Myeloproliferative Neoplasms

Question 1

what are myeloproliferative neoplasms

Answer 1

clonal proliferation of a cell line derived from the myeloid stem cell:
*polycythemia vera: too many erythrocytes
*essential thrombocytopenia: too many platelets
*CML: too many neutrophils
*chronic eosinophilia: too many eosinophils
*myelofibrosis: overactive megakaryocytes

Question 2

regulation of normal red blood cell production - in a hypoxic state

Answer 2

*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)

Question 3

regulation of normal red blood cell production - in a normal oxygen state (normoxic)

Answer 3

*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)

Question 4

anemia in chronic kidney disease

Answer 4

*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

Question 5

other causes of polycythemia (increased RBC production)

Answer 5

1. 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)
2. non-hematologic malignancies
   -renal cell carcinoma
   -hepatocellular carcinoma
   -hemangioblastoma
   -uterine fibroids

Question 6

polycythemia vera - overview

Answer 6

*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

Question 7

polycythemia vera - pathogenesis

Answer 7

*usually due to an acquired JAK2 mutation
-most often, V617F of JAK2
*results in constitutively active tyrosine kinase activity
*causes erythrocytosis

Question 8

polycythemia vera - lab values

Answer 8

*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

Question 9

polycythemia vera - signs/symptoms

Answer 9

*“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)

Question 10

polycythemia vera - criteria for diagnosis

Answer 10

*persistent polycythemia
*secondary causes of polycythemia are ruled out
*order JAK2 PCR and erythropoietin level
-results = JAK2+, low EPO

Question 11

polycythemia vera - bone marrow biopsy

Answer 11

*prominent erythroid and megakaryocytic proliferation
*fibrosis
*low M:E ratio

Question 12

polycythemia vera - natural history

Answer 12

*at risk for thrombotic events: MI, CVA, DVT, PE
-risk increases with age and white cell count
*risk of transformation to: myelofibrosis or AML

Question 13

polycythemia vera - treatment

Answer 13

*phlebotomy
*hydroxyurea
*aspirin (baby aspirin) - to prevent thrombotic events

Question 14

essential thrombocythemia - overview

Answer 14

*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

Question 15

essential thrombocythemia - diagnosis

Answer 15

*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

Question 16

essential thrombocythemia - blood counts

Answer 16

*elevated platelet count
*normal (or sometimes elevated) white blood cell count
*normal hemoglobin

Question 17

essential thrombocythemia - signs and symptoms & natural history

Answer 17

*bleeding due to abnormal platelet FUNCTION (despite high platelet count)
*thrombosis (CVA, TIA, MI, priapism)
*splenomegaly
*erythromelalgia
*risk for progression to myelofibrosis or AML

Question 18

essential thrombocythemia - treatment

Answer 18

*hydroxyurea
*aspirin

Question 19

chronic eosinophilic leukemia - overview

Answer 19

*clonal disorder
*excess number of circulating eosinophils
*some patients will respond to imatinib

Question 20

primary myelofibrosis - overview

Answer 20

*atypical megakaryocyte hyperplasia -> increased TGF-beta secretion -> increased fibroblast activity -> obliteration of bone marrow with fibrosis

Question 21

primary myelofibrosis - bone marrow

Answer 21

*“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”

Question 22

primary myelofibrosis - clinical presentation

Answer 22

*MARKED splenomegaly
*hepatomegaly present as well
*extramedullary hematopoiesis can be found in unusual places:
-pleural effusions
-pericardial effusions
-ascites
-CNS

Question 23

primary myelofibrosis - blood counts

Answer 23

*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

Question 24

primary myelofibrosis - treatment

Answer 24

*hydroxyurea
*splenectomy
*JAK2 inhibitors
*appropriate acute leukemia treatments with transformation
*bone marrow transplant