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33 Cards in this Set
- Front
- Back
What is hematopoiesis?
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Ordered production of mature blood, begins with pluripotent hematopoietic stem cells
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What influences the production and maturation of blood lineages?
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Growth factors
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What growth factor is produced by the kidneys in setting of hypoxia? Function?
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Erythropoietin (EPO) - stimulates RBC production
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What is the function of Thrombopoietin (TPO)?
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Increases megakaryocyte production and platelet formation
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What is the function of Granulocyte Colony Stimulating Factor (G-CSF)?
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Increases neutrophil production
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What can recombinant Growth Factors and Growth Factor Agonists be used to treat?
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- Anemia (epo)
- Thrombocytopenia (tpo) - Neutropenia (G-CSF) |
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What does this arrow point out?
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Cluster or hematopoietic stem cells - all circulating blood cells are derived from these cells
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What drives hematopoietic cell division?
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Growth factors and cytokines
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What do lymphoid stem cells mature into?
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B cells, T cells, NK cells
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What do myeloid stem cells mature into?
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RBCs, platelets, neutrophils, eosinophils, and basophils
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What is the name of G-CSF when produced for pharmaceutical use? Function?
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Filgrastim - stimulates neutrophil production
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What are the implications of growth factors binding to specific receptors?
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Causes down-stream phosphorylation of signaling proteins
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What is the mechanism of erythropoietin?
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- 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 |
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What is the end function of Erythropoietin?
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Stimulates maturation of erythroid precursors into more mature appearing RBCs w/in BM
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Where is Epo produced? What stimulates its production? What decreases its production?
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- >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) |
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What happens to Hypoxia-Inducible Factor (HIF) metabolism during normal O2 conditions?
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- 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 |
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What happens to Hypoxia-Inducible Factor (HIF) metabolism during hypoxic conditions?
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- 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 |
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What conditions is recombinant Epo used to treat?
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- CKD: ↓ circulating epo and anemia
- Anemia |
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What causes of anemia can be treated with recombinant Epo?
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- 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) |
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What are the side effects of recombinant Epo?
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* HTN
* Headache - Venous thrombosis - CV dz (including MI and stroke) - rare - Pure red cell aplasia (very rare) |
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What are the functions of Thrombopoietin (TPO)?
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- Primary regulator of platelet production (through feedback loop)
- Enhances megakaryocyte proliferation and maturation and platelet production |
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Where is Thrombopoietin produced?
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Liver
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What increases Thrombopoietin levels? Decreases?
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- Thrombocytopenia = absence of platelets → ↑TPO levels → megakaryocyte binding
- Thrombocytosis = increased platelets → binds TPO → ↓circulating TPO → ↓ megakaryocyte activity |
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What is the Thrombopoietin feedback loop?
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- 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 |
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How do you activate the TPO receptor?
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- 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 |
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What are the clinical uses of Thrombopoietin Receptor Agonists?
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- ↑ Platelet production
- Treatment for thrombocytopenia - Associated w/ decreased need for platelet transfusions |
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What are the side effects of Thrombopoietin Receptor Agonists?
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- Headache
- Venous thrombosis - Myelofibrosis - Often well tolerated |
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What kind of cells produce Granulocyte Colony Stimulating Factor (G-CSF)?
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- Monocytes
- Macrophages - Fibroblasts - ECs |
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What stimulates an increase in Granulocyte Colony Stimulating Factor (G-CSF)?
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Pro-inflammatory mediators, including IL-1 and TNF-α
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What is the function of Granulocyte Colony Stimulating Factor (G-CSF)?
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Increases production and maturation of myeloid cells (neutrophils)
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What ist he mechanism of Granulocyte Colony Stimulating Factor (G-CSF)?
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- G-CSF binds to receptor
- Receptor dimerizes - Phosphorylates down-stream signaling pathways - Increases production of myeloid cells (neutrophils) |
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What are the clinical uses of recombinant G-CSF?
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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 |
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What are the side effects of recombinant Granulocyte Colony Stimulating Factor (G-CSF)?
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* Bone pain (especially in pelvis and hips), related to medullary expansion
- Fever (less common) - Fluid retention and pulmonary edema |