Cardinal Manifestations of Hematologic Disease, Anemias, and Related Conditions

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[edit] Cardinal Manifestations of Hematologic Disease, Anemias, and Related Conditions

Jack E. Ansell

A wide range of hematologic disorders can be diagnosed and treated by the primary care physician, although many complex or life-threatening conditions, sometimes presenting very subtly, require referral for more specialized care. Given the vast knowledge encompassed by the field of hematology, what is a primary care physician expected to know, and when is referral to a hematologic subspecialist appropriate? A primary care physician must be familiar with the basic physiology of red blood cells (RBCs), white blood cells (WBCs), platelets, coagulation, and elements of the lymphoreticular system. This knowledge provides a background for understanding the relevant pathophysiology, developing a diagnostic approach, acquiring diagnostic acumen, and selecting therapeutic interventions.

[edit] GENERAL APPROACH TO HEMATOLOGIC DISORDERS

The diagnostic and therapeutic approach to hematologic disorders is quite simple. Symptoms and signs of disease are based on a derangement in the normal function of one of the cellular elements of the blood or of the hemostatic system. Hallmark findings include fatigue, fever, bleeding, or thrombosis. Similarly, the pathophysiology of blood disorders can be viewed in the context of abnormal production (too much or too little) or excessive destruction or loss of a cellular element. Although this is an oversimplified approach, it does set the framework for understanding hematologic disease.

When interviewing the patient and establishing the history of an illness, genetic and inheritable factors tend to play an important role in hematologic disease, and thus one must pay attention to ethnic background and family history. The cellular elements of the blood are also exquisitely sensitive to environmental toxins, medications, and illicit drugs. Thus work experience and social history must not be neglected. Finally, the interpretation of hematologic parameters must be done with the understanding that (1) each cell line has specific cellular pools, (2) the distribution that one measures in the circulating blood can be dramatically affected by hydration or fluid shifts, and (3) the peripheral blood does not always reflect what is happening in the bone marrow or peripheral tissues.

[edit] Red Blood Cell Disorders: Anemia

Anemia is best defined as a reduction in hemoglobin that leads to a reduction in oxygen supply to peripheral tissues. Anemia may be clinically difficult to identify, and a routine blood count is usually required. It is important to remember that anemia is not a disease, but a manifestation of an underlying illness, and its presence should lead to a search for its etiology.

[edit] Classification.

A common classification scheme of anemia is based on its pathophysiologic mechanism and the morphologic appearance of the red cells. Such an approach leads to an understanding of the etiology, as demonstrated in the algorithm presented in Fig. 113-1. According to this approach, anemia is due either to failure of the bone marrow to produce enough RBCs (hypoproliferative anemia) or excessive and premature destruction of RBCs in the circulation (hemolytic anemia). The former category also includes anemias due to red cell maturation abnormalities, and the latter includes anemias due to excessive loss of RBCs (i.e., bleeding). Morphologically, anemias can be characterized by RBCs that are large, normal, or small (macrocytic, normocytic, or microcytic) and normal colored or pale (normochromic, hypochromic). Densely colored cells are referred to as spherocytes.Table 113-1 categorizes a number of RBC shape abnormalities that might be seen on the peripheral blood smear.

Figure 113-1 Systematic laboratory approach to the patient with anemia is based on pathophysiologic and morphologic criteria and takes into consideration cost-effectiveness. Results of a CBC, red cell indices, reticulocyte count, and blood smear should indicate which pathway of analysis to pursue. Patients may have combined defects, thus disease processes do not always adhere to a textbook description. A disheartening observation is the all-too-frequent request for a CBC, serum iron, TIBC, serum ferritin, B₁₂, and folate level. This “shotgun” approach to the initial evaluation of anemia must be avoided. Consider the potential mechanism of the anemia and the RBC morphology and then order appropriate and specific diagnostic tests. MCV, Mean corpuscular volume;MCHC, mean corpuscular hemoglobin concentration;Fe, iron;BM, bone marrow;TIBC, total iron binding capacity;SAT, saturation;DIC, disseminated intravascular coagulation;TTP, thrombotic thrombocytopenic purpura;PNH, paroxysmal nocturnal hemoglobinuria;PK, pyruvate kinase;HGB, hemoglobin;HMS, hexose monophosphate shunt.

Table 113-1 Common Abnormalities in RBC Shape or Inclusions Seen in the Wright's Stain Blood Smear

[edit] Symptoms.

The symptoms of anemia depend on the duration of onset, the pathophysiologic mechanism, and the specific etiology. Anemias that develop over hours or a few days are usually due to blood loss. They produce symptoms of intravascular volume depletion (hypotension, cardiac strain, shock). Such rapidly developing anemias can also be the result of fulminant hemolysis, but in the latter, symptoms are primarily attributable to the deleterious effects of hemoglobin metabolites. Anemias that develop slowly are more likely to be better tolerated at lower levels of hematocrit than those that develop rapidly because of a compensatory plasma volume increase. Symptoms are primarily related to tissue hypoxia and cardiac strain (fatigue, irritability, headache, dyspnea, orthopnea, palpitations, and angina).

[edit] Diagnostic Approach.

