Hematology Exam 6 (All about hemoglobin) Flashcards
What is the basic structure of hemoglobin?
Tetramer composed of 4 polypeptide (Globin) chains and 4 heme groups
What is the basic structure of heme?
Protoporphyrin ring bound to ferrous (Fe2+) iron
How many oxygen molecules can each iron atom on heme bind?
1
List the heme precursors in order from succinyl-CoA and glycine to heme (ferroprotoporphyrin IX) AND where they are formed (mitochondria or cytosol?)
- Succinyl CoA + Glycine (mitochondria)
- Aminolevulinic acid (mitochondria)
- Porphobilinogen (cytosol)
- Hydroxymethylbilane (cytosol)
- Uroporphyrinogen III (cytosol)
- Coproporphyrinogen (cytosol)
- Protoporphyrinogen IX (mitochondria)
- Protoporphyrin IX (mitochondria)
- Heme (mitochondria)
What globin genes are present on chromosome 16? 11? How many of each?
Alpha chain –> 4 genes total, 2 on each chromosome 16 (genotype is aa/aa)
Beta chain –> 2 genes total, 1 on each chromosome 11 (genotype is B/B)
What type of iron does transferrin carry? what type of iron is it reduced to?
Transferrin carries FERRIC (Fe3+) iron
Reduced to FERROUS (Fe2+) iron to form heme
How many molecules of oxygen can hemoglobin carry?
4 molecules of oxygen – 1 per globin chain
Where does heme synthesis take place?
Mitochondria and cytoplasm of RBC precursors (Does not occur in adult RBC)
What is the globin chain composition of HGB A? What is the percentage found in adults?
2 alpha, 2 beta (95% in normal adults)
What is the globin chain composition of HGB F? What is the percentage found in adults?
2 alpha, 2 gamma (<3.5% in adults)
What is the globin chain composition of HGB A2? What is the percentage found in adults?
2 alpha, 2 delta (1-2% in adults)
What is the major hemoglobin at birth? What is the major hemoglobin after 6 months?
HGB F at birth; HGB A after 6 months
List the names of the 3 embryonic hemoglobins
Gower 1, Gower 2, Portland
What is the regulation of production of heme?
Negative feedback, so more heme = less ALA synthase produced and hypoxia = more EPO = increased RBC production
What is the shape of the hemoglobin oxygen dissociation curve?
Sigmoidal curve (S-shape)
What is a shift to the left on the hemoglobin oxygen dissociation curve?
Increased affinity for O2 because O2 levels are low in the body.
What is a shift to the right on the hemoglobin oxygen dissociation curve?
Decreased affinity for O2 because O2 levels are high/sufficient.
Compare the pO2 in lungs vs tissues
Lungs: high pO2, high O2 saturation
Tissues: low pO2, low O2 saturation
What is 2,3-BPG and what is its affect on hemoglobin/oxygen?
2,3-BPG controls hemoglobin affinity for oxygen.
Deoxyhemoglobin (tense form) = stabilized by 2,3-BPG when oxygen levels are low (INC BPG, LOW O2)
Oxyhemoglobin (relaxed form) = no 2,3-BPG bound because oxygen affinity is high and favors binding of oxygen (DECR BPG, HIGH O2)
When is 2,3 BPG high?
When oxygen levels are low (low oxygen affinity) - tensed state
When is 2,3 BPG low?
When oxygen levels are high (high oxygen affinity) - relaxed state
Oxygen affinity vs oxygen delivery
Oxygen affinity = favors binding of oxygen
Oxygen delivery = does not favor binding of oxygen, wants to deliver it to tissues
What are some causes of shifts to the left (HIGH OXYGEN AFFINITY)
DECREASED 2,3 BPG
DECREASED body temp
INCREASED pH (alkalosis)
Presence of HGB variants with high affinity for O2
What are some causes of shifts to the right (LOW OXYGEN AFFINITY) – Shift to the right, wont hold tight
INCREASED 2,3 BPG
INCREASED Body temp
DECREASED pH (acidosis)
Presence of HGB variants with low affinity for O2
Is oxygen affinity/pO2 higher in the lungs or the tissues?
