1 What is anemia and how is it defined?

Anemia is the lack of normally formed, properly functioning red blood cells (RBCs) in the circulation, which impairs the body’s ability to oxygenate the tissues at optimal levels. Anemia may be quantitative (decreased RBC count), qualitative (disordered cellular morphology or hemoglobin structure), or a combination of both. These abnormalities can be shown on a complete blood count (CBC), hemoglobin electrophoresis, peripheral blood smear, or rarely, a bone marrow aspirate if necessary.

2 What are the three pathophysiologic mechanisms resulting in anemia?

Simply put, anemia can result from decreased production of RBCs, increased premature destruction of RBCs, or loss of RBCs from leakage out of the circulation, as in bleeding.

Impaired marrow production is seen in substrate deficiency states (iron/folate deficiency), disorders of heme synthesis (sideroblastic anemias), disorders of hemoglobin synthesis (thalassemias), impaired marrow responsiveness to erythropoietin (anemia of chronic disease), bone marrow–infiltrative conditions (malignancies), and conditions associated with reduced erythropoietin production (renal failure).

Increased RBC destruction can be seen in a variety of inherited and acquired conditions. Some of these are associated with abnormalities in RBC structure and function, such as hereditary spherocytosis, sickle cell anemia, glucose-6-phosphate dehydrogenase (G6PD) deficiency, and paroxysmal nocturnal hemoglobinuria (PNH). Others are associated with autoimmune and drug reactions, often leading to hypersplenism as the damaged cells are removed from the circulation.

Chronic blood loss (as in a slow intestinal bleed) typically causes an underproduction anemia by depleting the body’s iron stores. This loss can also occur in a menstruating woman with heavy menstrual bleeding, endometriosis, or uterine fibroids.

2 What are reticulocytes? What is a normal reticulocyte count?

Reticulocytes are immature RBCs produced by the bone marrow and released into the blood. The number of reticulocytes present in the peripheral blood provides an indication of how effectively the bone marrow is producing RBCs, and thus responding to an anemia.

A normal reticulocyte count varies between approximately 0.5% and 1.5%. A low or normal reticulocyte count in a setting of anemia typically indicates an underproduction anemia. However, calculation of the reticulocyte index (RI) can help determine whether or not the marrow compensation is appropriate for the severity of the anemia. The RI can be calculated by correcting the reticulocyte count for the degree of anemia:

With severe anemia (hematocrit <25%), reticulocyte precursors are released from the marrow earlier than normal reticulocytes. These must be accounted for when determining RI. Simply divide the calculated RI by a factor of 2 to yield the percentage of reticulocytes.

Example: Assuming a severe anemia with a hematocrit of 10% and a reticulocyte count of 2.5%, we have

Here, we had to divide by 2 to account for the proreticulocytes found in circulation during severe anemia. Although this is useful to know for your clinical years, it is unlikely that you will be expected to make this calculation on boards. At the minimum, know how to calculate RI without worrying about the severity of anemia.

A normal RI is 1. In the preceding example, the bone marrow (BM) is not appropriately compensating for the severe anemia by increasing reticulocyte release into the circulation. We would expect the reticulocyte count to exceed 3% in cases of anemia. In this situation, we can say that the bone marrow is unable to produce enough RBC precursors to ameliorate the anemia.

Note: An absolute reticulocyte count can be obtained by multiplying the reticulocyte count by the concentration of RBCs. For example, in a normal patient with a reticulocyte count of 1% and a RBC count of 5 × 10⁶/μL, the absolute reticulocyte count is 50,000 RBCs/μL.

3 What are the hemolytic anemias and how are they typically classified?

Hemolytic anemias are anemias in which RBC destruction (hemolysis) is the cause of the anemia. The cause may be either hereditary or acquired. Hereditary causes include hereditary spherocytosis, PNH, G6PD deficiency, and sickle cell anemia. Acquired hemolytic anemias can be further classified as autoimmune (e.g., autoimmune hemolytic anemia), drug-induced, or traumatic (e.g., mechanical prosthetic heart valves).