The diagnostic approach to evaluating anemia starts with its signs and symptoms, but final conclusions regarding the etiology cannot be made until specific laboratory tests are performed. Most blood counts today are performed by electronic particle counters and are exceedingly accurate. A complete blood count (CBC) includes a WBC count, RBC count, hemoglobin, hematocrit (Hct), red cell indices, and differential count of the WBCs. RBCs can be morphologically categorized by examining the peripheral blood smear under a microscope, as well as by calculating the red cell indices, which denote average cell size, hemoglobin content, hemoglobin concentration, and distribution of RBC width (RDW) (Table 113-2). Microscopic examination of the peripheral blood smear may provide additional information about the potential etiology of anemia.

Table 113-2 Formulas Used to Determine MCV, MCH, MCHC, and RDW✢

Formula	Normal range
	80-100 fl (10−15 L)
		27-32 pg (10−12 g)
		32-36 g/dl
		11%-15%
MCV, Mean corpuscular volume;MCH, mean corpuscular hemoglobin;MCHC, mean corpuscular hemoglobin concentration;RDW, distribution of RBC width.

✢Normal ranges may vary from laboratory.

A reticulocyte count should always be considered when anemia is present. The reticulocyte percentage gives an indication of the bone marrow's capacity to respond toanemia by increased production. Reticulocytes show up as bluish-colored cells (polychromatophilia) on a standard peripheral smear, and this can provide a rough estimate of an elevated count. Otherwise, a specific stain must be made to determine the reticulocyte percentage. A reticulocyte count is a relative number and should be corrected by multiplying it by the patient's Hct divided by the normal Hct (corrected reticulocyte count) or by determining the absolute number of reticulocytes per microliter of blood by multiplying the reticulocyte count by the RBC count (absolute reticulocyte count). Examples are illustrated in Fig. 113-2. In general, corrections are not necessary when the reticulocyte count is markedly elevated or low in the setting of significant anemia.

Figure 113-2 Even though the reticulocyte count is elevated in both patients, patient A clearly has an inadequate response, with a corrected reticulocyte count of 1.8%, suggesting that the bone marrow is not responding to the anemia and that deficient or defective RBC production may be the cause or is contributing to the anemia. Patient B has a good response to the anemia, suggesting that the bone marrow is normal and that the cause may be hemolysis or blood loss. A normal bone marrow is able to increase erythroid production sixfold to eightfold. If the average absolute reticulocyte count is 50,000/μl (1% of 5 million RBCs), the maximum increase in reticulocyte count in response to hemolysis or blood loss should range between 250,000 and 400,000 reticulocytes/μl.

Examination of the peripheral blood smear to assess morphologic abnormalities of RBCs is imperative in the evaluation of anemias. Simple observation of the blood smear may lead directly to the diagnosis, avoiding the cost and time of various diagnostic rests.Table 113-1 lists the commonly seen abnormalities in RBC shape and their pathophysiologic significance. Included in this table are various red cell inclusions and their clinical significance.

[edit] White Blood Cell Disorders

Alterations in the WBC count occur frequently in response to other disorders, such as inflammation or infection, but few if any symptoms are directly produced by such changes. When confronted with an abnormal WBC count, the physician should obtain a differential count and determine the absolute number of specific cell types. Percentages are relative and may be abnormal when the absolute number of a cell type is normal. Granulocytes predominate in most inflammatory states and counts as high as 20,000/μl are not uncommon and rarely may be as high as 40,000 to 50,000/μl. Such a reaction is called a leukemoid response, and there may be a number of less mature forms present. A leukocyte alkaline phosphatase (LAP), which usually increases with increasing WBC, helpsdifferentiate a leukemoid response from some myeloproliferative diseases such as chronic myelocytic leukemia (LAP high in the former, very low in the latter). In polycythemia vera, agnogenic myeloid metaplasia, and essential thrombocythemia, which are the other myeloproliferative disorders, the LAP is inappropriately elevated in comparison to the mild elevation of the WBC count.

Extremely high WBC counts (∼100,000/μl or more), especially with immature cells as in acute leukemia, can produce leukostasis with signs of headache, dizziness, confusion, pulmonary congestion and hypoxia, retinal hemorrhages and papilledema, and digital ischemia.

A blood smear with granulocyte precursors and nucleated RBCs is characterized as a leukoerythroblastic blood smear. In agnogenic myeloid metaplasia, teardrop-shaped RBCs are also noted. Such findings also occur with other invasive diseases of the bone marrow, such as cancer or granulomas. This process is called myelophthisis and creates a myelophthisic anemia.

As with most cases of leukocytosis, leukopenia yields few symptoms unless the absolute granulocyte or lymphocyte count reaches significantly low levels. Infection is the major symptom of neutropenia. Its risk increases significantly when the absolute neutrophil count falls below 1000/μl. Patients with severe neutropenia may not be able to mount the same degree of inflammatory response normally seen (e.g., collections of pus), and thus infections may be difficult to diagnose. Drug reactions are often implicated as a cause of neutropenia and must be considered. Drug-induced agranulocytosis is a life-threatening emergency requiring cessation of all suspected medicines and close monitoring of the patient for infection.

Changes in the lymphocyte count present a different spectrum of possibilities. Lymphocytosis is typically seen in acute viral infections such as mononucleosis due to Epstein-Barr virus. Atypical appearing lymphocytes are also present (large cells with abundant cytoplasm, an immature nuclear chromatin pattern with or without nucleoli, and indentation or scalloped cytoplasmic membrane) and usually represent stimulated T cells. Stimulated B cells have a plasma cell–like appearance (smaller, dark blue cytoplasm, displaced nucleus, and clumped chromatin). Lymphopenia can occur in some inherited immunodeficiency disorders but is most often seen today in the setting of human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS).

