Hemoglobinopathies and Sickle Cell Disease: Types, Pathophysiology, and Diagnosis

What are hemoglobinopathies?

Conditions with qualitative or quantitative abnormalities in hemoglobin synthesis.

What percentage of hemoglobin variants are clinically significant hemolytic anemias?

About 200 of more than 1000 variants.

What causes most hemoglobin variants?

Single amino acid substitutions in the globin chains due to point mutations.

What are the components of normal hemoglobin?

Iron, protoporphyrin IX, and globin.

How many polypeptide chains compose hemoglobin?

Four polypeptide chains: alpha, beta, gamma, delta, epsilon, and zeta.

What is the primary structure of hemoglobin?

The number and sequence of amino acids in each globin chain.

What is the secondary structure of hemoglobin?

The helical conformation of the amino acid chain.

What is the tertiary structure of hemoglobin?

The bending of the secondary structure into a 3D shape.

What is the quaternary structure of hemoglobin?

The assembly of heme groups resulting in functional hemoglobin.

What are the two main classifications of hemoglobinopathies?

Qualitative and quantitative abnormalities.

What is thalassemia?

A type of hemoglobinopathy characterized by decreased production of hemoglobin chains.

What is the most common type of severe hemoglobinopathy?

Sickle cell anemia.

What is the estimated prevalence of sickle cell anemia in the U.S.?

1 in 375 African American live births.

What is the genetic basis of sickle cell anemia?

Homozygous form producing hemoglobin S (HbS).

What amino acid substitution causes sickle cell disease?

Valine replaces glutamic acid in the beta-globin chain.

What factors influence the sickling process in sickle cell anemia?

Oxygen tension, pH, and dehydration.

What are the clinical features of sickle cell anemia?

Chronic hemolytic anemia, vaso-occlusion, and tissue damage.

What are the three types of sickle crises?

Aplastic crisis, hemolytic crisis, and vaso-occlusive crisis.

What is an aplastic crisis?

An acute condition associated with infection where the marrow is overworked.

What characterizes a hemolytic crisis?

Acute anemia with a fall in hemoglobin, increased reticulocytes, and jaundice.

What is a vaso-occlusive crisis?

Painful tissue damage due to decreased blood flow and hypoxia.

What infections are common in patients with sickle cell anemia?

Bacterial infections, particularly from Streptococcus pneumoniae and Hemophilus influenzae.

What is hyposthenuria in the context of sickle cell anemia?

Inability of the kidney to concentrate urine, indicating kidney damage.

What is the hallmark of sickle cell anemia?

Vaso-occlusive crisis leading to painful tissue damage.

What is the significance of HbS in relation to malaria?

Individuals with HbS may have some protection against malaria, but severe infections are common due to splenic dysfunction.

What is the typical hemoglobin level in patients with HbSS?

Around 4 to 8 g/dL, indicating severe chronic anemia.

What is the role of hydration in managing sickle cell crises?

Adequate rehydration is a mainstay of treatment during painful crises.

What is the main cause of stroke in sickle cell patients?

Possibility of occlusion occurs in the brain.

What is sickle cell trait?

Found in individuals with one normal beta gene and one abnormal beta gene, producing both HbA and HbS in a 60:40 ratio.

What are common symptoms of sickle cell trait?

Patients are generally asymptomatic but may experience hyposthenuria and occasional hematuria.

What factors can promote sickling in sickle cell patients?

Severe respiratory infections, unpressurized air travel, anesthesia, and congestive heart failure.

What tests are involved in the laboratory diagnosis of sickle cell disease?

CBC, retic count, PB smear, Hgb electrophoresis, and measurement of Hgb A2 and F.

What is the typical hemoglobin level in sickle cell anemia?

Between 6 and 8 g/dL.

What types of cells are seen in a sickle cell anemia blood smear?

Target cells, fragment cells, polychromasia, NRBCs, and sickle cells.

What is the significance of Howell-Jolly bodies in sickle cell disease?

They indicate stressed erythropoiesis.

What is the definitive test for sickle cell disease?

Electrophoresis on cellulose acetate at alkaline pH, followed by citrate agar at acid pH if necessary.

What does a patient with sickle cell anemia produce in terms of hemoglobin?

No normal hemoglobin A, with HbS constituting 80% or more of total hemoglobin.

What is the treatment for infants with HbSS disease in the US?

Preventative therapy with penicillin due to the risk of S. pneumoniae infections.

What is the role of hydroxyurea in sickle cell disease treatment?

It increases levels of HbF, which helps decrease HbS polymerization.

What is Hemoglobin C disease?

A condition found almost exclusively in the black population, characterized by mild chronic hemolytic anemia.

What is the typical hemoglobin composition in HbC disease?

Approximately 95% HbC with no hemoglobin A present.

What is Hemoglobin D disease?

Caused by an amino acid substitution in the beta chain, typically asymptomatic in both homozygous and heterozygous states.

What are the clinical manifestations of Hemoglobin E disease?

Little to no anemia, target cells, and microcytic, hypochromic anemia.

What is the significance of high-affinity hemoglobins?

They result in less oxygen delivery to tissues, causing hypoxia and stimulating EPO production.

What is methemoglobinemia?

A condition where methemoglobin levels exceed 1% of total hemoglobin, leading to cyanosis.

What are the three main causes of methemoglobinemia?

Hemoglobin M variants, NADH-diaphorase deficiency, and toxic substances.

What is the role of electrophoresis in diagnosing hemoglobin disorders?

It identifies normal and abnormal hemoglobins based on their migration rates in an electric field.

What is the typical reticulocyte count in sickle cell disease?

Often elevated, reflecting increased erythropoiesis.

What does tube solubility testing indicate in sickle cell disease?

Presence of sickling hemoglobin will cause turbidity in the solution.

What is the expected reticulocyte count in sickle cell anemia?

Between 5-20%.

What is the significance of the tube solubility test?

It can yield positive results for other hemoglobins like HbC and HbM.

What is the expected morphology of RBCs in HbC disease?

Normochromic normocytic with microspherocytes, fragments, and folded cells.

What is the treatment for acute situations in sickle cell disease?

Transfusion may be required, but exchange transfusions are preferred.