General Considerations & Pathogenesis
Hereditary spherocytosis (HS) is the most common inherited defect of the RBC membrane. Patients with this condition inherit one of a series of mutations of the structural proteins of the RBC membrane,. The resulting decreased membrane elasticity causes loss of the normal biconcave shape of the RBC. These deformed, spherical RBCs are then detained and phagocytosed in the narrow fenestrations of the splenic cords. Less common related defects also exist, including hereditary elliptocytosis and hereditary stomatocytosis.
Hereditary spherocytosis can be classified as mild, moderate, or severe. Individuals with mild disease rarely manifest symptoms and signs. Increased erythropoietin levels compensate for early destruction of RBCs. Individuals with moderate disease represent 60–75% of HS patients and can develop intermittent episodes of jaundice, dark urine, abdominal pain, and splenomegaly in infancy or early childhood. Individuals with severe disease have more marked jaundice and splenomegaly.
If bilirubin levels are chronically elevated, bilirubin gallstones can form, leading to right upper quadrant abdominal pain and tenderness, nausea, and a positive Murphy sign.
Patients with moderate and severe disease often have low Hb, reticulocyte counts between 5% and 20%, and elevated serum bilirubin level.
The mean corpuscular Hb concentration (MCHC) is a useful test in diagnosing HS. It is generally elevated to 36 g/dL in patients with HS, reflecting decreased membrane surface area and increased Hb concentration in the RBC.
The peripheral blood smear of a patient with HS shows characteristic spherocytes—small RBCs that have lost their central pallor. Special tests can also be used to evaluate patients for HS. The osmotic fragility test involves suspending a patient’s RBCs in increasingly dilute salt solutions and observing for cell lysis. RBCs from patients with HS will be more sensitive to hypotonic solutions because of membrane instability. The newer acidified glycerol lysis test is also used.
Patients with moderate disease may need blood transfusions; however, for patients with severe disease, regular transfusions are essentially unavoidable. Folic acid supplementation is useful for patients with this and other hemolytic diseases.
The definitive treatment is splenectomy, which leads to significantly increased RBC lifespan. For patients who have had a splenectomy, immunization against Pneumococcus and Meningococcus is recommended for secondary prevention of sepsis.
N. Disorders of red cell membrane. Br J Haematol
Glucose-6-Phosphate Dehydrogenase Deficiency
ESSENTIALS OF DIAGNOSIS
X-linked inheritance pattern.
African or Mediterranean heritage.
Recent exposure to oxidizing substances such as primaquine, sulfa drugs, naphthalene (mothballs), or fava beans.
The World Health Organization (WHO) classifies glucose-6-phosphate dehydrogenase (G6PD) deficiency into five variants, from class I (the most severe enzyme deficiency) to class V (no clinical significance). The deficiency is most common in people of African and Mediterranean heritage. Although it is seen primarily in men, as are most X-linked disorders, women who carry the defective gene can also manifest symptoms, due to inactivation of their normal X chromosomes.
Overall, G6PD deficiency is the most common enzymatic disorder of RBCs in humans and affects 200–400 million people. Less common enzymatic deficiencies also exist. Pyruvate kinase deficiency, for example, has a similar clinical presentation.
The most common variants are G6PD A and G6PD Mediterranean. G6PD A is a variant in which patients have 10–60% of the normal level of G6PD and therefore experience intermittent hemolysis, generally associated with infections or drugs. G6PD Mediterranean also generally manifests with intermittent hemolysis, but the enzyme deficiency is usually more severe (eg, ~10% of normal enzymatic activity).
Glucose-6-phosphate dehydrogenase is a cytoplasmic enzyme that prevents oxidative damage to RBCs by reducing nicotinamide adenine dinucleotide phosphate (NADP) to NADPH. Individuals who are deficient in this enzyme are more susceptible to damage from oxidative substances such as superoxide anion (O2−) and hydrogen peroxide. In addition to being normal byproducts of cell metabolism, these substances are produced by certain drugs, household chemicals, and foods.
Persons affected with G6PD deficiency are often asymptomatic. However, a spectrum of clinical manifestations can occur, from infrequent mild episodic hemolysis to severe chronic hemolysis.
