Leukemoid reaction is usually defined as a nonleukemic WBC count more than 50,000/mm3 (50 х 109/L) or a differential count with more than 5% metamyelocytes or earlier cells. It is basically a more severe or pronounced form of ordinary nonneoplastic granulocyte reaction. Some conditions associated with leukemoid reaction are severe bacterial infections, severe toxic states (burns, tissue necrosis, etc.), extensive bone marrow replacement by tumor, severe hemolytic anemia, severe acute blood loss, and juvenile rheumatoid arthritis.
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Basophilia
Basophilia is most frequently found in chronic myelogenous leukemia. Basophils may be increased in the other “myeloproliferative” diseases and occasionally in certain nonmalignant conditions.
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Eosinophilia
Parasites. Eosinophilia is most often associated with roundworms and infestation by various flukes. In the United States, roundworms predominate, such as Ascaris, Strongyloides, and Trichinella (Trichina). The condition known as visceral larva migrans, caused by the nematode Toxocara canis (common in dogs) is sometimes seen in humans. In Trichinella infection an almost diagnostic triad is bilateral upper eyelid edema, severe muscle pain, and eosinophilia. (Eosinophilia, however, may be absent in overwhelming infection.)
Acute allergic attacks. Asthma, hay fever, and other allergic reactions may be associated with eosinophilia.
Certain extensive chronic skin diseases. Eosinophilia is often found in pemphigus; it also may appear in psoriasis and several other cutaneous disorders.
Certain bacterial infections. Eosinophilia may occur in scarlet fever and brucellosis.
Miscellaneous conditions. Eosinophilia is reported in 20% of polyarteritis nodosa cases and 25% of sarcoidosis patients. It also has been reported in up to 20% of patients with Hodgkin’s disease, but the degree of eosinophilia is usually not impressive. Eosinophilia is associated with certain types of pneumonitis such as Lцffler’s syndrome and the syndrome of “pulmonary infiltration with eosinophilia.” Eosinophilia may occur with various types of cancer, but the overall incidence is less than 1%. A substantial number of patients undergoing peritoneal dialysis for chronic renal failure are reported to have intermittent eosinophilia (about 60% of cases in one report), most often following insertion of the dialysis catheter. A number of other diseases have been reported to produce eosinophilia, but either the diseases are rare or there is a low incidence of eosinophilia.
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Monocytosis
Monocytosis may occur in the absence of leukocytosis. Monocytosis is most frequently found in subacute bacterial endocarditis (about 15%-20% of patients), disseminated TB (15%-20% of patients), during the recovery phase of various acute infections, in many types of hematologic disorders (including nonmonocytic leukemias, myeloma, and hemolytic anemias), in malignant lymphomas and carcinomas, in rheumatoid-collagen diseases, and in typhoid fever. Malaria and leishmaniasis (kala-azar) are frequent causes of monocytosis outside the United States. Monocytic leukemia and myelodysplastic syndromes (Chapter 7) also enter the differential diagnosis.
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Neutrophilic Leukocytosis Due To Infection and Inflammation
Inflammation is the most frequent condition associated with neutrophilic leukocytosis. Besides an increase in total neutrophil count, there often is some degree of immaturity (“shift to the left”*). Usually a shift to the left involves an increase in the early segmented and the band neutrophil stages. Occasionally even some earlier cells (metamyelocytes or even myelocytes) may appear; this is known as leukemoid reaction. Leukocytosis is most often seen with bacterial infection; viral infections tend to be associated with normal counts or even leukopenia. The granulomatous infections (tuberculosis, sarcoidosis) most often have normal WBC counts, but tuberculosis occasionally demonstrates a leukocytosis. Typhoid fever is a bacterial infection that usually does not have a WBC increase; on the other hand, a neutrophilic leukocytosis may be present in 30% or more of persons with severe enteric cytopathic human orphan (ECHO) virus infection. Overwhelming infection, particularly in debilitated persons or the elderly, may fail to show leukocytosis.
Deviation from usual white blood cell pattern in infection
The classic WBC picture of acute bacterial infection is leukocytosis with an increased percentage of neutrophils and band forms. Unfortunately, leukocytosis may be absent in approximately 15%-30% of cases (literature range, 10%-45%), and band forms may remain within reference limits in approximately 30%-40% (range, 21%-61%) of cases. The band count variation can be attributed at least partially to differences in individual technologist interpretation of folded bands versus segmented neutrophils (referred to previously), failure of individual laboratories to establish their own band reference range (rather than using values found in some publication), technical variance such as irregular distribution of cell types on the peripheral smear due to technique in making the smear and the areas chosen for cell counting, and very poor reproducibility (50%-200% variation reported) due to the small numbers involved and the other factors just cited.
