Silent Carrier

Two functioning alpha genes

Three functioning alpha genes

Figure 5.12 Clinical states of alpha thalassemia.

sents 5% to 40% on alkaline electrophoresis (see Chapter 8). Hemoglobin levels are less than 10 g/dL (average, 6 to 8 g/dL), and reticulocyte counts are in the range of 5% to 10%. There is a microcytosis and hypochromia observed in the peripheral smear with red cell fragments (Fig. 5.13). An unusual inclusion, hemoglobin H inclusion, is formed. On supravital staining, with brilliant cresyl blue or crystal violet, it looks like a pitted golf ball (Fig. 5.14). In peripheral circulation, this inclusion is usually pitted from the red cell, leaving the cell more fragile and less elastic with a shortened life span. Individuals with hemoglobin H disease have a lifelong anemia with variable splenomegaly and bone changes.

The final two clinical conditions are less severe: the two-gene deletion state, alpha thalassemia trait, and the one-gene deletion state, the silent carrier. The individual with the alpha thalassemia trait possesses only two viable hemoglobin A genes and may only have a mild anemia with many microcytic, hypochromic cells. Some hemoglobin Barts will be formed. The silent carrier will be hematologically normal or slightly micro-

cytic, and therefore the patient may be unaware of his or her alpha gene status. Since diagnosing patients from both of these alpha thalassemia subsets (alpha thal-

Figure 5.13 Peripheral smear from an individual with hemoglobin H.
Alpha Thalassemia Peripheral Smear

H Bodies in mature red cell

Figure 5.14 Hemoglobin H inclusions as seen after brilliant cresyl blue staining.

H Bodies in mature red cell

Figure 5.14 Hemoglobin H inclusions as seen after brilliant cresyl blue staining.

assemia trait/silent carrier) may be difficult, it is important to note that the presence of elliptocytes and target cells in their peripheral smears can present a high predictive value, if smears are carefully reviewed for these findings.16

Diagnosis and Treatment

If the most severe alpha thalassemic condition is suspected, especially in pregnancy, amniocentesis fluid or chronic villi sampling may be obtained and examined for the presence of alpha genes through molecular diagnostic procedures. In the case of hydrops Barts fetalis, most of these pregnancies are terminated or individuals are delivered of severely edematous fetuses that are not viable. Cord blood is usually tested for hemoglobin electrophoresis, which usually shows a high percentage of hemoglobin Barts. For these individuals and individuals in high-risk ethnic groups, genetic counseling is strongly advised. Hemoglobin H may be suspected if CBCs show slightly elevated red blood cell counts combined with extremely low MCVs, less than 60 fL, and RDW results that are extremely elevated (normal value, 11% to 15%) owing to the misshapened red cells and fragments in comparison to the more homogeneous microcytic hypochromic population as seen in IDA. Although hemoglobin H may be present at 5% to 40%, failure to demonstrate an abnormal hemoglobin band by electrophoresis should not eliminate the patient as suspect.17 Hemoglobin H, a fast-moving hemoglobin on alkaline electrophoresis, may be missed by traditional methods. The final two conditions— alpha thalassemia trait and the silent carrier condition—may not be recognized on peripheral smear analysis because their hematological pictures are not that abnormal.

Treatment for hemoglobin H disease is supportive, with transfusions given only if necessary. Iron deficiency must be eliminated as a reason for the microcytic indices so that the patient will not be given iron unnecessarily.

Beta Thalassemia Major: Cooley's Anemia, Mediterranean Fever

This inherited blood disorder affects million of individuals worldwide. In the United States alone, over 2 million individuals are carriers of the thalassemic gene, resulting in significant penetrance of this gene, which often results in disease. In beta thalassemia major, there is little or no beta chain being synthesized; consequently, there is no (or a very minor amount of) hemoglobin A being synthesized. This condition results from a union between two carriers, and according to Mendelian genetics, there is a one-in-four chance for a severely affected individual to be born (Fig. 5.15). The other offspring may be carriers. Beta thalassemia major is a serious genetic blood disorder, affecting multiple organs, quality of life, and longevity. Most infants born with thalassemia major will not be ill for the first 6 months. Because fetal hemoglobin is the majority hemoglobin at birth, infants do quite well. But, in the normal sequence of events, gamma chains are silenced and beta chains increase, forming hemoglobin A somewhere between 3 and 6 months. As there are no beta chains to combine with the alpha chains, hemoglobin F continues to be made; but there is an imbalance of alpha chains. When alpha chains cannot combine, they are unpaired and precipitate inside the red cell, causing a markedly decreased life span (7 to 22 days). Between 2 and 4 years old, most young children with beta thalassemia major begin to show a failure to thrive, irritability, enlarged spleens, symptoms of anemia, jaundice, and transfusion requirement.

