Chapter 101. Hemolytic Anemias and Anemia Due to Acute Blood Loss (Part 7) Clinical Presentation and Diagnosis The spectrum of clinical severity of HS is broad. Severe cases may present in infancy with severe anemia, whereas mild cases may present in young adults or even later in life. In women, HS is sometimes first diagnosed when anemia is investigated during pregnancy. The main clinical findings are jaundice, an enlarged spleen, and often gallstones; frequently it is the finding of gallstones in a young person that triggers diagnostic investigations. The variability in clinical manifestations that is observed among patients with HS is largely due to the different underlying molecular lesions (Table 101-3). Not only are mutations of several genes involved, but individual mutations of the same gene can also give very different clinical manifestations. In milder cases, hemolysis is often compensated (see above), and this may cause variation even in the same patient, due to the fact that intercurrent conditions (e.g., infection) cause decompensation. The anemia is usually normocytic, with the characteristic morphology that gives the disease its name. A characteristic feature is an increase in mean corpuscular hemoglobin concentration (MCHC): this is almost the only condition in which high MCHC is seen. When there is a family history, it is usually easy to suspect the diagnosis, but there may be no family history for at least two reasons: (1) The patient may have a de novo mutation, i.e., a mutation that has taken place in a germ cell of one of his parents or early after zygote formation; and (2) the patient may have a recessive form of HS (Table 101-3). In most cases the diagnosis is confirmed on the basis of red cell morphology and a test for osmotic fragility, a modified version of which is called the "pink test." In some cases a definitive diagnosis can be obtained only by molecular studies demonstrating a mutation in one of the genes underlying HS. This is carried out only in laboratories with special expertise in this area. Hereditary Spherocytosis: Treatment There is currently no treatment aimed at the cause of HS; no way has yet been found to correct the basic defect in the membrane-cytoskeleton structure. However, it has been apparent for a long time that the spleen plays a special role in HS, through a dual mechanism. On one hand, as in many other HAs, the spleen itself is a major site of destruction; on the other hand, transit through the splenic circulation makes the defective red cells more spherocytic and therefore accelerates their demise, even though lysis may take place elsewhere. For these reasons, splenectomy has long been regarded as a prime, almost obligatory therapeutic measure in HS. However, it also increases the risk of certain infections, and therefore current guidelines (not evidence-based) are as follows. 1. Avoid splenectomy in mild cases. 2. Delay splenectomy until at least 4 years of age, after the risk of severe sepsis has peaked. 3. Antipneumococcal vaccination before splenectomy is imperative, whereas penicillin prophylaxis postsplenectomy is controversial. 4. HS patients often may require cholecystectomy. It used to be considered mandatory to combine this procedure with splenectomy, but this may not be always necessary. Hereditary Elliptocytosis HE is at least as heterogeneous as HS, both from the genetic (Table 101-3) and from the clinical point of view. Again it is the shape of the red cells that gives the name to these conditions, but there is no direct correlation between elliptocytic morphology and clinical severity. In fact, some mild or even asymptomatic cases may have nearly 100% elliptocytes, whereas in severe cases, all sorts of bizarre poikilocytes may predominate (Fig. 101-3B, C). Clinical features and recommended management are similar to those for HS. Although the spleen may not have the specific role it has in HS, in severe cases splenectomy may be beneficial. The prevalence of HE causing clinical disease is similar to that of HS. However, an asymptomatic form, referred to as Southeast Asian ovalocytosis, has a frequency of up to 7% in certain populations, presumably as a result of malaria selection. Stomatocytosis This rare condition with autosomal dominant inheritance draws its name (mouth-like cells) from the fact that the normally round-shaped central pallor of red cells is replaced by a linear-shaped central pallor. Hemolysis is usually relatively mild. Splenectomy is contraindicated as it has been followed in a majority of cases by severe thromboembolic complications. Enzyme Abnormalities When there is an important defect in the membrane or in the cytoskeleton, hemolysis is a direct consequence of the fact that the very structure of the red cell is abnormal. Instead, when one of the enzymes is defective, the consequences will depend on the precise role of that enzyme in the metabolic machinery of the red cell, which, in its first approximation, has two important functions: (1) to provide energy in the form of ATP, and (2) to prevent oxidative damage to hemoglobin and to other proteins. . Chapter 101. Hemolytic Anemias and Anemia Due to Acute Blood Loss (Part 7) Clinical Presentation and Diagnosis The spectrum of clinical severity. prophylaxis postsplenectomy is controversial. 4. HS patients often may require cholecystectomy. It used to be considered mandatory to combine this procedure with splenectomy, but this may not. approximation, has two important functions: (1) to provide energy in the form of ATP, and (2) to prevent oxidative damage to hemoglobin and to other proteins.