Lectures 5 and 6 Flashcards
What does elevated CR indicate?
Elevated CR = premature RBC loss (hemolytic anemia)
Normocytic and normochromic
What does a below average CR indicate?
Low CR = Not enough RBC’s being made
What does it mean if MCV is above normal?
Elevated MCV = Impaired DNA synthesis (Vit B12/Folate deficiency)
Macrocytic
What does it mean if MCV is below normal?
Low MCV = Impaired HGB synthesis (iron deficiency)
Microcytic and Hypochromic
What does it mean if MCV is normal?
Anemia is due to LOSS of HSC’s in bone marrow or loss of bone marrow stimulation (insufficient EPO made due to kidney dysfunction)
What is the cause of pernicious anemia?
Lack of intrinsic factor
Under what conditions is there decreased RBC Division?
Vit B12/folic acid deficiency
If one has Vit B12/Folic Acid deficiency, do the erythropoietic progenitors in the bone marrow have smaller or larger nuclei? Does HGB continue to be made?
larger; HGB continues to be made
In macrocytic anemia due to decreased RBC division, why are mature RBCs in blood larger (megaloblastic)?
Higher protein (HGB) content
How is MCV, HGB, and MCH affected in macrocytic anemia (vit deficiency?)
MCV = elevated
MCH (mean corpuscular hb) = elevated
total HGB = elevated
HGB = normal
How is MCHC affected in macrocytic anemia?
MCHC is normal
Adequate Iron is required in _____AND for ____synthesis and ___ production.
proerythroblasts ; ribosome ; HGB
Iron deficiency leads to production of ____ RBCs (low MCV) that contain less __
microcytic; HGB
True or False: Iron is required for the synthesis of hemoglobin and subsequent cell
division or erythroid precursors
True
Sources of iron?
1) Recycled from HGB from old or damaged RBCs
2) Diet
What type of anemia is associated with low MCV levels, iron deficiency, and impaired HGB synthesis?
Microcytic, hypochromic
What type of anemia is associated with elevated MCV and Vit B12/folate deficiency?
Macrocytic anemia
If MCV is within reference range, what type of anemia is the cause?
Loss of HSC’s in bone marrow or kidney disease
(normochromic and normocytic)
What can be determined by considering whether CR (correct reticulocyte count) is low or high?
Whether anemia is due to premature blood loss (eleavted) or impaired RBC production (low CR)
What can considering MCV help you to determine about one’s anemia?
Whether anemia is due to
1) nutritional deficiency/impaired DNA synthesis or
2) impaired HGB synthesis (iron deficiency)
____ is a genetic disorder affecting HGB production
Thalassemia
Chronic iron deficiency can lead to decreased production of ____ and ___ , less RBCs, and RBC’s that are microcytic and hypochromic
RBC and HGB
Three possible causes of Normocytic, normochromic anemia?
1) Acute blood loss
2) Pre-mature destruction of RBC
3) kidney or bone marrow damage
Microcytic, hypochromia is associated with what type of anemia?
Iron deficiency anemia
What type of anemia are Vit B12 and folate deficiencies are associated with?
Macrocytic, normochromic anemia
A normal response to RBC loss is release of ____ from the bone marrow stimulated by EPO (elevated CR)
reticulocytes
Premature RBC destruction/loss due to hemolysis or blood loss
results in _____ CR.
elevated
Deficient production of RBCs (i.e., insufficient bone marrow response to anemia) results in CR that is ______
within or below ref. range
Why might CR be within or below RR?
- Decreased EPO production (kidney damage)
- Decreased bone marrow mass
- Decreased HGB synthesis
- Decreased RBC precursor cell division
True or False: the reticulocytes:RBC ratio may be artificially low in
patients with anemia, CR considers the patient’s HCT compared
to normal HCT (~45%)
False - True or False: the reticulocytes:RBC ratio may be artificially high in
patients with anemia
True or False: Elevated CR > 0.5% - 2% represents increased reticulocyte production
True
Why are reticulocytes are larger than mature RBCs?
They contain ribosomes, mitochondria and RNA
In Vit B12/folate deficiency anemia, ___ is normal but ___ is elevated
MCHC (normochromic)
-because cell volume increases proportionately
MCH (increased Hb per cell)
Impaired DNA synthesis decreases ______
cell division
Routinely LOW MCHC is diagnostic for what type of anemia?
Iron deficiency anemia
MCH and MCHC generally parallel ____ values, because protein
content can impact cell size.
MCV
What value can help you determine is anemia is normochromatic or hypochromatic?
Mean Corpuscular Hb Concentration (MCHC)
What value can help you determine whether the anemia is micro or macrocytic?
Mean Corpuscular Volume (MCV)
True or False: The three types of anemia are:
-Fewer RBCs, normal size and HGB content
-Fewer RBCs, smaller with less HGB
-Fewer RBCs, larger with more HGB
True
What are the three measured CBC Indices?
1) [RBC] Red Blood Cell Concentration (Count)
2) [HGB] Hemoglobin Concentration
3) [HCT] Hematocrit
Three causes of anemia?
