Question 1

A 4-year-old patient is presented in the pediatric clinic with microcytic anemia. An analysis of his blood by
Non-denaturing electrophoresis reveals the following composition of hemoglobin isoforms: HbF = 75%, HbA
1 = 23%, HbA2 = 2%, and HbS = 0%. Using these data, it is possible to determine that the infant is most likely homozygous for which of the following?
A) complete deletion of the a-globin locus
B) complete deletion of the b-globin locus
C) mutation in the promoter of the b-globin genes
D) nonsense mutation in the a-globin genes
E) nonsense mutation in the b-globin genes

Accepted Answer

A mutation in the promoter region of theb-globin genes would result in reduced expression. This is evidenced by the lower than normal amount of HbA1 in this child. Under these circumstances the body will tend to compensate by continuing to express the fetal hemoglobin genes at higher than normal levels resulting in potentially dramatic increases in measured HbF. Normal levels of HbF in a 4-year-old child would be around 0% to 2%, whereas, this child shows significant increase in HbF of 75%.

Question 2

When the malarial parasite invades a red blood cell, its metabolic waste products result in the acidification of the cytoplasm. Which of the following best describes the consequences of this acidification on the activity of hemoglobin (Hb)?
A) formation of carbaminohemoglobin is enhanced
B) hemoglobin tetramers become less stable and the complex dissociates
C) there is a shift to a more R state conformation
D) there is a shift to a more T state conformation
E) there is no effect from the acidification

Accepted Answer

Acidification of the cytoplasm leads to a decrease in pH, which stabilizes the T state (tense state) of hemoglobin, reducing its affinity for oxygen. This is known as the Bohr effect.  The principal negative regulator of the affinity of hemoglobin for oxygen is proton, H+. The acidification of the erythrocyte cytoplasm by malarial parasite metabolism would be reflected by a significant increase in [H+] which would, in turn, result in a higher level of T state hemoglobin

Question 3

In one form of b-thalassemia, patients have significantly reduced levels of b-globin transcripts. Notably these b-globin transcripts are less than half the length of the normal b-globin mRNA. These patients exhibit elevated levels of HbF and no detectable HbA₁. Which of the following best explains the molecular reason for these observations? A) addition of 7-methylguanosine to the b-globin mRNA B) covalent modification of the b-globin protein C) improper folding of the b-globin protein D) promoter mutations in the b-globin gene E) splicing alteration of the b-globin mRNA

Accepted Answer

The reduced length of b-globin transcripts suggests a splicing alteration, leading to improperly processed mRNA and reduced functional b-globin protein, explaining the absence of HbA1 and elevated HbF levels.

Question 4

Although HbF represents fetal hemoglobin, some level of this form of hemoglobin persists in the adult. Which of the following represents the value for HbF in adults above which it would likely reflect some underlying pathophysiology?
A) 0.1%
B) 0.5%
C) 2.0%
D) 5.0%
E) 15%

Accepted Answer

Normal levels of HbF in the adult are between 0% and 0.5%. An increase in HbF levels in the adult would result from circumstances where a decrease in the expression of the normal HbA1 was evident. The increase in HbF results from a compensatory mechanism that is attempting to normalize the amount of oxygen carrying hemoglobin in the blood.

Question 5

You are treating a patient who presents with microcytic anemia. Additional microscopic findings demonstrate the presence of inclusion bodies in the red blood cells. Electrophoresis of erythrocyte protein extracts shows a large excess of b-globins and a near complete lack of a-globins. Which of the following disorders most closely correlates to your findings?
A) hemoglobin H disease
B) hereditary persistence of fetal hemoglobin
C) hydrops fetalis
D) sickle cell anemia
E) b-thalassemia major

Accepted Answer

Hemoglobin H disease is characterized by the presence of inclusion bodies in red blood cells, microcytic anemia, and an excess of beta-globins due to a deficiency in alpha-globin production.  The a-thalassemias result when there is reduced expression at one or both of the a-globin genes. In the a-thalassemias, normal amounts of b-globins are made. The b-globin proteins are capable of forming homotetramers (b4) and these tetramers are called hemoglobin H, HbH. An excess of HbH in red blood cells leads to the formation of inclusion bodies commonly seen in patients with a-thalassemia. In addition, the HbH tetramers have a markedly reduced oxygen-carrying capacity. In b-thalassemia, where the b-globins are deficient, the a-globins are in excess and will form a-globin homotetramers. The a-globin homotetramers are extremely insoluble which leads to premature red cell destruction in the bone marrow and spleen. Clinically this is referred to as hemoglobin H disease

Question 6

You are studying the oxygen-binding characteristics of a synthetic oxygen transport compound. You want to design the compound so that it most closely mimics the oxygen affinity of native hemoglobin protein. If you are successful, addition of which of the following to a test solution would have the greatest negative effect on the ability of your compound to bind oxygen?
A) 2,3-BPG
B) bicarbonate ion
C) carbonic acid
D) phosphoric acid
E) water

Accepted Answer

Addition of carbonic acid (H2CO3) to the solution would result in its ionization to bicarbonate (HCO3−) and proton (H+). The increase in H+ would, therefore, be expected to exert a large negative effect on oxygen binding by the synthetic hemoglobin construct just as is the case for the negative effect of increasing H+ on the affinity of hemoglobin for oxygen.

