Blood Cells - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 78

Sickle cell anemia ,or drepanocytosis , is an autosomal recessive genetic disorder.
The HBB gene that encodes 1 of the 2 types of polypeptidic chains of adult
tetrameric hemoglobin is responsible for sickle cell anemia, characterized primarily
by chronic anemia (sickled RBCs lifespan 10-20 d). Patients inherit either 2 copies
of HBS variant or 1 copy of HBS and 1 copy of another variant. The substitution
of amino acid in position 6 (hydrophobic amino acid valine rather than hydrophilic
glutamic acid) creates a hydrophobic spot on the outside of the protein structure
that links to the hydrophobic region of an adjacent hemoglobin chain. This

polymerization of HbS molecules that creates rigid structures causes the “sickling”
of RBCs. 43 Several hundred HBB gene variants are known.
The hemoglobin variant — hemoglobin-S (HbS) — is the most common cause
of sickle cell anemia, in the case of homozygosity of a mutation in the HBB
gene. In heterozygous subject with a single sickle (S) gene and a normal adult
hemoglobin (A) gene (HbAS; i.e., hemoglobin genotype AS rather than normal
hemoglobin genotype AA), the abnormality is called sicklemia or sickle cell trait ,
without disease symptoms (healthy carrier subjects).
Hemoglobin-C results from a variation in the HBB gene. In homozygotes, nearly
all Hb is HbC that causes a mild chronic hemolytic anemia. A heterozygous form
with one sickle gene and another encoding hemoglobin-C, i.e., the gene for HbS
inherited from one parent and the gene for HbC inherited from the other parent,
causes hemoglobin-SC disease.
Like hemoglobin-S and -C, hemoglobin-E is generated by mutations of the HBB
gene. This variant causes a mild chronic hemolytic anemia.
Dyshemoglobins (dysfunctional Hb) are also caused by molecules that affect
binding of oxygen to Hb by competing with oxygen at heme, such as carbon
monoxide (CO) that leads to carboxyhemoglobin (COHb; Table 3.7 ). Hemoglobin
binding affinity for CO is 200 times greater than its affinity for oxygen. The stable
complex CO Hb (blood half-life 4-6 h) does not release carbon monoxide. Therefore,
hemoglobin cannot transport oxygen from lungs to the body's cells. Tobacco
smoking via carbon monoxide inhalation augments the blood CO Hb concentration.
However, CO, a element of the gaseous triumvirate with nitric oxide (NO) and
hydrogen sulphide (H 2 S), is a gasotransmitter (Vol. 4 - Chap. 10. Other Major
Signaling Mediators) with anti-inflammatory, vasodilatory, and pro-angiogenic
effects. Moreover, CO and NO are volatile and inhibitory coneurotransmitters [ 144 ].
Methemoglobins (MetHb) are caused by iron oxidation ( Fe 3 + ) in Hb heme.
Methemoglobin is unable to carry oxygen. NADH-dependent methemoglobin
reductase converts methemoglobin to hemoglobin. Nitrogen dioxide (NO 2 )and

β

43 Polymerization of hemoglobin-S occurs when RBCs have delivered oxygen to cells and
return to lungs. When hemoglobin binds oxygen, HbS molecules depolymerize or fragment.
Polymerization-depolymerization cycling stiffens RBC membranes. The erythrocytic rigidity is
associated with a distorted shape when RBCs do not carry oxygen; it provokes blockages of small
blood vessels.