LUNGS, tissues have low pO2 with low affinity
Shift to the left = _________ affinity and _______ delivery
Increased affinity, decreased delivery
Shift to the right = _______ affinity and ______ delivery
Decreased affinity, increased delivery
BRIEFLY list the order in which CO2 travels in tissues
CO2 enters RBC –> becomes H2CO3 (carbonic acid) –> becomes HCO3- (bicarbonate) after releasing H+ –> that H+ binds oxyHGB –> oxygen released into tissues
BRIEFLY list the order in which CO2 travels in lungs
O2 diffuses in cells –> binds deoxyHGB –> H+ released and binds HCO3- (bicarbonate) –> becomes H2CO3 (carbonic acid) –> becomes H2O and CO2 –> CO2 diffuses out of cell and exhaled by lungs
Define dyshemoglobins
Hemoglobins that are unable to properly transport oxygen
What are the 3 dyshemoglobins?
Methemoglobin, sulfhemoglobin, and carboxyhemoglobin
Describe methemoglobin
Heme bound to FERRIC iron so it cannot bind oxygen. High levels turn blood a BROWN color and can turn skin blue –> treat with IV methylene blue to reduce ferric iron to ferrous iron
Describe sulfhemoglobin
Hemoglobin bound to sulfur instead of iron –> turns blood a GREEN color and can form after use of certain drugs or sulfur chemicals
Describe carboxyhemoglobin
Heme bound to carbon monoxide –> binds 240X tighter than oxygen –> huge shift to the left turns blood CHERRY RED color. Treat with oxygen (seen with people in house fires)
Define hemoglobinopathy and thalassemia. How are they different?
Hemoglobinopathy: qualitative hemoglobin defect –> making abnormal globin chains
Thalassemia: quantitative hemoglobin defect –> not making enough globin chains
Differentiate heterozygous and homozygous hemoglobinopathies
Het = one affected gene (trait)
Homo = two affected genes (disease) more severe
What is the structural formula of the abnormal HGB in sickle cell anemia vs sickle cell trait?
They are both alpha2beta2 ^ 6Glu-Val
SCD = HGB SS
SCT = HGB SA
What is the zygosity of HGB SS vs HGB SA?
HGB SS = homozygous = more severe
HGB SA = heterozygous
What is the sickle solubility test results for HGB SS vs HGB SA?
They would both be positive since HGB S is present.
What does SCD refer to?
sickle cell disease - diseases that involve the production of HGB S
What information does the sickle solubility/dithionite solubility/sickle sol test provide?
Screening test to see if HGB S is present (if turbidity is present, then positive)
Clinical manifestations of SCD
vaso-occlusive crisis, acute chest syndrome, splenic sequestration, causing episodes of recurring pain
Sickle cell trait will only show symptoms in extremely hypoxic conditions
Peripheral smear findings of HGB SS vs HGB SA
HGB SS: sickle cells (drepanocytes), target cells, nRBCS, spherocytes, basophillic stippling, HJ bodies, Pappenheimer bodies, leukocytosis, polychromasia
HGB SA: target cells
Why is Sickle sol not performed on infants less than 6 months old?
Because there is high HGB F levels which can lead to false negatives/HGB S not developed yet
What information does the HGB electrophoresis provide?
Tells us how much HGB S is present
HGB electrophoresis results for HGB SS vs HGB SA
HGB SS = >80% HGB S, no HGB A, higher HGB F
HGB SA = >60% HGB A, <40% HGB S, normal other HGBs
Treatment for HGB SS?
Supportive care, bone marrow/stem cell transplants
What is the structural formula of HGB C?
alpha2beta2 ^ 6 Glu-Lys
HGB C disease vs trait
HGB CC = disease
HGB AC = trait, asymptomatic
What is the most common non-sickling HGB variant in the US?
HGB C
HGB C peripheral smear
Washington monument crystals, target cells, reticulocytes, nRBCs
HGB C sickle sol results
negative
HGB C disease vs HGB C trait Electrophoresis results
HGB C disease: no HGB A, >90% HGB C
HGB C trait: 70% HGB A, 30% HGB C
Why is there no HGB A present in a patient with HGB C disease?
There are no normal beta chains to make HGBA
Structural formula of HGB E
a2b2 ^ 26Glu-Lys
Population most commonly affected by HGB E
SE Asia, most common in Cambodia/Laos/Thailand
Sickle sol results with HGB E
Negative
HGB E disease vs HGB E results
HGB EE = >90% HGB E very low MCV
HGB AE = asymptomatic, 25-30% HGB E
What are the genetics behind HGB SC?
One HGB S gene and one HGB C gene = NO normal beta chains made
Clinical findings of HGB SC?
No significant symptoms until teenage years, can have vaso-occlusive complications but not as common as sickle cell anemia
Peripheral smear findings of HGB SC?
Few sickle cells, target cells, HGB SC crytals that look like “hands in gloves”
Sickle sol results for HGB SC?
