Polycythemia Vera and other Myeloproliferative Neoplasms. A.Mousavi
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1 Polycythemia Vera and other Myeloproliferative Neoplasms A.Mousavi
2 Chronic MPNs Multipotent hematopoietic progenitor cell is origin. Overproduction of one or more formed element of blood cells without significant dysplasia Predilection to extramedullary hematopoiesis mylofibrosis transformation at rarying rates to acute leukemia
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6 PV,PMF and ET Classified in chronic MPNs Substantial overlap in clinical and genetic features Distinct different clinical courses
7 PV Clonal disorder of multipotent hematopoitic progenitor cell Accumulation of phenotypicolly normal red cells, granulocytes and PLTs without physiologic stimulus Most common cmpns Incidence rate 2.5/ / in older population Female>male
8 Etiology Unknown etiology Deletion of 20q,trisomy 8 & 9 in up to 30% JAK2 V617F mutation have central role in the pathogenesis of PV. JAK2 serves as tyrosine kinase function for receptors of EPO and TPO. JAK2 functions as an obligate chaperone for EPO and TPO receptors in the Golgi apparatus and responsible for their cell-surface expression.
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10 Cont JAK2 on short arm of 9 th chromosome More than 95% is mutated in PV and 50% in ET and PMF Mutation may be homozygote in 30% of PV, 60% of PMF and rare patients with ET. Most PV patients without JAK2V617F mutation, express a mutation in exon 12 of the kinase. Clinicaly, no difference between hetro and homozygotes and patients with mutation in exon 12
11 Clinical features Incidental finding of high Hgb or Hct in CBC Aquagenic pruritus, distinguishing symptom of PV from other causes of erythrocytosis Hyperviscosity vertigo, tinnitus, headache, visual distrubances and TIA
12 Cont Systolic HTN Venous or arterial thrombosis cerebral, cardiac, mesentric Budd_Chiari syndrome Digital ischemia, easy bruising, epistaxis, acid-peptic disease and GI bleeding, erythromelalgia Hyperurecemia,gout Hypermetabolism symptoms
13 Diagnosis Easy with erythrocytosis in combination with leukocytosis and thrombocytosis and or splenomegaly Difficult in high Hgb or Hct alone High red cell mass and plasma volume JAK2 V617F mutation with normal O2 saturation Low or normal EPO level
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16 Complications Splenic infarction Myelofibrosis Stem cell failure in about 15% with extramedullary hematopoiesis, hepatosplenomegaly, anemia and myelofibrosis Erythromelalgia Ocular migraine Portal HTN, cachexia Thrombosis in vital organs (liver,heart,brain,lungs) in uncontrolled erythrocytosis
17 Treatment Phelebotomy goal : Hgb=<14g/dl, Hct <45% in men Hgb =<12g/dl, Hct <42% in women and iron deficiency state ASA Hydroxyurea for splenomegaly, leukocytosis or pruritus Allopurinol Anagrelide Inf a, pegylated Inf-a Ruxolitinib for splenomegaly
18 Primary myelofibrosis Clonal disorder of multipotent hematopoietic progenitor cell Marrow fibrosis Extramedullary hematopoiesis Splenomegaly Least common chronic MPNs Male and older age are prone to disease
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20 Etiology Unknown Nonrandom chromosome abnormalities such as 9p,20q-,13q-, trisomy 8,9,partial trisomy 1q are common. JAK2 V617F mutation, 50% MPL mutation 5% Most of the rest of patients have calreticulin gene (CALR) mutations Overproduction of TGF-B and tissue inhbitors of metalloproteinases are associated with fibrosis Angiogenesis due to high VEGF
21 Clinical features No specific symptoms or signs Splenomegaly and or abnormal CBC At presentation night sweats, fatigue, weight loss are common. Leukoerythroblastic picture in PBS Anemia WBC, PLTs usually high LDH & ALP
22 Cont Bone marrow, inaspirable Exuberant extramedullary hematopoiesis can cause portal, pulmonary or intracranial HTN, ascites, Splenic infarction Hyperurecemia and secondary gout
23 Diagnosis Leukoerythroblastic picture in PBS Tear drop RBCs in PBS Inaspirable bone marrow Hypercellular, trilineage hyperplasia in BM Autoimmune abnormalities Cytogenetic analysis Increased number of circulating CD34+ cells JAK2 V617F mutation, MPL and CALR mutation
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29 Complications Marrow failure transfusion dependent anemia, increased organomegaly and extramedullary hematopoiesis Acute leukemia in about 10% of patients
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33 Treatment Prednisolone for anemia Low dose thlidomide and prednisolone for anemia and thrombocytopenia Splenic irradiation Allopurinol INF-a Ruxolitinib, JAK2 inhbitor Allo-HSCT is only curative treatment
34 Essential thrombocytosis Clonal disorder Overproduction of PLTs Female > male 1-2/ incidence rate JAK2V617F mutation in about 50% of patient
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36 Etiology Unknown IL-3 and stem cell factor for early erythroid, myeloid and megakaryocytic progenitors proliferation Stromal cell drived factor 1 (SDF-1) Thrombopoietin JAK2V617F mutation and CALR mutation Inherited forms
37 Clinical features Most often identified incidentally in CBC. No specific symptoms or signs Hemorrhage easy bruising Thrombosis erythromelalgia, ocular migraine, TIA Mild splenomegaly Mild neutrophilia
38 Diagnosis JAK2V617F mutation in about 50% of patient Cytogenetic study in JAK2 negative patients CML or MDS FISH for bcr-abl in ph chromosome negative CALR mutation assay In presence of splenomegaly red cell mass determination is required. PBS and BM findings
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41 Complications More thrombosis in older than 60 year patients Tobacco use is most important risk factor for thrombosis in ET patients. Acquired vwd and bleeding Evolution to PMF
42 Treatment Survival of patients with ET is not different than for the general populations. No need for treatment of asymptomatic patients without CVD risk factors ASA Aminocaproic acid Plateletpheresis Hydroxyurea and ASA in TIA Anagrelide Pegylated INF-a
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