The most common clinical manifestations are jaundice, dark urine, pallor, abdominal pain, and back pain. These symptoms usually occur hours to days after an oxidative insult, which can be caused by a number of different agents. Chemicals that can cause such an insult include primaquine, sulfa drugs, dapsone, nitrofurantoin, and naphthalene (found in mothballs). Antimalarials, aspirin, and acetaminophen can precipitate hemolysis in certain individuals as well. Attacks can also be associated with infections (such as pneumonia, viral hepatitis, and Salmonella) and diabetic ketoacidosis. Finally, foods such as fava beans have been implicated. These beans are common in the Mediterranean and are harvested in late spring.
Infants with G6PD deficiency can also present with jaundice. Again a spectrum of disease exists, from mild transient jaundice to severe jaundice, kernicterus, and death. Those with class I G6PD deficiency can have lifelong, life-threatening chronic hemolysis.
Hemoglobin levels mirror the severity of disease.
During periods of active hemolysis, other laboratory measures can be abnormal. The absolute reticulocyte count is elevated above 2–3%, and sometimes above 10–15%. Haptoglobin levels are often depressed below 50 mg/dL, as this plasma protein binds Hb released from fragmented RBCs.
The peripheral blood smear in G6PD deficiency shows characteristic Heinz bodies, which represent masses of denatured, damaged Hb. “Bite cells,” which appear as RBCs with a small semicircular defect, can also be seen. The definitive test for G6PD deficiency is an enzymatic assay that measures in vitro production of NADPH.
Individuals with mild disease require no treatment except for avoidance, whenever possible, of oxidative triggers. Individuals with more severe disease may require inpatient treatment of acute exacerbations with transfusion, intravenous fluid support, and monitoring of renal function. Although vitamin E and splenectomy have been advocated as possible treatments in more severe cases, neither has provided consistent benefit.
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et al.: Wintrobe’s Clinical Hematology, 12th ed. Baltimore, MD: Williams & Wilkins; 2009: 933–955.
ESSENTIALS OF DIAGNOSIS
African, Mediterranean, or Asian heritage.
Characteristic pattern on Hb electrophoresis.
Sickle cell anemia (SCA) is a common genetic disorder. Traits that lead to SCA are common in those with African and South Asian heritage. The gene frequency for SCA in African Americans is approximately 4%.
A spectrum of other sickle cell syndromes exists. HbC results from a different mutation in the β Hb chain. Patients with HbSC disease have one of each mutation and generally experience a milder phenotype than those with homozygous sickle cell anemia (HbSS). Patients with the HbSA genotype have one sickle cell gene and one regular gene. They tend to have mild, if any, clinical manifestations of disease. Other permutations of abnormal Hb genes can cause similar syndromes. Patients with one sickle cell gene and one β-thalassemia gene, for example, can have significant clinical manifestations of hemoglobinopathy.
Patients with SCA are homozygous for a mutation in the β Hb chain. The resulting HbS, which consists of two normal α Hb chains and two abnormal β Hb chains, is poorly soluble when deoxygenated. The polymerization of HbS into elongated fibers within the RBC leads to the characteristic “sickle” shape. These abnormal RBCs occlude capillary beds and lead to the many clinical manifestations of SCA.
Newborn screening for HbSS, HbSA, and HbSC is highly recommended and required by law throughout the United States. Several prophylactic measures can reduce the likelihood of pain crises and other manifestations of disease in patients with SCA (ie, secondary prevention). First, adequate hydration and oxygenation reduce the risk of Hb polymerization and subsequent vasoocclusive crises. Folic acid should be supplemented, 1 mg orally every day. Some physicians recommend hydroxyurea, which seems to reduce the likelihood of RBC sickling by stimulating production of fetal Hb. Infectious complications can be reduced by immunization against Streptococcus pneumoniae, Haemophilus influenzae type B, hepatitis B, and influenza. Daily oral penicillin prophylaxis should be given until age 5 years. Use of penicillin prophylaxis, along with intensive medical care, has reduced the mortality of SCA from 25% to 3% during the first 5 years of life.
Patients with homozygous SCA manifest disease early. Approximately 30% of patients are discovered by 1 year of age and >90% by 6 years of age. Acute pain episodes are the most common presentations; they can occur in the extremities, abdomen, back, or chest. Although generally no inciting factor is found, stresses such as cold, infection, and dehydration can precipitate attacks. Fever, joint swelling, vomiting, and tachypnea can accompany pain episodes.
