Sickle cell and Thalassemia Flashcards Preview

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Explain the molecular bases for sickle cell disease and how specific mutation leads to the phenotype. Describe its mode of inheritance.

Sickle cell disease is a autosomal recessive genetic disorder of hemoglobin, in which both B-globin genes are mutated, at least one with the characteristic single amino acid substitution (B6(glu -> val)). Ned a B sickle + Babnormal. When deoxygenated, sickle hemoglobin polymerizes into 14-strand helical fibers (because of the hydrophobic Val) which distort the shape of the RBC into a “sickle form” or other irregular shapes and damages the RBC membrane. When reoxygenated, the polymers dissolve, and the RBC returns to its normal shape. After several deoxygenation-reoxygenation cycles, the cell becomes irreversibly sickled and is lysed (destroyed).


Describe the geographic distribution of sickle cell disease. Describe a situation where people heterozygous for sickle cell disease may have a survival advantage.

This sickle cell mutation occurs in many ethnic groups, including those of African, Indian, Middle Eastern, and Mediterranean descent. Those with sickle cell trait have a survival advantage in areas with high malaria. The red cell that is sickled is intolerant of the parasite and lyses early, preventing the spread of the parasite.


Describe the findings on the CBC and peripheral blood smear in patients with sickle cell disease.

Anemia with compensatory increase in reticulocyte count. The severity of the anemia varies with type of sickle cell disease (see table).Increased baseline white blood cell count (WBC) and platelet count in some patients due to exuberant bone marrow response to hemolytic anemia and other factors. An increased baseline WBC has been associated with increased mortality and morbidity in sickle cell anemia.Increased Red Cell Distribution of Width (RDW). Because sickle RBCs transition from sickled to unsickled, changing shape, and because reticulocytes are very young, large RBCs, there is significant variation in the size of RBCs as analyzed by automated cell counters.Abnormal peripheral smear with sickle forms, schistocytes (“broken”, irregular cells), polychromasia (blue-colored cells representing reticulocytes), anisocytosis (variation in size of RBCs), poikilocytosis (variation in shape of RBCs).


Describe what “sickle trait” is. Describe the consequences of having sickle cell trait.

Sickle cell trait, by contrast, occurs in a person with one sickle cell gene and one NORMAL gene. This normal gene, producing normal globin chains in normal quantities, protects against the development of sickle cell disease. Rare splenic infarct in white males at high altitude. Other rare diseases can occur.


What are the signs and symptoms (chronic and acute) of sickling?

Narrowing of the vessels and chronic organ damage due to slow or absent blood flow through this microcirculation.The large blood vessels of the central nervous system can be significantly damaged by sickle RBCs. Up to 10% of children with sickle cell anemia (Hb SS) experience an overt large vessel stroke due to this chronic injury, and a larger percentage experience learning disabilities and more subtle neurologic problems.Changes in circulation have large impacts on the spleen, lungs, kidneys, retinas, and humoral and femoral heads.Acute symptoms include hand and foot syndrome, acute chest syndrome, acute multi-organ failure syndrome, priapism, and bone infarction.


Explain the relationship between aplastic crisis and parvovirus B19.

Since sickle cell disease patients rely on an increased reticulocyte count to compensate for increased RBC destruction, anything that compromises the bone marrow’s ability to rapidly produce RBCs can result a sudden drop in hemoglobin, called an aplastic crisis. The characteristic finding is a low reticulocyte count.In children, an important cause of aplastic crisis is Parvovirus B19, which causes “fifth disease” and infects RBC precursors, arresting their development into mature RBCs. This infection is usually transient, but patients may require transfusion of RBCs if the hemoglobin falls significantly.Other severe infections, medications or vitamin (e.g. folic acid) deficiencies can also result in an aplastic crisis.


Describe some of the therapies to treat patients with sickle cell disease and the rationale for therapies such as folic acid, penicillin, exchange transfusion, hydroxyurea, and bone marrow transplantation.

Folic acid: used to treat developmental delays caused by anemiaPenicillin: used as prophylaxis to treat sepsis due to splenic deathExchange transfusion: if there is acute worsening of anemia (e.g. splenic sequestration, aplastic crisis) or acute end-organ injury (e.g. acute chest syndrome), transfusion of RBCs may rapidly reverse the life-threatening process. Transfusion can be given by simply administering RBCs (simple transfusion) or by simultaneously removing the patient’s RBCs as normal RBCs are being given (exchange transfusion).Hydroxyurea, an oral chemotherapy agent, is able to induce the production of fetal hemoglobin, which is otherwise “shut off” in most people within the first 6-12 months of life. Fetal hemoglobin significantly interferes with sickle hemoglobin polymerization;Allogenic bone marrow transplantation offers a potential cure for a patient with an HLA-matched full sibling unaffected by sickle cell disease, with >90% overall and disease-free survival.


Explain iron chelation therapy, its indications, and its drawbacks.

If multiple simple transfusions are given, iron overload develops, which can cause organ damage (especially of the liver and heart) unless the iron is removed by a chelation agent.Chelation therapy involves the administration of medications with bind excess iron stores and remove them from the body. The most common chelation agent, deferoxamine, is infused subcutaneously over 8-12 hours, usually in the abdominal area, 5 to 7 times a week. Compliance with this therapy is challenging for some patients.


Explain how newborn screens can be used to diagnose sickle cell disease.