Question 7

Which of the following is referred to as a qualitative hemoglobinopathy?
A) hemoglobin H disease
B) hydrops fetalis
C) sickle cell anemia
D) a-thalassemia
E) b-thalassemia

Accepted Answer

Sickle cell anemia is a qualitative hemoglobinopathy because it involves a structural abnormality in the hemoglobin molecule, specifically a mutation in the beta-globin chain, leading to the production of abnormal hemoglobin S.  Sickle cell anemia results from a single nucleotide mutation in the b-globin gene resulting in a single amino acid change in the protein. There is no effect of this mutation on the amount (quantitative) of the mutant b-globin protein. The defect is manifest in a change in the character (qualitative) of the resultant b-globin protein. When in the deoxy state, this hemoglobin sticks together resulting in long polymers that distort the shape of the erythrocyte.

Question 8

Aside from the obvious presence of HbS hemoglobin in individuals with sickle cell disease, which Of the following hemoglobins is also found at high frequency in these individuals? A) HbA _1c B) HbA ₂ C) HbC D) HbF E) HbH

Accepted Answer

HbF (fetal hemoglobin) is often found at higher levels in individuals with sickle cell disease, as it can help reduce the sickling of red blood cells.

Question 9

Which of the following is the primary source of the H⁺ that leads to displacement of O₂ from hemoglobin in the tissues? A) 2,3-BPG B) bicarbonate ion C) carbonic acid D) phosphoric acid E) water

Accepted Answer

Carbonic acid (H2CO3) is formed in the tissues when carbon dioxide (CO2) reacts with water. It dissociates to release H+ ions, which facilitate the release of oxygen from hemoglobin.

Question 10

The "Bohr effect" is best described by which of the following statements? A) binding of O₂ B) covalent attachment of CO₂ forming hemoglobin carbamate C) release of O₂ from hemoglobin in response to the buffering of Cl− by hemoglobin D) release of CO₂ from erythrocytes when they enter the high O2 concentration of the alveoli E) release of O₂ from hemoglobin in response to the buffering of H+ by hemoglobin

Accepted Answer

The Bohr effect describes how an increase in carbon dioxide and a decrease in pH (increase in H+ concentration) lead to the release of oxygen from hemoglobin.

Question 11

Beta-thalassemias are genetic disorders in the synthesis of the b-globin chains in hemoglobin. Affected individuals usually begin to exhibit some degree of anemia at about 6 months of age. Therapy for severe anemia involves multiple transfusions. What is the most serious complication of transfusion therapy?
A) cardiac arrhythmias
B) copper overload
C) globin overload
D) increased blood viscosity
E) iron overload

Accepted Answer

Iron overload is the most serious complication of transfusion therapy because repeated blood transfusions can lead to excess iron accumulation in the body, which can damage organs such as the heart, liver, and endocrine glands.  Iron is primarily absorbed from the diet, in the duodenum, as either organic or hemebound forms. Inside the enterocyte the iron binds to cytoplasmic proteins, ferritin, and mobilferrin. Depending on total body iron stores, the iron is either transferred to the plasma, where it binds to plasma transferrin, or it remains in the enterocyte until it is lost with cell shedding. Once absorbed, iron is avidly retained by the body. An adult male excretes only about 0.03% of his total body stores per day (about 1 mg), while the loss in premenopausal women is still only about twice that amount. Blood normally contains 15 g of hemoglobin per 100 mL. The concentration of hemoglobin in blood is thus about 2.3 millimolar (mM). Since each molecule of hemoglobin contains 4 molecules of iron, the total blood iron concentration is almost 10 mM. A transfusion of 1 unit of packed red blood cells (about 500 mL) would thus add a total iron burden of about 250 mg. Given the body's limited excretory capacity, multiple transfusions can elevate iron to toxic levels. The liver is particularly susceptible to damage.