Most patients experience autoinfarction of the spleen by early childhood due to occlusion of splenic capillary beds. For this and other reasons, patients with SCA are significantly vulnerable to infection, especially from encapsulated pathogens such as S. pneumoniae and H. influenzae. Pneumonia, meningitis, osteomyelitis, and bacteremia are causes of significant morbidity and mortality in these patients.
Pulmonary complications are the most common causes of death in patients with SCA. RBCs in the pulmonary system are particularly vulnerable to sickling because of its low PO2 and relatively low blood pressure. Acute chest syndrome refers to the clinical triad of chest pain, pulmonary infiltrate on x-ray, and fever, which can be due to pulmonary infarction, pneumonia, or both.
Sickled RBCs can occlude vasculature and cause infarction of nearly any tissue in the body. Therefore, other serious manifestations of SCA include stroke, myocardial infarction, bone infarction, retinopathy, leg ulcers, and priapism. Depression, low self-esteem, and social withdrawal are common, especially when adequate coping mechanisms are not in place.
Laboratory findings often reflect the chronic hemolysis that accompanies SCA. Classically the patient has a reticulocyte count increased to 3–15%, Hb mildly or moderately decreased to 7–11 g/dL, elevated direct bilirubin and lactate dehydrogenase, and a depressed haptoglobin level.
The peripheral blood smear shows sickling of half of the RBCs. Howell-Jolly bodies and target cells are also present on the smear, indicating hyposplenism. The white blood cell count can be elevated at 12,000–15,000/mm3, even in the absence of infection.
Despite the preventive measures discussed earlier, most patients with SCA require frequent hospitalization for acute painful vasoocclusive crises or infectious complications. During acute exacerbations, patients often require hydration and oxygenation, analgesia with nonnarcotic or narcotic medications, antibiotics if appropriate, and blood transfusions.
American Academy of Pediatrics; Section on Hematology/Oncology. Health supervision for children with sickle cell disease. Pediatrics
US Preventive Services Task Force. Screening for sickle cell disease in newborns: recommendation statement. Am Fam Physician
et al.. Newborn screening for sickle cell disease: effect on mortality. Pediatrics
D. Sickle cell disease in childhood: part II. Am Fam Physician. 2000;15:1309–1314.
Autoimmune Hemolytic Anemia
ESSENTIALS OF DIAGNOSIS
Positive direct Coombs test.
Elevated indirect bilirubin and decreased serum haptoglobin.
Inciting factor such as medication or illness.
Autoimmune hemolytic anemia (AIHA) results when a patient produces antibodies directed against the body’s RBCs AIHA can be classified by the temperature at which the antibodies are most reactive. “Warm” autoantibodies bind most strongly near 37°C (98.6°F), whereas “cold” autoantibodies bind RBCs near 0–4°C (32–39.2°F). Occasionally, a mixture of both types of autoantibodies is present.
Although the production of autoantibodies is idiopathic in nearly 50% of cases, at other times an inciting factor can be found. Lymphoproliferative disorders such as chronic lymphoblastic leukemia and autoimmune disorders such as rheumatoid arthritis, for example, can induce production of either warm or cold autoantibodies. Infections such as Mycoplasma and syphilis have been implicated, primarily in cold AIHA. Transfusion reactions are mediated by a similar process.
Medications can induce a warm antibody autoimmune reaction. Some drugs, such as methyldopa, alter RBC antigens so that they become targets of the host immune system. Other drugs bind with RBC antigens to form immunogenic complexes. This “hapten” reaction can occur with penicillin as well as a variety of other drugs.
Any patient who receives a splenectomy should also receive secondary prevention in the form of immunizations against Pneumococcus, Haemophilus, and Meningococcus.
Overall, a wide spectrum of possible manifestations exists. A typical patient with AIHA presents with pallor, fatigue, or headaches due to loss of circulating RBCs. Jaundice may also be present, due to elevation of indirect bilirubin resulting from the release and breakdown of RBC heme. A patient may also have splenomegaly due to increased sequestration of damaged RBCs within the splenic cords of Billroth. In some cases, hemoglobinuria can lead to renal failure. The rate of disease progression depends on the underlying cause of hemolysis. Although clinical manifestations progress slowly in some patients, in others severe symptoms can develop in a matter of hours.
A positive direct Coombs test helps diagnose AIHA.
