A 7-year-old African American boy is brought to the office by his parents. The parents state that the boy has been hospitalized several times for severe pains in his back and extremities. The patient is very active when he is not in pain but gets quite tired by the end of the day. He has no other medical problems and takes no medications except acetaminophen for pain control. On examination, the conjunctivae are pale. Blood count reveals a hemoglobin level of 7.8 mg/dL and a reticulocyte count of 15%. A valine for glutamic acid substitution at position 6 of the β globin chain of the hemoglobin molecule is suspected. This patient's hemoglobin would most likely aggregate upon which of the following?

Question

A 7-year-old African American boy is brought to the office by his parents.  The parents state that the boy has been hospitalized several times for severe pains in his back and extremities.  The patient is very active when he is not in pain but gets quite tired by the end of the day.  He has no other medical problems and takes no medications except acetaminophen for pain control.  On examination, the conjunctivae are pale.  Blood count reveals a hemoglobin level of 7.8 mg/dL and a reticulocyte count of 15%.  A valine for glutamic acid substitution at position 6 of the β globin chain of the hemoglobin molecule is suspected.  This patient's hemoglobin would most likely aggregate upon which of the following?

Quizplus · Accepted Answer

In sickle cell (hemoglobin S [HbS]) anemia, the nonpolar amino acid valine replaces the charged amino acid glutamate at position 6 of the β globin chain. This results in the alteration of a hydrophobic portion of the β globin chain that fits into a complementary site on the α globin chain of another hemoglobin molecule. As a result, hemoglobin molecules aggregate under anoxic conditions. After polymerization, HbS initially forms a gel and then a meshwork of fibrous polymers causing the red blood cells to distort into an abnormal sickle shape. Sickling is promoted by conditions associated with low oxygen levels, increased acidity, or low blood volume (dehydration). Sickled cells are not flexible enough to pass through microvasculature. As a result, they impede blood flow and cause microinfarcts in tissues and painful vasoocclusive crises. Organs in which blood moves slowly (eg, spleen, liver) are predisposed to lower oxygen levels or acidity. Organs with particularly high metabolic demands (eg, brain, muscles, placenta) promote sickling by extracting more oxygen from the blood (oxygen unloading). The sickling process is complex and incompletely understood. (Choices A and C) The molecule 2,3-bisphosphoglycerate (2,3-BPG) binds the 2 β globin chains ionically and stabilizes the taut (T) deoxyhemoglobin. This binding decreases hemoglobin's oxygen affinity, facilitating oxygen release at the tissue level. With 2,3-BPG depletion, hemoglobin affinity for oxygen increases (left shift on oxygen-hemoglobin dissociation curve), and this results in oxygen uptake by hemoglobin; therefore, erythrocyte sickling will decrease. Similarly, increased acidity or low pH is associated with sickling, so decreased acidity with elevated capillary pH values >7.4 would not promote sickling. (Choice B) The globin chains in the hemoglobin tetramer are folded compactly, with nonpolar hydrophobic residues in the interior and charged polar residues on the surface. A valine for glutamic acid substitution does not result in a significant change in β globin folding. It is the mature hemoglobin tetramer that undergoes polymerization, not individual globin chains during folding. (Choice D) HbS does not polymerize when fetal hemoglobin (HbF) is present, so patients with sickle cell anemia often do not have symptoms until the HbF fraction decreases a few months after delivery. Some patients with HbS may have fewer clinical manifestations because they produce larger amounts of HbF as adults. Educational objective: Hemoglobin S (HbS) aggregates in the deoxygenated state. HbS polymers form fibrous strands that reduce red blood cell membrane flexibility and promote sickling. Sickling occurs under conditions associated with anoxia including low pH and high levels of 2,3-bisphosphoglycerate. These inflexible erythrocytes predispose to microvascular occlusion and microinfarcts. __________ References: Newer aspects of the pathophysiology of sickle cell disease vaso-occlusion. (http://www.ncbi.nlm.nih.gov/pubmed/19205968) Sickle cell anemia, the first molecular disease: overview of molecular etiology, pathophysiology, and therapeutic approaches. (http://www.ncbi.nlm.nih.gov/pubmed/19112541)

A 7-Year-Old African American Boy Is Brought to the Office