Articles on Medical Diseases and Conditions

Tag: Red Blood Cell

  • Red Blood Cell Membrane Abnormalities

    The major conditions in this category are congenital spherocytosis and hereditary elliptocytosis. Also included in this group are the uncommon condition abetalipoproteinemia and the extremely rare hereditary stomatocytosis.

    Congenital spherocytosis

    Congenital spherocytosis is one of the more common hereditary hemolytic anemias after the hemoglobinopathies and G-6-PD deficiency. Most patients are English or northern European. About 75% of cases manifest an autosomal dominant inheritance pattern, with about 25% apparently being sporadic but in most cases actually having a recessive inheritance pattern.

    The basic RBC defect is partial deficiency of a protein called spectrin that forms an important part of the RBC cell membrane cytoskeleton. Patients with the autosomal dominant form are said to have 60%-80% of normal spectrin levels; patients with the recessive form have 30%-70% of normal levels.

    Symptoms may develop at any time. Splenomegaly is found in approximately 50% of young children with the disease and in about 80% of older children and adults (literature range 72%-95%). About 50% develop jaundice, which is usually intermittent. Jaundice occurs in a substantial minority of patients in the first 48 hours of life but occasionally may appear after the first week. Gallstones develop in 55%-75% of patients by the time of old age and even during childhood in a few cases.

    Hematologic findings. Some degree of ongoing hemolysis is present in more than 90% of cases. However, about 50%-60% of patients are able to compensate by continued bone marrow hyperactivity and do not manifest anemia except during crises. When anemia is present, it is usually mild or moderate, and hemoglobin values are normally more than 8 gm/100 ml. Patients who are symptomatic and thus are diagnosed during childhood tend to have more pronounced anemia than those diagnosed in adulthood. Reticulocyte counts are elevated in approximately 90% of patients, with a mean count of approximately 9%. The MCV and MCH values are within reference range in about 80% of cases; in the remaining 20% these values may be increased or decreased. The MCHC is also more often within reference range, but 20%-50% of affected persons may have an increased value, and an increased MCHC is a finding that suggests the possibility of congenital spherocytosis. Peripheral blood spherocytes are the trademark of congenital spherocytosis. The number of spherocytes varies and in 20%-25% of cases are few in number and frequently not recognized. Spherocytes are not specific for congenital spherocytosis and may be found in ABO transfusion reactions as well as in some patients with widespread malignancy, Clostridium welchii septicemia, severe burns, some autoimmune hemolytic anemias, and after transfusion with relatively old stored blood.

    Patients with congenital spherocytosis may experience two different types of crises, which are self-limited episodes in which the anemia becomes significantly worse. The most common type is an increased degree of hemolysis (hemolytic crisis), which is frequently associated with viral infections and in which the decrease in hemoglobin level is usually not severe. The other type is the aplastic crisis, sometimes accompanied by fever and abdominal pain, lasting 6-14 days, in which bone marrow production of WBCs, RBCs, and platelets comes to a halt and during which the hemoglobin level drops to nearly one half previous values. Folic acid deficiency leading to megaloblastic anemia has also been described in congenital spherocytosis.

    The spherocytes are not destroyed in the bloodstream but are sequestered, removed, and destroyed in the spleen. Splenomegaly usually is present. Splenectomy satisfactorily cures the patient’s symptoms because increased marrow RBC production can then compensate for the presence of spherocytes, which have a shorter life span than normal RBCs.

    Diagnosis of congenital spherocytosis. The most useful diagnostic test in congenital spherocytosis is the osmotic fragility test. Red blood cells are placed in bottles containing decreasing concentrations of sodium chloride (NaCl). When the concentration becomes too dilute, normal RBCs begin to hemolyze. Spherocytes are more susceptible to hemolysis in hypotonic saline than normal RBCs, so that spherocytes begin hemolyzing at concentrations above normal range. This occurs when there are significant degrees of spherocytosis from any cause, not just congenital spherocytosis. Incidentally, target cells are resistant to hemolysis in hypotonic saline and begin to hemolyze at concentrations below those of normal RBCs. Osmotic fragility is not reliable in the newborn unless the blood is incubated at 37°C for 24 hours before testing. Incubation is also necessary in 20%-25% of adults, so that a normal nonincubated osmotic fragility result does not rule out congenital spherocytosis.

