Hematopoiesis and its Impairments Flashcards
How are pluripotent stem cells defined?
They are defined by their ability to salvage all the elements of hematopoiesis after it has been wiped out.
What are BFU?
Burst Forming Units are early hematopoietic progenitor cell stages of erythroid and megakaryocytic cell lines characterized by their tissue culture growth pattern in which large colonies are produced.
What is (TPO) Thrombopoietin?
Platelet growth factor. Hormone produced by renal and hepatic tissue that recruits stem cells to the megakaryocyte cell maturation line and stimulates megakaryocyte mitosis and maturation in response to thrombocytopenia.
What is (EPO) Erythropoietin?
Glycoprotein hormone synthesized by the kidney in response to anoxia, the hormone acts to stimulate and regulate the bone marrow production of red blood cells.
Where does most lymphopoiesis occur?
Outside of the bone marrow. (except in early childhood)
“Blasts” make up what percentage of cells in the bone marrow?
3-4%
What is the first step of Granulopoiesis ?
Granulopoiesis begins with differentiation of “blasts” into Promyelocytes.
Describe promyelocyte
- Larger than Blasts
- Large immature nucleus with multiple nucleoli
- Has lots of blue primary granules in the cytoplasm
- Can self differentiate and replicate
What are some morphological differences as promyelocytes start to mature into myelocytes and metamyelocytes.
- Cells become smaller
- Have more prominent golgi apparatus
- Development of secondary (red) granules
What is indicative of the metamyelocyte stage?
Beginning of indentation of the nucleus.
What do metamyelocytes proliferate into?
Bands
What cells regulate the maturation of Granulocytes?
Bone marrow stromal cells through their secretion of G-CSF and GM-CSF.
What cells produce platelets?
Megakaryocytes.
Facts about Megakaryocytes?
- Large and easily spotted under low power microscope.
- Multinucleated
- Polyploid usually up to 16-32n
First identifiable form of erythrocyte production?
Pronormoblast
What does the Pronormoblast progress to?
The Basophilic Erythroblast. Stains blue due to chromatin.
What are the co-factors required for Heme synthesis?
- Iron
- Vitamin B6
- Succinyl CoA
- Glycine
- B12
- Folate
What are co-factors required for Globin synthesis?
- Normal Alpha globin genes
- Normal Beta globin genes
- Amino Acids (malnutrition causes anemia through this)
Erythrocyte generation requires DNA synthesis True or False?
True.
The nucleus is discarded but still necessary for maturation etc
Co-Factors required for DNA synthesis?
- Deoxynucleoside triphosphates
- Thymidine
- B12
- Folate
- Ribonucleotide reductase
What are other requirements for erythropoiesis?
- Normal Kidney
2. Normal Bone marrow environment
What is the form of iron best absorbed in the duodenum?
Fe2+ aka the Ferrous form
How can one increase their absorption of iron?
Create an acid environment i.e take vitamin c tablets with the iron etc
What happens to Ferrous iron once taken up?
Gets oxidized to ferric form
Why is free iron floating in the system a bad thing?
- Can catalyze reactions generating free radicals (fenton’s reaction)
- Would augment bacterial growth.
What molecule plays the major role in iron uptake?
Ferroportin in membrane of enterocytes.
How is iron transported in the blood?
Bound to Transferrin.
How is iron taken up by erythroid precursors?
Erythroid precursors have Transferrin receptors on their surface that facilitate uptake of iron.
Where are the body’s major stores of iron?
- In Bone marrow macrophages
- In the liver
- In the Spleen
How is Iron stored?
Bound to ferritin.
Serum iron assay measures?
Transferrin-bound iron (but does not assess iron stores)
What is the “soluble Transferrin receptor” amount?
Measure of the small number transferrin receptor molecules that are sloughed off the storage pool cells.
The amount of ferritin present in the serum is is proportional to what?
The amount of storage pool iron in the body.
What is the most useful measure of iron metabolism available.
Serum Ferritin
What is TIBC?
Measure of the amount of Transferrin in circulation.
How do macrophages react to low storage pool iron?
Increase surface transferrin receptor molecule.
Serum levels of soluble tranferrin receptor molecules increase when?
There is low storage iron.
In iron deficiency what gets upregulated?
Transferrin
The lab findings for anemia due to decreased dietary intake is identical to findings in?
Anemia of chronic blood loss.
What is the expected morphology in Beta Thalassemia?
- Microcytosis
- Hypochromia
- Sometimes target cells (but not specific for Beta Thalassemia)
What important finding can separate your microcytic anemia of Beta Thalassemia from iron deficiency?
NUMBER of red cells
On what chromosome is the Beta Globin chain gene located?
Chromosome 11
What is the normal structure of the Globin chain in haemoglobin?
A2B2 with traces of A2D2
How many copies of the Globin gene on each chromosome?
6
1 “Beta Globin” gene
4 Beta Globin homologues
1 pseudogene
What is the order in which the Globin genes are expressed?
- Epsilon
- G-Gamma
- A-Gamma
- Psi Beta (pseudo gene)
- Delta
- Beta
How is Alpha2Delta2 referred to?
It is referred to as Hemoglobin A2.
What are the chains present in fetal hemoglobin?
Alpha2Gamma2.
How does one conform a diagnosis of Thalassemia?
Haemoglobin Electrophoresis
Where is the Alpha locus (of Globin)
Chromosome 16
What happens in cases of beta globin allele mutation?
The relative amount of Delta globin in increase giving ingreased levels on haemoglobin A2 which migrates differently from Haemoglobin A (normal haemoglobin) on electrophoresis
What is haemoglobin F?
Haemoglobin made up of the Alpha2-Gamma2 chains.
What genes of the Alpha chains are expressed during fetal development?
Zeta2-Zeta1
What genes of the Alpha chains are expressed during adult life?
Alpha2-Alpha1
With one defective Alpha allele one would have?
Alpha Thalassemia 1 trait (almost no clinical findings)
With 2 defective Alpha alleles one would have?
Alpha Thalassemia 2 trait
What are the clinical symptoms of Alpha Thalassemia 2 trait?
- Mild microcytic anemia
- Excess Hgb Bart’s (gamma)4 at birth
- Normal Hgb electrophoresis as adults
How do you diagnose Alpha Thalassemia 2 trait?
PCR
What is Haemoglobin Barts?
Haemoglobin containing Globin chains of $ gamma molecules
What is Haemoglobin H disease?
Three alpha gene mutations. usually yeilding Beta4 molecules.
How is HbH disease diagnosed?
Hb electrophoreisis
What is Hydrops Fetalis?
Lethal inutero disease resulting from deletion of all 4 copies of the alpha gene.
What drugs can inhibit DNA synthesis and cause anemia?
Anti-neoplastic drugs.
What does the impairment of DNA synthesis cause in eerythroid precursors?
Megaloblastic Anemia
How is epo production regulated?
Oxygen sensors in peritubular cells in the renal cortex sense o2 conc and stimulate the kidney to increase epo production.
What is Hepcidin?
Antimicrobial peptide produced by the Liver.
How does Hepcidin affect iron metabolism etc
- Negative regulator of intestinal iron absorption
2. Suppresses release of iron from iron stores (macrophages)
How is Hepcidin production regulated?
During infection and inflammation certain cells, predominantly lymphocytes and macrophages to some extent release Il-6 to cause the liver to augment Hepcidin production.
