23 - Hematopoietic Growth Factors Flashcards
Lecture Overview: Simplified Diagram of the Hematopoietic Hierarchy
- Multipotent hematopoietic stem cells (HSC) give rise to
all of the final differentiated blood cells. - The subsequent survival of cells at each differentiation
stage is determined by the presence of specific
hematopoietic growth factors.
* The life span of differentiated hematopoietic cells can range from years in the case of T and B cells involved in immunological memory, to 3 months in the case of red blood cells, to days, in the case of granulocytes.
* Therefore, HSCs are constantly called upon to supply a steady stream of hematopoietic progenitors that can generate new hematopoietic cells.
- Given the massive rate of hematopoietic cell turnover
(e.g., in humans is estimated to be 1012 cells), a stable
pool of functional HSCs must be continuously
maintained.
Lecture Overview: Growth factors
- The subsequent survival of cells at each differentiation stage is determined by the presence of specific hematopoietic growth factors.
- Hematopoietic growth factors are glycoproteins that stimulate the proliferation and development of clonogenic precursor cell populations.
- If the stage - or lineage-specific hematopoietic growth factor is absent, the cells undergo apoptosis.
- Hematopoietic growth factors can be generally grouped into:
1. Stem Cell Growth Factors: Osteopontin, Angiopentin-like 2/3, etc.
2. Early Acting Hematopoietic factors: IL-3, IL-6, Granulocyte Macrophage Colony Stimulating Factor (GM-CSF), stem cell factor (SCF) and thrombopoietin** (TPO).
3. Lineage-specific hematopoietic factors: erythropoietin (EPO), G-CSF, macrophage colony-stimulating factor [M-CSF**], and TPO
Outline: Hematopoietic Growth Factors
Erythroid Growth Factors
Erythropoietin (EPO):
* Most important regulator of the proliferation of committed erythrocyte progenitors (EP) cells.
* It is a 34-39 kDa Glycoprotein, synthesized in the kidneys, that was originally isolated from patients with anemia
* EPO receptors (EPOR) is a tyrosine kinase receptor that signals mainly through JAK/STAT2 pathway.
* EPO synthesis increases 100-fold with anemia or hypoxemia (next slide)
* EPO production altered in patients with kidney disease, marrow damage, iron deficiency.
* Proinflammatory cytokines suppress EPO production
Erythroid Growth Factors - Erythropoiesis Stimulating Agents (ESA) - Overview
(Pharmacological substance that stimulates RBC production)
* Preparations: Epo-alpha, -Beta, -Omega, -Zeta, etc
- Recombinant human erythropoietin or rHUEPO (Epo alpha)
* IV half-life 4-13 hours, subcutaneous 16-67 hours
* Given 3 times per week – once weekly
* Effects on marrow last significantly longer
* Peak hemoglobin effect 2-6 weeks - Darbepoetin alfa (highly glycosylated)
* IV half-life: 21-46 hours, subcutaneous 46-74 hours
* Given once weekly – every 3 weeks
* Therapeutic use: treatment of symptomatic anemia associated with HIV (zidovudine therapy), chemotherapy, chronic kidney disease (CKD), myelodysplastic syndrome (off label) - Epoetin Beta and Methoxy polyethylene glycol-epoetin beta
* continuous erythropoietin receptor activator and is used monthly
* (half-life approx.130 hrs in patients with anemia associated with CKD
Erythroid Growth Factors - Erythropoiesis Stimulating Agents (ESA) - Benefits
- Benefits
- Reduces need for RBC transfusion
- Symptom relief not consistently shown in clinical trials
- Patients with endogenous erythropoietin < 100 IU/L most likely to respond, 100-500 IU/L may respond
- Note: Banned by athletic organizations
- Dosage adjustments to achieve hemoglobin (Hgb) goals
- Hgb increases in 2-6 weeks (reticulocytes in 10 days)
- Decrease dose if Hgb increases > 1 g/dL in 2 weeks
- Increase dose if Hgb doesn’t increase by >1 g/dL in 4 weeks
- Goal Hgb in CKD: 10 - 12 g/dL
- Most also need iron supplementation
- Cancer: use conservatively when Hgb < 10 g/dL and only when myelosuppressive therapy anticipated for > 2 months
Erythroid Growth Factors - Erythropoiesis Stimulating Agents (ESA) - ADE
Outline: Hematopoietic Growth Factors
Hematopoietic Growth Factors - HIF inhibitors — Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF PHIs)
- EPO synthesis increases 100-fold with anemia or hypoxemia.
