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89 Cards in this Set
- Front
- Back
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Define:
Erythropoiesis Thrombopoiesis Granulopoiesis |
Erythropoiesis - formation of RBC
Thrombopoiesis - formation of platelet Granulopoiesis - formation of granulocytes |
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Describe the development of hematopoiesis
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yolk sac -> liver -> bone marrow
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What do lymphoid and myelod multipotent stem cells give rise to?
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lymphoid - T-cells, B-cells, NK cells
myeloid - platelets, eosinophils, neutrophils, basophils, erythrocytes, macrophages, and dendritics cells |
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Where can hematopoietic stem cells be found?
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usually in bone marrow, but can be found in circulation
they do not differentiate in circulation as they need a special microenvironment. |
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What is another name for hematopoietic cytokines?
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hematopoietic GFs
mechanisms: autocrine, paracrine, endocrine |
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What are hematopoietic GFs made of? What is its action and functions?
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made of glycoproteins
its action is to bind to receptors on progenitor cells its functions are to regulate (promote) proliferation and differentiation, prevent apoptosis, and to enhance function of some end stage cells no GFs = apoptosis to prevent over abundance of cells |
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Three types of GFs
-Acting on pluripotential stem cells -Acting on early myeloid stem cells -Acting on later myeloid SCs and precursors |
Pluripotential
-IL-6, SC factor, Steel factor Early myeloid SC -GM (granulocyte/monocyte colony stimulating factor) Later myelod stem cells/precursors -GM-CSF, G-CSF, Erythropoietin, Thrombopoietin |
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How is specific blood cell production limited?
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-cells die if they don't divide and differentiate
-differentiating cells express specific receptors -the hematopoietic GFs bind to the specific receptors to promote division and differentiation -thus each cell requires GFs to prevent apoptosis |
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Describe erythropoietin:
-what does it do -site of synthesis -its stimulus for synthesis -effects -control |
-controls RBC production
-produced in kidney (renal cells) -stimulate by hypoxia (or shortage of erythrocytes) -it hastens maturation of all red cell precursors, and stimulate premature release of reticulocytes (immature RBC) into the bloodstream -as RBCs mature, they gradually lose their membrane erythropoietin receptors |
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Describe granulocyte colony stimulating factor (G-CSF)
-what does it do -where is it produced? -what is its stimulus -effects -control |
G-CSF
-controls neutrophil production -produced in fibroblast (endothelial cells) and macrophages -stimulated by inflammation -it hastens maturation of neutrophils precursors and stimulate premature release of band forms into the bloodstream -control by the losing of membrane receptors of mature neturophils |
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How is erythropoeitin used clinically?
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Bone marrow or renal insufficiency
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How is G-CSF used clinically?
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Neutropenia
-primary or induced by chemotherapy |
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Describe thrombopoietin
-what does it do -site of production |
Thrombopoietin
-stimulates megakaryocyte growth, maturation, and platelet release |
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Differentiate b/t aspirate and biopsy
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aspirate - liquid
biopsy - liquid plus bone |
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What can cause hypercellular bone marrow?
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increase of one or more cell lines
-granulocytic hyperplasia (infection) -erythroid hyperplasia (anemia) -megakaryocytic hyperplasia (platelet loss or destruction) |
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What can cause hypocellular bone marrow
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-genetic
-toxic -infectious -idopathic (spontaneous) |
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Basic information about hemoglobin
-structure -amount in human body -what does it transport |
-2 alpha and 2 beta chains
-human body contains 750g of Hb -Hb transports H+ and CO2 in addition to O2 |
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Fundamental role of Hb
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to maintain the ferrous state of iron (Fe2+) and protect it from irreversible oxidation
2 Fe(II) + O2 <---> 2 Fe(II)O2 instead of 2 Fe(II) + 3 O2 ---> 2 Fe(III)2O3 That is ferric and it is an oxidizing rxn, thus irreversible without an catalyst to reduce |
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Describe ligands in hemoglobin provided to bind to Fe2+
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4 ligands to Fe2+ from N in the heme group
5th ligand - N from His-93 in the globin group (aka proximal His) 6th ligand - O2, sandwiched between Fe2+ and N on the His-64 in the globin chain (aka distal His) |
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Describe Heme
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-4 pyrrole rings (A/B/C/D)
-stable, flat, hydrophobic -8 side chains, 2 on each ring -3 side chains: methyl, vinyl, propionic acid -4 N coordination ligands to Fe2+ |
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Definition of anemia and symptoms
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Definition:
-decrease in RBC, Hb, and hematocrit below established normal values of somebody similar Symptoms -appear pale -weakness, malaise, easy fatigability -brittle and misshapen fingernails -hypoxia induced angina -hypoxia induced headaches, dimmed vision and faintness |
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Describe microcystic anemia
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microcytic - small than usual RBC
paler than usual (hypochromic) |
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Describe macrosystic anemia
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larger than usual RBC, not enough hemoglobin for cell
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Where is heme synthesized?