4 Regarding hemolytic anemia, what is the difference between intravascular and extravascular hemolysis?

Intravascular hemolysis occurs when RBCs are directly lysed within blood vessels. Causative factors range from complement-mediated hemolysis in PNH to mechanical fragmentation of RBCs by mechanical prosthetic valves or by fibrin clot products, as in microangiopathic hemolytic anemias, which often occur in the setting of disseminated intravascular coagulation (DIC). Extravascular hemolysis, as the name implies, takes place outside the vasculature. In extravascular hemolysis, splenic macrophages or Kupffer cells in the liver destroy RBCs due to structural or morphologic abnormalities of the RBCs (e.g., hereditary spherocytosis, hypersplenism).

5 Why is there a greater degree of hemoglobinemia and hemoglobinuria in intravascular hemolysis than in extravascular hemolysis?

In intravascular hemolysis, lysed RBCs spill their hemoglobin directly into the bloodstream (hemoglobinemia), which may then be filtered out into the urine (hemoglobinuria). In extravascular hemolysis, the hemoglobin in phagocytosed RBCs is metabolized intracellularly to bilirubin, reducing the amount of hemoglobin that ends up in the blood or urine (Table 12-1).

Table 12-1 Characteristics of Hemolysis

Haptoglobin, a serum protein that sops up free heme in the circulation, will attempt to reduce the free heme secondary to hemolysis regardless of etiology, causing its levels to decrease. For reasons just explained, haptoglobin will be more greatly reduced in the setting of intravascular hemolysis than in extravascular hemolysis. You should keep this in mind for boards!

6 How are microcytic, macrocytic, and normocytic anemias defined?

This classification scheme used to categorize anemias is based on the size of the RBCs found in the patient’s bloodstream. RBC size is generally determined by mean corpuscular volume (MCV), which is calculated by dividing hematocrit by RBC count per liter. Normal reference range is 80 to 100 fL. Anemias that remain in this range are classified as normocytic. Those that fall below this range are microcytic, and those above the range are termed macrocytic. Various causes of these three types of anemias will be explored throughout the cases presented in this chapter.

7 What is the usual cause of anemia in end-stage renal failure?

In the setting of end-stage renal failure, anemia is principally due to reduced production of erythropoietin by the diseased kidneys. However, uremia from renal failure can also make the bone marrow less responsive to erythropoietin. Anemia caused by renal failure typically responds well to exogenously administered erythropoietin.

1 What is the differential diagnosis for normocytic anemia?

Aplastic anemia

Hemolytic anemias

Hereditary

Spherocytosis

PNH

Sickle cell anemia

G6PD deficiency

Pyruvate kinase deficiency

Acquired

Autoimmune

Drug-induced

Traumatic

Myelodysplasia

Renal disease

Anemia of chronic disease

Blood loss

Case 12-1 continued:

A peripheral blood smear reveals sickled RBCs and Howell-Jolly bodies (Fig. 12-1).

Figure 12-1 Peripheral blood smear for patient in Case 12-1.

(From Stein JH: Internal Medicine, 4th ed. St. Louis, Mosby, 1998.)

2 What is the expected diagnosis now and what is the confirmatory test?

Sickle cell anemia, a hereditary hemoglobinopathy caused by a point mutation in position 6 of the β-globin chain, is expected. Hemoglobin electrophoresis can provide definitive evidence to make a diagnosis of sickle cell anemia. In this test, RBCs are obtained from the patient, lysed to free up the hemoglobin proteins, and separated by size and charge on a gel. A banding pattern develops that corresponds with the size of the hemoglobin proteins. Each specific type of hemoglobin has an identical banding pattern based on the hemoglobin variant present. Therefore, a patient with sickle cell anemia should show a hemoglobin electrophoresis banding pattern consistent with hemoglobin S (HbS) (the sickle cell variant).

Note: The presence of sickled cells on peripheral smear is diagnostic of sickle cell anemia but is not the confirmatory test. Electrophoresis is the gold standard.

3 What are the three main types of hemoglobin found within normal adult red blood cells? How does this expression pattern differ in sickle cell anemia?

The three primary types of hemoglobin in adult RBCs are hemoglobin A (α₂β₂), hemoglobin A₂ (α₂δ₂), and fetal hemoglobin F (HbF) (α₂γ₂). The vast majority (>95%) of hemoglobin in adult RBCs is normally of the hemoglobin A (HbA) type. Because sickle cell anemia is caused by a substitution of the hydrophobic valine for the hydrophilic glutamic acid in the β-globin protein, there is deficient production of HbA with increased expression of abnormal HbS.