Disorders of leukocyte function are even more difficult to detect than quantitative disorders of leukocytes. They usually represent congenital disorders and may require the services of an experienced laboratory for detection. Qualitative disorders produce symptoms according to the cell line affected (see Chapter 114 ).

[edit] Platelet and Coagulation Disorders

Platelet and coagulation disorders are manifest by either bleeding or thrombosis. Hypercoagulability (thrombophilia) is more likely to predispose to thrombosis than is a platelet abnormality.

Thrombocytopenia as a risk for bleeding is usually not a problem until the count falls below 50,000/μl, and especially below 10,000/μl. If the cause of the low platelet count is failure of production, then the risk of bleeding may be greater at low counts than if the cause is peripheral destruction as in immune thrombocytopenia because of the presence of younger more hemostatically effective platelets in the latter. Platelet-related bleeding can also occur even with normal counts if the platelets are qualitatively defective.

The cardinal sign of a platelet defect is the presence of petechiae, which are pinpoint hemorrhages in the skin that often appear on the lower extremities where hydrostatic pressure is greatest. Coalesced petechiae are referred to as purpura. Ecchymoses, however, are deep-seated hemorrhages in the subcutaneous tissue, usually indicative of a coagulation disorder. Platelet-related bleeding also tends to occur in the oral mucosa or gastrointestinal tract (GI), and bleeding tends to be immediate in onset since platelets are responsible for the primary hemostatic plug. Coagulation disorders may predispose to more delayed-onset bleeding, and bleeding may occur in intramuscular tissues and joints, as well as the skin and GI tract.

Coagulation disorders may be inherited, in which case they are usually single factor deficiencies (e.g., factor VIII), or acquired, in which case multiple factors are affected (e.g., vitamin K deficiency, liver disease). Recently, a number of new inherited coagulation disorders have been uncovered, accounting for a propensity for thrombosis.

In the final analysis, the diagnosis of a hemostatic disorder of platelets or coagulation depends greatly on the laboratory, and the clinical history simply provides the clues as to where to focus the initial evaluation. Given the complexity of hemostatic disorders, it is helpful to have the assistance of a specialist in the field of coagulation (see Chapter 115 ).

[edit] ANEMIAS AND RBC DISORDERS

[edit] Microcytic Anemias

Microcytic anemias are characterized by RBCs with a mean corpuscular volume (MCV) that is usually less than 80 fl. Microcytosis is often but not always associated with hypochromia (mean corpuscular hemoglobin concentration [MCHC] < 32 g/dl). Iron deficiency produces microcytic, hypochromic RBCs, but other causes of small cells can be anemia of chronic disease, thalassemia, and lead poisoning.

[edit] Iron Deficiency

The most common cause of anemia in the United States is iron deficiency. It results in a maturation abnormality with decreased hemoglobin and red cell production, and it represents one-quarter of anemias seen in a population of hospitalized patients. Typical patients include infants on a prolonged milk diet with no other nutrients, multiparous women, and patients with bleeding from a GI or gynecologic neoplasm. When iron deficiency is diagnosed, the etiology must be ascertained because of the potential for serious underlying pathology.

Iron homeostasis is finely regulated by absorption, rather than excretion, to meet metabolic needs. Iron is absorbed most effectively in the duodenum and upper jejunum. Absorption is mainly responsive to changes in total RBC mass and tissue hypoxia and not simply to total body iron stores. Iron loss in the GI tract and elsewhere approximates 1 mg daily, the amount absorbed per day. In the menstruating woman, approximately 2 mg daily are lost when averaged over the month, and during pregnancy, the need for absorbed iron reaches 2.5 to 3 mg per day to meet the demands of the fetus.

[edit] Etiology.

Iron deficiency is almost exclusively caused by excessive blood loss in adults except in pregnancy where fetal needs can outstrip average daily intake. In the United States, dietary deficiency of iron is most often found in infants on a prolonged milk diet or in elderly people with inadequate diets. The daily recommended iron intake for infants is 1 mg/kg/day beginning at approximately 3 to 4 months of age. The infant consuming 1 quart of human milk per day receives only 0.4 mg of iron; those consuming cow's milk receive less than 0.1 mg. Female adolescents may developiron deficiency due to heavy menstrual bleeding as in adult women. Iron deficiency can also occur as a result of surgical resection of the proximal intestine, inflammatory bowel disease, and sprue. Chronic intravascular hemolysis as may be seen in a malfunctioning prosthetic cardiac valve can also result in iron deficiency due to loss of iron in the urine (hemosiderinuria).

[edit] Clinical Findings and Diagnosis.

The clinical manifestations of iron deficiency include fatigue, weakness, and headache as in many anemias. Iron deficiency may produce specific signs and symptoms including chelitis, stomatitis, a spoonlike deformity of the finger nails (koilonychia), dysphagia (esophageal webs), and pica (especially pagophagia or ice craving). Occasionally, iron deficiency can cause splenomegaly. The laboratory diagnosis is based on the presence of anemia with microcytic, hypochromic RBCs with varying RBC size and shape leading to an elevated RDW. The diagnosis is confirmed by the findings of a low serum iron, elevated total iron binding capacity (TIBC), and very low TIBC saturation or a low serum ferritin (Table 113-3). The serum ferritin is the preferred measure of iron stores since the serum iron and TIBC are more readily influenced by associated inflammatory conditions making them more difficult to interpret.

Table 113-3 Results of Laboratory Tests in Iron Deficiency, Anemia of Chronic Disease, or Both

[edit] Therapy.

