Cooley's anemia is also known as beta-thalassemia major and is the most severe type of beta-thalassemia, characterized by a total absence of beta globin chains in the hemoglobin. It may result in severe anemia, which may require regular blood transfusions.
There are three forms of beta thalassemias: beta thalassemia major, beta thalassemia minor, and beta thalassemia intermedia. Thalassemia major and intermedia carry a high risk of complications including gallstones and splenomegaly.
Beta-thalassemia major or Cooley's anemia presents in infancy with severe anemia, failure to thrive, growth retardation, and skeletal deformities. Other common symptoms include diarrhea and irritability. Hepatosplenomegaly is a classic feature of beta thalassemia major. Untreated, beta thalassemia major may lead to heart failure and death. Other features are osteoporosis and venous thrombosis.
Another complication of beta thalassemia major is iron toxicity, resulting from repeated blood transfusions. Iron overload is also induced by the increased gastrointestinal absorption of iron, increased hemolysis and ineffective erythropoiesis seen in beta thalassemia major. Iron overload causes iron deposition in tissues causing severe complications including liver cirrhosis, liver carcinoma, myocardial siderosis, testicular failure and failure of sexual development, pancreatitis and diabetes mellitus, insufficiency of the adrenal, thyroid, and parathyroid glands. Cardiopulmonary complications associated with beta thalassemia major include left ventricular dysfunction, valvulopathies, arrhythmias, pericarditis, and pulmonary hypertension.
In uncomplicated cases, skeletal deformities include genu valgum, frontal bossing, malar bone prominence, depression of the nasal bridge, and maxillae hypertrophy. In regularly transfused patients, growth retardation may be absent.
Diagnosis of Cooley's anemia can be made on clinical grounds, however, investigations are necessary to confirm the diagnosis and exclude other conditions. Peripheral blood film shows mild microcytic anemia, target cells and poikilocytes, brisk erythropoiesis and increased numbers of erythroblasts with a normal erythrocyte count. Heinz bodies, which indicate denatured hemoglobin, may also be present on a peripheral blood film .
Elevated HbA2 on electrophoresis or column chromatography is diagnostic of the beta thalassemia trait. The increased HbA2 may be masked in patients with concomitant iron deficiency and in patients with a delta-beta thalassemia trait. Furthermore HBA2 level is normal in patients with alpha thalassemia.
In cases where the investigations provide inconclusive results, free erythrocyte porphyrin (FEP) tests may be conducted. FEP is normal in patients with the beta thalassemia trait. The level of FEP may, however, be elevated in patients with lead poisoning and iron deficiency. Iron studies including serum iron, transferrin, and ferritin levels may be done to exclude iron deficiency and anemia of chronic disorders as the cause of the anemia.
Further blood tests may reveal indirect hyperbilirubinemia, elevated lactate dehydrogenase (LDH), and low haptoglobin levels. These indicate excessive hemolysis and ineffective erythropoiesis. Other hematological investigations required include bone marrow analysis and determination of the Mentzer index. Bone marrow analysis is necessary to exclude other causes of microcytic anemia such as sideroblastic anemia. The Mentzer index refers to the mean corpuscular volume for each red cell count. Mentzer index less than 13 indicates a diagnosis of the beta thalassemia trait, while a score greater than 13 suggests iron deficiency.
Imaging studies are necessary to determine the presence of complications of Cooley's anemia, particularly skeletal deformities and cardiac complications. Bone imaging reveals an expansion of the bone marrow cavity with thinning out of the bone cortex. This results from chronic stimulation of erythropoiesis. These bony changes are most commonly observed in the skull bones, vertebrae, long bones, and pelvis.
Abdominal imaging such as ultrasound scanning, MRI, or CT may show gallstones, liver cirrhosis, and hepatomegaly. Cardiac MRI is the gold standard for evaluating cardiac overload and cardiac indices . Echocardiography, chest X-rays, and electrocardiogram are necessary to exclude cardiac complications.
Management of beta thalassemia major involves lifelong blood transfusions, however, a bone marrow transplant provides a definitive cure for patients . Iron chelation is considered in patients who receive frequent blood transfusions and have developed iron overload. Iron chelation treatment has greatly reduced mortality from iron overload. Deferoxamine and deferiprone are the most commonly used iron chelators.
The goal of long-term transfusion is to achieve and maintain a hemoglobin level of 9-10g/dL. Regular transfusions help to correct the anemia and suppress endogenous erythropoiesis, which in turn, suppresses extra medullary stimulation. Alloimmunization can be prevented by performing an initial typing of the red blood cells for rhesus and ABO antigens and compatibility. The recommended transfusion regimen includes the administration of leukocyte-poor erythrocytes at 8-15ml/kg of body weight over 1-2 hours.