In addition, band counts vary substantially between different technologists. In one experiment, 15 well-trained ASCP technologists counting the same peripheral smear on two different occasions never obtained the same band count result; the different technologist band counts varied from 3% bands to 27% bands.
In general, absolute values (total number of neutrophils or bands per cubic millimeter) are more reliable than values expressed as a percent of the total WBC count, since the percentage of one cell type may reflect a change in the number of another cell type rather than a strict increase or decrease of the cell type in question. Total neutrophil count (percentage) is also more reliable because a minimum of subjective interpretation is needed. To illustrate this, I studied hematologic findings from 113 cases of well-documented culture-proven urinary tract infections (UTIs) and 79 patients with bacteremia; as well as 34 cases of acute cholecystitis and 42 cases of acute appendicitis proven by surgical specimens. In all categories of infection, the total neutrophil count was elevated more often than the band count (at least 10% and usually 20% more cases). In UTI and bacteremia, total neutrophil count was elevated more often (about 10% more cases) than the total WBC count; in acute appendicitis and acute cholecystitis, the reverse was true. In summary, the total neutrophil percentage appears to be the most sensitive and useful parameter of infection, while the band count is the least reliable.
Although an increase in band count is traditionally associated with bacterial infection, it may occur in some patients with viral infection. In one report, 29% of pediatric patients with influenza and no evidence of bacterial infection had elevated band count; also 23% of enterovirus infection; 22% of respiratory syncytial virus infection; and 10% of rotovirus infection.
Automated cell counter differential counts
Certain newer automated cell counters can produce a limited differential in percent and absolute numbers. These instruments have much better reproducibility than manual differential cell counts because the machine examines thousands of cells rather than only 100. Each of these instruments has some omissions compared to manual differentials, such as lack of a band count, failure to note WBC and red blood cell (RBC) inclusions, and failure to detect certain abnormally shaped RBCs. As discussed before, lack of a band count is not important, and for the great majority of patients an automated differential is more reliable than a manual differential. A technologist can quickly scan the slide to examine RBC morphology and detect any omission of the automated differential. If abnormal WBCs are found, a manual differential can be performed.
Special problems in neonates and younger children
First, age-related reference values are essential. However, reference values for neonates from different sources vary even more than those for adults. Second, as noted previously, total WBC and neutrophil values rise sharply after birth and then fall. Most, although not all, investigators do not consider total WBC or absolute neutrophil values reliable in the first 3 days of life. After that time, absolute neutrophil values are said to be more reliable than total WBC counts. However, although elevated results are consistent with bacterial infection, there may be substantial overlap with WBC values seen in nonbacterial infection, and values within the reference range definitely do not exclude bacterial infection. In fact, it has been reported that neonates with sepsis are more likely to have normal range or low WBC counts than elevated ones. It has been reported that violent crying can temporarily increase WBC and band counts over twice baseline values for as long as 1 hour.
Neutrophil cytoplasmic inclusions. Certain neutrophil cytoplasmic inclusions are associated with infection (although they are also seen in tissue destruction, burns, and similar toxic states); these include toxic granulation and D?hle bodies. Toxic granulation is accentuation of normal neutrophilic cytoplasm granules, which become enlarged or appear as short, rod-shaped structures of irregular width, either dark blue-black, or the same color as the nucleus. D?hle bodies are moderate-sized, light blue structures most frequently located next to the cytoplasmic border. The presence of vacuoles in the cytoplasm of peripheral blood neutrophils has repeatedly been cited as a clue to septicemia. However, although there is a strong association with bacteremia or septicemia, some neutrophils with a few cytoplasmic vacuoles may occur in patients without definite evidence of bacterial infection.
Neutrophilic leukocytosis due to tissue destruction. Tissue destruction may be due to burns, abscess, trauma, hemorrhage, infarction, carcinomatosis, active alcoholic cirrhosis, or surgery and is often accompanied by varying degrees of leukocytosis. The leukocytosis varies in severity and frequency according to the cause and amount of tissue destruction.
Neutrophilic leukocytosis due to metabolic toxic states. The most frequent metabolic toxic states are uremia, diabetic acidosis, acute gout attacks, and convulsions. A similar effect under nontoxic circumstances is seen after severe exercise and during the last trimester of pregnancy. During labor there is often a neutrophil leukocytosis that increases with duration of labor; in one report the majority of patients had total WBC counts less than 18,000/mm3 (18 Ч 109/L), but some rose as high as 24,000/mm3. In 100 consecutive obstetrical patients admitted to our hospital for childbirth, 38% had a count between 10,500 and 18,000/mm3. The highest WBC count was 23,000/mm3. Twenty percent had elevated band counts, and 26% had elevated total neutrophil counts.