Living With Thalassemia Major

Patients and families with thalassemia major balance multiple health issues on a daily basis as they struggle to maintain a normal life. Medical management of this disease is continuous, frustrating, and disruptive for children who have the disease and parents who are caregivers and carriers. Severe anemia underlies most of the other complications, with hemoglobin values, although variable, often in the range of 6 to 9 g/dL, about one-half the normal level. The patient's peripheral smear shows a severe microcytic hypochromic process with a high number of nucleated red blood cells, marked polychro-

78 Part II • Red Cell Disorders

IF Both parents carry the beta thalassemia trait

IF Both parents carry the beta thalassemia trait

Skull Beta ThalassemiaSkin Colours

masia, and a high degree of red cell morphology. (See Fig. 5.11.) Because this chronic anemic state has led to chronic overexpansion of the capable bone marrow, (the bone marrow increases its output up to 20 times), the quality of bone that is laid down is thin and fragile. Pathological fractures and bony changes in the facial structure (thalassemic facies) and skull are normally seen and give the thalassemic individual a strange look. Bossing or protrusion of the skull is prominent, as is orthodontic misalignment. The spleen reaches enormous proportions because abnormal red cells have been harbored and sequestered on a daily basis. Enlarged spleens cause excessive hemolysis and discomfort. Many patients have splenec-tomies and this does ameliorate some of the anemia issues, but it presents the patient with other challenges, because splenectomy is not a benign procedure (see Chapter 2). Yet one of the gravest problems is iron overload. Patients with beta thalassemia major absorb more iron through diet because of increased erythro-poiesis, and they accumulate iron as a result of taking in 200 mg additional iron with each transfusion of packed cells.18 Thalassemia major patients in the United States have an average transfusion regimen of blood once every 2 to 5 weeks, so iron accumulation is expected and needs to be medically monitored and managed. The author refers the reader to the Cooley's Anemia Foundation Website for more information (www. cooleysanemia.org).

Treating and Managing Thalassemia Major

Thalassemia major patients will be on either a low-transfusion or a high-transfusion protocol. A low-transfusion protocol treats the patient symptomatically, administering transfusion when symptoms warrant. A high-transfusion protocol aims to keep the patient's hemoglobin level close to 10 g/dL; the patient is transfused every 2 to 5 weeks. There are good arguments for both, bearing in mind that transfusion exposes the individual not only to excess iron but also to foreign red cell antigens and other blood-borne diseases. A hightransfusion protocol gives the patient the best hope for a normal quality of life, by increasing his or her hemoglobin and providing better bone quality, better growth, less iron, and near-normal spleen size. Yet, iron overload looms as a major outcome of the high-transfusion protocol and is the major focus of clinical management.

Patients need to be assessed for liver, pancreatic, endocrine, and cardiac iron. Although noninvasive procedures are available, they are specialized and not available at every clinical facility. Iron overload poses significant risk to cardiac function and leads to hepatic and endocrinological complications. Iron chelation is recommended once the serum ferritin level has reached about 1000 pg/L, and this usually correlates with about 10 to 20 transfusions from the onset of diagnosis.19 The procedure for chelation with Desferal has been explained earlier in this chapter. Compliance is critical in thalassemia major patients, yet difficult to maintain, as the patient moves from childhood to adolescence and becomes less willing to be hooked up to the infusion pump. In late 2005, an oral chelating agent, Exjade or ICL670 (Novartis), became available to this patient population. Despite compliance with chelating therapy, cardiac complications continue to be the leading cause of death in patients with thalassemia major.

Bone marrow transplantation and stem cell transplantation are therapeutic modalities that are also available for the severe thalassemic patient. For patients considering bone marrow transplant, finding a compatible donor is the necessary first step. If this can be accomplished, then bone marrow transplant should be considered early before the patient develops too many complications of thalassemia. The transplant procedure itself is rigorous and not without risks. Stem cell transplantation, although a viable alternative, takes much forethought and is often limited by the fact that stem cells have not been collected from the umbilical cord post delivery.

Thalassemia Intermedia and Beta Thalassemia Trait i it .c i

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