Bone marrow transplantation is indicated in severe cases and it provides a significant reduction in the patient's requirement for blood transfusion . Emerging medical therapies include gene therapy to deliver the globin gene into the cells and pharmacologic modalities which stimulate the production of fetal hemoglobin.
Allogeneic hematopoietic transplantation may provide a definitive cure for some patients. The first successful allogeneic stem cell transplant was reported in 1982 involving an HLA-identical sibling donor . This procedure is best done by an Italian group of hematologists led by Lucarelli . This group has reported a 90% long-term survival in favorable patients, that is, those of young age, HLA match or compatibility, and those with no organ damage. However, complications of transplantation such as graft versus host disease should be considered and prevented.
Dietary modifications may play a role in the treatment of beta thalassemia major, for example, tea may reduce iron absorption in the intestine and intake of vitamin C may improve the excretion of iron in patients who are on iron chelators. However, some reports have indicated that excessive consumption of vitamin C without concurrent administration of iron chelators may cause life-threatening arrhythmias.
Surgical management of beta thalassemia major involves splenectomy. Splenectomy is not routinely indicated in beta thalassemia minor. Splenectomy is indicated if the annual transfusion requirement of the patient is above 200-220ml RBCs/kg. Splenectomy serves to reduce extra medullary hemopoiesis and reduce the patient's transfusion requirement and, in turn, to prevent iron toxicity. This procedure is recommended only for patients above 6 years old, because of the risk of post-splenectomy sepsis in those younger than 6 years old. Furthermore, vaccination of the patient against pneumococcus, meningococcus, and Hemophilus influenza is essential before the procedure, to minimize the risk of post-splenectomy sepsis caused by these encapsulated organisms. Prophylactic penicillin is necessary because of the aforementioned risk. Of note, also, is that splenectomy may increase the risk of thrombocytosis.
In cases of symptomatic cholelithiasis, cholecystectomy may be considered. This procedure may be performed together with splenectomy.
Thalassemias are a result of mutations in the genes responsible for globin chain synthesis. Thalassemias are named according to the defective globin chains. The hemoglobin molecule consists of 2 alpha chains and 2 beta chains with heme molecules attached to each chain; defects in the alpha globin genes cause alpha-thalassemia while defects in the beta globin genes cause beta thalassemia.
Beta-thalassemia is an autosomal recessive disorder caused by a complete absence or a significantly reduced production of the beta-globin protein, referred to as beta-zero and beta-plus thalassemia respectively. The imbalance between the alpha and beta chains of the hemoglobin molecule results in hypochromic anemia  .
As with 50% of all genetic disorders , in Cooley's anemia, there is a mutation in the assembly of the messenger RNA (mRNA). The mutation causes the obliteration of the boundary between the introns and exons of the mRNA. This obliteration results in an abnormal assembly of the mRNA, that involves additional continuous length or breakage of the mRNA length. Although hemoglobin may still be formed normally if all the coding sections of the mRNA are present, the additional fragments result in functional defects of the hemoglobin molecule.
Thalassemias are amongst the most common genetic disorders, affecting persons of all ethnic groups and regions. The incidence of Cooley's anemia is 1 in 100,000 individuals annually worldwide, but with an incidence rate of 1 in 10,000 in Europe.
Worldwide, 15 million patients suffer from symptomatic thalassemias. Beta thalassemia is more common in the Mediterranean countries including Italy, Spain, and Greece. It also occurs frequently in North Africa, Eastern Europe, and the Middle East, while the incidence of alpha thalassemia is higher in Southeast Asia, Africa, and the middle East.
Insufficient production or total absence of beta globin chains results in the synthesis of an abnormal and functionally impaired hemoglobin. The defective gene in Cooley's anemia is on chromosome 11. The insufficient production of the globin chains results in microcytic anemia. This necessitates repeated blood transfusions to compensate for the lack of red blood cells with beta globin chains. However, excessive blood transfusions result in iron overload, with deposits in the tissues, causing myocardial hemosiderosis and heart failure.
As it is a genetic disorder, Cooley's anemia cannot be prevented. However, genetic testing and prenatal diagnosis may be essential for management.
Thalassemias are a group of hematological disorders caused by defective and insufficient synthesis of the globin chains of the hemoglobin molecule. Mutation of the genes responsible for the synthesis of the alpha chains is called alpha thalassemia and mutation in the genes responsible for the synthesis of the beta chains is called beta thalassemia.
Beta thalassemia is characterized by a mutation of one or both genes responsible for the synthesis of the beta globin chains. If the mutation is heterozygous, it is referred to as beta thalassemia minor or beta thalassemia trait, and if it is homozygous, it is classified as beta thalassemia major or Cooley's anemia. Both genes are located on chromosome 11. Beta thalassemia is inherited as an autosomal recessive disorder.
Beta thalassemia has a worldwide incidence rate of 1 in 100,000 . Beta thalassemia is most common in countries within the Mediterranean region including Greece, Spain, and Italy. It is less commonly found in North Africa and Eastern Europe.