    In the great majority of patients with congenital spherocytosis, the nonincubated or the incubated osmotic fragility tests yield clear-cut positive results. In a few cases the results are equivocal, and in rare cases they are negative. In these few cases the autohemolysis test may be helpful. Congenital spherocytosis produces a considerable increase in hemolysis under the conditions of the test, which can be corrected to a considerable degree by addition of glucose to the test media. The autohemolysis test was originally proposed as a general screening procedure for genetic hemolytic disorders, but problems with sensitivity and specificity have led some investigators to seriously question its usefulness except when osmotic fragility tests fail to diagnose a case of possible congenital spherocytosis.

    Spherocytes are often confused with nonspherocytic small RBCs (microcytic RBCs). A classic spherocyte is smaller than normal RBCs, is round, and does not demonstrate the usual central clear area. (The relatively thin center associated with normal biconcave disk shape is lost as the RBC becomes a sphere.)

    Hereditary elliptocytosis (ovalocytosis)

    Hereditary elliptocytosis occurs in Europeans and African Americans, it is inherited as a dominant trait. Eighty percent to 90% of affected persons have mild compensated hemolysis either without anemia or with a mild anemia. Reticulocyte counts are usually slightly elevated but are not greatly increased. More than 40% of the RBCs are elliptocytes. These are oval RBCs that look like thick rods when viewed from the side. Normal persons reportedly may have up to 15% elliptocytes. There are several uncommon variants of hereditary elliptocytosis in which hemolysis is more pronounced, and moderate or severe anemia may be present; these include a variant of severe neonatal hemolytic anemia with jaundice in which anisocytosis and poikilocytosis are prominent but elliptocytosis is not. Infants with this variant slowly revert to the more usual mild elliptocytic clinical and hematologic picture by age 6-12 months. There is also a form called hemolytic hereditary elliptocytosis with spherocytosis in which there is mild anemia and another very similar form called homozygous hereditary elliptocytosis in which anemia is severe. Both variants demonstrate spherocytes as well as elliptocytes.

    Abetalipoproteinemia (Bassen-Kornsweig syndrome)

    Patients with abetalipoproteinemia totally lack chylomicrons, very low-density lipoproteins, and low-density lipoproteins (Chapter 22) and have only high-density lipoproteins in fasting plasma. There is associated fat malabsorption, various neuromuscular abnormalities (especially ataxia), retinitis pigmentosa, and presence of acanthocytes (Chapter 2) constituting 40%-80% of the peripheral blood RBCs. There is mild to moderate anemia with mild to moderate reticulocytosis. A peripheral smear picture similar to abetalipoproteinemia may be present in Zieve’s syndrome (hemolytic anemia with hypertriglyceridemia in alcoholic liver disease).

    Congenital stomatocytosis (stomatocytic elliptocytosis)

    Congenital stomatocytosis is found in certain Pacific Ocean populations, is inherited as an autosomal recessive trait, consists clinically of mild anemia, and demonstrates slightly elliptocytic stomatocytes on peripheral smear. Stomatocytes are RBCs with the central clear area compressed to a linear rodlike shape. Stomatocytes may also be found in association with alcoholism and liver disease.

  • Red Blood Cell Enzyme Deficiencies

    These conditions are sometimes called congenital nonspherocytic anemias. The RBC contains many enzymes involved in various metabolic activities. Theoretically any of these may be affected by congenital or possibly by acquired dysfunction. The most frequent congenital abnormalities are associated with enzymes that participate in metabolism of glucose. After glucose is phosphorylated to glucose-6-phosphate by hexokinase, about 10% of the original molecules follow the oxidative hexose monophosphate (pentose) pathway and about 90% traverse the anaerobic Embden-Meyerhof route. The only common defect associated with clinical disease is produced by G-6-PD deficiency, which is a part of the hexose monophosphate shunt. The primary importance of this sequence is its involvement with metabolism of reduced glutathione (GSH), which is important in protecting the RBC from damage by oxidizing agents. The next most frequent abnormality, pyruvate kinase defect, a part of the Embden-Meyerhof pathway, is very uncommon, and other enzyme defects are rare. The various RBC enzyme defects (plus the unstable hemoglobins) are sometimes collectively referred to as the congenital nonspherocytic anemias.