4 What causes “sickling” of red blood cells in this disease?

In the deoxygenated form, HbS is significantly less soluble than HbA and is therefore predisposed to precipitate from the cytoplasm under conditions that cause higher concentrations of deoxyhemoglobin (e.g., hypoxemia, acidosis, hyperosmolarity/dehydration). Although the effects of hemoglobin precipitation are initially reversible, repeated bouts of hemoglobin precipitation lead to irreversible defects in structure and function of the RBC membrane, resulting in chronically sickled cells.

5 What is the mechanism of anemia in sickle cell anemia?

Anemia results from increased intravascular hemolysis due to mechanical fragmentation, although there is also a small component of impaired erythropoiesis at the level of the bone marrow.

6 If there is hemolysis producing the anemia, why is the spleen not palpable?

By the age of 5 years, 94% of sickle cell patients will have experienced autoinfarction of the spleen as a result of the tortuous circulation that the misshapen RBCs must pass through. Lacking adequate oxygenation, the spleen becomes small, dense, and fibrotic. Calification may be seen on abdominal x-ray films.

Note: Prior to autoinfarction, splenomegaly may occur. Splenomegaly occurs when RBCs occlude the efferent splenic vessels, leading to accumulation of blood within the spleen and consequent engorgement of the organ. This can sometimes lead to a splenic sequestration crisis, in which RBCs and platelets normally found within the general circulation pool in the enlarged spleen. Platelet counts and plasma levels of hemoglobin and hematocrit may fall below normal, causing hypovolemic shock and death.

7 Why are parents of children with sickle cell disease taught how to palpate the spleen whenever their children develop a febrile illness?

Various infections predispose to “splenic sequestration crises” in which the spleen enlarges acutely to aid in the immunologic response against the infection. This in massive RBC sequestration and hemolysis in sickle cell patients as the splenic cords are compressed, making it even more difficult for the rigid sickled cells to pass through. Such splenic sequestration causes a rapid drop in the hematocrit and may cause symptoms of intravascular depletion and hypovolemic shock. If access to medical care (e.g., RBC transfusion) is not available, the mortality rate for these sequestration crises can approach 15%.

8 What are vaso-occlusive crises?

This is a term to describe conditions under which increased RBC sickling occurs. The increased sickling of RBC occludes blood vessels, resulting in local lactic acidosis and pain secondary to tissue hypoxia.

9 What factors are thought to increase the risk of experiencing these crises?

The aforementioned factors that increase deoxyhemoglobin concentrations, such as dehydration, hypoxemia, and acidosis, may all “trigger” these crises.

10 Why should this boy receive vaccinations against encapsulated bacteria?

Recurrent vaso-occlusive crises in the spleen typically lead to fibrotic scarring of the spleen (referred to as autosplenectomy), which significantly increases susceptibility to infection by encapsulated bacteria such as Streptococcus pneumoniae and Haemophilus influenzae.

Note: Just as the lymph nodes filter bacteria from lymphatic fluid, the spleen filters encapsulated bacteria from the blood.

11 This boy has one brother who does not have the disease. Neither of his parents are affected. How would you describe the genetics of this disease?

The fact that no other members of his family are affected suggests autosomal recessive inheritance. Both parents must be unaffected carriers of sickle cell trait to pass the trait on to their son. Approximately 25% of the offspring generated by two carriers will be affected with sickle cell disease. This boy’s brother may also be a carrier of sickle cell trait, having gotten one copy of the mutation from one parent and a normal copy from the other, or he may be completely unaffected, having gotten normal copies of the gene from both parents.

12 How does sickle cell trait differ from sickle cell disease?

The heterozygous carrier of the sickle cell mutation is said to have the sickle cell trait, genotypically referred to as HbAS. These patients are relatively asymptomatic, with very minimal symptoms of anemia, and typically do not experience episodes of pain from vaso-occlusive crises. The predominant hemoglobin in sickle cell carriers is HbA, just as in unaffected individuals.

