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
		Peripheral Blood	Bone Marrow
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 Moderate leukocytosis Moderate thrombocytosis ↓ EPO (serum)	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	JAK2 (60%) Abnormal megakaryocyte growth stimulates collagen Fibrotic material invade BM and eventually other tissues	Immature granulocytes NRBCs Teardrops/abnormal poik Giant platelets Micromegakaryocytes	Initially, hypercellular marrow with abnormal megakaryocytes Reticulin fibrosis Progressive marrow failure with fibrosis	Must not match any other MPD criteria BM biopsy: Megakaryocyte proliferation with reticulin and/or collagen fibrosis JAK2, CALR, or MPL mutation (or another marker) BM aspirate "dry tap"	Stem cell transplants Chemotherapy JAK2 inhibitors

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
    • JAK2, CALR, or MPL mutations

Primary Myelofibrosis

• Abnormal megakaryocyte growth stimulates collagen production by BM fibroblasts
  • JAK2 V617F associated with 60% of cases
  • Fibrinoblastic growth factors support collagen production
  • BM tissue is replaced with fibrous materials, causing fibrosis
  • BM failure develops are cellularity is lost
• Extramedullary hematopoiesis
  • Infiltration of BM with fibrous materials results in stem cells being push out into other tissue
  • Hematopoiesis begins occurring outside of BM
    • Accumulation of cells in spleen, liver, and other organs
  • Can cause fibrosis of other organs (e.g., spleen)
    • anemia, thrombocytopenia
• Lab Results:
  • Bone Marrow
    • "Dry tap" where no aspirate is collected
    • BM biopsy showing fibrosis in >1/3 of biopsy section
• Myelofibrosis
  • Increased fine fibres (reticulin, type III collagen)
• Myelosclerosis
  • increased coarse, type I collagen
• Treatment
  • Stem cell transplants
  • Splenectomy
  • Chemotherapy
  • JAK2 inhibitors