    Red blood cell enzyme defects of the hexose monophosphate shunt and others involved in glutathione metabolism are sometimes called Heinz body anemias. The term also includes many of the unstable hemoglobins and a few idiopathic cases. Heinz bodies are small, round, dark-staining, intraerythrocytic inclusions of varying size that are visualized only when stained by supravital stains (not ordinary Wright’s or Giemsa). In most cases, the Heinz bodies must be induced by oxidizing agents before staining.

    Glucose-6-phosphate dehydrogenase defect

    G-6-PD defect is a sex-linked genetic abnormality carried on the female (X) chromosome. To obtain full expression of its bad effects, the gene must not be opposed by a normal X chromosome. Therefore, the defect is most severe in males (XY) and in the much smaller number of females in whom both X chromosomes have the abnormal gene. Those females with only one abnormal gene (carrier females) have varying expressions of bad effect ranging from completely asymptomatic to only moderate abnormality even under a degree of stimulation that is greater than that needed to bring out the defect clinically in affected males or homozygous females.

    The G-6-PD defect is found mainly in sub-Saharan Africans (10%-14% of African Americans) and to a lesser extent in persons whose ancestors came from Mediterranean countries such as Italy, Greece, or Turkey; from some areas of India; and some Jewish population groups. The defect centers in the key role of G-6-PD in the pentose phosphate glucose metabolic cycle of RBCs. As RBCs age, they normally are less able to use the pentose phosphate (oxidative) cycle, which is an important pathway for use of glucose, although secondary to the Embden-Meyerhof (nonoxidative) glycolysis cycle. When defective G-6-PD status is superimposed on the older erythrocyte, use of the pentose phosphate shunt is lost. This cycle is apparently necessary to protect the integrity of the RBCs against certain chemicals. Currently it is thought that these chemicals act as oxidants and that reduced nicotinamide-adenine dinucleotide phosphate (NADPH) from the pentose cycle is the reducing agent needed to counteract their effects. At any rate, exposure to certain chemicals in sufficient dosage results in destruction of erythrocytes with a sufficiently severe G-6-PD defect. About 11% of African-American males are affected. Their defect is relatively mild, since the younger RBCs contain about 10% of normal enzyme activity, enough to resist drug-induced hemolysis. As the RBCs age they lose nearly all G-6-PD activity and are destroyed. In affected persons of Mediterranean ancestry, all RBCs regardless of age contain less than 1% G-6-PD activity.

    As previously noted, susceptible persons do not have anemia before drug exposure. After a hemolytic drug is given, acute hemolysis is usually seen on the second day, but sometimes not until the third or fourth day. All the classic laboratory signs of nonspecific acute hemolysis are present. The degree of anemia produced in African Americans is only moderate, because only the older cell population is destroyed. If the drug is discontinued, hemolysis stops in 48-72 hours. If the drug is continued, anemia continues at a plateau level, with only a small degree of active hemolysis taking place as the RBCs advance to the susceptible cell age. Whites have a more severe defect and therefore more intense hemolysis, which continues unabated as long as the drug is administered.

    Many drugs have been reported to cause this reaction in G-6-PD–defective persons. The most common are the antimalarials, sulfa drugs, nitrofurantoin (Furadantin) family, aspirin, and certain other analgesics such as phenacetin. Hemolysis induced by various infections has been frequently reported and may also occur in uremia and diabetic acidosis.

    Screening tests for G-6-PD deficiency. Several different tests are available, among which are methemoglobin reduction (Brewer’s test), glutathione stability, dye reduction, ascorbate test, and fluorescent spot tests. G-6-PD assay procedures can also be done. During hemolytic episodes in African Americans, dye reduction and glutathione stability tend to give false normal results. Blood transfusions may temporarily invalidate all G-6-PD deficiency tests in African Americans and Europeans.

    The same caution applies to G-6-PD that was applicable to the hemoglobinopathies. Hemolytic anemia in populations known to have a high incidence of G-6-PD defect should always raise the suspicion of its presence. However, even if a patient has the defect, this does not exclude the possibility that the actual cause of hemolysis was something else.

