Sickle Cell Anemia Small Group Flashcards
Sickle cell disease (SCD) encompasses a group of conditions resulting from the inheritance of the βS-globin allele. In homozygous sickle cell anemia (SCA) both alleles of the βS-globin are inherited. Co-inheritance of other β-globin gene mutations such as the βC-globin (HbC) causes a relatively benign SCD (see Table 1). Discuss the differences between SCA and HbSC disease and the biochemical bases for the moderating effect of the βC-globin mutation on the deleterious effect of HbS.
The biochemical background of SCA is that in the gene both alleles have the mutation of a Glubeta6Val. This directly promotes the aggregation of the blood cells. This is a direct result of the mutation that occurs in the particular region of the gene. the hemoglobin undergoes conformational changes as it attaches/ detaches from oxygen, and thus exposes the Val in its deoxygenated form creating a sticky patch. The genetic transversion from and adenine to a thymine at the 6th codon changes this originally negatively charged amino acid a hydrophobic mutations. Because this is a recessive trait, it is not expressed as well in the HbC counterparts, in which the mutation changes from Glu to Lys, which is still a charged ion, making it less drastic of a change. Basically there are two reasons HbSC is much milder than SCA. Firstly because being heterozygous, and because this is a recessive allele it is not expressed. Secondly, because the change in amino acids is less drastic.
- There is more of a sticking and HBSC and this is to a lysine mutation which is a charged
- Glutamate to Lysine is the more conservative
In sickle anemia, the erythrocyte can function normally at high enough O2 partial pressures. Use the patient’s laboratory data to show that her erythrocytes have a hemoglobin concentration that is close to the normal average value.
The patient’s lab results show 7.1 g/dL Hb and 2.3x10^12/L RBC. Her Hb levels are low compared to the average normal rates, or even the normal range but her RBC count is also low. Comparing the ratio of Hb to RBC for the patient, gives a similar percentage to the ratio of the average normal values of Hb to RBC. The patient’s percentage is 32% and the average normal is 34%, showing that the patient’s RBC have a hemoglobin concentration that is close to the normal average value.
- She has less hemoglobin but it correlates to less oxygen so she is okay
Both hemoglobin S and hemoglobin G Makassar have amino acid substitutions at the position 6 Glu of each β-globin chain. For hemoglobin S the Glu is replaced by Val, whereas for hemoglobin G Makassar the Glu is replaced by Ala. However, hemoglobin G Makassar does not cause sickling. Speculate on why it doesn’t.
he main idea here is to look at the different amino acids and the differences in characteristics if these amino acids. Alanine is smaller and less hydrophobic than Valine.
In the article it talks about if there is a mutant valine in the B-globin chain then it will get inserted into a hydrophobic pocket that is located in between inte E and F alpha helices in the hemoglobin. This EF pocket contains hydrophobic regions and all of them combine and with a conformation change this region gets exposed on the outer surface of the hemoglobin. This then creates this sticky patch on the outside of the hemoglobin. The hemoglobin tetramers do not normally interact with each other
- My assumption is that Valine is not big enough to fit into the EF pocket or it is not hydrophobic enough to be attracted to the E and F alpha helices so the sticky patch does not get created and the same consequences do not arise.
Why do sickled erythrocytes move through the capillary beds with more difficulty than nonsickled erythrocytes? In addition to problems with transport and exchange, what physiological problems may arise due to irreversibly sickled cells (ISC)?
RBCs expressing normal HbA are deformable and able to traverse the circulation to deliver oxygen to all tissues of the body. The erythrocyte is a biconcave disc and under normal conditions it becomes deformed and flexible when flowing through capillaries. Sickling interferes with the passage of erythrocytes through capillaries because bundles of sickled fibers form and change the shape of the membrane. This makes the cell more rigid and less flexible to pass through the capillaries.
The clinical complications that result include intermittent, painful vaso-occlusive episodes, life-threatening infections as a result of splenic autoinfarction, acute chest syndrome, stroke, cumulative multi-organ damage, pulmonary hypertension (in adults) and shortened lifespan. Complications arise from decreased organ perfusion, with consequent tissue infarction due to mechanical obstruction of the microvasculature by rigid, sickled RBCs, inflammation, endothelial activation, RBC membrane abnormalities and altered availability of various vasoactive factors.
How does HbF in erythrocytes minimize the effects of HbS in persons with sickle cell disease?
The HbF molecule contains 2 alpha and 2 gamma-globin chains, which have an increased oxygen affinity. This allows for better oxygen transport, and also shifts the erythrocytes shape away from the sickling, fibrous form–allowing cellular flexibility through capillaries, and thus, reducing thrombosis (also likely to prevent organ damage in the spleen and kidney, and other sickling effects).
- We can express F-hemoglobin
- The more F-cells in the body means that they can oxygenate cells and break up the aggregates
- These F cells are in the body and some people have more of these cells.