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Any cell containing mitochondria
85% of heme is synthesized in erythroid cells in the bone marrow occurs in the BFU-E lineage: normoblasts and reticulocytes |
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How and where is heme synthesized at a subcellular level?
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Starts in mitochondria, continues in cytosol, finishes in mito
8 intermediates in pathway, 7 enzymatic steps (1 inside mito, 3 outside, then 3 inside) |
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What are to 2 rate limiting steps of heme synthesis
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first and last
Succinyl-CoA + Glycine ---> delta-ALA Protoporphyrin IX ---> Heme |
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Describe ALA-synthase
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-key enzyme in first step of heme synthesis
-ALA synathesis needs to bind to pyridoxyl phosphate (aka Vit B6) for full catalytic activity -enzyme is encoded by gene on the X-chromosome, thus follows sex-linked inheritance No Vit B6 = decrease heme syntehsis |
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Describe ferrochelatase
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-key enzyme in the last step of heme synthesis
-incorporates ferrous iron (not ferric) into protoporphyrin IX, displacing the H+ (2 of them) -contains two sulfhydryl groups (-SH) to hole Fe2+ If there's excess protoporphyrin IX = something wrong with ferrochelastase |
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How is heme synthesis upregulated?
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Increase Fe = increase ALAS mRNA translation = increase heme
mRNA + iron response element (IRE) = protein IRE modulates the rate of translation |
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How is heme synthesis downregulated?
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Heme feedback inhibition at two levels
With elevated heme level: 1.) transport of ALA-synthase from cytosol to mitochondria is inhibitied 2.) reduces iron uptake = limiting substrate for ferrochelatase decrease iron also slows ALA-synthase translation |
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What is plumbism?
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Anemia of Pb poisoning
It is a sub-class of sideroblastic anemia (iron available, but can't be incorporated into hemeglobin) caused by lead exposure targets ALA-dehydratase (2nd step) and ferrochelastase by inhibiting the enzymes, altering iron uptake Thus, if d-ALA is seen elevated clinically = Pb inhibiting ALA-deyhydratase |
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What are the presenting symptoms, clinical assays, hematology, and treatment of plumbism?
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Symptoms
-abdominal pain and motor neuropathy (palsy) Clinical assays -blood Pb levels -urinary ALA levels -measurements of Fe and protoporphyrin IX accumulation in RBCs Hematology -normocytic and normochromic -microcytic and hypochromic with chronic exposure -basopilic stippling due to iron induced aggregates of ribosomes Treatments -removal of Pb source -chelation therapy (to remove heavy metals) with EDTA or dimercapto-succinate (DMSA) |
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Describe ALA-synthase deficieny
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Sideroblastic anemia
-erthrocytes hypochromic and microcytic x-linked inheriance mutations causing bad enzyme active site as well as Vit B6 binding site |
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Describe Porphyrias
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Rare
Cause by defects in enzymes of heme biosynthetic pathway 2 types: acute intermittent (AIP) or congenital erythropoietic (CEP result from toxicity of accumulated porphyrin intermediates (3rd step) |
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Describe Acute Intermittent Porphyria (AIP)
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-neurological and psychiatric illness, visceral pain
-accumulation of ALA and PBG (2nd and 3rd) due to PBG deamination and up ALA-synthase level (caused by down heme production) -analgesics, infusion of hematin (Fe3+ heme) to inhibit ALA synthase, thus decreasing toxic precursors acculumation |
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Describe Congenital Erythropoietic Porphyria
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-manifests by cutaneous scarring due to photosensitivity
-accumulation of uro'gen (4th) and copro'gen (5th), causes damage when exposed to light -treatment includes spleenectomy or transfusion |
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Fun facts about globin chains
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2 alpha + 2 beta chains
alphas are unstable and form precipitates alpha/gamma dominate at birth, alpha/beta dominate throughout adulthood fetal Hb (HbF) has highest affinity for O2 |
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Where are alpha-like and beta-like genes located?