    Other red blood cell enzyme deficiencies

    There are numerous enzymes in both the anaerobic Embden-Meyerhof glycolytic pathway and the aerobic pentose phosphate shunt. Deficiency in any of these enzymes could result in clinical abnormality. After G-6-PD deficiency, by far the most common is pyruvate kinase deficiency, accounting for 90% of those hemolytic anemias from congenital RBC enzyme defects that are not produced by G-6-PD. Actually, pyruvate kinase deficiency is uncommon, and clinical abnormality from pyruvate kinase or other glycolytic enzymes is rare. Clinical abnormality from pyruvate kinase or other Embden-Meyerhof glycolytic enzyme deficiencies is usually manifest as a Coombs’-negative hemolytic anemia without the relationship to drugs or infections that is associated with G-6-PD.

  • Laboratory Tests in Hemolytic Anemias

    Certain laboratory tests are extremely helpful in suggesting or demonstrating the presence of hemolytic anemia. Which tests give abnormal results, and to what degree, depends on the severity of the hemolytic process and possibly on its duration.

    Reticulocyte count. Reticulocyte counts are nearly always elevated in moderate or severe active hemolytic anemia, with the degree of reticulocytosis having some correlation with the degree of anemia. The highest counts appear after acute hemolytic episodes. Hemolytic anemia may be subclinical, detected only by RBC survival studies, or more overt but of minimal or mild intensity. In overt hemolytic anemia of mild intensity the reticulocyte count may or may not be elevated. Studies have found reticulocyte counts within reference range in 20%-25% of patients with hemolytic anemia, most often of the idiopathic autoimmune type. In one study of 35 patients with congenital spherocytosis, reticulocyte counts were normal in 8.5% of patients; and in one study of patients with thalassemia minor, reticulocyte counts were less than 3% in one half of the patients. Nevertheless, the reticulocyte count is a valuable screening test for active hemolytic anemia, and reticulocyte counts of more than 5% should suggest this diagnosis. Other conditions that give similar reticulocyte response are acute bleeding and deficiency anemias after initial treatment (sometimes the treatment may be dietary only). It usually takes 2 to 3 days after acute hemolysis or bleeding for the characteristic reticulocyte response to appear, and occasionally 4 or 5 days if the episode is relatively mild.

    Lactic dehydrogenase. Total serum lactic dehydrogenase (LDH) consists of a group of enzymes (isoenzymes) that appear in varying amounts in different tissues. The electrophoretically fast-migrating fraction LDH-1 is found in RBCs, myocardial muscle fibers, and renal cortex cells. RBC hemolysis releases LDH-1, which elevates LDH-1 values and usually increases total LDH values. The LDH measurement is a fairly sensitive screening test in hemolytic disease, probably as sensitive as the reticulocyte count, although some investigators believe that LDH results are too inconsistent and unreliable in mild disease. Other conditions that increase LDH-1 levels include artifactual hemolysis from improper venipuncture technique or specimen handling, megaloblastic anemia, and acute myocardial infarction. In addition, the total LDH value may be elevated due to an increase in one of the other LDH isoenzymes, especially the liver fraction. Therefore, nonspecificity has limited the usefulness of total LDH values in the diagnosis of hemolytic anemia. The LDH-1 assay is more helpful. A normal total LDH value, however, would assist in ruling out hemolytic anemia if the degree of anemia were substantial. The LDH-1/LDH-2 ratio is reported to be reversed in about 60% of patients with hemolytic anemia when the lab uses electrophoresis on cellulose acetate and may or may not occur using agarose gel, depending on the method. According to one study, reversed LDH-1/LDH-2 ratio is more likely to occur in hemolytic episodes if there is a substantial degree of reticulocytosis.

    Serum haptoglobin. Haptoglobin is an alpha-2 globulin produced by the liver that binds any free hemoglobin released into the blood from intravascular or extravascular RBC destruction. Haptoglobin can be estimated in terms of haptoglobin-binding capacity or measured by using antihaptoglobin antibody techniques (Chapter 11). Under ordinary conditions a decreased serum haptoglobin level suggests that hemolysis has lowered available haptoglobin through binding of free hemoglobin. Total haptoglobin levels decrease within 8 hours after onset of hemolysis.

