypertension (PH)
  5. 5. WHO Classification of tumours of hematopoietic and lymphoid tissues (2008) MYELOPROLIFERATIVE NEOPLASMS <ul><li>Chronic myelogenous leukemia, BCR-ABL1 positive </li></ul><ul><li>Chronic neutrophilic leukemia </li></ul><ul><li>Polycythemia vera </li></ul><ul><li>Primary myelofibrosis </li></ul><ul><li>Essential thrombocythemia </li></ul><ul><li>Chronic eosinophilic leukemia, NOS </li></ul><ul><li>Mastocytosis </li></ul><ul><li>Myeloproliferative neoplasm, unclassifiable </li></ul>Classical Ph1-neg MPNs
  6. 6. Myeloproliferative Neoplasms (MPNs) CML CNL/MCD PV ET PMF
  7. 7. 1. Clonal proliferation of hematopoietic stem cell (mutational events like JAK2V617F) Current Biological Pradigm of MMM
  8. 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. 9. Primary myelofibrosis
  10. 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. 11. PERIPHERAL BLOOD HEMATOPOIESIS FIBROSIS BONE MARROW A Biological Model of MMM CD34+ CELLS HEMATOPOIESIS Anemia, thrombocytopenia SPLEEN Splenomegaly Blast transformation ANGIOGENESIS ANGIOGENESIS?
  12. 12. <ul><li>Relief of fatigue and constitutional symptoms </li></ul><ul><li>Relief of pruritus </li></ul><ul><li>Relief of severe anemia </li></ul><ul><li>Relief of transfusion dependent anemia </li></ul><ul><li>Treatment of transfusional iron overload </li></ul><ul><li>Relief of symptomatic splenomegaly </li></ul><ul><li>Relentless of spleen enlargement in progressive splenomegaly </li></ul><ul><li>Reversion of accelerated phase or blast transformation of the disease </li></ul><ul><li>Treatment of extramedullary non-hepatosplenic hematopoiesis </li></ul><ul><li>Treatment of pulmonary hypertension </li></ul><ul><li>Treatment of portal hypertension </li></ul><ul><li>Treatment of splanchnic vein thrombosis </li></ul><ul><li>Treatment of thrombotic or hemorrhagic complication </li></ul>Common clinical needs in PMF
  13. 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
  14. 14. Limitations of epidemiological studies in MPNs <ul><li>Diagnosis of PH was not established as recommended by guidelines (Overestimation of the incidence) </li></ul><ul><li>No distinction between post-embolic PH and primary PH </li></ul>
  15. 15. Clinical forms of PH in MPNs <ul><li>Chronic thromboembolic PH (CTEPH) </li></ul><ul><li>Precapillary PH, mimicking Primary PH </li></ul>
  16. 16. Mechanisms for the development of PAH–like disease in primary myelofibrosis <ul><li>Thrombocythosis </li></ul><ul><li>Non-hepatosplenic extramedullary hematopoiesis </li></ul><ul><li>Enhanced angiogenesis </li></ul><ul><li>Portal hypertension </li></ul>
  17. 17. Thrombocytosis Secretion of vasoactive cytokines Circulating TPO levels PDGF secretion Smooth muscle cells hyperplasia Pulmonary hypertension
  18. 18. Non-hepatosplenic extramedullary hematopoiesis Pulmonary myeloid infiltration Growth factors and cytokine secretion Pulmonary hypertension
  19. 20. Circulating megakaryocytes Megakaryocyte embolism Pulmonary capillary obstruction Pulmonary hypertension
  20. 21. Enhanced angiogenesis High serum VEGF levels, low number of circulating EPCs Pulmonary hypertension
  21. 22. The current recommendations for how to manage PH in PMF Tefferi, Mayo Clinic, 2011 <ul><li>MF-associated PH is suspected in the presence of dyspnea/hypoxia on exertion and peripheral edema. </li></ul><ul><li>It is important to rule out thromboembolic, infectious or inflammatory lung processes (high resolution CT scanning) </li></ul><ul><li>Increased systolic pulmonary artery pressure on echography and an abnormal pulmonary uptake during technetium 99m sulphur colloid scintigraphy should be documented </li></ul><ul><li>In the absence of an alternative explanation for pulmonary hypertension, treatment with single-fraction (100cGy) whole-lung irradiation is reasonable even if technetium scan was negative </li></ul>
  22. 23. PH-associated myelofibrosis <ul><li>Myelofibrosis is present in patients with PH. It is not a primary neoplastic hematopoietic disorder. Its mechanism remains to be elucidated (Popat U et al. Ann Intern Med, 2005 </li></ul><ul><li>Increased bone marrow hemangioblast number, alterations in erythroid/myeloid lineages, increased reticulin, and greater mobilization of bone marrow progenitor cells are integral part of PH disease (subclinical myeloproliferative process?) (Farha S et al. Blood 2011) </li></ul><ul><li>Elevation of bone marrow progenitors and reticulin was revealed in non affected family members of patients with familial PH. </li></ul>
  23. 24. Pulmonary vascular disease and myeloid abnormalities in PAH. Farha S et al. Blood 2011;117:3485-3493 ©2011 by American Society of Hematology

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