Iron therapy can start, even while the underlying cause is pursued. Ferrous sulfate, containing 60 mg of elemental iron, is the least expensive form of iron supplement. To avoid GI irritation, it may be advisable to start with one tablet daily and slowly increase to two or three per day depending on the severity of the iron deficiency. A response should be noted in 1 week with a mild increase in the reticulocyte count. Iron therapy should be continued for several months after correction of the Hct to replenish iron stores.

[edit] Anemia of Chronic Disease

Anemia of chronic disease denotes a chronic, mild-to- moderate normochromic normocytic or mildly hypochromic microcytic anemia that occurs in the setting of chronic inflammation from a variety of causes including autoimmune disorders, infections, cancer, and so on. In the presence of inflammatory mediators, but based on poorly explained mechanisms, the anemia is caused by a block in iron utilization by RBC precursors. Thus storage iron tends to increase, which results in an elevated ferritin, but circulating iron is low, which is reflected by a low serum iron. Transferrin production is also depressed, leading to a reduced TIBC. The RBC count settles in the range of a Hct of 30% and rarely goes below 28%. An anemia with a Hct below 28% may in part be due to chronic inflammation, but other factors should be considered as well. Anemia of chronic disease requires no specific treatment other than treatment of the underlying inflammatory process. Anemia of chronic disease and iron deficiency anemia often occur together or the potential for each may commonly be present. Since iron studies may be confusing, differentiating one from the other is not always easy.Table 113-3 summarizes the findings in each condition alone and when combined and recommends the most useful screening tests.

[edit] Macrocytic Anemia

Macrocytic anemia is characterized by large red cells in the peripheral blood smear and is defined by an elevated MCV. Many factors can lead to macrocytosis besides a deficiency of vitamin B₁₂ or folic acid. These include an elevation in the reticulocyte count (reticulocytes are younger and larger cells), the presence of target cells typically seen in liver disease or post splenectomy (large cells with excess membrane), hypothyroidism, the myelodysplastic syndromes and in response to a number of cancer chemotherapeutic drugs.

[edit] Vitamin B₁₂ and Folic Acid Deficiency

In vitamin B₁₂ and folic acid deficiency, RBC maturation is characterized as megaloblastic, which refers to a specific maturation abnormality and morphologic appearance of RBC precursors. RBCs show a delay in nuclear maturation (immature nuclear appearance) while cytoplasmic maturation proceeds. The pathophysiology can be traced to the folic acid cycle and impaired production of purine nucleotides (Fig. 113-3). This is certain for folic acid, but it is not entirely clear whether the B₁₂ defect is mediated through its relationship to the folic acid cycle or through some other mechanism.

Figure 113-3 Folic acid metabolism and interaction with vitamin B₁₂. Dietary folates enter the cycle as formyl, methyl, and methylene THF. Vitamin B₁₂ serves as a cofactor in the conversion of 5-methylene THF to THF and homocysteine to methionine. Nucleic acid synthesis is integrated at the 5,10-methylene THF to dihydrofolate (DHF) step. THF, Tetrahydrofolate.

[edit] Etiology.

In theory, deficiencies of vitamin B₁₂ or folic acid can occur as a result of inadequate intake, absorption, or excessive demand. In some cases there may be interference with folate metabolism. In practice, however, vitamin B₁₂ deficiency is virtually always due to a problem withabsorption, while folate deficiency spans the whole spectrum of possibilities.Box 113-1 summarizes the potential causes of deficiency of each vitamin. Pernicious anemia is a special case of vitamin B₁₂ deficiency. Pernicious anemia may be an autoimmune disorder resulting in a deficiency of intrinsic factor, a protein secreted by parietal cells of the stomach that facilitates vitamin B₁₂ absorption in the terminal ileum.

[edit] Clinical Findings and Diagnosis.

Anemia develops insidiously and symptoms may not appear until the Hct is severely reduced. Folic acid stores are limited and a deficiency can develop over a 3 month period with inadequate intake. Vitamin B₁₂ stores are enough to sustain an individual for up to 3 or more years. Since vitamin B₁₂ is required for normal neurologic function, a disorder of impaired vibratory and position sense and ataxia or spastic gait can develop called subacute combined systems disease (affects lateral and dorsal columns of spinal cord). Mental status changes may also develop with B₁₂ deficiency. If left untreated, these findings may become irreversible. It has recently become clear that these problems can develop in the setting of vitamin B₁₂ deficiency without significant anemia.

The peripheral blood shows macrocytic RBCs (typically, oval macrocytes) and hypersegmented neutrophils. A diagnosis is established by measuring a low B₁₂ or folate level. Sometimes, the RBC folate level can be helpful since it remains low for some time even after correction of the plasma level. A bone marrow, if necessary, if usually hypercellular and shows megaloblastic maturation in all three cell lines. In vitamin B₁₂ deficiency, the presumed site of malabsorption can be determined by performing a Schilling test, which involves administering oral radioactively-labeled vitamin B₁₂ with or without intrinsic factor attached, followed by an intramuscular injection of vitamin B₁₂ to saturate binding sites, and then measuring urinary excretion of absorbed, labeled B₁₂.

[edit] Therapy.

Therapy consists of administering folic acid daily, 1 mg per day, in the case of folate deficiency or vitamin B₁₂, 100 μg intramuscularly once monthly. Vitamin B₁₂ deficiency is initially treated with higher doses (1000 μg) weekly for the first 4 weeks. It is imperative to make a correct diagnosis of the cause of a megaloblastic anemia because the administration of folic acid can improve the anemia of vitamin B₁₂ deficiency, but it has no effect on the neurologic impairment that can become irreversible if untreated.

