Hematology
Gerald L. Logue
CLINICAL PEARLS
Anemia should be evaluated for its cause in all patients without assuming that it is a natural consequence of aging.
The most common cause of anemia (approximately 50%) is secondary to systemic disease, referred to as anemia of chronic disease.
Normocytic anemia requires an evaluation of the patient’s entire status, including the presence of thyroid or renal disease.
Patients with early iron deficiency may have normocytic anemia.
A low serum ferritin always means iron deficiency.
Iron deficiency in older patients should be diagnosed definitively because it is often associated with gastrointestinal (GI) malignancy.
Marked reduction in mean corpuscular volume (MCV) with nearly normal red blood cell counts is usually caused by thalassemia minor.
Patients with iron deficiency, who are refractory to iron therapy, should be tested for gluten-induced enteropathy.
Nonmegaloblastic macrocytic anemia is common and should be considered when a high MCV is noted.
Patients with macrocytic anemia should have a reticulocyte count done to exclude hemolytic anemia.
Initial evaluation of thrombocytopenia requires careful evaluation of the peripheral blood smear.
Heparin-induced thrombocytopenia may produce paradoxical arterial and venous thrombosis. Patients on heparin should have platelet counts monitored daily.
Drug-induced thrombocytopenia is common in older patients.
Chronic neutropenia is often well tolerated without infections in older individuals.
The most important information regarding the risk of bleeding with surgery is a history of prior bleeding.
A prolonged partial thromboplastin should be initially evaluated with a “mixing study.”
Older patients with prolonged partial thromboplastin time (PTT) due to antiphospholipid antibodies are not at increased risk of bleeding with surgery.
Screening for multiple myeloma can be done with serum and urine electrophoreses. Ninety-nine percent of patients with multiple myeloma will test positive. Negative tests essentially exclude the diagnosis.
Approximately one quarter of patients with monoclonal gammopathy of unknown significance will progress to
a more aggressive plasma cell proliferative disease in 10 years.
Cigarette smoking produces erythrocytosis by causing chronic carbon monoxide poisoning.
Patients with erythrocytosis should be carefully examined for splenomegaly, which is often associated with a myeloproliferative disease.
Measurement of erythropoietin is important in determining the cause of erythrocytosis.
Patients with thrombocytosis should be screened for iron deficiency and GI or pulmonary neoplasia.
Venous thrombosis in older patients does not generally require screening for underlying inherited thrombophilic states unless there is a family history of clotting.
ANEMIA
Anemia occurs with increasing frequency in older patients. There are two competing theories regarding this observation. One is that decreased production of red cells is a natural consequence of the aging process (presbypoiesis). The decreasing amount of marrow dedicated to hematopoiesis as aging progresses lends support to this theory. Children have active hematopoiesis in all bones, including long bones. But with aging the proportion of marrow that produces blood diminishes. Animal models suggest that the number of hematopoietic stem cells lessens with age.
A second theory of anemia in older patients is that the elderly accumulate chronic diseases that are associated with secondary anemia. There are certainly many healthy older individuals who have normal blood counts. From a practical point of view, anemia should be evaluated in all patients because treatable illnesses are often identified; that is, anemia should not be attributed to age alone.1
Anemia in older patients is associated with increased morbidity and mortality independent of concurrent diseases. Exogenous therapeutic erythropoietin has improved the life of many patients with concurrent diseases such as renal failure, cancer, and human immunodeficiency virus (HIV), as well as those undergoing cancer therapy. At this point, there are no studies to suggest that erythropoietin is useful to treat anemia in older patients who do not have a specific disease indication, but studies are ongoing.2
To evaluate the causes of anemia in older patients, it is useful to categorize it according to the size of the red cells (the mean red cell volume or mean corpuscular volume [MCV]) as determined by automated blood counting.
Normocytic Anemia
Normocytic anemia accounts for most patients who have low red cell counts, including some who are anemic secondary to other systemic diseases. The differential diagnosis of normocytic anemia includes a large number of primary hematologic diseases such as multiple myeloma, aplastic anemia, and myelodysplastic syndrome. Normocytic anemia is also common in many chronic diseases, requiring careful consideration of the entire clinical status. Early iron deficiency can present with normocytic anemia, but continued iron-deficient hematopoiesis will eventually cause the MCV to fall.
Evaluation of normocytic anemia may require a bone marrow examination. Myelodysplastic syndromes usually present with anemia in older individuals. These syndromes include refractory anemia with and without ringed sideroblasts. The latter present a hypercellular bone marrow with increased red cell precursors. Refractory anemia with excess blast cells may resemble acute leukemia and needs to be monitored for further transformation. Myelodysplastic syndromes are associated with prior chemotherapy and toxic chemical exposure. Current therapy is directed at blood cell support but newer therapeutic approaches are being tested.3
Microcytic Anemia
The differential diagnosis of anemia with a low MCV is outlined in Table 39.1. Iron deficiency is a common consideration and is almost always due to blood loss in older patients. There are multiple tests available to determine a patient’s iron status. Measurement of serum ferritin is useful because there are very few false positives (if patients have a low serum ferritin, they are very likely to be iron deficient) (Evidence Level C).1 In contrast, there is an incidence of false negatives with a serum ferritin. Some patients with iron deficiency may have normal ferritin.
