Haematopoietic Growth Factors & Agents

Haematopoietic Growth Factors & Agents

1. Hematopoiesis & the physiology of growth-factor regulation

• Hematopoiesis is the continuous replacement of mature blood cells from a small pool of self-renewing pluripotent hematopoietic stem cells (HSCs); in the normal adult, steady-state output exceeds 200–400 billion blood cells per day, occurring mainly in the marrow of skull, vertebrae, pelvis and proximal long bones (G&G 14e Ch.45, pp.899–900; Katzung 16e Ch.33, pp.623–4).
• Production is demand-responsive: erythrocyte production can rise >20-fold with anaemia/hypoxaemia, leukocyte production rises sharply with systemic infection, and platelet production can rise 10- to 20-fold in thrombocytopenia (G&G 14e Ch.45, p.899).
• HSCs differentiate through a hierarchy demonstrable in clonal semisolid (in vitro) cultures: large immature burst-forming units (BFUs) → small mature colony-forming units (CFUs), lineage-committed for each blood-cell type. Early progenitors amplify ~30-fold, and CFU proliferation/maturation amplifies the mature product a further ~30-fold, yielding >1000 mature cells per committed stem cell (G&G 14e Ch.45, pp.899–900).
• Lineage map (Figure 45–1 logic): SCF, FLT3-ligand (FL), IL-3 and GM-CSF drive stem cells to form CFU-GEMM → CFU-GM, CFU-Meg, BFU-E/CFU-E; terminal differentiation is then driven by the lineage-specific factors — erythropoietin (red cells), G-CSF/M-CSF (granulocytes/monocytes), thrombopoietin (platelets) (G&G 14e Ch.45, pp.901–2).
• Networking & redundancy principle: growth factors are glycoproteins active at very low concentration, typically act on more than one lineage, and interact synergistically ("networking"). Early-acting factors are redundant (loss is compensated), but loss of a nonredundant lineage-specific factor produces a specific cytopenia — e.g. EPO deficiency → anaemia of CKD (G&G 14e Ch.45, p.900–902).
• All receptors for EPO, G-CSF and GM-CSF are members of the cytokine-receptor (JAK/STAT) superfamily — ligand binding dimerises the receptor, activates Janus kinases, and phosphorylates STAT transcription factors to drive proliferation/differentiation genes (Katzung 16e Ch.33, p.633; G&G 14e Ch.45, p.904).
• Stimulants of hematopoiesis fall into three therapeutic groups paralleling the deficient lineage: erythropoiesis-stimulating agents (ESAs) for anaemia, myeloid growth factors for neutropenia, and thrombopoietic/megakaryocyte growth factors for thrombocytopenia (Katzung 16e Ch.33, p.632; G&G 14e Ch.45, p.899).

ERYTHROPOIESIS-STIMULATING AGENTS (ESAs)