Haematopoietic Growth Factors Quiz

Haematopoietic Growth Factors

• Haematopoietic growth factors are glycoprotein hormones that regulate the proliferation and differentiation of haematopoietic progenitor cells in the bone marrow.
• Examples of haematopoietic growth factors include erythropoietin (EPO), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin 11 (IL-11).

Erythropoietin (EPO)

• EPO is a 34- to 39-kDa glycoprotein produced primarily by peritubular interstitial cells in the kidney.
• Tissue hypoxia leads to increased EPO production, which increases red blood cell production, correcting anemia.
• Examples of erythropoiesis-stimulating agents include:
  • Recombinant human erythropoietin (rHuEPO, epoetin alfa)
    • Given IV every 3 times a week
    • Not cleared by dialysis
  • Darbepoetin alfa
    • Modified form of erythropoietin with a 2-3 times longer half-life
    • Given once a week
  • Methoxy polyethylene glycol–epoetin beta
    • Isoform of EPO covalently attached to a long polyethylene glycol polymer
    • Given IV or SC every 2 weeks or once a month

Mechanism of Action of EPO

• EPO binds to erythropoietin receptors on red cell progenitors, stimulating proliferation and terminal differentiation of erythroid precursor cells.
• EPO also induces the release of reticulocytes from the bone marrow.

Clinical Uses of EPO

• Anaemia secondary to chronic kidney disease
  • Improves hemoglobin levels
  • Decreases need for blood transfusions
  • Improves quality of life
• Patients undergoing myelosuppressive cancer chemotherapy with a Hb less than 10g/dl

Illegal Use of EPO

• By endurance athletes to enhance performance

Response to EPO

• Inverse relationship between EPO level and hemoglobin
• Patients with normal Hb- EPO levels usually less than 20IU/L
• Moderately severe anaemia- EPO usually 100-500IU/L
• Severe anaemia- EPO usually >1,000IU/L

Granulocyte Colony-Stimulating Factor (G-CSF)

• Stimulates proliferation and differentiation of granulocytic progenitor cells
• Mobilizes hematopoietic stem cells, increasing their concentration in peripheral blood
• Used in hematopoietic stem cell transplantation

Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF)

• Broader biologic actions than G-CSF
• Stimulates proliferation and differentiation of early and late granulocytic progenitor cells, erythroid and megakaryocyte progenitors
• Stimulates the function of mature neutrophils
• Acts together with interleukin-2 to stimulate T-cell proliferation
• Mobilizes peripheral blood stem cells, but is less efficacious and more toxic than G-CSF

Clinical Uses of G-CSF and GM-CSF

• Cancer chemotherapy-induced neutropenia
• Treatment of neutropenia associated with:
  • Congenital neutropenia
  • Cyclic neutropenia
  • Myelodysplasia
  • Aplastic anaemia
• Hematopoietic stem cell transplantation

Adverse Effects of G-CSF and GM-CSF

• G-CSF: bone pain (reversible)
• GM-CSF:
  • Fever, malaise, arthralgias, myalgias
  • Capillary leak syndrome (peripheral edema & pleural or pericardial effusions)
  • Allergic reactions
  • Splenic rupture may rarely occur with use of G-CSF for PBSC mobilization

Megakaryocyte Growth Factors

• Thrombopoietin (TPO) and IL-11 are key endogenous regulators of platelet production
• Novel, nonimmunogenic agonists of the thrombopoietin receptor (Mpl) include:
  • Romiplostim
  • Eltrombopag
• Approved for management of thrombocytopenia

Interleukin 11 (IL-11)

• 65- to 85-kDa protein produced by fibroblasts and stromal cells in the bone marrow
• Oprelvekin is a recombinant form produced by expression in Escherichia coli
• Administered SC, half-life is 7–8 hours

Romiplostim

• Thrombopoietin agonist peptide covalently linked to antibody fragments that extend the half-life
• Administered SC once a week
• Eliminated by the reticuloendothelial system
• Half-life of 3–4 days, inversely related to the serum platelet count

Eltrombopag

• Small nonpeptide thrombopoietin agonist
• Given orally, peak levels in 2–6 hours
• Half-life of 26–35 hours, excreted primarily in the faeces
• Peak platelet response in 2 weeks

Clinical Uses of IL-11, Romiplostim, and Eltrombopag

• IL-11: secondary prevention of thrombocytopenia in patients receiving cancer chemotherapy
• Romiplostim and Eltrombopag: management of chronic immune thrombocytopenia refractory to steroids, immunoglobulins, and splenectomy

Adverse Effects of IL-11, Romiplostim, and Eltrombopag

• IL-11:
  • Fatigue, headache, dizziness
  • Anemia, dyspnea (due to fluid accumulation in the lungs)
  • Transient atrial arrhythmias
  • Hypokalemia
• Eltrombopag: hepatotoxicity
• Both:
  • Portal vein thrombosis
  • Marrow fibrosis (reversible on discontinuation)
  • In patients with myelodysplastic syndromes, romiplostim increases the blast count and risk of progression to acute myeloid leukemia
  • Rebound thrombocytopenia may occur following discontinuation