Hematopoiesis Flashcards
List the cells that fall under the common lymphoid progenitor cell line.
B, T, NK
List the cells that fall under the common myeloid progenitor cell line.
RBCs, platelets, monocytes, neutrophils, basophils, eosinophils
The common myeloid and lymphoid progenitor cell lines stem from what type of stem cell?
Pluripotent stem cells (make up 1 in 20 million cells in BM)
Drugs can be given to mimick which growth factors that signal for hematopoietic differentiation and division? What are the products of each?
TPO-> platelets EPO-> RBCs GM-CSF -> monocytes, neutrophils, eosinophils G-CSF -> neutrophils
List the granulocyte precursors in order of their differentiation starting with the “blast”.
Blast, promyelocyte, myelocyte, metamyelocyte, Bands and neutrophils.
List the red cell precursors in order of their differentiation starting with the “blast”.
Blast, pronormoblast, basophilic erythroblast, polychromatophilic erythroblast, normochromic erythroblast
Normal maturation of erythroid precursors takes place in ____ (#) divisions.
5
List the 3 stages of maturation for megakaryocytes, beginning with “blast”.
Blast, immature megakaryocyte, mature megakaryocyte
What cell line (of erythroid, thromboid, myeloid, lymphoid) represents the greatest population of maturing cells in the BM?
myeloid (monocytes, neutrophils, eosinophils, basophils) make up 70% of cells in the BM.
What must happen to Fe before it is transported from the lumen of the bowel across the lumenal epithelium?
It must be reduced (by ascorbate via duodenal reductase). (it is usually oxidized). It will be re-oxidized once it gets into the plasma (by serum oxidases, mainly ceruloplasmin) for proper transport.
Why are vitamins (particularly ascorbic acid) important in Fe uptake from the gut?
Ascorbate is needed to reduce Fe to its ferrous form which will allow transport across the GI epithelium to plasma where it will be re-oxidized (by serum oxidases, mainly ceruloplasmin) to ferric form.
Heme synthesis requires these components:
Iron *
B6
Succinyl CoA
glycine: req’s B12 & folate
An Fe deficiency will present with this morphology:
1) Small red cells (microcytosis) without much Hb (hypochromia) 2) Lots of variation in red cell size (anisocytosis) and shape (poikilocytosis)
What is the role of ferritin as it relates to iron in the body?
Storage in macrophages in liver, spleen, and bone marrow.
What is the role of transferrin as it relates to iron in the body?
transport of iron in plasma (Fe binding in plasma)
Total Iron Binding Capacity (TIBC) refers to Fe transport, storage or both?
Just transport
Besides ascorbic acid, what other environmental factors are needed for Fe uptake from the gut?
Low pH (provided by ascorbate?)
ceruloplasmin is dependent on what divalent metal for conversion of ferrous Fe to ferric Fe?
Cu2+
Too much zinc in the diet leads to deficiency of this divalent metal, leading to this form of anemia:
Cu2+; microcytic hypochromic anemia (because Fe remains in ferrous form and can not be used in heme synthesis)
Dietary iron is transported via this transporter into the enterocyte in the gut epithelium:
DMT-1 (divalent metal transporter 1)
Ferrous iron is transported via this metal transporter extracellularly (eventually to plasma):
Ferroportin
What is hepcidin’s role in Fe transport/storage?
Traps Fe in storage form within macrophages/hepatocytes. Decreases gut absorption of Fe
Give 3 examples of routes of chronic blood loss that can lead to iron deficiency and thus, anemia.
GI tract Urinary tract Dysfunctional uterine bleeding
Impaired globin synthesis due to abnormal globin genes (alpha/beta) leads to:
Alpha or Beta thalassemia
Describe the microscopic morphology of Beta thalassemia.
Microcytosis, hypochromia (just like Fe deficiency) Frequent target cells homozygous: severe heterozygous: can be mild and not clinically obvious
Globin synthesis requires these components:
Normal globin genes: alpha/beta Amino acids
Describe the quantitative outcome of RBCs in beta thalassemia.
Normal or increased # of RBCs
How do you confirm a Dx of beta thalassemia?
Hemoglobin electrophoresis
The beta globin locus is found on what chromosome?
Chr 11
Normal hemoglobin (tetramer) has 4 subunits. Describe the subunits in terms of number of each and what gene they derive from.
Normally: Alpha2beta2 with traces of Alpha2Delta2
What is HbA2?
alpha2delta2 Finding this in adult RBCs means beta globin homologue locus was mutated or missing
What is HbF?
Fetal hemoglobin: alpha2gamma2 Finding this in adult RBCs means beta globin homologue locus was mutated or missing
The alpha globin locus is located on what chromosome?
