Myeloproliferative Neoplasms and Myelodysplastic Syndrome Flashcards
classically, myeloproliferative neoplasms contain which mutation? what are the classic MPNs?
GOF mutation in JAK2 (non-receptor tyrosine kinase) —> increased growth and survival of myeloid precursors, constitutively active
“classic” MPNs:
1. polycythemia vera (RBC)
2. essential thrombocythemia (platelets)
3. primary myelofibrosis (stroma)
*”non-classic” is chronic myeloid leukemia (CML), caused by BCR-ABL fusion protein
describe the JAK2 mutation that is seen in all “classic” myeloproliferative neoplasms
“classic” MPNs: polycythemia vera, essential thrombocythemia, myelofibrosis
GOF (constitutively active) JAK2 tyrosine kinase —> increased growth and survival of myeloid precursors
usually activated by erythropoietin, thrombopoietin, GM-CSF receptors
polycythemia
abnormal elevation of RBC mass (hemoglobin or hematocrit)
*can be relative due to decrease in plasma volume (dehydration)
primary vs secondary absolute (not relative) polycythemia
primary: increased RBC mass due to intrinsic RBC problem - erythropoietin is normal or low
secondary: increased RBC mass due to increased EPO production
chronic hypoxemia, hemoglobinopathy, and paraneoplastic syndrome are all secondary causes of _____ due to increased EPO synthesis
secondary causes of polycythemia, due to increased EPO
chronic hypoxemia - EPO regulated by O2 levels
hemoglobinopathy - increased affinity of hemoglobin for O2
paraneoplastic syndrome - produces EPO (renal cell carcinoma, hepatocellular carcinoma)
*also high altitude, pulmonary disease, sleep apnea, CO, renal tumors
polycythemia vera
most common myeloproliferative disorder
mutation in hematopoietic stem cells —> unregulated growth and survival of mostly RBC
mutation: JAK V617F —> constitutively active tyrosine kinase
how do patients with polycythemia vera present?
asymptomatic with high Hgb/Hct
or
symptoms due to hyperviscosity of blood: neurological, HTN/flushing, unusual venous/arterial thrombosis (Budd-Chiari syndrome), bleeding (platelet dysfunction)
unusual signs: pruritis (itch) following warm shower, erythromelalgia (increased platelets - warmth/pain in extremities), plethora (red skin because of excess blood)
*Budd-Chiari = hepatic vein thrombosis
what do these signs collectively indicate?
- HTN
- Budd-Chiari syndrome
- acquired vWF deficiency (bleeding)
- pruritis following warm shower
- erythromelalgia (warm/pain in extremities)
- plethora
polycythemia vera: increased RBC, increases blood viscosity
Budd-Chiari: hepatic vein thrombosis (unusual location)
erythromelalgia: increased platelets
acquired vWF deficiency and bleeding: basically thick blood pushes clotting factors away
plethora: conjunctival or facial, “excess blood” (look red)
how is polycythemia vera diagnosed? (4)
primary increase in RBC
- elevated hgb/hct
- EPO normal or low
- hypercellular bone marrow
- JAK V617F mutation
how is polycythemia vera managed? (3)
- phlebotomy to keep hct low
- aspirin to prevent thrombosis
- hydroxurea (blocks DNA synthesis) to lower RBC mass
essential thrombocythemia
primary cause of thrombocytosis
overproduction of platelets (unregulated megakaryocytes) without definable cause
associated with JAK V617F mutation (common mutation of myeloproliferative neoplasms)
mostly in elderly, F>M
how does essential thrombocythemia present?
asymptomatic with increased platelets, or…
microvascular disturbances (erythromelalgia), arterial and venous thrombosis
bleeding if count very high (too many platelets interfere with vWF function)
how can you diagnose essential thrombocythemia, a primary cause of thrombocytosis? (3)
- unexplained or persistent thrombocytosis (>450K)
- bone marrow biopsy essential - megakaryocyte proliferation (largest cells in bone marrow)
- JAK V617F mutation
*exclude polycythemia vera and primary myelofibrosis
how is essential thrombocythemia treated?
patients can be stable for decades
goal - prevent complications (thrombosis), alleviate symptoms
—> low dose aspirin
—> hydroxyurea - reduces cell proliferation (disrupts DNA synthesis)
primary myelofibrosis
neoplastic transformation of hematopoietic stem cells
—> bone marrow fibrosis, lower cell counts
—> extramedullary hematopoiesis (hepatosplenomegaly)
what are 3 signs/symptoms of primary myelofibrosis?
- hepatosplenomegaly (extramedullary hematopoiesis)
- hypermetabolism (increased cytokines - low grade fever, weight loss, night sweats)
- anemia (bone marrow fibrosis)
what 2 key things will you see in a peripheral smear of a patient with primary myelofibrosis?
- dacrocytes (tear drop cells, due to squeezing through bone marrow)
- leukoerythroblastic peripehral smear: WBC/RBC precursors
how can you diagnose primary myelofibrosis?
- bone marrow aspirate - “dry tap” due to fibrosis
- silver stain of bone marrow demonstrates fibrosis
a patient with marrow fibrosis, extramedullary hematopoiesis, and splenomegaly likely has what going on?
myelofibrosis: neoplastic transformation of hematopoietic stem cells in bone marrow
how can you treat myelofibrosis?
goal is to control symptoms
low risk: hydroxurea
high risk: allogeneic stem cell transplant (curative)
myelodysplastic syndromes
clonal disorder resulting in abnormal (dysplastic) maturation of myeloid progenitor cells —> cytopenia
cells have alerted appearance and function (nucleated RBC, hypolobation of PMNs)
what are 2 major risk factors for myelodysplastic syndrome?
- ionizing radiation
- chemotherapeutic agents (alkylating agents, DNA top inhibitors)
what are the clinical features of myelodysplastic syndrome?
most patients asymptomatic but found to have abnormal cell counts and morphology
symptoms related to peripheral cytopenia or functional deficit: anemia (macrocytic), neutropenia (hypolobation), thrombocytopenia
what kind of anemia can myelodysplastic syndrome cause?
RBC maturation is impaired —> macryoctic (non-megaloblastic) anemia with sideroblasts
what is a Psuedo-Pelger-Huet abnormality?
bilobed nucleus of PMN
can be seen in peripheral smear of myelodysplastic syndrome
can be genetic (AD) mutation in lamin B gene (non-pseudo and benign), but if seen needs to be investigated
myelodysplastic syndrome can present with increased number of blast cells, putting patients at risk for progression to…
acute myeloid leukemia (AML)
