Hemoglobin & disorders

What are normal levels of methemoglobin? What happens when it reaches 3%

1%, methemoglobinemia causing chocolate cyanosis

What allosteric effector helps the body to adapt quickly to hypoxia or anemia by enhancing its ability to deliver oxygen to tissues?

23BPG

What allosteric effector responds to chronic hypoxia or anemia?

23BPG; at high altitudes or w/COPD where circulating hemoglib may have difficulty receiving sufficient oxyge, 23BPG increases, leading to unloading of O2 at tissues; in anemia, there are fewer RBC to deliver O2

What is the pO2 in venous vs. arterial blood?

40; 80-100

What is hydroxyurea?

Antitumor drug that increases circulating levels of HbF, which decreases RBC sickling

Sickle cell anemia (MIM*604903) was one of the first disorders selected for newborn screening despite concerns about stigmatization from the African American community The disease results from homozygous mutation causing substitution of valine for glutamate at position 6 on the 𝜷𝜷 chain of hemoglobin, producing hemoglobin S. Which of the following techniques might be considered for hemoglobin S screening? A. Decreased polymerization of deoxyhemoglobin B. Altered electrophoretic mobility C. Increased solubility of deoxyhemoglobin D. More Oexible red blood cells E. Unchanged primary structure

B

b. An increased affinity of hemoglobin for O2 may result from which of the following? A. Acidosis B. Lower 2,3-bisphosphoglycerate (BPG) levels within erythrocytes C. High CO2 levels D. More ferric ion E. Initial binding of O2 to one of the four sites available in each deoxyhemoglobin molecule

B

bright red lips and decreased O2 levels indicate what?

CO poisoning

Which one of the following statements concerning the hemoglobins is correct? A. Fetal blood has a higher affinity for oxygen than does adult blood because Hb F has a decreased affinity for 2,3-BPG. B. Purified Hb F (stripped of 2,3-BPG) has a higher affinity for oxygen than does purified Hb A. C. The globin chain composition of Hb F is α2δ2. D. Hb A1c differs from Hb A by a single, genetically determined amino acid substitution. E. Hb A2 appears early in fetal life.

Correct answer = A. Because 2,3-BPG reduces the affinity of hemoglobin for oxygen, the weaker interaction between 2,3-BPG and Hb F results in a higher oxygen affinity for Hb F relative to Hb A. In contrast, if both Hb A and Hb F are stripped of 2,3-BPG, they have a similar affinity for oxygen. Hb F consists of α2γ2. Hb A1c is a glycosylated form of Hb A, formed nonenzymically in red cells. Hb A2 is a minor component of normal adult hemoglobin, first appearing shortly before birth and rising to adult levels (about 2% of the total hemoglobin) by 6 months of age.

Which one of the following statements concerning the ability of acidosis to precipitate a crisis in sickle cell anemia is correct? A. Acidosis decreases the solubility of Hb S. B. Acidosis increases the affinity of hemoglobin for oxygen. C. Acidosis favors the conversion of hemoglobin from the taut to the relaxed conformation. D. Acidosis shifts the oxygen dissociation curve to the left. E. Acidosis decreases the ability of 2,3-BPG to bind to hemoglobin.

Correct answer = A. Hb S is significantly less soluble in the deoxygenated form, compared with oxyhemoglobin S. A decrease in pH (acidosis) causes the oxygen dissociation curve to shift to the right, indicating a decreased affinity for oxygen. This favors the formation of the deoxy, or taut, form of hemoglobin, and can precipitate a sickle cell crisis. The binding of 2,3-BPG is increased, because it binds only to the deoxy form of hemoglobins.