Question 12

The thermodynamics of oxygen binding to hemoglobin are highly ordered. Which of the following Reflects the physical characteristics relating the binding of O₂ to hemoglobin? A) causes a large shift of the surrounding secondary structures leading to decreased affinity of the deoxy subunits for CO₂ B) is cooperative, meaning that after the first O2 binds, the other subunits are more readily oxygenated C) occurs with equal affinity at all 4 subunits D) results in a release of the heme from the interior to the exterior of the a-subunits, leading to an increase in O₂ affinity of the b-subunits E) results in a release of the heme from the interior to the exterior of the b-subunits leading to an increase in O₂ affinity of the a-subunits

Accepted Answer

The binding of oxygen to hemoglobin is cooperative, meaning that the binding of one oxygen molecule increases the affinity of the remaining subunits for oxygen, facilitating further oxygen binding.

Question 13

Carbon monoxide (CO) poisoning is a significant cause of mortality in the United States. Which of the following statements about CO is correct? A) competes with CO₂ for a common binding site on hemoglobin B) competes with O₂ for a common binding site on hemoglobin C) has a lower affinity for hemoglobin than does O₂ D) irreversibly binds to hemoglobin E) is normally a perfusion-limited gas

Accepted Answer

Carbon monoxide competes with oxygen (O₂) for the same binding site on hemoglobin, and it has a much higher affinity for hemoglobin than oxygen does.

Question 14

A 35-year-old apparently healthy man undergoes a medical examination while applying for life insurance. He is not anemic. His hemoglobin electrophoresis is reported as: HbA₁, 62%; HbS, 35%; HbF, 1%; HbA₂, 1%; no variant C, D, G, or H bands are detected. The most likely diagnosis is which of the following? A) sickle cell disease B) sickle thalassemia minor C) sickle trait D) thalassemia major E) thalassemia minor

Accepted Answer

The presence of 35% HbS and 62% HbA1 indicates sickle cell trait, where individuals have one normal hemoglobin gene and one sickle cell gene.

Question 15

You are a third-year emergency room (ER) resident tending to a 48-year-old woman who has come to the ER complaining of increasing fatigue and mild shortness of breath. Blood work reveals a hypochromic anemia with a hemoglobin of 10.4 g/dL, MCV of 76 m/m³, MCHC of 29 g/dL, and a decrease in the absolute reticulocyte count. WBC and platelet counts are within normal limits. Serum iron and ferritin levels are low and total iron-binding capacity is elevated. Which of the following conditions best accounts for these findings? A) anemia of chronic disease B) aplastic anemia C) hypothyroidism D) iron deficiency E) pernicious anemia

Accepted Answer

The lab findings are consistent with iron deficiency anemia, characterized by low hemoglobin, low MCV (microcytic anemia), low serum iron and ferritin, and elevated total iron-binding capacity.

Question 16

A 27-year-old female who is 5 months pregnant has come to her ob-gyn due to a fear that something wrong with her baby. Following her previous routine visit she noted that her baby was moving frequently but in the past 2 days she has not felt any movements. Her physician performs a routine physical exam and notes that the fetal heart rate is tachycardic. The physician orders an ultrasound and during this exam notes a significant pleural and pericardial effusion. A diagnosis of potential hydrops fetalis is made with additional diagnostic tests ordered. Which of the following is most closely associated with non-immune (Rh)-mediated hydrops fetalis?
A) Cooley's anemia
B) hemoglobin Barts
C) hemoglobin H disease
D) thalassemia major
E) thalassemia minor

Accepted Answer

Hemoglobin Barts is associated with non-immune hydrops fetalis, often due to alpha-thalassemia major where there is a deletion of all four alpha-globin genes, leading to severe anemia and heart failure in the fetus.  Hydrops fetalis is the result of the loss of expression of all four copies of the a-globin gene. This leads to a loss of any functional embryonic or fetal hemoglobin tetramers being synthesized. Instead, the fetus expresses only the gamma (g) globin gene which forms homotetramers that are referred to as hemoglobin Barts. This hemoglobin has very high affinity for oxygen resulting in poor oxygen release and thus, oxygen starvation in the fetal tissues. Heart failure results as the heart tries to pump more oxygenated blood to oxygen starved tissues leading to marked edema evidence as pleural and pericardial effusions by ultrasound.

Question 17

Hemoglobin and myoglobin are proteins composed primarily of which of the following types of secondary structures?
A) amide bond
B) disulfide bond
C) a-helix
D) b-pleated sheet
E) triple helix

Accepted Answer

Hemoglobin and myoglobin are primarily composed of alpha-helices (a-helix) as their secondary structure.  Both hemoglobin and myoglobin structure are determined by the high degree of a-helices present in these proteins. Indeed, most of the amino acids in hemoglobin form a-helixes, connected by short nonhelical segments.

