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33 Cards in this Set

  • Front
  • Back
What is hematopoiesis?
Ordered production of mature blood, begins with pluripotent hematopoietic stem cells
Ordered production of mature blood, begins with pluripotent hematopoietic stem cells
What influences the production and maturation of blood lineages?
Growth factors
What growth factor is produced by the kidneys in setting of hypoxia? Function?
Erythropoietin (EPO) - stimulates RBC production
What is the function of Thrombopoietin (TPO)?
Increases megakaryocyte production and platelet formation
What is the function of Granulocyte Colony Stimulating Factor (G-CSF)?
Increases neutrophil production
What can recombinant Growth Factors and Growth Factor Agonists be used to treat?
- Anemia (epo)
- Thrombocytopenia (tpo)
- Neutropenia (G-CSF)
What does this arrow point out?
What does this arrow point out?
Cluster or hematopoietic stem cells - all circulating blood cells are derived from these cells
Cluster or hematopoietic stem cells - all circulating blood cells are derived from these cells
What drives hematopoietic cell division?
Growth factors and cytokines
What do lymphoid stem cells mature into?
B cells, T cells, NK cells
What do myeloid stem cells mature into?
RBCs, platelets, neutrophils, eosinophils, and basophils
What is the name of G-CSF when produced for pharmaceutical use? Function?
Filgrastim - stimulates neutrophil production
What are the implications of growth factors binding to specific receptors?
Causes down-stream phosphorylation of signaling proteins
What is the mechanism of erythropoietin?
- Epo binds to R
- JAK protein recruited to Epo R dimer
- Tyrosine kinase activation
- Phosphorylation of cell signaling proteins
- Downstream pathways (including MAPK) cross nuclear membrane and act as transcription factors
- Alters gene transcription and translation to affect differentiation of hematopoietic stem cell towards RBCs
What is the end function of Erythropoietin?
Stimulates maturation of erythroid precursors into more mature appearing RBCs w/in BM
Where is Epo produced? What stimulates its production? What decreases its production?
- >85% is produced in kidney, small amount produced in liver's parasinusoidal cells
- Stimulated in response to hypoxia
- Decreased in response to normoxia or polycythemia (excess Hb)
What happens to Hypoxia-Inducible Factor (HIF) metabolism during normal O2 conditions?
- HIF-1α is hydroxylated by proline hydroxylases (PHD)
- Binds to Von Hippel Lindau (VHL) protein
- Marks HIF-1α for ubiquitination

* Leads to proteolytic degradation and destruction of HIF-1α
What happens to Hypoxia-Inducible Factor (HIF) metabolism during hypoxic conditions?
- HIF-1α cannot be appropriately hydroxylated
- Increased HIF-1α levels which crosses nuclear membrane
- Binds HIF-1β and forms complex
- Acts as promoter of target genes and recruits co-regulators

* Upregulates cellular functions, including Epo production
What conditions is recombinant Epo used to treat?
- CKD: ↓ circulating epo and anemia
- Anemia
What causes of anemia can be treated with recombinant Epo?
- Patients receiving chemo - ↓ need for transfusions, improves QOL
- Associated with Myelodysplastic syndrome (MDS)
- Associated with HIV
- Patients who refuse blood transfusions (prior to surgeries)
- In low birth weight babies (<1250g) and premies (impaired endogenous Epo production)
What are the side effects of recombinant Epo?
* HTN
* Headache
- Venous thrombosis
- CV dz (including MI and stroke) - rare
- Pure red cell aplasia (very rare)
What are the functions of Thrombopoietin (TPO)?
- Primary regulator of platelet production (through feedback loop)
- Enhances megakaryocyte proliferation and maturation and platelet production
Where is Thrombopoietin produced?
Liver
What increases Thrombopoietin levels? Decreases?
- Thrombocytopenia = absence of platelets → ↑TPO levels → megakaryocyte binding

- Thrombocytosis = increased platelets → binds TPO → ↓circulating TPO → ↓ megakaryocyte activity
What is the Thrombopoietin feedback loop?
- Liver constitutively produces stead amount of TPO
- TPO binds MPL R in megakaryocytes
- TPO taken up in BM
- Megakaryocytes ↑ platelet production
- As platelet production ↑ → ↓ circulating TPO and ↓ final amount of TPO available to BM
How do you activate the TPO receptor?
- TPO binds MPL receptor, inducing a conformational change in R
- Recruits JAK2 protein to R
- Phosphorylates STAT and MAPKK pathways leading to signal transduction
- ↑ Platelet production
What are the clinical uses of Thrombopoietin Receptor Agonists?
- ↑ Platelet production
- Treatment for thrombocytopenia
- Associated w/ decreased need for platelet transfusions
What are the side effects of Thrombopoietin Receptor Agonists?
- Headache
- Venous thrombosis
- Myelofibrosis
- Often well tolerated
What kind of cells produce Granulocyte Colony Stimulating Factor (G-CSF)?
- Monocytes
- Macrophages
- Fibroblasts
- ECs
What stimulates an increase in Granulocyte Colony Stimulating Factor (G-CSF)?
Pro-inflammatory mediators, including IL-1 and TNF-α
What is the function of Granulocyte Colony Stimulating Factor (G-CSF)?
Increases production and maturation of myeloid cells (neutrophils)
What ist he mechanism of Granulocyte Colony Stimulating Factor (G-CSF)?
- G-CSF binds to receptor
- Receptor dimerizes
- Phosphorylates down-stream signaling pathways
- Increases production of myeloid cells (neutrophils)
What are the clinical uses of recombinant G-CSF?
Tx of Neutropenia:
- Chemo-associated
- Tx of fever and infections in patients w/ neutropenia
- HIV-associated neutropenia
- Chronic neutropenia syndrome
- Mobilization of stem cells prior to autologous BM transplant
What are the side effects of recombinant Granulocyte Colony Stimulating Factor (G-CSF)?
* Bone pain (especially in pelvis and hips), related to medullary expansion
- Fever (less common)
- Fluid retention and pulmonary edema