    The usefulness of serum haptoglobin levels in the diagnosis of hemolytic conditions is somewhat controversial, although the haptoglobin level is generally considered to have a sensitivity equal to or better than that of the reticulocyte count. The actual sensitivity for minimal or mild hemolytic disease is not well established. There are reports that haptoglobin values may be normal in 10%-20% of cases. Serum haptoglobin levels have been used to differentiate reticulocytosis due to hemolytic anemia from reticulocytosis due to acute bleeding or iron deficiency anemia under therapy. However, some reports indicate that occasionally haptoglobin levels may be mildly decreased in patients with iron deficiency anemia not known to have hemolytic anemia. Most patients with megaloblastic anemia have decreased haptoglobin levels. Haptoglobin levels also may be decreased in severe liver disease, from extravascular hematomas (due to absorption of hemoglobin into the vascular system), and with estrogen therapy or pregnancy. Congenital absence of haptoglobin occurs in approximately 3% of African Americans and about 1% (range, less than 1%-2%) of Europeans. About 80%-90% of newborns lack haptoglobin after the first day of life until 1-6 months of age. Haptoglobin is one of the “acute-phase reaction” serum proteins that are increased in conditions such as severe infection, tissue destruction, acute myocardial infarction, and burns, and in some patients with cancer; these conditions may increase the haptoglobin level sufficiently to mask the effect of hemolytic anemia or a hemolytic episode.

    Plasma methemalbumin. After the binding capacity of haptoglobin is exhausted, free hemoglobin combines with albumin to form a compound known as methemalbumin. This can be demonstrated with a spectroscope. The presence of methemalbumin means that intravascular hemolysis has occurred to a considerable extent. It also suggests that the episode was either continuing or relatively recent, because otherwise the haptoglobins would be replenished and would once again take over the hemoglobin removal duty from albumin.

    Free hemoglobin in plasma or urine. Circulating free hemoglobin occurs when all of the plasma protein-binding capacity for free hemoglobin is exhausted, including albumin. Normally there is a small amount of free hemoglobin in the plasma, probably because some artifactual hemolysis is unavoidable in drawing blood and processing the specimen. This is less when plasma is used instead of serum. If increased amounts of free hemoglobin are found in plasma, and if artifactual hemolysis due to poor blood-drawing technique (very frequent, unfortunately) can be ruled out, a relatively severe degree of intravascular hemolysis is probable. Marked hemolysis is often accompanied by free hemoglobin in the urine (hemoglobinuria). In chronic hemolysis, the urine may contain hemosiderin, located in urothelial cells or casts.

    Direct Coombs’ test. This test is helpful when a hemolytic process is suspected or demonstrated. It detects a wide variety of both isoantibodies and autoantibodies that have attached to the patient’s RBCs (see Chapter 9). The indirect Coombs’ test is often wrongly ordered in such situations. The indirect Coombs’ test belongs to a set of special techniques for antibody identification and by itself is usually not helpful in most clinical situations. If antibody is demonstrated by the direct Coombs’ test, an antibody identification test should be requested. The laboratory will decide what techniques to use, depending on the situation.

    Serum unconjugated (indirect-acting) bilirubin. The serum unconjugated bilirubin level is often elevated in hemolysis of at least moderate degree. Slight or mild degrees of hemolysis often show no elevation. The direct-acting (conjugated) fraction is usually elevated to less than 1.2 mg/100 ml (2.05 µmol/L) and less than 30% of total bilirubin unless the patient has coexisting liver disease. Except in blood bank problems, serum bilirubin is not as helpful in diagnosis of hemolytic anemias as most of the other tests and often shows equivocal results.

    Red blood cell survival studies. RBC survival can be estimated in vivo by tagging some of the patient’s RBCs with a radioactive isotope, such as chromium 51, drawing blood samples daily for isotope counting, and determining how long it takes for the tagged cells to disappear from the circulation. Survival studies are most useful to demonstrate low-grade hemolytic anemias, situations in which bone marrow production is able to keep pace with RBC destruction but is not able to keep the RBC count at normal levels. Low-grade hemolysis often presents as anemia whose etiology cannot be demonstrated by the usual methods. There are, however, certain drawbacks to this procedure. If anemia is actually due to chronic occult extravascular blood loss, radioisotope-labeled RBCs will disappear from the circulation by this route and simulate decreased intravascular survival. A minor difficulty is the fact that survival data are only approximate, because certain technical aspects of isotope RBC tagging limit the accuracy of measurement.

