Hematopoiesis Flashcards
Hematopoiesis
the formation and development of blood cells.
Hematopoiesis includes:
Erythropoiesis, Leukopoiesis, Thrombopoiesis
Erythropoiesis
formation and development of red blood cells
Leukopoiesis
formation and development of white blood cells.
Thrombopoiesis
formation and development of platelets.
mesoblastic stage
The yolk sac 0-2 months
hepatic stage
The liver and spleen are the main organs involved in hemopoiesis from two months to seven months of fetal life, and they continue to produce blood cells until about two weeks after birth
myeloid stage
5-9 months BM
the most important hemopoietic site, and it is the only source of new blood cells during normal childhood and adulthood
BM
spongy tissue in the middle of the bones where new blood cells are formed.
BM
when is the marrow in all bones is active and contributes to blood cell formation; red marrow.
at birth
The red marrow is gradually replaced() and becomes inactive; ()
by fibrous and fatty tissues
yellow marrow
By the age of 20 years, the red marrow is limited to the
flat bones and the ends of long bones.
There are two types of stem cells in the BM:
- Haematopoietic stem cells: form blood cells; WBC’s, RBC’s, platelets.
- Stromal stem cells: generate other types of cells; fat, cartilage, bone
Hematopoiesis is regulated by glycoproteins ()
known as hemopoietic growth factors
hemopoietic growth factors,
which can regulate the proliferation and differentiation of hemopoietic progenitor cells as well as the function of mature blood cells.
The biological effects of growth factors are mediated through
specific receptors on target cells.
The main sources of growth factors are: 5
- T-lymphocyte.
- Monocyte.
- Endothelial cells.
- Fibroblast.
- Kidney (erythropoietin and thrombopoietin)
Hemopoietic Growth Factors act on stromal cells
IL1 TNF
Hemopoietic Growth Factors pluripotent stem cells
stem cell factor VEGF
Hemopoietic Growth Factors multipotent progenitor cells
IL3 GM-CSF IL-6 G-CSF thrombopoietin
Hemopoietic Growth Factors on committed progenitor cells
IL-5 G-CSF M-CSF thrombopoietin erythropoietin
Hemopoiesis Requirements
1-Hemopoietic growth factors
2-Nutrients
3- Vitamins
4- Metals
Erythropoeisis stages
- Proerythroblast: the first cell to be identified as belonging to the red blood cell line.
- Basophil erythroblasts: first generation cells resulting from divisions of proerythroblasts; with little hemoglobin produced.
- Polychromatophil and orthochromatic erythroblasts: hemoglobin concentration increases; nucleus condenses.
- Reticulocyte: nucleus remnant extruded from cell and endoplasmic reticulum reabsorbed; cells pass from bone marrow to blood capillaries (diapedesis).
- Mature erythrocyte: remaining basophilic material of reticulocyte disappears.
Erythropoietin
Is a glycoprotein hormone, mainly produced by the kidneys (90%) in response to hypoxia; 10% produced in the liver.
Renal tissues hypoxia leads to
increased level of hypoxia inducible factors HIF (1 and 2)à secretion of erythropoietin.
Erythropoietin stimulates erythropoiesis by
increasing the number of progenitor cells committed to erythropoiesis:
* Stimulates production of proerythroblasts.
* Promotes the rapid development of proerythroblasts.
Factors That Enhance RBCs Production
Vitamin B12 (Cobalamin)
Folic acid
Iron
Vitamin B12 is required for
DNA synthesis, maturation of RBCs, and myelin formation
Cobalamin Daily requirement is
about 1-3 microgram.
B12 is absorbed from the
terminal ileum.
Absorption requires binding of B12 to the intrinsic factor that is produced
gastric parietal cells in the stomach.
B12 deficiency can cause
- Megaloblastic anemia.
- Impairment in myelination of the nervous system; subacute combined degeneration of the cord.
Vit b12 absorption mechanism 3 sites
◦ Stomach: Cobalamin is released from ingested proteins by pepsin and binds to the glycoprotein haptocorrin (R-protein){released by salivary glands}, which protects it from gastric acid.
◦ Duodenum: Cobalamin is released from haptocorrin by trypsin and binds to intrinsic factor (IF), a protein produced by the parietal cells of the stomach that facilitates cobalamin absorption in the ileum.
◦ Terminal ileum: cubilin receptor‐mediated endocytosis of the intrinsic factor-cobalamin complex → breakdown of IF in enterocytes, release of cobalamin, followed by binding to carrier protein transcobalamin II and then enters the plasma → cobalamin is either delivered to metabolically active tissues or stored in the liver
B12 deficiency is usually due:
- Inadequate intake:
- Vegetarian diet. * Malabsorption:
- Lack of intrinsic factor or parietal cells:
- Pernicious anemia, damage of the parietal cells by
autoantibodies. - Post-gastrectomy. * Atrophic gastritis.
- Diseases of the terminal ileum: * Crohn’s disease.
- Bacterial overgrowth.
- Transcobalamin deficiency.
Causes of folic acid deficiency:
- Inadequate folate intake.
- Malabsorption: barbiturates, phenytoin, and oral contraceptives. * Impaired metabolism: methotrexate or rare enzyme deficiencies
The biochemical basis of megaloblastic anaemia caused by
vitamin B12 or folate deficiency
Vitamin B12 is needed to convert
methyl THF, which enters the cells from plasma, to THF, from which polyglutamate forms of folate are synthesized.
