Hematopoietic Growth Factors

Hematopoietic growth factors are a family of glycoproteins responsible for the proliferation and differentiation of hematopoietic progenitor cells in the bone marrow. Pharmacologic erythropoietin, thrombopoietin, granulocyte colony-stimulating factor (G-CSF), and granulocyte macrophage colony-stimulating factor (GM-CSF) are used in certain cases in which normal hematopoiesis is impaired owing to treatment (e.g., chemotherapy) or underlying disease (e.g., aplastic anemia). Commonly, erythropoiesis-stimulating agents (ESAs) are given as part of the treatment of chemotherapy-induced anemia and anemia secondary to CKD. G-CSF and GM-CSF are administered to treat chemotherapy-induced neutropenia. Thrombopoiesis-stimulating agents are used in the prevention or treatment of thrombocytopenia.

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Overview

Definition

Hematopoietic growth factors are glycoproteins that regulate the proliferation, differentiation, and maturation of progenitor cells, as well as the function of the mature cells.

Hematopoiesis

  • Hematopoiesis is the formation of blood cells:
    • Blood cells have a limited life span, so the ability to produce such cells is an important function of the body for continual renewal.
    • Adult hematopoiesis occurs in the bone marrow. 
    • Fetal hematopoiesis occurs in different organs as the fetus develops: 
      • Yolk sac: 3–8 weeks
      • Liver: 6 weeks–birth
      • Spleen: 10–28 weeks
      • Bone marrow: after 18 weeks
  • Hematopoietic stem cells (HSCs) develop in a complex microenvironment consisting of extracellular matrix and stromal cells: 
    • Undergo a series of steps → give rise to the common lymphoid progenitors and common myeloid progenitors (which are colonies of mixed blood cell lineage)
    • Common myeloid progenitors give rise to committed progenitors → colony-forming units (CFUs), which undergo proliferation and differentiation
  • CSFs impact development at the most mature stage.

Major hematopoietic growth factors and pharmacologic agents

Table: Major hematopoietic growth factors and pharmacologic agents
Cytokines/growth factorsActivitiesPharmacologic agent(s)
Erythropoietin (EPO)Stimulates erythropoiesis, including differentiation
  • Epoetin alfa
  • Darbepoetin alfa
  • Methoxy polyethylene glycol–epoetin beta
Granulocyte macrophage colony-stimulating factor (GM-CSF)Stimulates myeloid progenitor cellsSargramostim
Granulocyte colony-stimulating factor (G-CSF)Stimulates neutrophil precursor cells
  • Filgrastim
  • Pegfilgrastim
Thrombopoietin (TPO)Stimulates thrombopoiesis
  • Romiplostim
  • Eltrombopag
  • Avatrombopag
  • Lusutrombopag
IL-11Stimulates thrombopoiesisOprelvekin
Bone marrow hematopoiesis

Bone marrow hematopoiesis: proliferation and differentiation of the formed elements of blood.
IL-3: interleukin-3
CFU-GEMM: colony-forming unit–granulocyte, erythrocyte, monocyte, megakaryocyte
IL-2: interleukin-2
IL-6: interleukin-6
CFU-GM: colony-forming unit–granulocyte-macrophage
GM-CSF: granulocyte-macrophage colony-stimulating factor
M-CSF: macrophage colony-stimulating factor
G-CSF: granulocyte colony-stimulating factor
IL-5: interleukin-5
NK: natural killer
TPO: thrombopoietin
EPO: erythropoietin

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Erythropoiesis-Stimulating Agents

Definition

Erythropoiesis-stimulating agents (ESAs) are pharmacologic substances that stimulate the production of RBCs and are used to treat anemia due to a variety of conditions.

Agents

  • Epoetin alfa: recombinant human erythropoietin
  • Darbepoetin alfa: erythropoietin analog with additional oligosaccharide chains
  • Methoxy polyethylene glycol–epoetin beta: long-acting erythropoietin receptor activator
Table: Mechanism of action, pharmacokinetics and indications for erythropoiesis-stimulating agents
AgentMechanism of actionPharmacokineticsIndications
Epoetin alfa
  • Stimulate the proliferation and differentiation of progenitor cells
  • Bring about the release of reticulocytes
  • Increase hemoglobin and hematocrit
  • IV, SC
  • Slow SC absorption
  • ↑ Reticulocyte in 10 days
  • Peak effect: ↑ hemoglobin in 2–6 weeks
  • Distribution similar to extracellular plasma
  • Half-life elimination:
    • ≤ 67 hours (SC)
    • 4–13 hours (IV): CKD
  • Anemia 2 degrees to:
    • CKD
    • Chemotherapy
    • Medication (zidovudine)
  • ↓ Allogeneic transfusion for elective noncardiac, nonvascular surgery
Darbepoetin alfa
  • IV, SC
  • Slow SC absorption
  • Peak effect: ↑ hemoglobin in 2–6 weeks
  • IV: longer half-life than epoetin alfa
  • Half-life elimination:
    • 21 hours (IV)
    • 70 hours (SC); shorter in dialysis
Anemia 2 degrees to:
  • CKD
  • Chemotherapy
Methoxy polyethylene glycol–epoetin beta
  • IV, SC
  • Peak effect: ↑ hemoglobin in 7–15 days
  • Half-life elimination:
    • 119 hours (IV)
    • 124 hours (SC)
Anemia 2 degrees to CKD