Other laboratory findings reflect the general hemolytic process. Levels of bilirubin and lactate dehydrogenase are increased, haptoglobin levels tend to decrease, and the corrected reticulocyte count is increased. Other appropriate laboratory investigations specific to underlying causes—such as collagen vascular diseases, cancer, and infections—may be warranted.
Although further hemolysis can result, blood transfusion should be given when the Hb level is significantly low (5–7 g/dL). Corticosteroids are often considered the treatment of choice, especially when autoantibodies are warm. Those who need long-term treatment and cannot take steroids can use other immunomodulating agents such as azathioprine, cyclosporine, and rituximab. Intravenous immunoglobulin is advocated for the acute treatment of adults with AIHA, but it is not as effective in children. Exchange transfusion, which not only delivers new RBCs but also removes destructive autoantibodies and complement, can also be useful. Splenectomy should be considered in refractory cases; as previously noted, any patient who receives a splenectomy should also receive immunizations against Pneumococcus, Haemophilus, and Meningococcus. Finally, underlying disorders should be treated as appropriate.
DJ. Normocytic anemia. Am Fam Physician
RC. Autoimmune hemolytic anemia. Am J Hematol
Extrinsic Nonimmune Hemolytic Anemia
There are many causes of extrinsic hemolysis not related to immunity (Table 32-3). The first group of conditions results from mechanical damage to RBCs. Any process that enlarges the spleen, for instance, can lead to an acquired hemolytic process because the spleen is the major organ recycling RBCs. Mechanical damage can also occur as RBCs rush past a prosthetic valve or other internal machinery. Disseminated intravascular coagulation and thrombotic thrombocytopenic purpura can result in hemolysis of RBCs that flow through areas of intravascular coagulation. Mechanical destruction of RBCs can also be due to exposure to heat, burns, or even repeated trauma such as that encountered in the feet while marching long distances.
Table 32–3.Nonimmune causes of hemolysis. ||Download (.pdf) Table 32–3.Nonimmune causes of hemolysis.
Disseminated intravascular coagulation
Thrombotic thrombocytopenic purpura
Snake, spider venom
Infectious diseases such as malaria, babesiosis, and leishmaniasis can also cause an acquired hemolysis. This is due to both to direct parasitic action and increased activity of macrophages within the spleen.
Finally, drugs and toxins can lead to hemolysis. Medications such as primaquine, dapsone, nitrites, and even topical anesthesia can induce oxidative stress, damaging RBCs. This can occur even in patients without G6PD deficiency. Toxins such as lead, copper, and arsine gas, as well as venom from snakes, insects, and spiders, can also cause hemolysis.
Symptoms and signs, laboratory findings, and treatments will be based on the specific diagnosis. Rather than a specific disorder, extrinsic nonimmune hemolytic anemia is a general categorization of heterogeneous disease processes.
DJ. Normocytic anemia. Am Fam Physician
Aplastic anemia is characterized by the suppression of all bone marrow lines—erythroid, granulocytic, and megakaryocytic—leading to pancytopenia. Most commonly the disorder is idiopathic. However, drugs, toxins, radiation, infections (eg, hepatitis, parvovirus), and pregnancy can all induce aplastic anemia. Although it is uncommon—affecting only two to four persons per million per year—it is often an important consideration for differential diagnoses for undiagnosed anemias.
The etiology is unclear. Although some causative agents have been shown to be directly toxic to the bone marrow, others seem to induce an autoimmune process. The specific etiology plays a role in prognosis; drug-induced aplastic anemia carries a more favorable prognosis than idiopathic aplastic anemia. The more severe the pancytopenia, the worse is the prognosis.
Anemia leads to pallor, fatigue, and weakness. Neutropenia increases susceptibility to bacterial infections. Thrombocytopenia can present as mucosal bleeding, easy bruising, or petechiae. Splenomegaly is common in advanced disease.
Pancytopenia is the hallmark of aplastic anemia. The associated anemia can be severe and is generally normocytic. The reticulocyte count is often low. The white blood cell count can be lower than 1500/mm3, and the platelet count is generally <150,000/mL. Bone marrow aspirate, which reveals marrow hypocellularity, is essential to the diagnosis of aplastic anemia and important in distinguishing it from other causes of pancytopenia.