[edit] Hemolytic Anemias

The pathophysiologic abnormality in hemolysis is a shortening of the red cell survival, which is normally 100 to 120 days. Regardless of the primary cause, the final hemolytic event is a result of injury to the RBC membrane. Any disorder that affects the membrane may result in a shortened red cell survival. The hemolytic anemias are broadly categorized as those resulting from an intrinsic defectof red cells, usually congenital, and those related to an extrinsic defect, usually acquired. They can also be categorized by the site of RBC destruction: in some situations the major site is in the circulation (intravascular), whereas in others it is extravascular, primarily by macrophages in the spleen. The usual response of the bone marrow to hemolysis is an increase in erythropoiesis, reflected by an elevated reticulocyte count.

Symptoms due to hemolysis depend on its severity and the rapidity with which anemia develops. Jaundice is a common underlying finding. A history of cholelithiasis and splenomegaly may be found in association with congenital or long-standing hemolysis. Similar hereditary forms may exist in the family, and a study of parents or siblings may reveal reticulocytosis, splenomegaly, or both in otherwise compensated, silent cases. In chronic hemolytic syndromes, exacerbation of hemolysis may produce a hemolytic crisis with a severe worsening of anemia. Hemolysis should be suspected whenever the reticulocyte count is increased without evidence of blood loss. Depending on the cause of the hemolysis, spherocytes or other abnormalities in red cell shape may be present on the peripheral blood smear. In fulminant cases of hemolysis, the diagnosis is often not difficult. In more subtle cases, the physician may be confronted with the question of whether or not hemolysis is present. In this case, one needs to look for the breakdown products of hemoglobin.Fig. 113-4 is an illustration of the pathways of hemoglobin metabolism in the setting of either intravascular or extravascular hemolysis.

Figure 113-4 Pathways of hemoglobin metabolism in extravascular or intravascular hemolysis. Items enclosed in rectangles indicate assays routinely obtained that reflect hemolysis. These tests are more likely to be positive with intravascular hemolysis than with extravascular hemolysis. Note that certain tests are not included here, e.g., a Coombs test. A Coombs test is a diagnostic test looking at a specific etiology for hemolysis, whereas these tests are more generic in that they simply reflect the presence of hemolysis and not necessarily its etiology. Once the presence of hemolysis is determined, tests are ordered that look for specific etiologies. HGB, Hemoglobin;HPT, haptoglobin;HPX, hemopexin;LDH, lactic dehydrogenase.

[edit] Hemolysis Due to Extrinsic RBC Defects

[edit] Immune Hemolysis.

Immune hemolysis resulting from antibody damage to the RBC membrane may be a result of an autoimmune, alloimmune, or drug-induced process. Autoimmune hemolytic anemias (AIHA) can occur in the setting of a well-characterized autoimmune disease, or more commonly may be idiopathic. IgG-mediated AIHAs are more common and primarily produce extravascular breakdown of RBCs (Box 113-2). IgM-mediated AIHAs, also called cold AIHA or cold agglutinin disease because the antibodies are most reactive at low temperatures, produce complement activation and intravascular hemolysis. The Coombs test or direct antiglobulin test is positive in the vast majority of cases of AIHA. The reticulocyte count is typically elevated, and breakdown products of hemoglobin may be present in variable amounts depending on the intensity of hemolysis and whether it is predominantly intravascular or extravascular. Treatment for AIHAs always involves looking for an underlying cause such as lupus, lymphoma, or infection. Adrug-induced cause must also be considered, and if found, removal of the drug resolves the process in most cases. Steroids are the mainstay of treatment for IgG-mediated AIHA, and splenectomy may be necessary in some cases. Intravenous IgG may also be beneficial. Steroids are not as beneficial in IgM-mediated cold agglutinin AIHA, and various chemotherapeutic agents may be tried.

[edit] Mechanical Hemolysis.

Mechanical or physical injury to RBCs is characterized by a microangiopathic hemolytic anemia and the finding on blood smear of RBC fragments called schistocytes and helmet cells. These nonpliable cells circulate poorly and are rapidly removed from the circulation. This problem may be seen in such conditions as disseminated intravascular coagulation (DIC), thrombotic thrombocytopenic purpura (TTP), and damaged prosthetic cardiac valves. Specific treatment involves removing the offending underlying problem or process.

[edit] Hemolysis Due to Intrinsic RBC Defects.

Intrinsic defects include direct abnormalities of the RBC membrane (e.g., hereditary spherocytosis) or abnormalities of hemoglobin or enzymes of the Embden-Meyerhof pathway.

[edit] Hereditary Spherocytosis.

Hereditary spherocytosis (HS) is typically an autosomal dominant disorder characterized by anemia, jaundice, splenomegaly, and spherocytes. There is usually a positive family history of anemia. The RBC membrane abnormality most often involves a deficiency of spectrin, one of the major supporting elements of the membrane, although HS can result from defects of other structural elements. Patients are often symptomatic in childhood. Cholelithiasis is common. Aplastic crises can develop (temporary decrease in bone marrow RBC production). The spherocytic cells typically show greater fragility in the osmotic fragility test. Treatment in patients with recurrent problems usually involves splenectomy.

[edit] Hemoglobinopathies.