Positive
Electrophoresis results for HGB SC?
45% HGB S, 45% HGB C, normal HGBF, no HGB A
What is alpha+
deletetion of one a-globin gene leading to decreased production of a-chains
What is alpha0
deletion of both a-globin genes, leading to absent production of a-chains
What is beta+
mutations of B-globin gene leading to partial deficiency of b-chains
What is beta0
mutations of b-globin gene in which no b-chains are produced
How does an imbalanced globin chain ratio and reduced/absent production of a globin chain lead to clinical manifestations in thalassemias?
It leads to decreased HGB synthesis, decreased survival of RBCs, leading to microcytic/hypochromic RBCs and ineffective erythropoiesis
Which globin chains increase to compensate for a decrease in b-chains in b-thalassemia?
delta chains and gamma chains leading to excess HGBA2 and HGBF
Why are patients with b-thalassemias often asymptomatic until ~6 months?
You only make HGBF until ~6 months and there are no beta chains on HGB F, only alpha and gamma.
What causes bone deformities in patients with untreated, severe forms of b-thalassemia?
The anemia stimulations EPO production leading to erythroid hyperplasia in BM
What are two abnormal HGBs that develop in patients with A-thalassemia? Why do they develop in these patients and not in patients with B-thalassemia? What is the globin chain composition of each?
HGB H (4 beta chains) and HGB Bart (4 gamma chains). These do not develop in patients with B-thalassemia because beta chains are not present at birth (not in HGB F).
What is the mechanism/why is anemia caused by a B-thalassemia?
Excess alpha chains precipitate leading to damage to RBC membrane causing premature death of RBC precursors in BM –> ineffective erythropoiesis
Describe HGB Lepore thalassemia
Fusion of delta-beta globin genes
homozygotes: no normal delta or beta chains made so no HGB A, mostly HGB F
heterozygotes: decreased HGB A with increased HGB F
What is silent carrier b-thalassemia? (including genetics, clinical presentations, and lab results)
Normal a/b chain ratios
No clinical presentations
Small decrease in beta chain production
What is b-thalassemia minor? (including genetics, clinical presentations, and lab results)
B-thalassemia trait
One affected globin gene, one normal gene
Mild, asymptomatic anemia
Microcytic/hypochromic with target cells, elliptocytes, basophilic stipping
What is b-thalassemia major? (including genetics, clinical presentations, and lab results)
AKA Cooley’s Anemia
HGB A absent or severely decreased depending on B+ or B0
Severe anemia
Microcytic/hypochromic with target cells, dacrocytes, elliptocytes, HJ bodies, pappenheimer bodies, low retic count, erythroid hyperplasia in the bone marrow
What is HPFH?
Hereditary persistence of fetal hemoglobin
Increased HGB F production as an adult; assessed using Kleihauer Betke
What is HGB Lepore?
Fusion of delta-beta globin genes
homozygote: no HGB A
heterozygote: decreased HGB A
What Is silent carrier a-thalassemia? (including genetics, clinical presentations, and lab results)
1 a gene deleted, 3 functional a genes (-a/aa)
No abnormalities
SLIGHT decrease in alpha chains
What is a-thalassemia minor? (including genetics, clinical presentations, and lab results)
2 deleted genes, 2 functional genes
Homo form = (-a/-a)
Het form = (–/aa)
Asymptomatic
What is HGB H disease? (including genetics, clinical presentations, and lab results)
3 genes deleted, 1 functional (–/-a)
Characterized by tetramer of B chains (B4)
10-40% HGB Bart at birth, then switch to HGB H
Causes denaturation of hemoglobin and decreased RBC survival
What is HGB Bart Hydrops Fetalis Syndrome?(including genetics, clinical presentations, and lab results)
All 4 a genes deleted, NO functioning genes
(–/–)
Tetramer of gamma chains
Incompatible with life, baby will die due to cardiac failure/no oxygen delivery to tissues
*Which poikilocyte can be seen in large amounts in patients with thalassemias
Target cells (Codocytes)
What thalassemia is associated with ineffective erythropoiesis?
B-thalassemia
Supravital staining may allow for visualization of inclusion bodies in which type of thalassemia? What are the inclusions made of? What is the terminology used to describe these cells?
Can detect HGB H alpha thalassemia with the use of Brilliant cresyl blue or new methylene blue. They look like greenish-blue bodies with a “golf ball” appearance.
How can a patient have a hemoglobinopathy AND thalassemia?
If they inherited thalassemia gene from one parent, HGB S gene from the other, for example.