1) Premature RBC destruction (or blood loss)
2) Insufficient stimulation of erythropoiesis (kidney dysfunction)
3) Insufficient RBC production (Iron, folate and vitamin B12deficiencies)
Two substances that support adequate hemoglobin synthesis?
Substances that support adequate DNA synthesis and cell division of RBC precursors?
Iron and protein
Vit B12, folate, protein
What are the Corpuscular Indices?
-MCV
-MCH
-MCHC
True or False: Both hemoglobin and myoglobin are hemeproteins that contain heme as a prosthetic group
True
___: cofactor comprised of
iron (Fe2+) permanently associated with a
heterocyclic porphyrin ring
Heme
True or False: Heme is required for
the reversible binding of O2 by Hb and Mb
True
True or False: Hemoglobin undergoes irreversible cooperative binding of O2 via heme
False - hemoglobin undergoes reversible cooperative binding of O2 via heme
Hemoglobin carries O2 from the ___ to oxidatively active tissues to be released to fuel ___ of nutrients
lung; metabolism
True or False: Hemoglobin collects CO2 to be returned to the lungs, to be expelled
True
True or False: Myoglobin increases O2 availability to tissues by about 100-fold
False - Hemoglobin increases O2 availability to tissues by about 100-fold
Under what conditions does myoglobin store O2? release O2?
Stores O2: in resting muscle (due to high O2 binding affinity)
Releases O2: After muscle contraction (to replenish O2 supply)
Myoglobin has a ___ structure while hemoglobin has a ___ structure
tertiary; quaternary
Myoglobin contains a globin fold, which is comprised of 8 α-helical regions (80%) disrupted by a ___residue or by β-
____ and ___
proline; beta bends and loops
True or False: Myoglobin is a monomer bound to Heme
True
Myoglobin is stabilized by hydrophobic interactions between non-polar AA
in interior. Among these, are two basic ___ involved in binding heme
histidine
In myoglobin, F8 binds ____ while E7 stabilizes ___ binding
heme Fe2+; O2
Why is myoglobin water soluble?
Charged amino acids on surface form H2 bonds with each other and H2O
Hemoglobin is a ___ comprised of 2 α-chains and 2 β-chains
tetramer
Which has two identical α,β-dimers: Hemoglobin or Myoglobin?
Hemoglobin
What is responsible for forming α,β-dimers in Hemoglobin?
Hydrophobic interactions in interior and exterior
Which interactions maintain tetramer of Hb?
Weak ionic and hydrogen bonds
Each globin subunit in Hb covalently binds ____ in heme, and each heme binds ___
Fe2+ iron; O2
True or False: In Hb, no ionic and hydrogen bonds b/w alpha-beta dimers are broken in the oxygenated state
False
Since there are low O2 levels in tissues, what state is Hb in while in tissues?
T state (deoxyhemoglobin)
- low O2 binding affinity
There are __ O2 levels in tissues and __ O2 levels in the lungs
low; high
What type of state is hemoglobin in while in the lungs?
R state (oxyhemoglobin)
- high O2 binding affinity
True or False: In the lungs, globin subunits in tight conformation around heme iron does not allow O2-binding with high affinity
False - in low O2 levels in tissues, globin subunits in tight conformation around heme iron does not allow O2-binding with high affinity
Where does O2 binding induces conformational change that relaxes globin binding to heme?
The lungs
O2 binding to one Hb subunit alters its tertiary structure and increases the O2 binding affinity of other Hb subunits which alters the quaternary
structure of Hb – this “all or none” is also known as ____
cooperativity
Balance shifts toward __ state in low O2
Balance shifts toward _ state in high O2.
T; R
____: change in shape and/or activity of a protein induced by the binding of a
regulatory substance
Allosteric effects
True or False: Hb is an allosteric protein
True
____ is a positive homotropic effector
O2
How many O2 molecules does hemoglobin bind? myoglobin?
Hemoglobin binds 4 O2 while myoglobin binds 1 O2
Which has stronger O2 affinity — hemoglobin or myoglobin?
Myoglobin
In the lungs….
___ is released from Hb
___ binds to Hb
CO2; O2
In the tissues
____ binds to Hb
____ is released from Hb
CO2
O2
T to R state transition occurs in the lungs or tissues?
Lungs
Where is the high pO2? low pO2?
High pO2: lung alveoli
Low pO2: tissues
Where is the O2 dissociation curve the steepest? How is this beneficial?
At the O2 concentration that occur in tissues
- Permits O2 delivery to respond to small changes in pO2
When is Hb saturated with O2? When does OxyHb unloads O2 for oxidative metabolism?
lungs; in tissues
Hemoglobin displays a ___ curve while myoglobin displays a ____curve
sigmoidal; hyperbolic (monomer)
The higher the O2–binding affinity, the ___the P50
lower
Where does Hb unloads O2 to Mb in?
In muscle
Are CO2 (TCA cycle) and 2,3-BPG positive or negative allosteric effectors?