Serum iron and iron-binding capacity have a higher incidence of false positives than ferritin; that is, patients may have low serum iron and low iron saturation but may not be iron deficient. Serum iron measurements also have a relatively high incidence of false negatives because serum iron may change relatively quickly and transiently after an intake of oral iron. Detection of bone marrow iron stores are generally felt to be a “gold standard” for determining a patient’s iron status, but the procedure is more invasive.
Oral iron therapy should be used in older patients if at all possible (Evidence Level A).4 Parenteral iron preparations are available but carry increased risks of complications in older patients. The gastrointestinal (GI) symptoms of cramping and bowel irregularity seen with oral iron preparations diminish after the first 1 to 2 weeks of therapy. Patients who continue to be iron deficient despite oral iron therapy should be tested for glutin-sensitive enteropathy (celiac disease).
Thalassemic syndromes are disorders of globin chain synthesis. There are two types of globin chains in the most prevalent adult hemoglobin (hemoglobin A): α Chains and β chains. Disordered production of globin chain synthesis is usually inherited but rare instances of acquired disorders have been seen in myelodysplastic
syndromes. β Thalassemia minor is the reduced ability to produce β chains. These patients have mild, asymptomatic anemia with a low MCV and can be mistakenly diagnosed as being iron deficient. Iron therapy is contraindicated in these patients because they tend to have abnormally enhanced iron absorption and the potential to develop iron overload (hemosiderosis). These patients can be diagnosed by measuring the amount of the two other types of hemoglobin found in healthy adults (i.e., quantitation of Hb A2 and Hb F) or hemoglobin electrophoresis. Because Hb A2 and Hb F do not have β chains, they will be present in greater amounts in patients with β thalassemia.
syndromes. β Thalassemia minor is the reduced ability to produce β chains. These patients have mild, asymptomatic anemia with a low MCV and can be mistakenly diagnosed as being iron deficient. Iron therapy is contraindicated in these patients because they tend to have abnormally enhanced iron absorption and the potential to develop iron overload (hemosiderosis). These patients can be diagnosed by measuring the amount of the two other types of hemoglobin found in healthy adults (i.e., quantitation of Hb A2 and Hb F) or hemoglobin electrophoresis. Because Hb A2 and Hb F do not have β chains, they will be present in greater amounts in patients with β thalassemia.
TABLE 39.1 DIFFERENTIAL DIAGNOSIS OF COMMON BLOOD DYSCRASIAS | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Thalassemia due to the decreased production of α globin chains is more difficult to diagnose. These patients will appear clinically identical to patients with β thalassemia minor, except that their hemoglobin A2 and F levels will be normal. α Thalassemia should be suspected in patients with long-standing mild anemia with marked reduction in MCV but with normal iron stores.
Other causes of anemia with reduced MCV include anemia secondary to chronic inflammatory diseases. These patients have a disorder of iron reutilization. They have increased iron stores but macrophages do not release iron efficiently for red cell production. Anemia with a low MCV can also be seen in lead poisoning and rarely in myelodysplastic syndromes such as sideroblastic anemia. In the latter, there is an acquired defect in iron metabolism, which leads to pathologic iron depositions in mitochondria of developing erythroid cells, producing “ringed sideroblasts.”
Macrocytic Anemia
The differential diagnosis of anemia with a high MCV is outlined in Table 39.1. It is important to distinguish megaloblastic anemia from the various causes of macrocytic anemia without a megaloblastic process. The latter disorders are more common than diseases with megaloblastosis. Megaloblastic anemia is caused by a variety of
processes which alter the synthesis of deoxyribonucleic acid (DNA). This inhibition of DNA synthesis in turn causes an impaired nuclear maturation and a morphologic abnormality of the marrow and blood, which is described as megaloblastic anemia.
processes which alter the synthesis of deoxyribonucleic acid (DNA). This inhibition of DNA synthesis in turn causes an impaired nuclear maturation and a morphologic abnormality of the marrow and blood, which is described as megaloblastic anemia.
Megaloblastic anemia was originally described in patients with deficiencies of vitamin B12 or folate. Vitamin B12 and folate are required for normal synthesis of DNA precursors. B12 and folate deficiencies are easily treated and should be excluded in all patients with macrocytic anemia. Serum B12 level is an accurate and inexpensive analysis. In adults, folate deficiency is caused by inadequate diet and should be suspected from the diet history. Serum folate levels are accurate but change rapidly with folate intake. Red cell folate levels are also available. These levels are more stable because they reflect folate concentrations when the red cells were produced.
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