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Chromosome 16 and 11 respectively
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What are the promoters of the a-like and b-like genes?
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a-like
-hypersensitivity domain (HS) b-like -locus control region (LCR) They're both essential for transcription |
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How does heme regulate globin synthesis?
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Through heme-controlled inhibitor (HCl)
increase heme = inactivation of HCl HCl inhibits protein translation (globin polypeptide), not at the transcriptional level |
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Describe Thalassemia
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imbalance production of a and b chains
Presents by -hypochromic and microcytic RBCs -premature hemolysis of peripheral RBCs with destruction of erythroid cells in the marrow 2 types: alpha and beta thalassemia |
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Describe a-thalassemia vs. b-thalassemia
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Alpha
-large deletions in genes -HbH and Hb Barts -higher affinity for O2 but not effective in transporting Beta -no beta-chain produced -point mutations, deletions rare -heterozygotes mildly affected -homozygosity life-threatening -no beta = alpha chain precipitate, forming Heinz bodies -causes RBC deformity, membrane instability, hemolysis -HbF production can persist to partially compensate |
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Describe Sickle cell disease
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aka HbS
result from mutation in b-chain, Glu to Val AA change in position 6 in b-chain fibril formation preceipitates from deoxy form of HbS |
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Describe the shape of oxygen dissociation curve for:
-myoglobin -hemoglobin |
Myoglobin
-hyperbolic -incapable of releasing sufficient O2 in working muscle Hemoglobin -sigmoidal (sign of cooperativity) |
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Describe Hb conformational states
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Tight (T) and Relaxed (R)
OxyHb = R DeoxyHb = T Binding will change the heme structurally O2 binds preferentially to the R state due to less steric hinderance in the opening of the heme pocket |
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What is the time for O2 release from hemoglobin
and describe k_on, k_off |
50ms
k_on = kinetic parameters of "grabbing on" of O2 k_off = kinetic parameters of "letting go" of O2 The important physiological aspect is how fast does Hb/HbO2 reach equilibrium it takes about 1-2 secs for RBC to travel through a capillary |
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Describe the allosteric effectors of hemoglobin binding
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allosteric activators
-stabilizes the R state and promote O2 binding allosteric inhibitors -stabilizes T state making O2 binding less favorable, also promote O2 release |
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Describe the role of allosteric effectors: BPG
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2,3-bisphosphoglycerate
high concentrations in RBCs an allosteric inhibitor of Hb-O2 binding, promoting the release of O2 from Hb Fetal Hb will not react with BPG = tighter binding to O2 as a result |
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Describe the role of H+ in O2 binding
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HbH+ + O2 <----> HbO2 + H+
H+ is displaced upon O2 binding to Hb, increase in H+ will drive rxn backwards |
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Describe the Bohr effect
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Lower pH (High H+ concentration) will causes release of O2
good for working muscles since increase of lactic acid of muscle will allow an increase of O2 supply to muscle |
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Describe the role of temperature in O2 binding
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heme-O2 binding is exothermic
O2 affinity of Hb drops with elevated temperature same idea as the Bohr effect |
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Describe the role of CO2 in O2 binding
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CO2 - product of glycolysis
reacts with H2O to form carbonic acid dissociated carbonic acid lowers pH and promotes dissociation from Hb |
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How is CO2 transported by Hb?