Neutrophilic leukocytosis due to certain drugs and chemicals. Adrenal cortical steroids even in relatively low doses often produce a considerable increase in mature segmented neutrophils, with total WBC counts rising within 48 hours to levels that are often double baseline values. Peak counts remain for 2-3 weeks and then slowly decline somewhat, although not to baseline. Therapy with lithium carbonate for psychiatric depression produces an average WBC elevation of about 30%. Epinephrine therapy for asthma frequently produces a significant leukocytosis. Poisoning by various chemicals, especially lead, is another cause of leukocytosis. On the other hand, certain drugs may cause leukopenia from idiosyncratic bone marrow depression.
Neutrophilic leukocytosis due to other etiologies. Cigarette smokers, especially heavy smokers, are reported to have total WBC counts that average 1,000/mm3 (1.0 Ч 109/L) or even more above those for nonsmokers. Other causes of neutrophilic leukocytosis are acute hemorrhage or severe hemolytic anemia (acute or chronic), myelogenous leukemia, and the myeloproliferative syndromes, including some cases of polycythemia vera.
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Neonatal Leukocytosis
At birth, there is a leukocytosis of 18,000-22,000/ mm3 (18-22 Ч 109/L) for the first 1-3 days. This drops sharply at 3-4 days to levels between 8,000 and 16,000/mm3. At roughly 6 months, approximately adult levels are reached, although the upper limit of normal is more flexible. Although the postnatal period is associated with neutrophilia, lymphocytes slightly predominate thereafter until about age 4-5 years, when adult values for total WBC count and differential become established (see Table 37-1). Capillary (heelstick) blood WBC reference values are about 20% higher than venous WBC values on the first day of life and about 10% higher on the second day.
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Pelger-Hu?t Anomaly
Of various hereditary abnormalities of WBC morphology, the most important is the Pelger-Huлt nuclear anomaly. This is manifested by WBC nuclear hyposegmentation. In the neutrophil series, many of the segmented cells appear to have bilobed nuclei shaped like a dumbbell or a pair of eyeglasses. There is also an increase in bandlike forms and forms with round or oval nuclei resembling myelocytes. Eosinophils normally may have a bilobed nuclear form. Although occasional normal neutrophils may have this nuclear shape, it is not a common finding, and more than two or three neutrophils with a bilobed nucleus per 100 WBCs would be unusual. The Pelger-Huлt anomaly may be congenital, inherited as a mendelian dominant trait; the congenital form is not common and is asymptomatic. An increased number of neutrophils with similar appearance may represent an acquired change (known as pseudo-Pelger-Hu?t); this is most often seen in myeloproliferative disorders, myeloid leukemia, and agranulocytosis, in some patients with metastatic tumor to bone marrow, or under conditions of drug toxicity. Neutrophils of the Pelger-Hu?t anomaly must be differentiated from true neutrophil immaturity such as that seen with infection or chronic myelogenous leukemia.
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White Blood Cell Maturation Sequence
Normal WBC maturation sequence begins with the blast form, derived from hematopoietic stem cells that, in turn, are thought to be derived from tissue reticulum cells (Fig. 6-1). In the myelocytic (granulocytic or neutrophilic) series, the blast is characterized by a large nucleus with delicate very uniform-appearing light-staining chromatin and with one or more nucleoli. Typically, a blast has relatively scanty basophilic cytoplasm without granules,* but the French-American-British (FAB) group (Chapter 7) describes a category of blasts with cytoplasm that may contain a few “azurophilic” granules. Next in sequence is the progranulocyte (promyelocyte), which is similar to the blast but has a variable number of cytoplasmic granules. The promyelocyte gives rise to the myelocyte. Myelocyte nuclear chromatin is more condensed, there is no nucleolus, and the nucleus itself is round or oval, sometimes with a slight flattening along one side. The cytoplasm is mildly basophilic and is granular to varying degrees, although sometimes granules are absent. Often there is a small, localized, pale or clear area next to the flattened portion (if present) of the nucleus, called the myeloid spot. Next, the nucleus begins to indent; when it does, the cell is called a metamyelocyte (juvenile). As the metamyelocyte continues to mature, the nucleus becomes more and more indented. The nuclear chromatin becomes more and more condensed, clumped, and darkly stained, and the cytoplasm becomes progressively less basophilic. The entire cell size becomes somewhat smaller, with the nucleus taking up increasingly less space. Finally, the band (stab) neutrophil stage is reached. There is some disagreement as to what constitutes a band as opposed to a metamyelocyte or band as opposed to an early mature polymorphonuclear leukocyte. Basically, a band is distinguished from a late metamyelocyte when the nucleus has indented more than one half its diameter and has formed a curved rod structure that is roughly the same thickness throughout. As the band matures, nuclear indentation continues and may also occur in other areas of the nucleus. When at least one area of nuclear constriction becomes a thin wire, the cell has reached the final stage of maturity, called the polymorphonuclear (poly) or segmented neutrophil. The nucleus has segmented into two or more lobes, at least one of which is connected only by a threadlike filament to the next. The nuclear chromatin is dense and clumped. The cytoplasm is a very slightly eosinophilic color, or at least there is no basophilia. There usually are small irregular granules, which often are indistinct.