A 67-year-old man presented to the emergency department with a 1 week history of angina and shortness of breath. He complained that his face and extremities had a "blue color." His medical history included chronic stable angina treated with isosorbide dinitrate and nitroglycerin. Blood obtained for analysis was chocolate-colored. Which one of the following is the most likely diagnosis? A. Sickle cell anemia B. Carboxyhemoglobinemia C. Methemoglobinemia. D. β-Thalassemia E. Hemoglobin SC disease

Correct answer = C. Oxidation of the heme component of hemoglobin to the ferric (Fe3+) state forms methemoglobin. This may be caused by the action of certain drugs, such as nitrates. The methemoglobinemias are characterized by chocolate cyanosis (a brownish-blue coloration of the skin and mucous membranes), and chocolate-colored blood as a result of the dark-colored methemoglobin. Symptoms are related to tissue hypoxia, and include anxiety, headache, dyspnea. In rare cases, coma and death can occur.

Which one of the following statements concerning the binding of oxygen by hemoglobin is correct? A. The Bohr effect results in a lower affinity for oxygen at higher pH values. B. Carbon dioxide increases the oxygen affinity of hemoglobin by binding to the C-terminal groups of the polypeptide chains. C. The oxygen affinity of hemoglobin increases as the percentage saturation increases. D. The hemoglobin tetramer binds four molecules of 2,3-BPG. E. Oxyhemoglobin and deoxyhemoglobin have the same affinity for protons (H+).

Correct answer = C. The binding of oxygen at one heme group increases the oxygen affinity of the remaining heme groups in the same molecule. Carbon dioxide decreases oxygen affinity because it lowers the pH; moreover, binding of carbon dioxide to the N-termini stabilizes the taut, deoxy form. Hemoglobin binds one molecule of 2,3-BPG. Deoxyhemoglobin has a greater affinity for protons and, therefore, is a weaker acid.

β-Lysine 82 in hemoglobin A is important for the binding of 2,3-BPG. In Hb Helsinki, this amino acid has been replaced by methionine. Which of the following should be true concerning Hb Helsinki? A. It should be stabilized in the T, rather than the R, form. B. It should have increased O2 affinity and, consequently, decreased delivery of O2 to tissues. C. Its O2 dissociation curve should be shifted to the right relative to Hb A. D. It results in anemia

Correct answer is B. Substitution of lysine by methionine decreases the ability of negatively charged phosphate groups in 2,3-BPG to bind the β subunits of hemoglobin. Because 2,3-BPG decreases the O2 affinity of hemoglobin, a reduction in 2,3-BPG should result in increased O2 affinity and decreased delivery of O2 to tissues. The R form is the high-oxygen-affinity form of hemoglobin. Increased O2 affinity (decreased delivery) results in a left shift in the O2 dissociation curve. Decreased O2 delivery is compensated for by increased RBC production

The ability of hemoglobin to serve as an effective transporter of oxygen and carbon dioxide between lungs and tissues is explained by which of the following properties? A. The isolated heme group with ferrous iron binds oxygen much more avidly than carbon dioxide. B. The a- and ~-globin chains of hemoglobin have ve ry different primary structures than myoglobin. C. Hemoglobin utilizes oxidized ferric iron to bind oxygen, in contrast to the ferrous ion of myoglobin. D. In contrast to myoglobin, hemoglobin exhibits greater changes in secondary and tertiary structure after oxygen binding. E. Hemoglobin binds proportionately more oxygen at low oxygen tension than does myoglobin.

D

1. 2,3-Bisphosphoglycerate acts by: A. attaching to each of the hemes in hemoglobin B. alleviating some of the effects of sickle cell anemia C. raising the O2-binding capacity of hemoglobin D. raising the PO2 for 50% saturation of hemoglobin E. dissociation of hemoglobin into alpha and beta subunits

D.

2. Methemoglobin reductase in red cell blood cells: A. uses tocopherol (vitamin E) B. requires cytochrome a3 C. requires cadmium D. Uses NADH E. requires Fe+2

D.

How does 23BPG affect oxygen affinity in hemoglobin?

During hypoxic conditions, glycolysis will increase, creating more 23BPG; 23BPG binds to positivley charged pocket in heme, stabilizing T state and lowering O2 affinity

What is the ferrous oxidation state?

Fe2+

What is the ferric oxidation state?