  • Hypoplastic Marrow

    Anemia due to inadequate erythropoiesis without factor deficiency may be classified in several ways. One system is based on the mechanism involved, including (1) marrow failure to incorporate adequate supplies of hematopoietic raw materials (e.g., iron) into red blood cell (RBC) precursors, (2) failure to release mature RBCs from the marrow, or (3) destruction of RBC precursors in the marrow. From a clinical point of view, it is easier to divide production-defect anemias into two categories: those due to a hypoplastic bone marrow and those with normally cellular marrow that are associated with certain systemic diseases.

    Conditions that produce a hypoplastic marrow affect the bone marrow directly either by actual replacement or by toxic depression of RBC precursors. Bone marrow examination is the main diagnostic or confirmatory test.

    Replacement of marrow by fibrosis. This condition, commonly termed myelofibrosis, is usually idiopathic and leads to a clinical syndrome called myeloid metaplasia. The peripheral blood picture is similar in many ways to that of chronic myelogenous leukemia. Many include this condition with the myeloproliferative syndromes.

    Replacement of marrow by neoplasm. The types of tumors most commonly metastatic to bone marrow, the laboratory abnormalities produced, and the main hematologic findings are described in Chapter 33. The anemia of neoplasia is usually normocytic and normochromic. Iron deficiency anemia secondary to hemorrhage may be present if the tumor has invaded or originated from the gastrointestinal (GI) tract. Besides extensive marrow replacement (myelophthisic anemia), neoplasia may produce anemia with minimal bone involvement or even without any marrow metastases; in these patients, there seems to be some sort of toxic influence on the marrow production and release mechanism. In occasional cases of widespread neoplasm, a hemolytic component (shortened RBC life span) has been demonstrated.

    Multiple myeloma is a neoplasm of plasma cells that is difficult to distinguish for classification purposes from leukemia on one hand and malignant lymphoma on the other. Myeloma initially or eventually involves the bone marrow and produces a moderate normocytic-normochromic anemia. Despite proliferation of plasma cells in the bone marrow, appearance of more than an occasional plasma cell in the peripheral blood is very uncommon. Peripheral blood RBCs often display the phenomenon of rouleau formation, a piling up of RBCs like a stack of coins. This is not specific for myeloma and is most often associated with hyperglobinemia.

    Aplastic anemia. Aplastic anemia is defined as peripheral blood pancytopenia (decrease in RBCs, white blood cells [WBCs], and platelets below population reference range) due to below-normal numbers and function of bone marrow cell precursors without cytologic marrow abnormality or marrow replacement by fibrosis or malignancy. Among the various etiologies are agents that predictably damage the bone marrow (e.g., radiation, certain chemicals such as benzene, and certain cytotoxic antitumor drugs). Another category, sometimes called idiosyncratic or acquired aplastic anemia, includes medications or chemicals that ordinarily do not produce cytopenia. Effects of some medications in this group are dose-related (e.g., chloramphenicol) and in others occur completely unpredictably. A third category of aplasia appears to have some autoimmune component. This includes aplasia (usually temporary) that uncommonly occurs in association with certain viral infections (e.g., parvovirus B-19, Epstein-Barr, rubella, herpes zoster-varicella) and a permanent type rarely seen in non-A, non-B (type C) hepatitis virus infection. A fourth category, probably related to category 3, might include aplasia associated with pregnancy or thymoma (the latter most often affecting RBCs only). The aplastic“crisis” of sickle cell anemia might also fit here. Some of these temporary aplastic crises may be due to parvovirus B-19 infection. A fifth category includes congenital diseases in which aplasia appears with varying frequency, of which the best known are Fanconi’s syndrome and the Diamond-Blackfan syndrome. Finally, some investigators create a more controversial category into which they place certain conditions involving bone marrow that frequently, but not always, develop into typical hematopoietic malignancies. Even more controversial is the status of other hematopoietic or nonhematopoietic malignancies that affect bone marrow function without actual marrow involvement.