Beta thalassemia minor may be asymptomatic or present with mild to moderate anemia. Cooley's anemia mostly presents with severe anemia, usually beginning at infancy, failure to thrive, irritability, and delayed milestone attainment. In Cooley's anemia, there is increased splenic hemolysis and extramedullary erythropoiesis. This results in splenomegaly, hepatomegaly, and changes in the bones including frontal bossing and cortical thinning.
Diagnosis of Cooley's anemia is necessary because of myriads of overlapping differentials. A peripheral blood film is required and may reveal microcytic anemia with target cells and poikilocytes. Other tests include iron studies, lactate dehydrogenase levels, serum bilirubin, electrophoresis, and free erythrocyte porphyrin test. Imaging studies including cardiac magnetic resonance imaging (cardiac MRI), electrocardiography, and abdominal computed tomography (CT) scans that may be necessary to exclude complications of Cooley's anemia.
Treatment of Cooley's anemia involves regular blood transfusions. However, the major complication of frequent blood transfusions in these patients is iron overload. Iron overload causes iron deposition in various tissues leading to liver cirrhosis, myocardial damage, pancreatic damage, diabetes mellitus, and testicular failure. The definitive treatment of Cooley's anemia is bone marrow transplant.
The red blood cells have a functional molecule called hemoglobin, which carries oxygen in the blood. Hemoglobin has a basic structure, comprising two pairs of protein chains called globin chains, each pair having an alpha and beta pair, and a heme molecule in each chain. Any defect in this basic structure impairs the functional ability of the hemoglobin molecule and, in turn, of the red blood cell. Conditions which result from an abnormality of the alpha and beta chains are called alpha and beta thalassemias respectively.
Each of the two beta globin chains is coded for by a gene in the chromosomes. If one gene is affected, the condition is called beta thalassemia minor, and beta thalassemia major if both genes are affected. Beta thalassemia major is also referred to as Cooley's anemia.
Cooley's anemia is a genetic disorder, that is, a condition which occurs due to mutations or changes in the genetic coding of a structure. This disorder is transmitted from parents to their offspring. The problem in Cooley's anemia is the production of an abnormal hemoglobin, hence a functionally impaired red blood cell. These abnormal red blood cells also have shortened life-spans, as they are frequently destroyed by an organ called the spleen. This causes the body to try and replenish the lost red blood cells by stimulating the structures ( bone marrow, liver, and spleen) in which red blood cell production occurs.
Symptoms of Cooley's anemia usually present within the first two years of a child's life. Because the red blood cells which are produced in this condition are abnormal and functionally impaired, it results in anemia. Anemia is a condition of a reduced level of normal red blood cells or the reduced ability of the red blood cells to carry oxygen to tissues. Anemia could be severe in Cooley's anemia.
As a result of the anemia, the liver, spleen and bone marrow are stimulated to produce more red blood cells, but this stimulation is excessive, leading to the enlargement of the liver and spleen, and thinning of the bones of the skull, spine, and the long bones. In the skull, the patient presents with a prominent and enlarged forehead referred to as frontal bossing.
Other symptoms include diarrhea, growth retardation, irritability, poor mental and social development. These patients are often treated with frequent blood transfusions, so another set of symptoms to be looked out for in these patients are symptoms of iron overload which results from the excessive breakdown of the hemoglobin molecule in red blood cells from the repeated blood transfusions. The complications of iron excess in the body include heart damage, liver disease, delayed sexual maturity from damage to the testes, and damage to other important organs.
A diagnosis is very important to manage this case. Blood studies are done to check for typical features of the disease such as an abnormal shape of the red blood cells, reduced size of the red blood cells, and signs of hemolysis such as too much bilirubin in the blood.
Other necessary investigations include imaging studies, such as magnetic resonance imaging (MRI), X-rays, or computed tomography (CT) scans to determine the presence of the complications aforementioned.
Treatment of Cooley's anemia is regular blood transfusions to replace the abnormal red blood cells and prevent the stimulation of red blood cell production in the liver and spleen. However, blood transfusion doesn't provide a definitive cure for patients with Cooley's anemia. The main complication with regular blood transfusion is iron overload which may cause damage to a lot of organs including the pancreas, liver, heart, and other glands. However, administration of certain drugs called iron chelators may be necessary to clear iron from the blood stream.
A bone marrow transplant provides a definitive cure for patients with Cooley's anemia and it involves a transplantation of the the primary cells which give rise to red blood cells from a matching donor. However, this procedure has a number of complications.
Surgical removal of the spleen, called splenectomy, is also necessary to treat Cooley's anemia. Splenectomy serves to reduce frequent red blood cell break down, and therefore, reduce a patient's need for blood transfusion. Splenectomy comes with certain risks which should be considered and avoided including infections and formation of blood clots.