Dietary folates are all converted to
methyl THF (a monoglutamate) by the small intestine.
Iron absorption occurs in the
upper small intestine; mainly duodenum and upper jejunum.
* Free iron must be in the reduced form [Fe++].
Factors that help in iron absorption:
- HCl of the stomach.
- Vitamin C.
Factors inhibiting iron absorption:
- Phosphates and phytates (in plants): form insoluble complexes.
- Some drugs: e.g. tetracyclin. * Alkalis.
Iron Transport And Storage
- Absorbed from the intestinal tract by the aid of apotransferrin.
- Iron in the blood is transported mainly bound to transferrin.
- Transferrin is normally about 30% saturated.
- Excess iron is stored mainly in the liver as ferritin.
- Ferritin is soluble and readily gives iron when it is needed.
- Another storage form of iron is haemosidrin, it is insoluble,
formed when the iron body contents are abnormally large. - Deposition of haemosidrin in soft tissues in large amounts (haemosidrosis) may cause damage (Bronze diabetes).
Iron Requirements
- Daily iron needs in males is 1 mg and in females is 2 mg.
- Iron absorption efficiency in the intestine is only 10–15 %,
therefore, dietary requirements for iron is 10-20 mg/day. - Daily loss in males is 0.6-1 mg and in females 1-2 mg.
- Increased iron demand: * Pregnancy.
- Lactation.
- Growing children.
Iron Deficiency
- Iron deficiency causes anaemia characterized by small, pale red cells (microcytic hypochromic anaemia).
- Causes of iron deficiency:
- Poor intake.
- Increased needs:
- Early childhood and adolescence, pregnancy and lactation.
- Decreased absorption:
- Achlorhydria, inflammatory bowel diseases.
- Increased loss:
- Heavy menstrual cycles.
- Bleeding (ulcers, intestinal worms).
where do leukocytes originate from
pluripotent hematopoietic stem cells
Pluripotential cells differentiate into
myeloid stem cells and lymphoid stem
cells.
Myeloid stem cells become
myeloblasts or monoblasts.
Myeloblasts develop into
eosinophils, neutrophils, and basophils.
Monoblasts develop into
monocytes.
Lymphoid stem cells become and develop into
lymphoblasts.
* Lymphoblasts develop into lymphocytes
what are small, granulated bodies that lack nuclei and are 2–4 μm in diameter; normally have a half-life of about 4 days.
platelets
The sequential developmental pathway of platelet is
hemocytoblast, megakaryoblast, promegakaryocyte, megakaryocyte, and platelets.
what is the major regulator of platelet formation
Thrombopoietin (TPO)
where is Thrombopoietin (TPO) formed
95% is produced by the liver.
Between 60 and 75% of the platelets that have been extruded from the bone
marrow are in
in the circulating blood, and the remainder are mostly in the spleen.
what causes an increase in platelet count
Splenectomy
As ATP becomes depleted how will the RBC look
cell will become a sphere and loose the ability to deform (becomes rigid)
The main metabolic pathways in RBCs, which in turn affect their life span, are:
Glycolysis
Hexose MonoPO4 shunt
Luebering-Rapoport shunt
provides necessary ATPS for existence; maintenance of red cell volume, shape and flexibility.
Glycolysis:
provides NADPH for keeping glutathione in reduced form, which is necessary to prevent hemolysis.
Hexose MonoPO4 shunt:
produces 2,3-DPG, which decreases Hb affinity for oxygen.
Luebering-Rapoport shunt
Hemoglobin and red blood cell membrane are usually protected from oxidant stress by
GSH
converts Glu-6-P to 6-Phosphogluconate by G-6-PD thereby producing NADPH.
HMP shunt
G6PD def
impaired synthesis of NADPH & GSH
&
RC r susceptible to oxidant stress
Provides 90% of ATP
Embden-Meyerhof Glycolytic Pathway
Provides adequate amounts of ATP necessary to
o Maintain erythrocyte shape, flexibility, and membrane
integrity
o Regulate intracellular cation concentrations o Sodium, potassium, calcium pumps
Embden-Meyerhof Glycolytic Pathway
Embden-Meyerhof Glycolytic Pathway Utilizes the enzyme
Utilizes the enzyme pyruvate kinase
Also referred to as Phosphogluconate pathway
Hexose Monophosphate Shunt
G6PD is the enzyme utilized
Hexose Monophosphate Shunt
NADPH together with glutathione protects against oxidative injury from toxic reducing oxidants
Hexose Monophosphate Shunt
Ifpathwayisdefective,globinchainsinhemoglobin denature and precipitate as aggregates called
Heinz bodies
Heinz bodies damage
the red cell membrane and causes the cell to be destroyed
Folic acid is normally found in
in green vegetables, some fruits and liver; easily destroyed by cooking.
folic acid daily requirement
Daily requirement is 100-200 microgm and storage in the body is relatively small
folic acid Deficiency develops
rapidly in case of inadequate intake or increase needs.
Folic acid is needed for
DNA synthesis and is essential for cell replication and the normal neural tube development.
Causes of folic acid deficiency:
- Inadequate folate intake.
- Malabsorption:
- Impaired metabolism
Deficiency of folic acid leads to
Deficiency leads to maturation failure and production of fewer red cells with large size; macrocytic anaemia.
Malabsorption of folic acid caused by which drugs
barbiturates, phenytoin, and oral contraceptives.
which enzyme causes folic acid deficiency
methotrexate