Adverse effects

  • Cardiovascular:
    • Hypertension
    • ↑ Risk of MI
    • Cerebrovascular accident (stroke)
    • Venous thromboembolism
    • Thrombosis of vascular access
  • Nausea and vomiting
  • Arthralgia
  • Rash, pruritus, and in severe cases: toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS)
  • Tumor progression in certain cancers
  • Seizures

Contraindications

  • Hypersensitivity reactions
  • Uncontrolled hypertension
  • Pure RBC aplasia after treatment with ESAs
  • Formulations containing benzoyl peroxide are contraindicated in neonates and during the peripartum and breastfeeding periods.

Myeloid Growth Factors

Definition

Myeloid growth factors are agents that stimulate proliferation and differentiation of ≥ 1 myeloid cell types and are used to treat low neutrophil counts. 

Agents

  • Recombinant G-CSF:
    • Filgrastim (Neupogen)
    • Pegfilgrastim (Neulasta) is a pegylated form of G-CSF: formulation allows longer half-life.
  • Recombinant GM-CSF: sargramostim
Table: Mechanism of action, pharmacokinetics and indications for myeloid growth factors
AgentMechanism of actionPharmacokineticsIndications
Filgrastim
  • Stimulate CFU-G
  • ↑ Neutrophil production
  • IV, SC
  • Time to peak: 2–8 hours (SC)
  • Half-life elimination: approximately 3.5 hours
  • Systemically degraded
  • AML (after induction)
  • Myelosuppression from chemotherapy
  • Bone marrow transplantation (BMT) (↓ neutropenia)
  • Peripheral blood progenitor cell for apheresis collection
  • Hematopoietic radiation injury syndrome
  • Severe chronic neutropenia
Pegfilgrastim
  • IV, SC
  • Time to peak: 24 hours
  • Half-life elimination: 15–80 hours
  • Excreted by binding to neutrophils
  • Hematopoietic radiation injury syndrome
  • Prevent neutropenia in chemotherapy
Sargramostim
  • CSF
  • ↑ Myelopoiesis (proliferation, differentiation, and activity of neutrophils, eosinophils, macrophages, monocytes)
  • IV, SC
  • Time to peak: up to 4 hours (SC)
  • ↑ WBC in 1–2 weeks
  • ↓ WBC in 2–10 days after discontinuation
  • Half-life elimination: 3.8 hours (IV), 1.4 hours (SC)
  • AML (after induction)
  • Allogeneic or autologous BMT
  • To mobilize autologous peripheral blood progenitor cells for collection (by leukapheresis)
  • Speed up myeloid reconstitution after BMT
  • Hematopoietic radiation injury syndrome
BMT: bone marrow transplantation
CFU-G: colony-forming unit-granulocyte

Adverse effects

  • Filgrastim and pegfilgrastim:
    • Bone pain
    • Diarrhea, nausea, vomiting
    • Splenic rupture
    • ARDS, alveolar hemorrhage
    • Aortitis, chest pain
    • Nephrotoxicity
    • Cutaneous vasculitis
    • Capillary leak syndrome
    • Sweet syndrome: acute febrile neutropenia with dermatologic findings
    • Sickle cell crisis
    • Leukocytosis (WBCs ≥ 100,000/mm³)
    • Myelodysplastic syndrome, AML
  • Sargramostim:
    • Cardiac dysrhythmias, hypertension, edema, chest pain
    • Nausea, vomiting, diarrhea, abdominal pain, ↑ bilirubin
    • ↑ Creatinine
    • Capillary leak syndrome
    • Intraocular hemorrhage
    • Leukocytosis
    • Infusion reaction
    • Tumor growth (especially myeloid malignancies)

Contraindications

  • Severe allergic/hypersensitivity reaction
  • For sargramostim: contraindicated with > 10% leukemic myeloid blasts (in BM or peripheral blood)

Thrombopoietic Growth Factors

Definition

Thrombopoietic growth factors stimulate thrombopoiesis via the action of IL-11 or through the activation of TPO receptor.