More than 300 types of hemoglobinopathies have been described, most being characterized by single or rarely multiple amino acid substitutions in the globin chains, which reduce the solubility of hemoglobin leading to increased RBC intracytoplasmic viscosity, decreased membrane pliability, and shortened RBC survival. Two major hemoglobinopathies are considered here: the sickle cell syndromes and the thalassemias. A hematologist should be involved in managing patients who are severely affected (usually homozygotes). The thalassemias are characterized by reduced synthesis of either α-chains (α-thalassemia) or β-chains (β-thalassemia), which results in precipitation of the normal (but excess) β- orbeta;-or α-chains, respectively, and causes membrane rigidity and shortened RBC survival. In both situations the final hemolytic event is precipitated by a change in the properties of the cell membrane. The electrophoretic mobility of hemoglobins with amino acid substitutions is usually abnormal and can be identified by hemoglobin electrophoresis.

[edit] Sickle Cell Disease

[edit] Etiology.

Homozygous sickle cell anemia is an inherited disease found primarily in people of African ancestry, the gene having originated in two regions of West Africa and providing a possible survival advantage to individuals infected with the malarial parasite. The basic defect in sickle cell disease is replacement of glutamic acid by valine at position 6 of the β-chain, leading to hemoglobin S (two normal α and two β_s chains). Polymerization of deoxyhemoglobin is the ultimate cause of the sickling phenomenon. The end result of sickling is occlusion of precapillary arterioles and infarction of surrounding tissues. Hemolysis occurs because of increased membrane rigidity of the deformed cells.

Patients with sickle cell trait or the heterozygous condition have erythrocytes that contain 20% to 40% hemoglobin S, with most of the remainder being normal adult hemoglobin (hemoglobin A₁). Sickle cell trait may be associated with a mild renal tubular defect that results in an inability to concentrate urine, but generally the condition is completely asymptomatic. Rarely, on exposure to severe hypoxia, the sickling phenomenon can be induced and can lead to symptoms. Sickle cell trait is present in approximately 8% to 10% of African-Americans. Hemoglobin S also occurs in association with other abnormal hemoglobins, such as hemoglobin C and hemoglobin D, or with thalassemia trait. These are called sickle cell variants and produce symptoms of varying severity.

[edit] Clinical Findings and Diagnosis.

Sickle cell anemia is a severe, constant, hemolytic anemia interrupted by vasoocclusive (painful) or aplastic crises. Symptoms first occur during the second half of the first year of life when most fetal hemoglobin has been replaced by hemoglobin S. Patients become progressively more anemic and develop splenomegaly. Eventually splenic function is lost from repeated thromboses (autosplenectomy), which can lead to an increased risk of infections during childhood.

Pain crises (vasoocclusive episodes) are caused by infarctions that lead to recurrent attacks of pain involving the chest, abdomen, and skeleton. Aplastic crises resulting in acute exacerbation of anemia develop as a result of infections when compensatory RBC production is impaired. Bone disease develops because of multiple infarctions and expansion of the bone marrow cavity. Vascular occlusions may cause avascular necrosis of the hip or shoulder. Osteomyelitis caused by Salmonella organisms is not an uncommon sequela. The sequence of marrow infarction, necrosis, and the healing process results in new bone formation, which produces characteristic radiographic changes. Cardiomegaly and pulmonary disease develop secondary to anemia and repeated infections and infarctions. The acute chest syndrome is a complication characterized by fever, pleuritic pain, lung infiltrates, and hypoxemia. It is fatal in 2% to 14% of cases due to infection, infarction, or both.

Stroke may be another catastrophic complication of sickle cell anemia. If CT scan or MRI examination is considered, one must be careful with the use of contrast dyes, even the nonionic contrast agents, unless the hemoglobin is at least 5 g/dl. Hyposthenuria, hematuria, priapism, and the nephrotic syndrome are occasionally encountered. Retinal detachment, blindness, and vitreous hemorrhages are common ocular complications. As a result of complications and repeated crises, patients often do not survive beyond the third decade.

Hemoglobin electrophoresis demonstrates only a hemoglobin S band in sickle cell anemia, and both hemoglobin A₁ and hemoglobin S in sickle cell trait. Hemoglobin F may be slightly elevated. Screening tests are based on rapid sickling of red cells under hypoxic conditions on peripheral smears or on solubility properties that allow distinction between Hb AS, SS, and A. In sickle cell anemia the presence of numerous sickled cells on Wright-stained blood smears is easily seen. Technical advances in amniocentesis have enabled the diagnosis of sickle cell anemia as early as the sixteenth weekof gestation. When this is not feasible, fetoscopy and fetal blood sampling are required, although these procedures are associated with an increased risk of fetal loss and occasional false-positive or false-negative results. Because one out of four offspring has the homozygous disease if both parents have sickle cell trait, genetic counseling of young couples carrying the sickle cell gene can prevent the trauma of caring for a child afflicted with sickle cell anemia.

Treatment of sickle cell anemia is aimed at relieving the painful vasoocclusive crises, treating the secondary effects of the chronic anemia, and if possible correcting the anemia. Treatment also requires supplementation with folic acid (1 mg daily) and prevention of infections with prompt antibiotic treatment or by vaccination (pneumococcal vaccine). The treatment of vasoocclusive crises relies on supporting measures: analgesics, intravenous fluids, and oxygen. With severe and prolonged pain, narcotic analgesics are often necessary. Oxygen is commonly used to diminish hypoxia, but its benefits have not been substantiated. If acidosis is present, sodium bicarbonate is added, usually one ampule (44 mEq) to each liter of 0.45% saline in 5% glucose, but as with oxygen therapy its benefits have not been proved. Partial exchange transfusions may be indicated in situations of prolonged vasoocclusive crises, before elective surgery, for priapism, or during pregnancy. It is advisable to maintain the hematocrit at 25% throughout pregnancy, since sickle cell blood is closest to normal viscosity at this level. At delivery, regional or spinal anesthesia should be used and proper oxygenation ensured. Recently efforts to optimize erythropoiesis by administering erythropoietin and to increase fetal hemoglobin with hydroxyurea or butyrate have undergone initially promising trials.