Fig. 6-1 Maturation sequence of granulocytic (myelocytic) series. A, Blast; B, promyelocyte; C, myelocyte (top, early stage; bottom, late stage); D, metamyelocyte (top, early stage; bottom, late stage) E, band granulocyte (top, early stage; bottom, late stage) F, segmented granulocyte (top, early stage; bottom, hypersegmented late stage).
Table 6-1 Terminology of blood cells
In some cases there may be a problem differentiating bands from segmented neutrophils when a bandlike nucleus is folded over itself in such a way as to hide the possibility of a thin wirelike constricted area (Fig. 6-2). The majority of investigators classify this cell as a segmented form. However, many laboratorians consider these cells bands; unless the reference range takes into account the way these cells will be interpreted, the number of bands reported can differ considerably between persons or between laboratories and could lead to incorrect diagnosis. When there is multiple nuclear segmentation and the lobes connected only by a thin wire number more than five, the cell is termed hypersegmented. Some investigators believe that hypersegmentation is present if more than 5% of the neutrophils have five lobes. Naturally, there are transition forms between any of the maturation stages just described (Fig. 6-1).
Fig. 6-2 Folded segment versus folded band. A, One end folded (“mushroom” effect). B, Nuclear fold closer to center. a, True band; b, segment with hidden constriction.
Monocytes are often confused with metamyelocytes or bands. The monocyte tends to be a larger cell. Its nuclear chromatin is a little less dense than chromatin of the myeloid cell and tends to have a strandlike configuration of varying thickness rather than forming discontinuous masses or clumps. The nucleus typically has several pseudopods, which sometimes are obscured by being superimposed on the remainder of the nucleus and must be looked for carefully. Sometimes, however, a monocyte nuclear shape that resembles a metamyelocyte is found. The monocyte cytoplasm is light blue or light gray, is rather abundant, and frequently has a cytoplasm border that appears frayed or has small irregular tags or protrusions. The granules of a monocyte, when present, usually are tiny or pinpoint in size, a little smaller than those of a neutrophil. In some cases, the best differentiation is to find undisputed bands or monocytes and compare their nucleus and cytoplasm with that of the cell in question.
The reference range for peripheral blood WBCs is 4,500-10,500/mm3 (4.5-10.5 Ч 109/L). Most persons have WBC counts of 5,000-10,000/mm3, but there is significant overlap between normal and abnormal in the wider range, especially between 10,000 and 11,000/mm3. The mean WBC count in African Americans may be at least 500/mm3 (0.5 Ч 109/L) less than those in Europeans, with some investigators reporting differences as much as 3,500/mm3. This difference would be important, since it would produce a greater than expected incidence of apparent leukopenia and less than expected leukocyte response to infection and inflammation. However, not all reports agree that there is a consistent difference between the two racial groups. Normal WBC differential values are listed here:
The value for each cell type traditionally is known as the cell “count” (i.e., band count), although the findings are expressed as a percentage of 100 WBCs rather than the actual cell number counted.
Some investigators report a diurnal variation for neutrophils and eosinophils. Neutrophil peak levels were reported about 4 P.M. and lowest values reported about 7 A.M., with an average change of about 30%. Eosinophil levels roughly paralleled serum cortisol levels, with highest values about 7 A.M. and lowest values about 4 P.M. The average change was about 40%. The remainder of this chapter describes anomalies of WBC morphology or count and associated disease states.