* The body’s adaptation to low oxygen levels (hypoxia) is largely influenced by signaling from hypoxia-inducible factors (HIFs). - The HIFs that primarily control this response are HIF-1 and HIF-2, with HIF-3 playing a less defined role.
- cDNA microarrays have identified at least 70 hypoxia-responsive genes have been identified which are under HIF control.
- There are two types of HIF-1, ⍺ and β, which are codified by different genes on chromosome 14 and 1, respectively.
- HIF-1α is a ubiquitously expressed protein containing an oxygen-dependent degradation domain that under normal conditions regulates its constant degradation. HIF-1β is a stable constitutively expressed protein that localizes to the nucleus.
* HIF-1⍺ isoforms serve as the oxygen-regulated subunit that controls HIF transcriptional activity in response to hypoxia, while HIF-1β is a constitutive binding partner needed to form an active HIF complex.
HYPOXIA-INDUCIBLE FACTOR (HIF) PATHWAY.
- HIF-1α is constitutively produced and rapidly degraded under normoxic conditions.
- Degradation of HIF-1α is mediated by prolyl hydroxylasedomain (PHD) 1, PHD2, and PHD3 enzymes, which hydroxylate specific proline residues within HIF-α.
- Hydroxylated HIF-α is ubiquitylated by the von Hippel–Lindau (VHL)–E3 ubiquitin ligase complex, leading to its proteasomal degradation.
- PHDs utilize O2 and 2-oxoglutarate as substrates in an iron-dependent reaction, resulting in the formation of hydroxylated HIF-α, succinate, and CO2.
-
Hypoxia or HIF–PHD inhibitors (PHIs such as Daprodustat) reduce PHD catalytic activity, which leads to cellular accumulation of HIF-α, its nuclear translocation,
heterodimerization with HIF-1β - This leads to increased transcription of HIF-regulated genes, which are involved in multiple biological processes.
Blood Doping?
Myeloid Growth Factors
Growth factors that stimulate proliferation and differentiation of one or more myeloid cell lines
Myeloid Growth Factors: Recombinant Human G-CSF
- Filgrastim (recombinant human G-CSF), pegfilgrastim (pegylated recombinant human G-CSF)
- Primary effects
- Stimulates proliferation & differentiation of progenitor cells committed neutrophil lineage
- Activates phagocytic activity of mature neutrophils & prolongs survival
- Mobilizes hematopoietic stem cells increasing concentrations in peripheral blood when blood is being collected for leukapheresis
- Therapeutic uses
- Treatment of neutropenia after stem cell transplant or
chemotherapy - Severe congenital neutropenia, cyclic neutropenia
- Peripheral blood stem cell collection (promotes release of CD34+ progenitor cells)
- Anemia along with erythropoietin (off label)
Myeloid Growth Factors: Recombinant Human G-CSF - PK and ADE
* Pharmacokinetics
* Filgrastim half-life: 3.5 hours
* Pegfilgrastim half-life: 42 hours
* Response in 7-21 days
* Usually started within 24-72 hours after completing chemotherapy
* Filgrastim (IV, sc) dosed daily for up to 14 days
* Pegfilgrastim (sc) one dose per chemo cycle
* Benefits
* Reduced duration of febrile neutropenia
* Reduced morbidity secondary to bacterial, fungal infections
* Reduced length of hospital stay, interruptions in chemotherapy
* No benefit on long-term survival
* Adverse Effects
Innocuous: **Bone pain **(mild/moderate) and local skin reactions following, rarely necrotizing vasculitis
Serious but rare: Allergic reactions (produced in E. Coli); mild splenomegaly with chronic use - rarely splenic rupture
Myeloid Growth Factors: Stem Cells Mobilizer and Recombinant GM-CSF
Hemapoietic Growth Factors: Megakaryocyte Growth Factors - Overview
