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Polycythemia Veraand other
Myeloproliferative Neoplasms
A.Mousavi
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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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PV,PMF and ET
Classified in chronic MPNs
Substantial overlap in clinical and
genetic features
Distinct different clinical courses
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PV
Clonal disorder of multipotent hematopoiticprogenitor cell
Accumulation of phenotypicolly normal red cells, granulocytes and PLTs without physiologic stimulus
Most common cMPNs
Incidence rate 2.5/100000
10/100000 in older population
Female>male
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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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Cont…
JAK2 on short arm of 9th 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
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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
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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
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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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Complications Splenic infarction
Myelofibrosis
Stem cell failure in about 15% with extramedullaryhematopoiesis , hepatosplenomegaly , anemia and myelofibrosis
Erythromelalgia
Ocular migraine
Portal HTN , cachexia
Thrombosis in vital organs (liver,heart,brain,lungs)
in uncontrolled erythrocytosis
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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
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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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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
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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
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Cont… Bone marrow , inaspirable
Exuberant extramedullary hematopoiesis can cause portal , pulmonary or intracranial HTN, ascites ,…
Splenic infarction
Hyperurecemia and secondary gout
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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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Complications
Marrow failure
transfusion dependent anemia , increased
organomegaly and extramedullary
hematopoiesis
Acute leukemia in about 10% of patients
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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
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Essential thrombocytosis
Clonal disorder
Overproduction of PLTs
Female > male
1-2/100000 incidence rate
JAK2V617F mutation in about 50% of patient
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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
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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
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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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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
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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