[edit] Hemoglobin C Disease.

Hemoglobin C disease is found in approximately 3% of heterozygotes in the United States. The interaction between hemoglobin S trait and hemoglobin C trait is quite common, occurring once in every 833 births to African-Americans. Individuals with hemoglobin SC disease tend to have a variable course, with complications occurring less frequently than with sickle cell anemia but with more symptoms than either trait alone. These patients have been reported to develop thromboembolic complications, retinopathy, and renal papillary necrosis more frequently than patients with sickle cell anemia.

[edit] Thalassemias.

The thalassemia syndromes are a heterogenous group of inherited disorders resulting from suboptimal synthesis of either the α- oralpha;-or β-globin chains, called, respectively, α- andalpha;-and β-thalassemia. They result from genetic defects at any one of a number of sites in the production of globin. The clinical expression of the thalassemic defect depends on the globin chain involved, the extent of the defect, and the adequacy of compensatory adjustments in the production of other globin chains. The normal globin chains become unbalanced because of a decrease in the affected chains, forming intraerythrocytic inclusions that damage the RBC membrane and lead to hemolysis. For instance, in homozygous β-thalassemia, excess α-chains precipitate on the red cell membrane, forming inclusions called Heinz bodies. These inclusions in turn cause increased red cell rigidity, membrane damage, and subsequent hemolysis. The homozygous thalassemias should be treated in specialized centers.

[edit] β-Thalassemia.

β-Thalassemia major (Cooley's anemia, Mediterranean anemia) is a severe, transfusion-dependent anemia that can be fatal by late childhood or early adolescence. It is found in persons homozygous or doubly heterozygous for a mutation that affects the capacity for synthesis of β-globin subunits of hemoglobin. In the full-blown case a severe anemia with drastically reduced MCV and MCHC is always found. In β-thalassemia trait (heterozygous β-thalassemia) normal α-chains are synthesized in parallel with decreased (but not absent) β-chains. Patients develop hypochromic, microcytic indices, mild poikilocytosis, and anisocytosis and are often misdiagnosed as having iron-deficiency anemia. In β-thalassemia trait, however, the RBC count is normal or even elevated in relation to the hematocrit, whereas it is decreased in iron-deficiency anemia. The two conditions must be distinguished and a firm diagnosis of β-thalassemia trait established for purposes of genetic counseling and to avoid iron therapy. With β-thalassemia trait, hemoglobin A₂ levels average 5.1% (normal upper limit is 3.7%), and in 50% of cases the hemoglobin F levels are mildly elevated to 2% to 5% (the upper normal limit being 2%).

The major problem in β-thalassemia major is the severity of the anemia. Compensatory mechanisms result in extramedullary hematopoiesis with hepatosplenomegaly. Expansion of the bone marrow leads to skeletal abnormalities, secondary thinning of cortices of long bones, and pathologic fractures. Patients require frequent transfusions, which result in hemosiderosis. Elimination of excess iron may be achieved with iron chelators (e.g., deferoxamine B) administered intramuscularly or via continuous intravenous infusion. Such treatment may result in a significant decrease in iron accumulation in tissues and hopefully longer and healthier survival. Bone marrow transplantation or molecular manipulations that would allow insertion of messenger RNA containing normal genetic information for the synthesis of β-chains are in preliminary stages of research.

[edit] α-Thalassemia.

The α-thalassemia syndromes are a group of inherited disorders with decreased synthesis of α-chains. They are especially common in Chinese and southeast Asians but may also be encountered in people originating from Africa, the Middle East, and the Mediterranean area. In contrast to β-thalassemia, hemoglobins A₂ and F are decreased because of decreased α-chains, which are constituents of both A₂ and F hemoglobins. α-Thalassemia trait should be suspected in a patient belonging to the appropriate ethnic group who presents with microcytic, hypochromic anemia, normal or decreased hemoglobins A₂ and F, and in whom iron-deficiency anemia has been ruled out. A definitive diagnosis is made by proving defective synthesis of α-chains. This can be done only in specialized laboratories, since it will not show on routine hemoglobin electrophoreses.

[edit] Enzymopathies.

Hemolytic anemias due to hereditary red cell enzyme deficiencies are exceedingly rare except for the deficiency of glucose-6-phosphate dehydrogenase (G6PD). G6PD is an enzyme vital to the RBC integrity, since it catalyzes the first step in the hexose monophosphate shunt, counteracting oxidative processes (Fig. 113-5). The gene for its synthesis is carried on the X chromosome. G6PD deficiency is fully expressed in heterozygous men and homozygous women and only partially expressed in heterozygous women. The enzyme deficiency appears to offer a selective advantage against the malarial parasite. There are two normal variants of the enzyme differing by one amino acid and designated A+ and B+ (+ denotes the presence ofthe enzyme and − denotes its absence), the former of which is prevalent in people of African ancestry. In the United States the most common deficiency is the A− type: approximately 12% of African-Americans are affected, and 20% of African-American women are heterozygous. Among Mediterranean persons a more severe type of G6PD deficiency is common, designated G6PD Mediterranean or B−. The mechanism of hemolysis in G6PD deficiency is related to the inability of RBCs to regenerate reduced glutathione (GSH) when it has been oxidized. Individuals with the A− variant are usually not anemic unless exposed to an oxidant drug (Box 113-3), whereas in the Mediterranean variant hemolysis is chronically present and exacerbated by exposure to oxidants. In the A− variety the clinical manifestations are episodic, with complete recovery between hemolytic episodes. This can occur even if the chemical exposure is continued because the new, younger RBCs contain greater amounts of the G6PD.