13 What is the evolutionary pressure for sickle cell trait?

The sickle cell mutation is more common in African Americans because in its heterozygous form it provides protection from infection with Plasmodium falciparum. In fact, in regions of Africa where malaria is common, up to 25% to 30% of the population is heterozygous for this mutation.

14 What infection do you suspect and what serious complication should be considered?

The slapped cheek appearance is characteristic of parvovirus infection. Parvovirus is known to infect erythrocyte progenitor cells and cause aplastic crisis in sickle cell anemia. The combination of increased RBC hemolysis (sickled cells have a severely reduced life span) and impaired erythropoiesis in sickle cell anemia can precipitate a severe state of anemia.

15 What is the likely diagnosis and why does it occur in sickle cell anemia?

Acute chest syndrome is caused by occlusion of the pulmonary vasculature by sickled cells. This can also cause pulmonary edema and elevated white blood cell (WBC) count and may be indistinguishable from pneumonia on chest x-ray film. Treatment includes respiratory support, exchange transfusion, and empiric antibiotics for pneumonia due to fluid stasis in the lungs.

16 What are the indications for exchange transfusion in sickle cell disease?

Stroke or transient ischemic attack (TIA), acute chest syndrome, priapism, third-trimester pregnancy, and intractable vaso-occlusive crisis are all indications for exchange transfusion.

17 Why is this boy is at risk for papillary necrosis of the kidneys?

The conditions of hypoxemia, acidosis, and hyperosmolarity specifically present in the renal medulla (an area that is especially prone to hypoxia) increases sickling of RBCs, resulting in vaso-occlusion of the vasa recta in the renal papillae. This result eventually leads to papillary necrosis.

18 Why are patients with sickle cell disease at an increased risk for gallstones?

About 70% of patients with sickle cell disease will get symptomatic cholelithiasis. Recall that these gallstones will be pigmented due to hyperbilirubinemia secondary to chronic hemolysis. Having a prophylactic cholecystectomy can also help distinguish gallbladder pain from cholelithiasis and abdominal pain secondary to vaso-occlusive crises.

19 Patients with sickle cell disease can develop complications in many other organ systems as well. What two bone “diseases” are these patients predisposed to and why? To which other conditions are patients with sickle cell disease prone?

Vaso-occlusive phenomena in sickle cell anemia can cause avascular necrosis of bones, particularly avascular necrosis of the femoral head. These avascular areas of bone are then more susceptible to the development of infection (osteomyelitis). Salmonella osteomyelitis is seen more frequently in sickle cell anemia, yet Staphylococcus aureus is the most frequent cause of osteomyelitis in the general population.

Note: The reason for this discrepancy is attributed to the fact that Salmonella is an encapsulated organism. Patients with sickle cell crisis who undergo autosplenectomy are at risk for infection by encapsulated organisms.

Other conditions affecting sickle cell patients include the following:

20 Some patients with sickle cell disease are treated with the chemotherapeutic drug hydroxyurea. What would be your rationale for starting this patient on this treatment?

Hydroxyurea is a chemotherapeutic drug that increases the production of fetal hemoglobin (HbF), which presumably decreases the amount of HbS expression and therefore decreases HbS polymerization and RBC sickling. However, the precise mechanism of action of hydroxyurea remains poorly understood. Some authors believe that its main mechanism of action is through stabilizing RBC membranes. Nevertheless, students should know that it is an important therapeutic agent for sickle cell disease.

21 What are sickle cell trait and Hemoglobin C (HbC)?

Sickle cell trait occurs when a person has one abnormal sickle cell allele (HbS) but is not homozygous for the mutation. Because the alleles are codominant, heterozygous patients produce normal and abnormal hemoglobin. Approximately 90% abnormal hemoglobin product is required to produce sickle cell symptoms, so individuals with sickle cell trait are often asymptomatic.

HbC is the product of an alternative mutation in position 6 of the β-globin gene in which glutamic acid is substituted for lysine. In the same fashion as for the sickle cell mutation, individuals who are heterozygous for the mutation often do not have any anemia, and homozygous individuals have a mild hemolytic anemia. Individuals who are HbSC have a milder form of sickle cell disease than HbSS patients.

