Myeloproliferative Neoplasms Flashcards
what are myeloproliferative neoplasms
clonal proliferation of a cell line derived from the myeloid stem cell:
1. polycythemia vera: too many erythrocytes
2. essential thrombocytopenia: too many platelets
3. CML: too many neutrophils
4. chronic eosinophilia: too many eosinophils
5. myelofibrosis: overactive megakaryocytes
regulation of normal red blood cell production - in a hypoxic state
*HIF-1alpha is not degraded
*HIF-1alpha/HIF-1beta bind to the Epo (erythropoietin) gene
*stimulates transcription of Epo (leading to increased erythropoietin, stimulating increased production of RBCs)
regulation of normal red blood cell production - in a normal oxygen state (normoxic)
*vHL protein targets HIF-1alpha for destruction by proteosomes (ubiquitination)
*no HIF-1alpha/HIF-1beta complex
*Epo gene is NOT transcribed (so there is not an increase of erythropoietin)
anemia in chronic kidney disease
*REPOS cells (Renal Epo Producing and Oxygen Sensing cells) - similar to fibroblasts
*as renal function declines, this includes the kidney’s ability to make erythropoietin
*erythroid precursors are no longer seeing normal, baseline levels of epo to maintain normal RBC production in a normal homeostatic state
*this results in a normocytic, normochronic anemia
*treatment: erythropoietin stimulating agents
other causes of polycythemia (increased RBC production)
- mutations:
-high oxygen affinity Hb mutants (shifts curve to left)
-2,3 DPG deficiency (shifts curve to left)
-von Hippel Lindau mutation (doesn’t bind HIF-1alpha) - non-hematologic malignancies
-renal cell carcinoma
-hepatocellular carcinoma
-hemangioblastoma
-uterine fibroids
polycythemia vera - overview
*clonal disorder
*RBC production is INDEPENDENT of erythropoietin (Epo) and its receptor:
-do not need Epo to form RBCs
-blocking Epo receptor does not “turn off” RBC production
-the Epo receptor has no mutations
-Epo level will be LOW
polycythemia vera - pathogenesis
*usually due to an acquired JAK2 mutation
-most often, V617F of JAK2
*results in constitutively active tyrosine kinase activity
*causes erythrocytosis
polycythemia vera - lab values
*elevated hemoglobin and hematocrit
*often, elevated platelet and white cell counts
*bone marrow overall cellularity is increased
*M:E ratio is lower than normal (normal is 3:1)
*low EPO levels
polycythemia vera - signs/symptoms
*“congestion”:
-headaches, visual changes, dizziness, paresthesias, facial plethora (red face)
*AQUAGENIC PRURITIS (intense itching after shower)
*bleeding/bruising
*thrombosis (MI, DVT, PE, CVA)
*splenomegaly
*ERYTHROMELALGIA (severe burning pain and red-blue coloration)
polycythemia vera - criteria for diagnosis
*persistent polycythemia
*secondary causes of polycythemia are ruled out
*order JAK2 PCR and erythropoietin level
-results = JAK2+, low EPO
polycythemia vera - bone marrow biopsy
*prominent erythroid and megakaryocytic proliferation
*fibrosis
*low M:E ratio
polycythemia vera - natural history
*at risk for thrombotic events: MI, CVA, DVT, PE
-risk increases with age and white cell count
*risk of transformation to: myelofibrosis or AML
polycythemia vera - treatment
*phlebotomy
*hydroxyurea
*aspirin (baby aspirin) - to prevent thrombotic events
essential thrombocythemia - overview
*clonal disorder characterized by massive proliferation of megakaryocytes and platelets
*independent of thrombopoietin or its receptor (c-MpI)
*TPO levels are normal or elevated:
-decreased clearance due to decreased c-MpI receptors on these abnormal platelets
*JAK2 mutation seen in 50-65% of ET patients
essential thrombocythemia - diagnosis
*sustained platelet count >450K
*rule out secondary causes and CML
*JAK2+ (but NOT in everyone)
*hyperplasia of megakaryocytes on bone marrow biopsy
*diagnosis of exclusion
essential thrombocythemia - blood counts
*elevated platelet count
*normal (or sometimes elevated) white blood cell count
*normal hemoglobin
essential thrombocythemia - signs and symptoms & natural history
*bleeding due to abnormal platelet FUNCTION (despite high platelet count)
*thrombosis (CVA, TIA, MI, priapism)
*splenomegaly
*erythromelalgia
*risk for progression to myelofibrosis or AML
essential thrombocythemia - treatment
*hydroxyurea
*aspirin
chronic eosinophilic leukemia - overview
*clonal disorder
*excess number of circulating eosinophils
*some patients will respond to imatinib
primary myelofibrosis - overview
*atypical megakaryocyte hyperplasia → increased TGF-beta secretion → increased fibroblast activity → obliteration of bone marrow with FIBROSIS
primary myelofibrosis - bone marrow
*“scarring” of the bone marrow
*abnormal megakaryocytes secrete excess amounts of cytokines that cause bone marrow fibroblasts to make excess collagen, resulting in fibrosis
*reticulin and/or collagen fibrosis
*bone marrow cellularity starts hypercellular; becomes hypocellular
*often have “dry taps”
primary myelofibrosis - clinical presentation
*MARKED splenomegaly
*hepatomegaly present as well
*extramedullary hematopoiesis can be found in unusual places:
-pleural effusions
-pericardial effusions
-ascites
-CNS
primary myelofibrosis - blood counts
*leukoerythoblastic picture:
-Pseudo-Pelger-Huel cells (neutrophils are bilobed)
-giant platelets
-TEARDROP red cells
-all signs of marrow replacement
*patients are usually anemic
*WCC and platelet count may be high or low
primary myelofibrosis - treatment
*hydroxyurea
*splenectomy
*JAK2 inhibitors
*appropriate acute leukemia treatments with transformation
*bone marrow transplant