Negative allosteric effectors
True or False: Combined effect of positive and negative allosteric effectors allows O2 availability to be fine-tuned in
tissues
True
True or False: the T form of Hb is associated with low pH, high H binding, and high O2 release
True
True or False: the R (oxyhemoglobin) form of Hb is associated with low pH, high H release, and high O2 binding
False - The R form of Hb is associated with HIGH pH, high H release, and high O2 binding
Under what conditions do pCO2 and pH act as negative effectors, which DECREASE Hb affinity for O2?
High pCO2 and low pH
Under what conditions is the T state stabilized and curve shifts to the right?
High pCO2 and low pH
Does a decrease in pH result in a decreased or increased oxygen affinity of hemoglobin?
Decreased in pH causes decrease in O2 affinity of hemoglobin (right shift)
True or False: At a lower pH, a greater pO2 is required to achieve any given O2 saturation
True
____ explains how increased H+s and
pCO2 decrease O2 binding to Hb.
The Bohr effect
Does DeoxyHb have a lower or higher affinity for H+ than oxyHb does?
higher
True or False: There is a pH gradient between the lungs (higher pH) and tissues (lower pH) that permits RAPID loading or
unloading of O2 to tissues as required
True
H+s bind to ionizable_____ side chains of Hb
and stabilize T state, which results in O2 release
histidine
True or False: H+s that lower pH are also released when CO2 binds Hb
True
CO2 is hydrated to ____ which binds to ____ amino groups of Hb subunits
carbamate ; N-terminal
Where is this taking place?
Is 2,3-BPG a positive or negative effector of Hb O2 affinity?
Negative effector
2,3-BPG has a strongly negative charge
and allows strong ionic bonding to positively
charged amino acids located where?
Beta subunits of interior of deoxyHb
True or False: When 2,3 BPG is present,
R state is stabilized and there is decreased O2-binding affinity
False - T state is stabilized and there is decrease O2 binding affinity
2,3-BPG dissociates upon binding of ___ by Hb. The ____ charges in interior repel and the __ state is favored
O2; positive; R
2,3-BPG shifts O2 dissociation curve to the ____
right
What is a potential consequence of
giving a severely ill individual a
transfusion of stored blood having
decreased 2,3-BPG levels?
Inadequate O2 delivery due to favored
Hb R state.
Carbon monoxide (CO) binds tightly (220X
greater than O2), but reversibly, to the Fe2+ ion in Hb to form _____
Carbon monoxyhemoglobin
CO binding to 1 or more heme sites favors the __ form, and the O2 dissociation curve shifts to the ___. Why is this the case?
R; left
remaining globin subunits bind O2 with
increased affinity
Is CO is a positive or negative allosteric effector of Hb?
Positive
Under what conditions is there a transition from sigmoidal to hyperbolic curve?
CO exposure
Hemoglobins are each comprised of two ___ subunits and two ___ or β-globin-like
subunits
α-globin; β-globin
What is the major Hb in adults?
What Hb is found in fetus and newborn?
Hb A
Hb F
Which has a higher affinity for O2: Hb F or Hb A? Why?
Hb F has higher affinity for O2 due to WEAK binding to 2,3 BPG (less positive larged AA in gamma-globin)
____: family of genetic disorders caused by production of structurally abnormal Hb, synthesis of
insufficient quantities.
Hemoglobinopathies
What are three diseases that can arise from
synthesis of abnormal globin subunits?
1) Sickle cell anemia (Hb S)
2) Hb C disease (Hb C)
3) Hb SC disease
____ is characterized by insufficient synthesis of globin subunits
Thalassemias (α and β)
____ is caused by a single base pair point
mutation (T to A) in the β-globin gene
Hb S
In Hb S, a negatively charged ___ is substituted for a nonpolar, hydrophobic ___
glutamate, valine
True or False: In Hb S, there is polymerization in the deoxygenated state
True
_____ Hb S polymers form a network of fibers that stiffen and distort RBCs into the characteristic “sickle” cell shape
Deoxygenated
True or False: The life span of an Hb S RBC is less than 20 days compared to 120 days for a normal RBC (premature destruction)
True
True or False: variables that promote oxyHb can increase sickling!
False - variables that promote oxyHb can increase sickling!
_____:Glutamate substitution with Lysine (Glu6Lys) to cause relatively mild,
chronic hemolytic anemia
Hb C disease (Hb C)
____:Combination of βS and βC mutations in the same individual in the
“double heterozygous” state; less severe than Hb S with wide-ranging clinical variability
Hb SC disease (Hb SC)
___: hereditary hemolytic diseases in which an imbalance occurs in the synthesis of globin
chains
Thalassemias
β- (____) and α- (___) thalassemias
point mutations; deletions
If one has thalassemias and
2 copies of β-globin gene, clinical onset is likely to occur several months after birth – with symptoms being: aggregation and
precipitation of excess α-subunits
True
What happens to 2,3-BPG upon binding of O2 by Hb? positive charges in interior repel and the __state is favored
R state