Summary Box: Sickle Cell Disease

Sickle cell disease is inherited in an autosomal recessive manner.

Carriers of sickle cell trait are usually asymptomatic and are protected from falciparum malaria. Africans are more often affected.

Examination may show scleral icterus, mild jaundice, and hepatosplenomegaly in patients younger than 5 years.

Blood tests show normocytic anemia, reticulocytosis, and elevated indirect bilirubin.

Blood smear shows sickled cells, Howell-Jolly bodies, and reticulocytosis.

Hemoglobin electrophoresis shows hemoglobin S (HbS).

Treatment includes hydroxyurea, pneumococcal and Haemophilus influenzae vaccines, and analgesia and hydration for treatment of acute crises.

Sickle cell crises are precipitated by infection, dehydration, and hypoxemia.

Complications include the following:

Cholelithiasis

Renal papillary necrosis

Aseptic necrosis of femoral head

Infection with encapsulated bacteria: H. influenzae, Streptococcus pneumoniae, Salmonella

Parvovirus infection causing aplastic anemia

Priapism

Splenic sequestration crisis

1 What is the differential diagnosis for a microcytic anemia?

Iron deficiency, anemia of chronic disease, thalassemia, sideroblastic anemia, and lead poisoning are considerations.

2 How does this change your differential diagnosis?

This largely rules out the two most common causes of hypochromic, microcytic anemia—iron deficiency and anemia of chronic disease. Both of these conditions demonstrate decreased serum iron.

3 What is the diagnosis?

Thalassemia major, also known as Cooley’s anemia. If there was partial expression of β-globin, then the diagnosis would be thalassemia minor, but this is usually either very mild or completely asymptomatic.

4 What is the pathogenesis of thalessemia major?

Impaired synthesis of the β-subunit of hemoglobin due to a homozygous mutation. Normally, HbA is a tetramer made of two α chains and two β chains. Impaired production of the β chains leads to polymerization of the α chains within RBCs. These aggregates are insoluble and precipitate and damage the RBC membrane, causing premature hemolysis within the spleen and ineffective erythropoiesis in the bone marrow. The combination of the accelerated destruction and the impaired production of RBCs explains the severe anemia.

5 Why did it not manifest until the age of 6 months?

For the first 6 months, this boy was asymptomatic, because he still had large amounts of HbF, fetal hemoglobin, present in his circulation. Remember, HbF contains two α chains and two δ chains and does not require β-globin synthesis at all for proper functioning. As he transitioned to synthesis of adult hemoglobin (HbA contains two α and two β chains), the symptoms began to manifest as he became reliant on hemoglobin A production.

6 Why do you see scleral icterus and organomegaly?

RBC hemolysis releases heme, which is degraded into bilirubin. The unconjugated bilirubin accumulates and deposits in the sclera, causing icterus. This eventually results in generalized jaundice.

Hepatosplenomegaly occurs for two reasons. First, there is increased hemolysis of abnormal RBCs by macrophages in the spleen and liver. Second, there is extramedullary erythropoiesis in response to impaired bone marrow erythropoiesis. (However, this is no more effective than in the bone marrow because of the genetic defect in β-globin.)

Step 1 Secret

You may be given a radiograph of a skull that demonstrates a “crew cut” appearance (see Fig. 12-2). This is a sign of bone marrow expansion and is associated with thalassemia and sickle cell disease.

Figure 12-2 Thalassemia: x-ray film of the skull showing new bone formation on the outer table, producing perpendicular radiations resembling a crewcut.

(Courtesy of Dr. Jack Reynolds, Department of Radiology, University of Texas Southwestern Medical School, Dallas, TX.)

7 Why might this boy be more susceptible to fractures?

Ineffective erythropoiesis in the bone marrow results in markedly hyperplastic bone marrow and bone marrow expansion (Fig. 12-2). This bone marrow expansion erodes away the cancellous and cortical bone, resulting in significant structural weakness.

Case 12-2 continued:

This patient does well for many years, receiving frequent blood transfusions. At the age of 35, he is seen for a routine checkup and is found to have a fasting glucose level of 130 mg/dL. His skin is noted to be tanned although he spends little time in the sun. The electrocardiogram (ECG) shows some nonspecific ST-T wave changes.

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