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85%
-diffuses down gradient into RBC in capillaries 15% -CO2 forms a bond with the globin chains to form carbaminohemoglobin -occurs preferntially with deoxyHb |
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What is carboxyhemoglobinemia?
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CO binding to the heme pocket in place of O2
CO is 250x greater affinity can't transport oxygen, slowly reversible, severe effects on HbF |
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What is methemoglobinemia?
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auto-oxidized Hb (Fe2+ to Fe3+) is known as MetHb
Normal:1% Methemoglobinemia: >20% Fatal: 70% Presence of metHb shifts dissociation curve to left can be repaired by reduction to oxyHb or deoxyHb, by using MetHb-reductase and NADH as repair mechanism |
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What are the symptoms of methemoglobinemia?
Treatments? |
cyanosis, chocolate colored blood, black tongue, hemolytic anemia
heinz bodies can also be seen in RBCs Treatments -removal of offending agents -infusion of reducing agents such as ascorbic acid or methylene blue |
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Types of methemoglobinemia
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Acquired:
-exposure to drugs: nitrites, NO, nitroglycerins, acetominophen, primaquine -exposure to chemicals: copper, nitrate, nitroglycerin, naphthalene Inherited -HbM: more susceptible to oxidation, His to Tyr mutation in heme pocket -Deficiencies in metHb-reductase, affect the RBCs ability to reduce metHB |
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Brushing up on the basis of the Ebden-Myerhof pathway (glycolysis) in the aspect of RBC maintenence
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net gain = 2 ATP
2,3-BPG (Rapaport-Luebering pathway) production of NADH feeds the Methemoglobin reductase pathway (important in using it to restore Hb in oxidative state) G6P can generates NADPH for glutathion synthesis |
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What are the 3 rate limiting enzymes in glycolysis?
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hexokinase (HK)
phosphofructokinase (PFK) pyruvate kinase (PK) |
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Describe the Methemoglobin reductase pathway
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NADH from
G3P --- G3PDH ---> 1,3 BPG acts as a reducting cofactor for the metHb-reductase enzyme MetHb-reductase is needed for reducing metHb to functional Hb |
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What is the Rapoport-Luebering shunt?
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a shunt for:
1,3 BPG ---BGPmutase--> 2,3 BPG 2,3 BPG binds to deoxyHb and stabilizes the T-state, making oxygen harding to bind and easier for O2 to release to tissue read: high 2,3 BPG during high energy demand |
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What are reactive oxygen species (ROS)?
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O2 undergone reductions = ROS intermediates
can cause oxidation and denaturation of proteins and lipids, causing them to become dysfunctional O2- (superoxide ion) most common in metHb formation from Hb, also promotes cell lysis via membrane lipid oxidation H2O2 (peroxide) and OH (hydroxyl radical) both oxidize and denature Hb as well |
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What is the purpose of Glutathione (GSH)? and how is it an antioxidant
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it's a reducing agent in RBC, primary antioxidant defense mechanism
GSH is synthesized from 3 AA's: Glu, Cys, Gly GSH synthesis requires ATP The SH group of cysteine provides the powerful antioxidant reducing potential GSSG is formed from GSH when reduction rxn is couple to the oxidation rxn |
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Describe the hexose monophosphate (HMP) pathway?
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GSSG ---glutathione reductase--> 2 GSH
G6P dehydrogenase produces NADPH's NADPH is an essential cofactor to convert GSSG back to GSH |
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Describe the following antioxidant mechanisms:
-superoxide dismutase (SOD) -catalase -glutathione peroxidase (a reductase) |
Superoxide dimutase
-O2- back to either O2 or H2O2 Catalase -H2O2 to O2 or H2O2 to H2O Glutathione peroxidase -H2O2 to H2O (requires GSH as a cofactor) |
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Describe G6PD deficiency
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recessive x-linked inheritance
inability to maintain reduced form of GSH = compromise the RBC defense of oxidation Patients experience hemolytic anemia Treatment: avoidance of oxidant promoting compounds, transfusion, spleenectomy |
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Describe PK deficiency
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Heterozygous, autosomal recessive
Reduced APT production Accumulation of glycolytic intermediates Decrease in ATP will compromises repair = hemolytic anemia |
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Fun fact about iron demand
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Fe demand correspond primarily with the need for erythropoiesis
Fe2+ more soluble and easier to absorbed than Fe3+ |
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What is the adsorption mechanism of iron?