Fever or other signs of infection should be aggressively investigated. Often, empiric broad-spectrum antibiotics should be used. Other means of decreasing risk of infection include the use of stool softeners and antiseptic soaps. Menstrual blood loss can be suppressed with oral contraceptive pills. Although replacement of blood products is often necessary, it should be used as little as possible, to avoid sensitizing potential candidates for bone marrow transplantation. Hematopoietic growth factors (erythropoietin and granulocyte colony-stimulating factor) are seldom used, due to transient or nil effect.
In a patient aged <50 years with a human leukocyte antigen (HLA)-matched sibling, immediate bone marrow transplantation is the treatment of choice. The toxicity associated with treatment increases with age, along with the risk of graft-versus-host disease. If successful, transplantation is curative. The 5-year survival rate is approximately 70%.
In those lacking matched siblings or those aged >50 years, treatment consists of immunosuppression with antithymocyte globulin, augmented with high-dose cyclosporine. Most patients relapse, but remission rates with additional antithymocyte globulin treatments are encouraging. Survival at 5 years is ~75%.
NS. Acquired aplastic anemia. Ann Intern Med. 2002; 136:534.
J. The pathophysiology of acquired aplastic anemia. N Engl J Med
Anemia of Chronic Renal Insufficiency
Although anemia of chronic renal insufficiency (CRI) commonly occurs in patients with a creatinine clearance of 30 mL/min per ≤1.73 m2, it can appear in patients with serum creatinine as low as 2 mg/dL.
Patients may exhibit bleeding or bruising due to thrombocytopenia and platelet dysfunction. Pallor and fatigue are also common. Early symptoms of uremia include nausea, vomiting, weight loss, malaise, and headache. As the blood urea nitrogen (BUN) level rises, paresthesias, decreased urine output, and waning level of consciousness can be seen. Other signs and symptoms depend on the etiology of the patient’s renal insufficiency.
Blood urea nitrogen and serum creatinine are generally both elevated, above 30 and 3.0 mg/dL, respectively. The anemia tends to be normocytic and normochromic, but in some cases it can be microcytic. Hyperphosphatemia, hypocalcemia, and hyperkalemia can occur, as can metabolic acidosis. Reticulocyte count tends to be normal or decreased. Bone marrow is inappropriately normal for the degree of anemia.
Treatment involves erythropoietin replacement. Erythropoietin or darbepoetin is indicated when the Hb level is ≤10 g/dL. Darbepoetin has a longer half-life and more predictable bioavailability. Prior to initiation of therapy, the patient should be screened and treated for deficiency of iron, folate, and vitamin B12 as well as for occult blood loss.
Erythropoietin is given at 80–120 U/kg per week. The most common side effect of erythropoietin therapy is hypertension. The target Hb level is 11–12 g/dL.
DJ. Normocytic anemia. Am Fam Physician
Anemia Associated with Marrow Infiltration
ESSENTIALS OF DIAGNOSIS
Anemia with abnormally shaped RBCs on peripheral smear, along with abnormalities of other cell lines.
Bone marrow study showing infiltration or a “dry tap.”
Underlying neoplastic, inflammatory, or metabolic disease with nonspecific systemic signs and symptoms.
The bone marrow can tolerate fairly extensive infiltration. When marrow infiltration causes anemia or pancytopenia, however, it is referred to as myelophthisic anemia. The most common cause of myelophthisic is metastatic carcinoma of the lung, breast, or prostate. Other causes include hematologic malignancies (leukemia, lymphoma), infections (tuberculosis, fungi), and metabolic diseases (Gaucher disease, Niemann-Pick disease).
Anemia is most commonly manifested by pallor or fatigue. Thrombocytopenia can cause petechiae, bleeding, or bruising. Neutropenia can lead to frequent or atypical infections. Fractures, bony pain, bony tenderness, hepatomegaly, and splenomegaly may occur. Other presenting signs and symptoms are usually related to the underlying cause of marrow infiltration.
The anemia tends to be normocytic and mild to moderate. White blood cells and platelets may also be decreased. Because of the hypocellular marrow, aspirate often yields few cells (“dry tap”).
Treatment targets the underlying disease. Successful treatment of the malignancy, through radiation, chemotherapy, or bone marrow transplantation, can resolve the anemia. Erythropoietin or blood transfusion may be used to augment the RBC count. Platelet transfusions may be needed. The prognosis in patients with marrow metastases is generally poor.
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