Virtually all infants born in the United States are screened at birth for hemoglobinopathies, using the blood from a heel stick placed on filter paper, as is done for the PKU and other sponsored newborn screening tests.The purpose is early identification of sickle cell disease, so that parental education and prophylactic penicillin can be provided to prevent early mortality. However, it is also an opportunity to identify children with other forms of hemoglobinopathies, including B-thalassemia major.


Review the normal structure of hemoglobin and indicate the globin chains that typically make it up. Describe how the composition of globin chains in hemoglobin changes during fetal development and after birth.

The hemoglobin molecule is a heterodimer that contains 2 alpha-globin chains and another pair of different globin chains, normally Beta and delta; gamma chains are produced by the fetus and newborn. The major hemoglobin in human red blood cells (RBCs) after 4-6 months of age is hemoglobin A1, which consists of 2 alpha chains and 2 beta chains (A2B2). Production of A-globin chains is controlled by 4 genes, 2 on each chromosome 16. Production of other globin chains is controlled by one gene cluster on each chromosome 11, which is depicted below. The timing of production of various hemoglobins throughout development, and their composition, are also shown.


Describe what thalassemia is and explain in a general way the molecular basis for it. Describe the basic genetic differences between alpha-thalassemia and beta-thalassemia.

Thalassemia is a condition in which there is underproduction of a hemoglobin chain due to a variety of mutations that result in poor or absent function of the globin gene. In A-thalassemia, the A-globin chain is underproduced, most often due to an absence of one or more of the four genes which control production. In B-thalassemia, the B-globin chain is underproduced, most often due to point mutations which result in dysfunctional genes.


Explain the meaning of the terms thalassemia major, thalassemia intermedia, and thalassemia minor.

Thalassemia major, or Cooley's Anemia: a beta thalassemic disorder in which the body is making very little or no beta globin due to two completely silenced beta globin genes. The body compensates by trying to use fetal and A2 hemoglobin.Thalassemia intermedia: 2 mildly to moderately silenced beta globin genes.Thalassemia trait: 1 silenced beta globin gene, 1 normal.


Describe clinical manifestations and findings on the CBC and peripheral blood smear in patients with thalassemia.

Low MCV, low MCHC, sombrero shaped RBC’s and target cells, Anemia, Chronic hemolytic anemia, elevated reticulocyte count, microcytosis, polychromasia, mild anisocytosis, increased biliruben, splenomegaly, expanded bone marrow and associated bone problems, increased iron absorbtion, delayed growth and development, endoctrinopathies, pulmonary hypertension


Describe the geographic distribution of thalassemia. Describe a situation where people heterozygous for thalassemia may have a survival advantage.

A-thalassemia is most common in persons of southeast Asian, African and Mediterranean descent. B-thalassemia occurs most commonly in persons of Mediterranean, African and southeast Asian descent. When carried as a genetic trait in the heterozygous state (one gene normal, one gene mutated), the presence of these abnormal hemoglobins likely reduces the morbidity and mortality of malaria, providing the carriers with a survival advantage.


Explain why Southeast Asians with alpha-thalassemia are more likely than Africans with alpha-thalassemia to have a child with hydrops fetalis.

In those of southeast Asian descent, both genes on the same chromosome are usually missing, which means the person has one normal chromosome (with 2 Alpha genes) and one without any Alpha genes (- - / AA). This person can pass on a chromosome with no functional A genes, and if the other parent contributes a similar chromosome, the offspring will inherit no A genes. The fetus will be unable to make any normal form of hemoglobin, since ! chains are necessary for all normal hemoglobin molecules, which leads to death in utero (called “hydrops fetalis”) or at birth. Bone marrow transplantation has been successfully performed in utero to prevent hydrops fetalis in affected pregnancies.


Describe approaches to treatment for thalassemia.

In severe thalassemias, RBC transfusions are started within the first 2 years of life to maintain hemoglobin values generally between 8 and 10 g/dL, which avoids excessive bone marrow expansion and extramedullary hematopoiesis, and permits adequate growth and development. However, within 1-2 years of the initiation of transfusion, significant iron overload occurs, and within 10 years, significant cardiac dysfunction develops unless chelation therapy is started. In B-thalassemia, there is an excess of ! chains.In the absence of B chains, increasing the production of G chains provides a pool of chains to combine with the excess A chains, reducing their harmful effects in the RBC. Hydroxyurea, butyrate, and decitabine have variable effects on G-chain and Hb F production, and may benefit some patients with B-thalassemia major.Thalassemia can be cured by successful bone marrow transplantation. Thalassemia-free survival at 20 years is about 70% in those who receive bone marrow from HLA-identical unaffected siblings. Unfortunately, only about 30% of patients have a matched sibling; ongoing work suggests that the use of HLA-matched unrelated donors may be an alternative. Sibling cord blood transplantation, as a source of stem cells, has not generally been successful to date due to graft rejection.


Explain how newborn screens can be used to diagnose thalassemia.

Virtually all infants born in the United States are screened at birth for hemoglobinopathies, using the blood from a heel stick placed on filter paper, as is done for the PKU and other sponsored newborn screening tests. The purpose is early identification of sickle cell disease, so that parental education and prophylactic penicillin can be provided to prevent early mortality. However, it is also an opportunity to identify children with other forms of hemoglobinopathies, including B-thalassemia major.