- There is a compensation for the deficiency in the HBS and it
Malaria is one of the most common causes of anemia in the world. The malaria parasite, Plasmodium falciparum, generates two processes: 1) It penetrates the erythrocytes and on completion of its intracellular life cycle, causes lysis of the RBCs; and 2) There is increased macrophage activity, probably stimulated by malarial antigens. Why is sickle cell trait a better protective factor against malaria for a population than sickle cell disease? What mechanisms have been proposed for the biochemical basis of resistance to malaria?
The Sickle cell trait is a better protective factor against malaria for a population than sickle cell disease due to the protective effect of the sickle cell trait over the lethal forms of malaria. The biochemical basis for this protection is not understood, but a number of hypotheses have been explored.
The biochemical basis for resistance against malaria has the following proposed hypotheses. Protection may be linked to the more rapid clearance of red cells from the circulation, or the more limited survivability of the malaria Plasmodium within red cells containing hemoglobin AS (HbAS).
Protection may also be linked to increased levels of free HbS and free heme, which is toxic to the malaria plasmodium. A recent study suggests a novel mechanism, whereby HbS heterozygous individuals may be tolerant to Plasmodium infection due to up-regulation of heme oxygenase-1 (HO-1), an enzyme that normally recycles the contents of spent red blood cells in the spleen (Ferreira et al). Sickle hemoglobin confers tolerance to Plasmodium infection. MicroRNAs (miRNAs) may also play a role in HbS-mediated malaria resistance in erythrocytes carrying the HbS variant.
Although SCT individuals do not exhibit overt SCD, carriers do exhibit a propensity for susceptibility to organ damage and hypoxic stress. Sickle cell trait has been implicated as a factor for sudden death during intense physical training in college sports. Why might this occur in these individuals and what measures have been implemented to prevent these deaths?
Most evidence of SCT individuals dying suddenly from intense physical training have been anecdotal, and scientific research regarding the relation between SCT individuals and intense physical exercise is sparse. The Sickle cell trait may increase the risk of sudden death due to intense exercise. Recently, the risk of exercise-related death has been linked to a series of environmental conditions such as heat exposure, dehydration, and very intense physical activity. Overall, it may be that sudden death during intense physical exercise occurs in SCT individuals because hypoxic stress can amplify the defective Hemoglobin form (HbS/HbAS) manifesting in various problems.
After implementing some rules with intense physical activity (i.e. training in colder environments, ensuring repeated hydration), the number of sudden deaths of those with the SCT reduced significantly. The NCAA also recently required college athletes to be tested for their SCT status to ensure protection and prevention for athletes. This mandated testing, however, has unintentionally lead to a question of ethics in regards to discrimination based on a person’s genetic code.
- Dehydration – Increases aggregation
Hydroxyurea (HU) and Decitabine, a compound related to 5-azacytidine, are used to treat SCDs. Describe their effects on the pathophysiology of sickle cell. Why is HU such an effective drug relative to other treatment regimens?
Both HU and Decitabine are used to increase expression of HbF (fetal hemoglobin) by restoring γ-globin gene activity through histone deacetylase inhibition or demethylation of the γ-globin promoters. HU is a ribonucleotide reductase inhibitor that arrests DNA synthesis, and thus is largely used as a chemotherapeutic agent. HU increases HbF, decreases leukocyte count, and affects RBC dehydration, adhesion and NO production. Together, these effects will prevent sickle polymer formation, decrease HbS concentration, decrease inflammation, induce vasodilation for improved blood flow, and decrease adherence of erythrocytes for further improvement of flow. It also does not induce the adverse toxic side effects seen with use of 5-azacytidine. It is also emphasized that use of HU can be used at relatively low doses to reduce frequency of sickle crises.
Sickle cell anemia may be cured by gene therapy in the near future. List the reasons
why SCA is a disease that is particularly amenable to gene therapy.
1) The exact mutation is known making targeting therapies more realistic
2) SCA involves a single gene mutation instead of multi-gene diseases.
Bone marrow – You can fix the mutation the bone marrow by replacing it
SCDs largely afflict members of minority populations and often those of limited economic means. This can result in preconceived opinions by both patients and physicians about each other, ultimately affecting treatment compliance and outcome. As a physician, how can you overcome misperceptions and deliver proper medical care?
Having basic knowledge of the disease can highly impact treatment. For example, the fact that crises can last up to six days is huge. Physicians need to know their patient could be in severe pain for six days, which could be viewed as drug seeking. Also, empathy needs to still exist towards patients, especially those of different backgrounds. Following empathy, hopefully the patient will feel a sense of trust, which can make communication between the patient and physician more open and truthful. Lastly, follow the four habits model: invest in the beginning, elicit the patient’s perspective, exhibit empathy, and invest in the end.