    About 50% (in some reports, up to 70%) of aplastic anemia cases are unexplained or the cause is unproven. To make matters even more difficult, in some cases marrow aplasia may develop days or weeks after beginning treatment or exposure to the causative agent; and in some cases it may appear some time after exposure has ceased (in the case of radiation, even years later). Also, certain other conditions, such as hypersplenism, megaloblastic anemia, or marrow replacement by tumor, can simulate aplastic anemia.

    A great variety of drugs and chemicals have been reported to cause idiosyncratic reactions. The effects range from pancytopenia to any combination of single or multiple blood element defects. Bone marrow aspiration usually shows a deficiency in the particular cell precursor involved, although, especially with megakaryocytes, this is not always true. Patients most often recover if they can be supported long enough, although a considerable number die of superimposed infection.

    The drugs most often implicated in idiosyncratic reaction aplastic change are listed here according to blood element defect:

    Pancytopenia. Chloramphenicol (Chloromycetin), phenylbutazone (Butazolidin), indomethacin, mephenytoin (Mesantoin), gold preparations, nitrogen mustard compounds (e.g., busulfan [Myleran]) and other antileukemic drugs. In addition, chloramphenicol may produce the“gray syndrome” in premature infants and newborns.

    Leukopenia. Chlorpromazine (Thorazine), promazine (Sparine), phenylbutazone, thiouracil, antileukemic drugs, sulfonamides.

    Thrombocytopenia. Quinidine, nitrofurantoin (Furadantin), sulfonylureas, chlorothiazide.

    Aplastic anemia is most often normocytic-normochromic. Reticulocyte counts are usually low (although they sometimes are slightly elevated if the patient is in a recovery phase). About one third of aplastic anemia patients have a macrocytic peripheral blood smear.

    As noted, bone marrow aspiration is usually essential for diagnosis and can be used to follow any response to therapy. However, certain problems are associated with this method of diagnosis and must be taken into account. A false impression of marrow hypocellularity may be produced by hemodilution of the marrow specimen, by aspiration at a place that has unusually large amounts of fatty tissue, and by poor slide preparation technique. An occasional completely dry puncture may occur in normal persons due to considerable variability in the bone marrow distribution. Therefore, the diagnosis should never be made on the basis of a single failure to obtain marrow. Also, a bone marrow biopsy specimen, or at least a clot section (clotted marrow aspirate, processed as an ordinary histologic specimen), is more reliable than a smear for estimating cellularity. This is especially true for megakaryocytes. On the other hand, a smear is definitely more valuable for demonstrating abnormal morphology. Both can usually be done at the same time.

    Certain conditions may be associated with episodes of transient bone marrow RBC hypoplasia. These include congenital spherocytosis, sickle cell anemia, and RBC hypoplasia associated with thymoma. Aplastic pancytopenia may occur in paroxysmal nocturnal hemoglobinuria, either preceding onset of the disease or after onset as a transient episode.

    Pancytopenia in children may be caused by Fanconi’s anemia or Diamond-Blackfan congenital hypoplastic anemia. Fanconi’s anemia is an autosomal recessive disorder characterized by pancytopenia and congenital abnormalities such as short stature, web neck, cleft lip, mental retardation, and renal anomalies. More than 10% of peripheral blood lymphocytes display chromosome abnormalities. Anemia may appear in children up to age 10 years with the disease. Diamond-Blackfan syndrome also has an autosomal recessive inheritance pattern and displays congenital anomalies, but it consists of pure RBC aplasia, and onset of anemia occurs either at birth or by age 6 months.

    In children, apparent aplastic anemia or pancytopenia must be differentiated from acute leukemia.

  • Red Blood Cell (RBC) Count

    The number of RBCs per cubic millimeter gives an indirect estimate of the Hb content of the blood. Manual blood cell counting chamber (hemocytometer) methods give errors of 7%-14% or even more, depending on the experience of the technician. Automatic counting machines reduce this error to about 4%. However, many smaller laboratories do not have these machines. Reference values are 4.5-6.0 million/mm3 (4.5-6.0 Ч 106/L) for men and 4.0-5.5 million/cu mm (4.0-5.5 Ч 106/L) for women.