Myeloproliferative Disorders

Myeloproliferative disorders are stem cell disorders that that result in excess production and overaccumulation of erythrocytes, granulocytes, and/or platelets. These abnormalities may appear in bone marrow, peripheral blood, and body tissues.

The main types include:

1. Chronic myelogenous leukemia (CML)
2. Polycythemia vera (PV)
3. Essential thrombocythemia (ET)
4. Primary myelofibrosis (PMF)

Condition	Cause	Lab Findings	Diagnostic Tests	Treatment
Chronic Myelogenous Leukemia	t(9,22) BCR/ABL fusion ↑ tyrosine kinase activity	Significant neutrophilia and left shift Myeloid hyperplasia, M:E ratio 10:1	PBF/BM Cytogenetics or molecular genetics for t(9,22) PCR for BCR/ABL LAP testing (lack activity, score <13)	BM/stem cell transplants Chemotherapy Tyrosine kinase inhibitors
Polycythemia Vera	JAK2 mutation (V617F) grow in absence of erythropoietin divide normally, but do not undergo apoptosis	Absolute erythrocytosis Decreased EPO Moderate leukocytosis and thrombocytosis BM myelopoiesis	JAK2 mutation ↑ HGB BM Hypercellularity Decreased serum EPO	Therapeutic phlebotomy Hydroxyuria treatment (myelosuppressive drugs) JAK2 inhibitors
Essential Thrombocythemia	JAK2, CALR, or MPL mutation		Must not match any other MPD criteria or be caused by reactive thrombocytosis ↑ platelets >450x10^9/L BM: megakaryopoiesis JAK2, CALR, or MPL mutation	Suppress BM megakaryocyte production Hydroxuria treatment (suppresses platelets in PB)
Primary Myelofibrosis

General Features

• Tend to affect adult and geriatric populations
• Begin as chronic disorders, which may transform into subacute, and then acute disorders
  • Subacute
  • Acute: aggressive growth (acute myeloid leukemia)
• May cause marrow hypoplasia/depletion of cells
• Common lab features:
  • Splenomegaly (60-100%)
  • Cytogenetic abnormalities

Chronic Myelogenous Leukemia

• caused by translocation of genes in pluripotent hematopoietic stem cells
  • Philadelphia chromosome (Ph) in >90% of leukemic cells
  • reciprocal translocation between chromosomes 9 and 22. t(9,22)
  • BCR/ABL fusion proteins affect tyrosine kinase activity
    • Unregulated cell growth, failure to undergo apoptosis
• clonal overproduction of myeloid cell line
  • increased immature neutrophils
• Has 3 phases:
  • Chronic: <10% blasts
  • Accelerated: 10-19% blasts, basophilia in peripheral blood
  • Acute: >20% blasts
• Lab findings:
  • Peripheral Blood:
    • Neutrophilia, with all phases of maturation
      • Leukocytosis
      • Left shift (promyelocytes and blasts)
    • Basophilia
    • Eosinophilia
    • Thrombocytosis
  • Bone Marrow:
    • Myeloid hyperplasia
    • Hypercellularity
    • M:E ratio increased (10:1)
  • Chemistry
    • ↑ uric acid (due to ↑ cell turnover)
    • ↑ lactate dehydrogenase
    • ↑ serum B12 (due to ↑ breakdown of WBCs)

Polycythemia Vera

• Caused by substitution in JAK2 gene (90-97% caused by V617F)
  • Mutated protein is active without requiring erythropoietin
  • Upregulation of anti-apoptotic protein
  • Cell divides normally but doesn't undergo apoptosis
• Signs and Symptoms:
  • Ruddy cyanosis (reddish-purple colour to face)
  • Vascular complications
  • Splenomegaly
  • Lab Findings:
    • Peripheral Blood:
      • Absolute erythrocytosis
      • ↑ HGB, HCT
      • IDA may develop
      • Moderate leukocytosis and thrombocytosis

Essential Thrombocythemia

• Marked thrombocytosis >450x10^9L
• Large masses of platelet aggregates
• Abnormal platelet morphology
  • Giant platelets, megakaryocyte fragments
• Possibly ↑ WBC (neutrophilia with slight left shift)
• Lab Findings:
  • Abnormal coagulation studies
    • Abnormal platelet aggregation
  • BM: Megakaryopoiesis (large, mature megakaryocytes with no other increases in cell types)
  • Genetics
    • JAC2, CALR, or MPL mutations