Fe3+

Describe the compositional changes of Hb throughout life

Fetal has two zeta, two episilon; infant has HbF two alpha two gamma; adults have HbA

How would you treat someone with lactic acidosis?

Give them bicarb to increase the pH

How would you treat someone with ketoacidosis?

Give them insulin

What is HbA1c and its characteristics?

Glycalated form of adult hemoglobin, made of two alpha two beta and slowing glycolated by hexose in the blood, attached to n-terminal of beta chains

What are the 3 heterotropic allosteric effectors? (bind at a site different than O2)

H+ (Bohr effect), CO2, 23BPG

What is HbC and its characterisitics?

Hemoglobin C disease; single AA substitution lysine for glutamate; causes chronic mild hemolytic anemia

What is HbSC?

Hemoglobin SC disease; one mutation from HbS and one from HbC; painful crises but less severe than HbS

What is HbA and its characteristics?

Human hemoglobin, made of two alpha and two beta subunits; an alpha and beta subunit create a dimer held togehter by strong hydrophobic interactions; ab dimers are conected by weak ionic/H bonds; 90% of total hemoglobin in adults

What is HbA2 and its characteristics?

Human hemoglobin, made of two alpha and two delta subunits; 2-3% in adults

How does blood act as a pH buffer?

It binds H+ (Bohr effect)

Why would 23BPG increase during hypoxic conditions?

It would lead to the unloading of O2 at the tissue level

A 37-year-old comes into your Emergency and is dizzy and unable to take more than three steps due to dyspnea, but denies fever, cough, or chest pain. On examination, he is afebrile, but appears pale; his lips are a dark grayish-brown color. His oxygen saturation on room air is 86%. The blood is a brownish color when drawn. What does he have high levels of?

Methemoglobin if there is an issue with his NADH cytochrome b5 reductase; methemoglobin M Boston if there is a mutation in a/b chain, causing HbM which is resistant to reductase

What is HbS and its structure?

Sickle cell anemia, caused by point mutation in beta globin subunit, glutamate at position 6 is replacced with valine

A set of twins come into your office for their 1 week old checkup. You noticed that both seem to have yellow eyes and a yellowish tint to their skin color (the lighter one seems to have more of a yellowish tint than the other). Examination of the babies revealed that they had hepatomegaly. Complete Blood Count indicates that they had hyperchromic microcytic anemia. Labs revealed hyperbilirubinemia and red blood cells that appear sphere-shaped rather than bi-concave disk shaped. What do they have?

Spectrin deficiency

Why does HbF bind oxygen with higher affinity than HbA?

The gamma chains in HbF lack some of the positively charged amino acids found in beta chains, so HbF only weakly binds to 2,3BPG

A 22 year old Vietnamese women presents for a routine gyn exam. Her menstrual cycle is normal, and there is no evidence of other bleeding. Guaiac is negative. Her hemoglobin is at 11 (12-16), RBC is 5.8 (3.5-5.5), and an MCV of 70 (80-100) with a normal Red cell distribution width (RDW) of 10. WBC and platelets are normal. Hemoglobin electrophoresis shows an increase in amount of Hgb A2, and Hgb F. What is happening?

The patient has reduced synthesis of beta chains in hemoglobin

At birth the baby with thalassemia major seems entirely normal. Why?

This is because the predominant hemoglobin at birth is still fetal hemoglobin (HbF). HbF has two alpha chains (like Hb A) and two gamma chains (unlike Hb A). It has no beta chains so the baby is protected at birth from the effects of thalassemia major.

What is the function of myoglobiin?

To store oxygen in myscles; binds O2 tighter than hemoglobin

What happens to damaged RBC?

Trapped in spleen and destroyed by macrophages

How do you treat Cooley anemia? What are symptoms?

Treatment option is only hematopoietic stem cell transplant; symptoms are severe anemia, skeletal changes, required transfusions

How long does HbF persist in the blood in high levels?

Until 6mo of age

What two main deficinecies cause macrocytic anemia? >100fL MCV?