Question 18

Sickle cell disease is associated with a mutated form of hemoglobin (HbS) that aggregates to produce long rods within erythrocytes. Which of the following best explains how the mutation leads to aggregation of HbS?
A) creation of a hydrophobic area on the surface of the b-chain
B) creation of an abnormal ratio of a-chains to b-chains
C) prevention of assembly of b-chains with a-chains
D) prevention of b-chain from binding heme
E) production of a truncated b-chain

Accepted Answer

The mutation in sickle cell disease results in the substitution of valine for glutamic acid at the sixth position of the beta-chain, creating a hydrophobic patch that promotes aggregation.  HbS is the form of hemoglobin that results due to a missense mutation in the b-globin gene that causes sickle cell anemia. The mutation causing sickle cell anemia is a single nucleotide substitution (A-T) in the codon for amino acid 6. The change converts a glutamic acid codon (GAG) to a valine codon (GTG). Whereas, glutamate is an acidic and hydrophilic amino acid, leucine is hydrophobic. The presentation of this hydrophilic amino acid on the surface of the hemoglobin protein when in the deoxy state allows the proteins to aggregate via hydrophobic interactions. This aggregation leads to deformation of the erythrocyte, making it relatively inflexible and unable to traverse the capillary beds.

Question 19

Which of the following types of bonds is primarily responsible for the aberrant aggregation of deoxy HbS molecules resulting from the glutamate to valine mutation in the sixth position of the b-globin chain?
A) amide
B) covalent
C) disulfide
D) hydrophobic
E) ionic

Accepted Answer

The glutamate to valine mutation in sickle cell hemoglobin (HbS) creates a hydrophobic patch on the surface of the hemoglobin molecule, leading to abnormal aggregation through hydrophobic interactions.  HbS is the form of hemoglobin that results due to a missense mutation in the b-globin gene that causes sickle cell anemia. The mutation causing sickle cell anemia is a single nucleotide substitution (A-T) in the codon for amino acid 6. The change converts a glutamic acid codon (GAG) to a valine codon (GTG). Whereas, glutamate is an acidic and hydrophilic amino acid, leucine is hydrophobic. The presentation of this hydrophilic amino acid on the surface of the hemoglobin protein when in the deoxy state allows the proteins to aggregate via hydrophobic interactions. This aggregation leads to deformation of the erythrocyte making it relatively inflexible and unable to traverse the capillary beds.

Question 20

During an experiment on hemoglobin function, knockout mice that are unable to synthesize globin proteins are created. Absence of which of the following globin proteins is most likely to be incompatible with life in these mice?
A) a
B) b
C) δ
D) g

Accepted Answer

a-globin is essential for the formation of hemoglobin A, the major oxygen-carrying protein in red blood cells. Without a-globin, mice would not be able to transport oxygen effectively and would likely die shortly after birth.  The a-thalassemias result when there is reduced expression at one or both of the a-globin genes. In the a-thalassemias normal amounts of b-globin are made. Theb-globin proteins are capable of forming homotetramers (b4), and these tetramers are called hemoglobin H (HbH). An excess of HbH in red blood cells leads to the formation of inclusion bodies commonly seen in patients with a-thalassemia. In addition, the HbH tetramers have a markedly reduced oxygen-carrying capacity. High level of HbH results in the disorder known as HbH disease.

Quiz 6: Hemoglobin and Myoglobin

When the malarial parasite invades a red blood cell, its metabolic waste products result in the acidification of the cytoplasm. Which of the following best describes the consequences of this acidification on the activity of hemoglobin (Hb) ?

Although HbF represents fetal hemoglobin, some level of this form of hemoglobin persists in the adult. Which of the following represents the value for HbF in adults above which it would likely reflect some underlying pathophysiology?

Which of the following is referred to as a qualitative hemoglobinopathy?

Aside from the obvious presence of HbS hemoglobin in individuals with sickle cell disease, which Of the following hemoglobins is also found at high frequency in these individuals?

Which of the following is the primary source of the H⁺ that leads to displacement of O₂ from hemoglobin in the tissues?

The "Bohr effect" is best described by which of the following statements?

The thermodynamics of oxygen binding to hemoglobin are highly ordered. Which of the following Reflects the physical characteristics relating the binding of O₂ to hemoglobin?

Carbon monoxide (CO) poisoning is a significant cause of mortality in the United States. Which of the following statements about CO is correct?

Hemoglobin and myoglobin are proteins composed primarily of which of the following types of secondary structures?

Sickle cell disease is associated with a mutated form of hemoglobin (HbS) that aggregates to produce long rods within erythrocytes. Which of the following best explains how the mutation leads to aggregation of HbS?

Which of the following types of bonds is primarily responsible for the aberrant aggregation of deoxy HbS molecules resulting from the glutamate to valine mutation in the sixth position of the b-globin chain?

During an experiment on hemoglobin function, knockout mice that are unable to synthesize globin proteins are created. Absence of which of the following globin proteins is most likely to be incompatible with life in these mice?