Agents

  • Oprelvekin: recombinant IL-11
  • Romiplostim: peptide TPO receptor agonists
  • Eltrombopag, lusutrombopag, avatrombopag: nonpeptide TPO receptor agonists
Table: Mechanism of action, pharmacokinetics and indications for thrombopoietic growth factors
AgentMechanism of actionPharmacokineticsIndications
OprelvekinStimulates megakaryocytopoiesis and thrombopoiesis
  • IV, SC
  • Half-life: approximately 7 hours
  • ↑ Platelets in 5–9 days
Prevent severe thrombocytopenia in those undergoing chemotherapy for nonmyeloid cancer
Romiplostim↑ Platelets by binding TPO receptor
  • SC
  • Half-life: 3.5 days (median); up to 34 days
  • Peak platelet increase: 12–16 days
  • Immune thrombocytopenia
  • Hematopoietic syndrome of acute radiation syndrome
Eltrombopag
  • Oral
  • Half-life: approximately 32 hours
  • Peak platelet increase: 1–2 weeks
  • Fecal excretion
  • Immune thrombocytopenia
  • Severe aplastic anemia
  • Chronic hepatitis C–associated thrombocytopenia

Adverse effects

  • Oprelvekin:
    • Nausea, vomiting, diarrhea
    • Dyspnea, cough, pleural effusions
    • Atrial arrhythmias
    • Edema
    • Conjunctival injection
    • Blurred vision
    • Injection-site reaction
  • Romiplostim:
    • Thromboembolism
    • Upper respiratory infection (URI)
    • Dizziness, headache
    • Abdominal pain, diarrhea
    • Arthralgias
    • Rash
    • Progression of myelodysplastic syndrome → AML
    • Neutralizing antibodies against romiplostim
  • Eltrombopag:
    • Thromboembolism
    • URI
    • Cough, pharyngitis
    • Diarrhea, vomiting
    • Myalgia
    • Anemia
    • Cataract 
    • Hepatotoxicity
    • Progression of myelodysplastic syndrome → AML

Contraindications

For all agents, hypersensitivity to drug or components is a contraindication.

References

  1. Medscape Drug Information. (2020). Darbepoetin alfa (Rx). Retrieved June 25, 2021, from https://reference.medscape.com/drug/aranesp-darbepoetin-alfa-342150#5
  2. DeVita, V. T., Jr., Lawrence, T. S., Rosenberg, S. A. (2019). Devita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology, 11th ed. Philadelphia: Wolters Kluwer, pp. 1746–1748.
  3. Elliott, S., Pham, E., Macdougall, I.C. (2008). Erythropoietins: a common mechanism of action. Exp Hematol 36:1573–1584. https://pubmed.ncbi.nlm.nih.gov/18922615/
  4. Medscape Drug Information. (2020). Epoetin alfa (Rx). Retrieved June 25, 2021, from https://reference.medscape.com/drug/epogen-procrit-epoetin-alfa-342151#5
  5. Medscape Drug Information. (2020). Filgrastim (Rx). Retrieved June 26, 2021, from https://reference.medscape.com/drug/g-csf-neupogen-filgrastim-342164#4
  6. Ghanima, W., Cooper, N., Rodeghiero, F., Godeau, B., Bussel, J. B. (2019). Thrombopoietin receptor agonists: ten years later. Haematologica 104:1112–1123. https://doi.org/10.3324/haematol.2018.212845
  7. Hubulashvili, D., Marzella, N. (2009). Romiplostim (Nplate), a treatment option for immune (idiopathic) thrombocytopenic purpura. Pharmacy and Therapeutics 34:482–485. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2799136/
  8. Kuter, D. (2021). Clinical applications of thrombopoietin growth factors. UpToDate. Retrieved September 13, 2021, from https://www.uptodate.com/contents/clinical-applications-of-thrombopoietic-growth-factors
  9. Medscape Drug Information. (2019). Methoxy polyethylene glycol/epoetin beta (Rx). Retrieved June 25, 2021, from https://reference.medscape.com/drug/mircera-methoxy-polyethylene-glycol-epoetin-beta-342153#5
  10. Medscape Drug Information. (2019). Oprelvekin (Rx). Retrieved June 26, 2021, from https://reference.medscape.com/drug/neumega-interleukin-11-oprelvekin-342165#4
  11. Medscape Drug Information. (2021). Pegfilgrastim (Rx). Retrieved June 26, 2021, from https://reference.medscape.com/drug/neulasta-fulphila-pegfilgrastim-342167#4
  12. Medscape Drug Information. (2021). Romiplostim (Rx). Retrieved September 14, 2021, from https://reference.medscape.com/drug/nplate-romiplostim-342177#5
  13. Medscape Drug Information. (2019). Sargramostim (Rx). Retrieved September 14, 2021, from https://reference.medscape.com/drug/leukine-sargramostim-342166#4
  14. Schoener, B., Borger, J. (2021). Erythropoietin. StatPearls. Retrieved June 25, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK536997/
  15. Zehnder, J. L. (2017). Agents used in cytopenias; hematopoietic growth factors. In: Katzung, B. G., et al. (Eds.), Basic & Clinical Pharmacology. New York: McGraw-Hill Medical, pp. 600–606. 

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