Figure 113-5 Embden-Meyerhof pathway and hexose monophosphate shunt in RBCs.

[edit] POLYCYTHEMIAS

The term polycythemia refers to an absolute increase in the red cell mass as reflected by the hematocrit. However, if there is a significant reduction in plasma volume, a false or spurious polycythemia exists, such as in stress erythrocytosis and excessive use of diuretics. A true increase in red cell mass is either primary or secondary, the former being known as polycythemia vera. Determination of the red cell mass is often not needed if the hemoglobin and hematocrit are extremely elevated but may be of help with moderate elevations.Table 113-4 describes criteria for distinguishing these three entities. The various conditions resulting in secondary polycythemia are listed in Box 113-4. In these cases, erythropoietin is increased and the primary stimulus for its secretion must be found.

Table 113-4 Differential Diagnosis of Relative Erythrocytosis, Secondary Erythrocytosis, and Polycythemia Vera

[edit] Polycythemia Vera

Polycythemia vera is a chronic myeloproliferative disease. It occurs mostly after the fifth decade and is characterized by an increased production of RBCs with variable increases in granuloycytes and platelets. The red cells are responsive to but not dependent on erythropoietin for their maturation. The disease starts insidiously with fatigue and weakness. When hyperviscosity develops, the patients present with dizziness, headaches, and visual problems. Occasionally the disease is discovered after an episode of acute thrombosis or during investigation of a bleeding tendency. Some patients complain of itching, particularly after a warm bath. The typical patient is plethoric with congestion of the oral mucosa and a ruddy complexion. Splenomegaly is present in more than two-thirds of patients.

To establish the diagnosis of polycythemia vera, two groups of criteria have been established (Box 113-5). The diagnosis is considered firmly established if the three major criteria are present or if the first two major criteria plus two minor criteria are documented.

Polycythemia vera is a chronic disorder with a median survival of 9 years. The disease transforms into acute nonlymphocytic leukemia in some patients. Most patients become progressively anemic with increasing bone marrow fibrosis and reduction of hematopoietic tissue (i.e., spent polycythemia). Extramedullary hematopoiesis may develop, and the spleen may become enormous. Complete bone marrow failure with severe pancytopenia develops in the final phase of such cases.

Once the diagnosis of polycythemia vera has been established, the red cell mass should be reduced to normal levels. This is best managed in collaboration with a hematologist. Therapy must be individualized for the stage of disease and for symptoms. Therapeutic approaches include phlebotomy, myelosuppressive agents, interferon-α, and radioactive phosphorus (³²P), although the latter is used less in recent years. Phlebotomy and hydroxyurea tend to be the mainstay of therapy. Recent studies indicate that Interferon-a is a promising agent. Elective surgery should not be performed until polycythemia vera has been well controlled because of the high incidence of postoperative thrombotic and hemorrhagic complications.

[edit] ADDITIONAL READINGS

• NI Berlin: Polycythemia vera. Semin Hematol 1997; 34:1 - 80.
• EJ Bini, PL Micale, EH Weinshel: Evaluation of the gastrointestinal tract in premenopausal women with iron deficiency. Am J Med 1998; 105:281 - 286.
• HF Bunn: Pathogenesis and treatment of sickle cell disease. N Engl J Med 1997; 337:762 - 769.
• R Carmel: Prevalence of undiagnosed pernicious anemia in the elderly. Arch Intern Med 1996; 156:1097 - 1100.
• MT Gladwin, AN Schecter, JH Shelhamer,et al.: The acute chest syndrome in sickle cell disease. Possible role of nitric oxide in its pathophysiology and treatment. Am J Respir Crit Care Med 1999; 159:1368 - 1376.
• GJ Izaks, RGJ Westendorp, DL Knook: The definition of anemia in older persons. JAMA 1999; 281:1714 - 1717.
• AC Looker, PR Dallman, MD Carroll,et al.: Prevalence of iron deficiency in the United States. JAMA 1997; 277:973 - 976.
• AC Massey: Microcytic anemia: Differential diagnosis and management of iron deficiency anemia. Med Clin N Am 1992; 76:549 - 566.
• DF Moore, DA Sears: Pica, iron deficiency, and the medical history. Am J Med 1994; 97:390 - 393.
• NF Olivieri: The β-thalassemias. N Engl J Med 1999; 341:99 - 109.
• DA Sears: Anemia of chronic disease. Med Clin N Amer 1992; 76:567 - 579.
• CF Snow: Laboratory diagnosis of vitamin B₁₂ and folate deficiency: A guide for the primary care physician. Arch Intern Med 1999; 159:1289 - 1298.
• CM Wilcox, LN Alexander, S Clark: Prospective evaluation of the gastrointestinal tract in patients with iron deficiency and no systemic or gastrointestinal symptoms or signs. Am J Med 1997; 103:405 - 409.