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Absorbed by microvilli of the mucosal lining of the duodenum
Ferroreductase (apical) converts Fe3+ to Fe2+ Fe2+ is then updaked by divalent metal ion transport (DMT-1) Most iron is stored in ferritin in the enterocyte Remainder is transported to plasma via Ferroportin (basal) |
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What is ferritin?
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24 subunits molecule that can store iron inside enterocyte
Iron can pass in and out of the shell of ferritin |
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What is hemosiderin?
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storage compartment for iron when ferritin capacity is maxed out
hemosiderin deposits in tissues result from iron overload and contribute to organ failure |
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What is transferrin?
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a protein that transport iron between tissues in plasma and EC fluids
transferrin w/o iron = apotransferrin only binds to Fe3+ |
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What is the predominant role of transferrin?
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to deliver iron to erythroid cells for heme synthesis
needs transferrin receptor in order to be uptake by cells apotransferrin = low affinity for receptor while iron-bound transferrin bind to receptor iron releases from transferrin via acidification of endomsome |
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How can iron be measured?
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Total iron binding capacity (TIBC)
-how much iron blood will take up with unlimited amount of Fe Unsaturated iron binding capacity (UIBC) -how much iron there is given an amount of blood Both will indicate the amount of transferrin in blood and its ability to bind and release iron |
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What is acute iron toxicity?
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-ingestion of iron pills
-free iron causes oxidative damage -vomiting, diarrhea, bleeding Causes by: accumulation of Fe from transfusion, defective erythropoiesis, hereditary hemachromatosis |
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What is hereditary hemochromatosis?
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-auto recessive
-affects transferrin and ferrportin -targets: liver, heart, pancreas, skin -treatments: phlebotomy to remove iron |
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What is the source of CO?
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Incomplete combustion of carbon based fuels
improperly ventilated heating systems |
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What is the mechanism of toxicity of CO?
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CO combines with Hb at an affinity of 250x of O2, shifts O2 dissociation curve to the left (O2 not letting go)
shape also changes from sigmoid to more like myoglobin |
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What is the treatment for acute CO poisoning?
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remove from exposure
100% O2 |
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Why is CO produced in the body?
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a byproduct of heme breakdown
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What is cyanide?
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colorless gas, with a faint bitter almond-like odor
widely used chemical and a lethal poison |
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How can one be exposed to cyanide?
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Inhalation of the burning of synthetic material
Ingestion of organic nitriles converted to cyanide in the body |
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What is the mechanism of toxicity of CN?
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Inhibition of cytochrome oxidase, thus paralyzing electron transport chain (no aerobic metabolism)
Anaerobic respiration: pyruvate is converted to lactate causing metabolic acidosis |
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What is the treatment for CN poisoning?
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Removal from source
100% O2 even though it doesn't do much for CN poisoning Generating methemoglobinemia? |
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Why does generating methemoglobinemia alleviate CN poisoning?
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CN- binds to MetHb (containing Fe3+)
Thus it will bind to that Fe3+ rather than the Fe3+ in the OTC Binding to MetHb will create cyanMetHb |
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What is needed to get rid of cyanMetHb?
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Sodium thiosulfate
coverts cyanMetHb to thiocyanate, sulfite, and Hb Thiocyanate is then excreted in urine |
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What is another treatment for CN poisoning?
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Vitamin B12
Binds cyanide to form cyanocobalamin (eliminated in urine) |
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How can Lead poisoning be diagnosed? and what is treatment?
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Serum lead levels?
Treat with chelation (formation of a metal ion complex) Chelating agent binds to heavy metal with very high affinity (low affinity for essential metals) The complex becomes stable, toxic, and water soluble (read: can be excreted) |
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What are some potent chelator?
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-Ca Na2 EDTA (IV)
-DMSA (oral) |
