Which of the following is most common haemoglobinopathy
Correct Answer: Sickle cell anemia
Description: On deoxygenation, HbS molecules form long polymers by means of intermolecular contacts that involve the abnormal valine residue at position 6. These polymers disto the red cell, which assumes an elongated crescentic, or sickle, shape (Fig. 11-3). The sickling of red cells initially is reversible upon reoxygenation. However, the distoion of the membrane that is produced by each sickling episode leads to an influx of calcium, which causes the loss of potassium and water and also damages the membrane skeleton. Over time, this cumu- lative damage creates irreversibly sickled cells, which are rapidly hemolyzed. Many variables influence the sickling of red cells in vivo. The three most impoant factors are * The presence of hemoglobins other than HbS. In heterozygotes approximately 40% of Hb is HbS and the remainder is HbA, which interacts only weakly with deox- ygenated HbS. Because the presence of HbA greatly retards the polymerization of HbS, the red cells of het- erozygotes have little tendency to sickle in vivo. Such persons are said to have sickle cell trait. HbC, another mutant b-globin, has a lysine residue instead of the normal glutamic acid residue at position 6. About 2.3% of Ameri- can blacks are heterozygous carriers of HbC; as a result, about 1 in 1250 newborns are compound heterozygotes for HbC and HbS. Because HbC has a greater tendency to aggregate with HbS than does HbA, HbS/HbC com- pound heterozygotes have a symptomatic sickling disorder called HbSC disease. HbF interacts weakly with HbS, so newborns with sickle cell anemia do not manifest the disease until HbF falls to adult levels, generally around the age of 5 to 6 months. * The intracellular concentration of HbS. The polyA merization of deoxygenated HbS is strongly concentration- dependent. Thus, red cell dehydration, which increases the Hb concentration, facilitates sickling. Conversely, the coexistence of a-thalassemia (described later), which decreases the Hb concentration, reduces sickling. The relatively low concentration of HbS also contributes to the absence of sickling in heterozygotes with sickle cell trait. * The transit time for red cells through the micro- vasculature. The normal transit times of red cells through capillaries are too sho for significant polymeriza- tion of deoxygenated HbS to occur. Hence, sickling in microvascular beds is confined to areas of the body in which blood flow is sluggish. This is the normal situation in the spleen and the bone marrow, two tissues promi- nently affected by sickle cell disease. Sickling also can be triggered in other microvascular beds by acquired factors that retard the passage of red cells. As described previ- ously, inflammation slows the flow of blood by increasing the adhesion of leukocytes and red cells to endothelium and by inducing the exudation of fluid through leaky vessels. In addition, sickle red cells have a greater tendency than normal red cells to adhere to endothelial cells, appar- ently because repeated bouts of sickling causes mem- brane damage that make them sticky. These factors conspire to prolong the transit times of sickle red cells, increasing the probability of clinically significant sickling. Two major consequences arise from the sickling of red cells (Fig. 11-4). First, the red cell membrane damage and dehydration caused by repeated episodes of sickling produce a chronic hemolytic anemia. The mean life span of red cells in sickle cell anemia is only 20 days (one sixth of normal). Second, red cell sickling produces widespread microvascular obstructions, which result in ischemic tissue damage and pain crises. Vaso-occlusion does not cor- relate with the number of irreversibly sickled cells and there- fore appears to result from factors such as infection, inflammation, dehydration, and acidosis that enhance the sickling of reversibly sickled cells. Ref Robbins 9/e pg 412
Category:
Pathology
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