Chr 16
There are 2 adult alpha globin genes. Name them
alpha 1, alpha 2
Name the 4 beta globin homologous.
epsilon, g-gamma, a-gamma, delta
Name the 2 fetal alpha globin genes
zeta 1, zeta 2
1 defective alpha thalassemia allele, presenting as Alpha thalassemia 1 trait his this clinical presentation:
almost no clinical/lab findings
2 defective alleles (one on each chromosome from each parent), presenting as alpha thalassemia 2 trait, has this clinical presentation:
mild microcytic anemia Excess Hgb Bart’s (gamma4) @ birth Normal Hgb electrophoresis as adults Dx is PCR based (electrophoresis and/or sequencing) found in 3% of African Americans
3 defective alpha alleles, presenting as Hgb H disease (beta4) [alpha thalassemia], has these clinical presentations:
Variable degree of microcytic anemia Hgb electrophoresis: 15-30% Hgb H Can be misDx’d as Fe deficiency
Alpha thalassemia involving 4 defective alpha alleles: Hgb Bart’s (gamma4) has this clinical presentation:
lethal in utero or soon after birth The allele is common in Southeast Asia
What factors are required for DNA synthesis?
Deoxynucleotide triphosphates - req: ribonucleotide reductase, thymidine - req: B12 and folate
Where is B12 needed in DNA synthesis?
conversion of n5-methyl THF and homocysteine to THF and methionine –> Purines
Impaired DNA synthesis in red cell production leads to:
Fewer cells produced Normal/enhanced maturation of cytoplasm But- impaired nuclear maturation (due to impaired DNA synthesis) What does all this lead to??–> MEGALOBLASTIC ANEMIA
What are the causes of megaloblastic anemia?
Impaired B12 uptake (pernicious anemia) Impaired folate uptake (malabsorption, malnutrition) Drug effect: nucleoside analogues (HAART), ribonucleotide reductase inhibitors (hydroxyurea) Intrinsic bone marrow dysfunction: myelodysplastic syndrome(s)
EPO regulates erythropoiesis and is produced by this organ:
kidney
Inflammation and IL-6 have what effect on RBC production and why?
Decrease RBC maturation/production because IL-6 causes the liver to release hepcidin which signals for Fe to remain in macrophages and hepatocytes and not be used in heme synthesis.
Describe the anemia of chronic inflammation due to chronic infectious/inflammatory disease.
Normocytic anemia
**Increased bone marrow iron stores**
**Increased ferritin**
Reduced or normal serum iron
A weird mutation causes the fetal beta globin gene (gamma) to not shut off at birth. If a kid inherits that allele AND a beta thalassemia allele, what effect would you expect that to have on their clinical thalassemia?
Milder anemia. The fetal beta globin gene (gamma globin) will compensate a little for the beta deficiency.
The JAK2 kinase is acted upon by which hematopoietic growth factors?
EPO and TPO
Consitutive activation of the JAK2 kinase woud result in what pathological condition mediated by platelets and why?
excessive blood clotting. The JAK2 kinase, under normal circumstances, is activated by EPO and TPO and then self-phosphorylates and initiates a cascade that results in transcription of genes that encode proteins necessary for cell proliferation and differentiation. With regard to platelets, constitutive activation of the JAK2 kinase would result in an over production of platelets and blood clotting.
Excess use of GM-CSF could result in what microscopic presentation in the bone marrow?
Overproduction of granulocytes (hyperplasticity of granulocytes)
Destruction of gastic parietal cells will result in *pernicious* anemia. Why?
Gastric parietal cells produce intrinsic factor (IF) needed for uptake of vit. B12. B12 is needed for DNA synthesis (to make THF–> purines)
No DNA synthesis, no mature RBCs
Accumulation of homocysteine and N5-methyl THF could be a marker for deficiency of this factor necessary for DNA synthesis:
B12
Name one more way of detecting B12 deficiency.
methylmalonate accumulation. (B12 needed for further metabolizing odd # carbon fatty acid chains, since they are fed into FA oxidation only 2 at a time)
Accumulation leads to subacute combined degeneration of spinal cord. Neurological condition
Hepcidin has what effect on the gut absorption of Fe and why?
reduces gut absorption of Fe by signalling for internalization and degradation of surface transporter ferroportin
A deficiency in hepcidin would have what effect on Fe absorption from gut and Fe deposition in tissues.
Increased absorption from gut.
Increased deposition in tissues = hemochromatosis (not good)
Describe one reason why increased hepcidin expression by the liver may be caused by chronic inflammation/infection.
Bacteria need Fe for survival. If you decrease available Fe to bacteria, you will mitigate the infection.
