Prerequisite Hemoglobin structure and function concepts. Background Normal adult
ID: 823282 • Letter: P
Question
Prerequisite
Hemoglobin structure and function concepts.
Background
Normal adult hemoglobin is called Hemoglobin A (Hb A). Ninety-eight percent of adult hemoglobin
is Hb A and 2% is Hb A
. There are other forms of hemoglobin. For example, the developing fetus has a
different kind of hemoglobin than most normal adults. Fetal hemoglobin (or Hemoglobin F) consists of
two ? chains and two ? chains, whereas adult hemoglobin (Hemoglobin A) consists of two ? chains and
two ? chains. Fetal hemoglobin is synthesized beginning at the third month of gestation and continues
up through birth. After the neonate is born, hemoglobin F synthesis declines (because synthesis of the ?
chain declines) and hemoglobin A is synthesized (because synthesis of ? chains begins). By the time
the baby is six months old, 98% of its hemoglobin is Hemoglobin A.
There is also a mutant form of hemoglobin called Hemoglobin S which is found in persons with the
disease sickle cell anemia. The disease sickle cell anemia is one of the major health problems facing the
African-American community. The World Health Organization estimates that 250,000 babies world-
wide are born with sickle cell anemia. Currently there is no cure. A person afflicted with sickle cell
anemia has inherited a defective gene from each parent. (Parents who are carriers of the sickle cell gene
are heterozygous AS, whereas the person afflicted with sickle cell anemia is SS; non-carriers are
designated AA.) The defective gene is the one coding for the ?-chain. The amino acid at position 6 on
each ? chain has been mutated from a glutamate to a valine. Normal ? chains have a decreased affinity
for the mutated ? chains; thus assembly of the HbS tetramer is more difficult. Red blood cells containing
HbS form a sickle shape because the Hb S molecules polymerize. Hb S molecules are more likely to
polymerize when in the deoxygenated T form than in the oxygenated R form. The polymerized Hb
deforms the normal discoid shape of the red blood cells, producing a sickle-shaped cell. The sickle
shaped red blood cells become trapped in capillaries and organs, depriving the victim of adequate
oxygen supply and causing chronic pain and organ damage.
In this case we will consider our patient, a 10-year-old black male child named Michael B., who was
admitted to the hospital because he was experiencing severe chest pain. He had been hospitalized on
several previous occasions for vaso-occlusive episodes that caused him to experience severe pain that
could not be managed with non-prescription drugs such as ibuprofen. He was slightly jaundiced, short of
breath and easily tired, and feverish. A chest x-ray was taken and was abnormal. An arterial blood
sample showed a pO2 value of 6 kPa (normal is 10-13 kPa).
Questions
4. You recall reading in the medical literature about a dramatic new drug treatment for sickle cell
anemia, and you?d like to try it on this patient. The drug is hydroxyurea, and is thought to function
by stimulating the afflicted person?s synthesis of fetal hemoglobin. Exactly how hydroxyurea
stimulated fetal hemoglobin synthesis is unclear, but it is believed that hydroxyurea is metabolized
to NO, which binds to a soluble guanylate cyclase enzyme which then catalyzes the synthesis of a
second messenger, cyclic GMP (cGMP). The cGMP interacts with transcription factors in a manner
that is not completely understood to induce the transcription (and then translation) of the fetal
hemoglobin gene.
a. In a clinical study, patients who took hydroxyurea showed a 50% reduction in frequency of
hospital admissions for severe pain, and there was also a decrease in the frequency of fever and
abnormal chest x-rays. Why would increasing the synthesis of fetal hemoglobin result in
alleviating the symptoms of sickle cell anemia?
b. Medical practioners who used hydroxyurea as a treatment for sickle cell anemia noted that their
patients seemed to benefit from the administration of the drug long before the synthesis of fetal
hemoglobin had time to take effect. It has recently been determined that hydroxyurea can react
directly with the iron ion of oxy- and deoxyHb to form iron nitrosyl hemoglobin (HbNO). Why
would this be of benefit to the sickle-cell anemic patient?
c. And finally, hydroxyurea has been shown to produce NO directly, in less than an hour after
hydroxyurea administration. It?s also possible that HbNO could produce NO, either directly or
indirectly. NO is an important second messenger which, even in nanomolar amounts, stimulates
vasodilation. How could NO production help the sickle-cell anemic patient?
Explanation / Answer
Chemical reactions help no production the sickle cell anemic patient