Microcytic Anemia: Overview & Thalassemias

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Pathophysiology

Summary

Microcytic anemia is a subtype of anemia characterized by a mean corpuscular volume (MCV) less than 80. This form of anemia is commonly remembered by the mnemonic T.A.I.L.S, which stands for Thalassemia, Anemia of chronic disease, Iron deficiency, Lead, and Sideroblastic Anemia. In microcytic anemia, reticulocytes, which are immature RBCs with "net-like" chromatin, remain normal, but their count is typically low (less than 3%). The condition manifests as RBCs with microcytosis and hypochromia.

A hallmark feature of microcytic anemia is the appearance of target cells, which are formed due to an excess membrane on microcytic RBCs that lead to folded cell membranes and a characteristic target appearance.

Among the various causes of microcytic anemia, thalassemia stands out as a condition caused by dysfunctional hemoglobin production, which can arise from defects in either alpha or beta globin chains. Normal hemoglobin A1 is composed of two alpha and two beta subunits. Alpha globin chains are encoded on chromosome 16, and each chromosome carries two alpha globin alleles, making for a total of four alleles. Conversely, beta globin chains are encoded on chromosome 11.

Alpha thalassemia is categorized into different types based on the severity and genetic background. Alpha thalassemia minima is usually asymptomatic. Alpha thalassemia trait is caused by the deletion of two alpha subunits and leads to mild anemia, may can result in a compensatory increase in RBC count. However, the newly formed RBCs less functional, resulting in a microcytic anemia with hypochromic RBCs.

Hemoglobin H disease is a form of alpha thalassemia caused by the deletion of three alpha globin genes. Hemoglobin H is composed of a tetramer of beta globin chains and has an abnormally high affinity for oxygen, resulting in decreased oxygen delivery to tissues and subsequent hypoxia. On electrophoresis, hemoglobin H migrates faster than normal hemoglobin A1. This form of hemoglobin also tends to precipitate, forming inclusion bodies that damage RBC membranes and lead to extravascular hemolysis. Clinically, hemoglobin H disease presents as microcytic anemia with hypochromic RBCs and ranges from moderate to severe in severity.

Alpha thalassemia major is an even more severe condition, caused by deletions in all four alpha globin genes. This leads to the formation of Hemoglobin Bart’s, which is a tetramer of gamma subunits. Like hemoglobin H, hemoglobin Bart's has high oxygen affinity, causing minimal oxygen delivery to tissues. Hemoglobin Bart’s can cause hydrops fetalis through precipitation of hemoglobin Bart’s, which leads to hemolysis ad severe hypoxia, resulting in a high-output heart failure that leads to total body edema (hydrops in fetus).

Beta thalassemias are caused by mutations in the beta globin gene and can occur as mRNA splicing defects or premature stop codons, resulting in fewer or no subunits produced. Beta thalassemia minor is caused by a mutation in one beta allele and leads to mild anemia. In this form, excess alpha subunits precipitate to form inclusion bodies, which trigger extravascular hemolysis, primarily in the spleen. Beta thalassemia minor leads to increased production of HbF (alpha & gamma globins) and HbA2 (alpha & delta globins).

Beta thalassemia intermedia is caused by mild splicing defects in both beta genes and results in moderate anemia. Beta thalassemia major, on the other hand, is a severe form caused by complete deficiency of both beta genes. This form leads to extramedullary hematopoiesis in the liver, spleen, and bones, resulting in hepatosplenomegaly and characteristic facial changes like ‘chipmunk facies’ and a ‘crew cut’ appearance of the skull bones on X-ray. It's also associated with dramatic poikilocytosis—an abnormal RBC morphology—including microcytes, target cells, and teardrop cells. Beta thalassemia major patients often require chronic RBC transfusions, which may cause secondary hemochromatosis. Additionally, these patients are at risk for aplastic crisis due to infection with Parvovirus B19.

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FAQs

What is microcytic anemia and what are its common etiologies?

Microcytic anemia is characterized by red blood cells that are smaller than normal, with a mean corpuscular volume (MCV) of less than 80. The condition is commonly caused by factors summarized by the acronym T.A.I.L.S: Thalassemia, Anemia of chronic disease, Iron deficiency, Lead exposure, and Sideroblastic Anemia. In microcytic anemia, the reticulocyte count is typically low, and RBCs often display microcytosis and hypochromia.

How does the reticulocyte count relate to microcytic anemia?

In microcytic anemia, the reticulocyte count is typically low, falling below 3%. Reticulocytes are immature red blood cells with a ‘net-like' chromatin structure. A low reticulocyte count suggests that the bone marrow is not effectively compensating for the anemia by increasing red blood cell production. This is often due to the inability to increase hemoglobin synthesis, which is a common feature in conditions like thalassemia and iron deficiency that lead to microcytic anemia.

What is thalassemia and how does it contribute to microcytic anemia?

Thalassemia is a hereditary form of anemia resulting from impaired hemoglobin production. Normal hemoglobin is composed of two alpha and two beta subunits. In thalassemia, either the alpha or beta globin chains are defective or absent, leading to dysfunctional hemoglobin. This results in microcytic anemia characterized by red blood cells that are smaller and paler than normal.

What is the impact of hemoglobin H disease on microcytic anemia?

Hemoglobin H disease is a form of alpha thalassemia caused by the deletion of three alpha globin genes. This condition leads to the formation of hemoglobin H, which is composed of four beta globin chains. Hemoglobin H has a high affinity for oxygen, impairing its delivery to tissues and causing hypoxia. Additionally, hemoglobin H can form inclusion bodies that damage red blood cell membranes, leading to extravascular hemolysis and moderate to severe microcytic anemia.

What are the key characteristics and complications associated with beta thalassemia major?

Beta thalassemia major is the most severe form of beta thalassemia, resulting from a complete deficiency of both beta genes. This leads to severe anemia and a range of complications including extramedullary hematopoiesis in the liver, spleen, and bone, causing hepatosplenomegaly and facial and skull bone deformities. The red blood cells show significant morphological abnormalities, such as microcytes, target cells, and teardrop cells. Complications may include iron overload due to frequent transfusions and the risk of aplastic crisis. Treatment involves chronic red blood cell transfusions.