Vit B12 and folate deficiencies

When do symptoms of sickle cell start to appear?

When sufficient HbS starts to replace HbF

what is on x and y axis of oxygen binding curve?

X= pO2, Y=O2 saturation

As pH decreases, what way does the oxygen-dissociation curve shift and why?

as CO2 is produced during aerobic metabolism CO2 dissolves in plasma and gets inside RBC; CO2 joins with water and is converted to bicarbonate and H+ ions via carbonic anhydrase; excess H+ lowers the pH; CO2 binds to terminal AA and H+ binds to AA side chains in globin subunits, stabilizing T state and lowering hemoglobin's affinity for O2; it shifts the curve to the right

What is CO + hemoglobin?

carboxyhemoglobin

What is methemoglobinemia characterized by?

chocolate cyanosis; blue skin/membranes and brown blood

Symptoms of sickle cell anemia

chronic hemolytic anemia, pain crises, hyperbilirubenemia, susceptibility to infection, reduced life expectantacy

What is alpha thalassemia?

decreased or absent alpha chains; four copies of alpha globin gene on chromosome 16, 1 defect - silent carrier, 2 defects - trait, 3 defects - HgB H B4; hemolyric anemia of variable severity, all 4 defective gene HgB Bart y 4 fetal death since alpha chains are used to make HbF

What form of HbS causes sickling and tissue anoxia?

deoxy state: deoxyhemoglobin S polymerizes inside the RBC, forming fibrous polymer network

What is the result of lowered pO2 for people with HbS?

deoxyhemoglobin S polymerizes within the RBC and forms a fibrous network that makes the cell rigid

What is HbF & its characteristics?

fetal hemoglobin; made of two alpha and two gamma subunits; has a higher binding affinity for oxygen than does HbA; <2% in adults

How much of bound O2 can hemoglobin and myoglobin deliver?

hemglobin = 40-45%, myoglobin 6%

Treatments for HbS?

hydration, analgesics, antibiotic therapyf ro infection, intermittent transfusions, hydroxyurea (antitumor drug)

At moderate altitude change, there will be a right shift due to what?

increase in 23BPG

What are the two most common causes of microcytic anemia?

iron deficiency anemia and thalassemia

How does CO inhibit electron transport?

it inhibits complex 4 (cytochrome c oxidase, COX)

What is lifetime of cells with sickle cell anemia?

less than 20 days

What does low vs. high Km indicate?

low Km = high affinity for O2

what does hemoglobin make when Fe is oxidized?

methemoglobin

What reduced methemoglobin to hemoglobin?

methemoglobin reductase (cytochrome b5 reductase)

What hemoglobin disorder can be inherited or aquired?

methemoglobinemia

How to you treat methemoglobenmias?

methylene, which is oxidized as Fe3+ is reduced

What causes methemoglobenmias?

oxidation of heme iron to Fe3+ caused by certain drugs, reactive oxygen species, deficiency of NADH cytochrome b5 reductase which converts Fe3+ to Fe2+, or mutations in globin chain producing HbM (resistance to reductase)

what allosteric effectors affect oxygen affinity?

pH, 2,3BPG, temperature, pCO2

What disease converts hydrophilic AA to hydrophobic AA and intracellular polymerization?

sickle cell anemia

descrbibe the oxygen-disaccoiation curve for hemoglobin

sigmoidal shape; increasing oxygen affinity as number of bound oxygen molecules increases = positive coopertivity; affected by allosteric effectors; as curve shifts to the right, it lowers hemoglobin's affinity for oxygen

What causes beta thalassemia?

synthesis of beta globin chain is decreased or absent; there are two copies of beta gene on chromosome 11, if one gene is mutated you have beta-thalassemia trait minor but if both genes are mutated you have beta thalassemia major (Cooley anemia)

Which way does the oxyhemoglobin curve shift with CO?

to the left, as it inhibits the delivery of oxygen to the body

When do people with sickle cell trait show symptoms?

with severe dehyradtion and physcial exertion