Myeloproliferative Disorders Flashcards
Hypercellular marrow with abnormal megakaryocytes early on
Primary Myelofibrosis
Appearance of a “spent” phase with fibrosis and cytopenias
myeloproliferative disorders
Progress to a “spent” phase‐later in the disease course • Extreme marrow fibrosis • Extramedullary hematopoiesis (liver , spleen )‐ organomegaly
Polycythemia vera
Tyrosine kinase induces signaling via (1) pathways
RAS and JAK/STAT
Bone marrow cells mature via growth factors that bind receptors on progenitor cells which activate (1) which activate pathways for cell growth and survival
- tyrosine kinases
What are the clinical signs of polycythemia vera?
Plethoric, cyanosis, headache, dizziness, HTN, pruritis at night, hyperuricemia
Symptomatic hyperuricemia‐ increased cell turnover
Polycythemia vera and primary myelofibrosis
What is the most characteristic symptom of polycythemia vera? What causes it?
Pruritus at night due to basophils releasing histamine
Inappropriate release of fibrogenic factors from neoplastic megakaryocytes
Primary Myelofibrosis Platelet derived growth factor and TGF‐beta
CML has markedly hypercellular bone marrow containing hyperplasia of what cell types?
myelocytes metamyelocytes bands eosinophils basophils megakaryocytes
but not erythrocytes
How is CML diagnosed?
High WBC, peripheral smear and bone marrow findings BCR/ABL fusion detected –chromosome analysis or by PCR
Death within months if untreated due to bleeding or thrombosis
Polycythemia vera
70% of blast crises are (1) leukemia
acute myeloid
refers to CML
How do you distinguish polycythemia vera from secondary polycythemia?
P. vera high oxygen saturation and low erythropoetin Secondary polycythemia low oxygen saturation and high erythropoetin
participates in JAK.STAT pathway downstream from hematopoietic growth factors
JAK2
Mutated (1) lead to growth factor independent proliferation and survival of (2)
- tyrosine kinases 2. marrow progenitors refers to myeloproliferative disorders
Major bleeding and thrombotic events occur
Polycythemia vera
Absence of fibrosis
essential thrombocytosis
mutations in essential thrombocytosis
JAK2 activating mutations MPL mutation thrombopoietin activated protein kinase Calreticulin mutation‐functions in the endoplasmic reticulum
Features of Primary Myelofibrosis
Pancytopenia • Extramedullary hematopoiesis
presence of a chimeric BCR‐ABL fusion gene coding an active BCR‐ABL tyrosine kinase resulting in?
growth factor independent proliferation and survival of marrow progenitors refers to CML (Chronic myelogenous leukemia)
Iron deficiency from bleeds has a beneficial effect
Polycythemia vera
CML peripheral blood findings
Leukocytosis (high WBC count) Entire spectrum of marrow cells present Basophilia Blast count < 10%
Osteosclerosis replaces the marrow spaces
Primary Myelofibrosis
Mutations originate in (1) level or (2) level
- multipotential myeloid progenitor 2. pluri‐potential stem cell refers to myeloproliferative disorders
Transforms to AML‐up to 20% of cases
Primary Myelofibrosis
Increased HCT, blood viscosity,abnormal platelet function
Polycythemia vera
How is CML treated?
Hematopoietic stem cell transplant for young stable patients Therapy with BCR/ABL tyrosine kinase inhibitors
Obliterative bone marrow fibrosis in primary myelofibrosis leads to?
pancytopenia and extra medullary hematopoesis
6mos or so‐enters “blast crisis” acute leukemia; 50% enter blast crisis without the accelerated period
CML
In myeloproliferative disorders, (1) is not impaired and increased numbers of (2) are therefore produced
- differentiation 2. mature blood elements
Identical to “spent “phase of other myeloproliferative disorders
Primary Myelofibrosis
In essential thrombocytosis progenitors undergo (1) independent‐proliferation
thrombopoietin
Pancytopenia
Primary Myelofibrosis
BCR gene –chromosome ?
22
Slow progression (3 yr. survival even if untreated) Followed by “accelerated phase”‐increasing anemia and thrombocytopenia
CML
major clinical manifestations of essential thrombocytosis
Thrombosis and hemorrhage from defective platelet function • DVT • Portal and hepatic vein thrombosis • MI; throbbing/burning sensation of hands and feet
Leukoerythroblastosis (myelocytes, metamyelocytes and early erythroid forms in peripheral blood)
Primary Myelofibrosis AND infiltrative marrow processes such as metastatic tumor
How does CML present?
Hypermetabolism resulting in fatigue, weakness, weight loss, anorexia Dragging sensation or pain from splenic infarcts
Hyper cellular marrow of all cell lines but mostly red cell series; basophilia
Polycythemia vera
Reciprocal translocation Philadelphia chromosome (9;22)(q34;q11)
CML (Chronic myelogenous leukemia)
Marked megakaryocyte increase with bizarre abnormal forms
essential thrombocytosis
Infections; Bleeding and thrombotic episodes
Primary Myelofibrosis
Mild hepatosplenomegaly‐extramedullary hematopoiesis‐50%
essential thrombocytosis
throbbing/burning sensation of hands and feet
Erythromelalgia; due to platelet aggregates occurs in essential thrombocytosis
Treatment for polycythemia vera
Simple regular phlebotomy and low dose aspirin
(1) to (2) substitution at residue 617
- Valine 2. phenylalanine refers to Polycythemia vera
Large platelets in peripheral blood
essential thrombocytosis
thrombopoietin activated protein kinase
MPL - mutated in essential thrombocytosis and primary myelofibrosis
Primary Myelofibrosis mutations
Activating JAK2 mutations‐50% • MPL mutations
Median survival‐up to 15 yrs with long asymptomatic periods
essential thrombocytosis
Variable transformation to (1) in myeloproliferative disorders
acute leukemias
Progressive replacement of marrow with (1)
- collagen Primary Myelofibrosis
Primary Myelofibrosis treatment
JAK2 inhibitors can decrease the splenomegaly somewhat Hematopoietic stem cell transplant for younger pts
essential thrombocytosis elevated (1) without (2)
- platelet counts 2. polycythemia or marrow fibrosis
panmyelosis of proliferation red cells, white cells, and platelets
Polycythemia vera
functions to promote cell proliferation and manufacturing in the ER
Calreticulin - mutated in essential thrombocytosis
S/S of Primary Myelofibrosis
Dragging sensation –massively enlarged spleen Fatigue, weight loss, night sweats Hyperuricemia‐increased cell turnover
Strong association with activating point mutations in JAK/2 TYROSINE KINASE
Polycythemia vera, essential thrombocytosis, primary myelofibrosis
obliterative marrow fibrosis
Primary Myelofibrosis
ABL gene‐chromosome ?
9
1% transform to AML
Polycythemia vera
Dacrocytes (Tear‐drop Rbc’s)
Primary Myelofibrosis
Progressive marrow fibrosis and hypo cellularity and atypical megakaryocytes
Primary Myelofibrosis
Mild organomegaly; Minimal extramedullary hematopoiesis
Polycythemia vera
Other CML findings
splenomegaly and hepatomegaly, splenic infarcts
mild organomegaly is seen in which conditions?
polycthemia vera and essential thrombocytosis
dragging sensation or pain from splenic infarcts is seen in which myeloproliferative disorders?
CML and primary myelofibrosis
High WBC count
CML
Very high hematocrit
polycythemia vera
elevated platelet counts
essential thrombocytosis