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White Blood Cells
White blood cells (WBCs, leukocytes) form the first line of defense of the body against invading microorganisms. Neutrophils and monocytes respond by phagocytosis; lymphocytes and plasma cells primarily produce antibodies. In addition to a nonspecific response to bacterial or viral infection, there are alterations in the normal leukocyte blood picture that may provide diagnostic clues to specific diseases, both benign and malignant. Nonneoplastic leukocyte alterations may be quantitative, qualitative, or both; qualitatively, leukocytes may demonstrate an increased degree of immaturity, morphologic alteration in cellular structure, or the increased production of less common types of WBCs.
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Hemolytic Anemias Due to Extracorpuscular Agents
Anemias due to isoagglutinins (isoantibodies)
These anemias are hemolytic reactions caused by antibodies within the various blood group systems. The classification, symptomatology, and diagnostic procedures necessary for detection of such reactions and identification of the etiology are discussed in Chapter 9 and Chapter 11.
Anemias due to autoagglutinins (autoantibodies)
Autoagglutinins are antibodies produced by an individual against certain of his or her own body cells. This discussion concerns autoantibodies produced against his or her own RBCs. The anemia associated with this condition has been called autoimmune hemolytic anemia or acquired hemolytic anemia.
Autoantibodies of the autoimmune hemolytic anemias form two general categories: those that react best in vitro above room temperature (37°C, warm autoantibodies) and those that react best in vitro at cold temperatures (cold autoantibodies or cold agglutinins). For each type there are two general etiologies, idiopathic and secondary to some known disease.Warm autoantibodies are IgG antibodies usually directed against Rh antigens on the RBC membrane. They comprise about 50%-70% of Coombs’-positive autoantibodies. The presence of the autoantibody and the RBC antigen against which it reacts can often (not always) be proven by detaching (eluting) the antibody from affected RBC. Clinical disease from warm autoantibodies is more frequent than clinical abnormality from cold autoantibodies, and the idiopathic variety is twice as frequent as that secondary to known disease. Clinically, anemia due to warm-reacting autoantibodies appears at any age and may be either chronic or acute. When chronic, it is often low grade. When acute, it is often severe and fatal. The laboratory signs are those of any hemolytic anemia and depend on the degree of anemia. Thus, there are varying degrees of reticulocyte elevation. The direct Coombs’ test result is usually, although not always, positive. Most patients have spherocytes in peripheral blood, especially if the anemia is acute; and splenomegaly is frequent.
Cold agglutinins are IgM antibodies usually directed against the I antigen on RBC membranes. These comprise about 15%-30% of Coombs’-positive autoantibodies. Complement can often be detected on affected RBC but no antibody usually can be eluted. Clinical disease from cold-reacting agglutinins is seen much less frequently than hemolytic disease from warm-reacting autoantibodies. Cold agglutinin disease is seen predominantly in adults, particularly in the elderly. The most common cause of symptomatic hemolytic anemia induced by cold agglutinins is mycoplasma infection. After mycoplasma-induced disease, the idiopathic and the secondary forms occur in nearly equal incidences. Clinically, the disease is often worse in cold weather. Raynaud’s phenomenon is common. Splenomegaly is not common. Laboratory abnormalities are not as marked as in the warm autoantibody type, except for a usually positive direct Coombs’ test result, and the anemia tends to be less severe. The reticulocyte count is usually increased but often only slightly. Spherocytes are more often absent than present. WBCs and platelets are usually normal unless altered by underlying disease. However, exceptions to these statements may occur, with severe hemolytic anemia present in all its manifestations. As noted in the discussion of mycoplasma pneumonia (Chapter 14), cold agglutinins may occur in many normal persons but only in titers up to 1:32. In symptomatic anemia due to cold agglutinins the cold agglutinin titer is almost always more than 1:1,000.
Paroxysmal cold hemoglobinuria (PCH)
Paroxysmal cold hemoglobinuria is a rare syndrome in which an antibody (Donath-Landsteiner antibody) of the IgG class binds to and sensitizes RBCs at cold temperatures and then produces complement-activated RBC lysis at warmertemperatures. PCH comprises about 2%-5% of Coombs’-positive autoantibodies, much more common in children than in adults. Paroxysmal cold hemoglobinuria was originally associated with syphilis, but more cases occur idiopathically or following viral infection than from syphilis. Hemoglobinuria is produced after patient exposure to cold temperatures and may be accompanied by back or leg pain, chills, and cramps, similar to symptoms of hemolytic transfusion reaction. The IgG-specific Coombs’ reagent produces positive direct Coombs’ test results at cold temperatures and Coombs’ reagents containing non-gamma non-IgG-specific antibody (sometimes called broad-spectrum Coombs’ reagent) produce positive direct Coombs’ test results at the usual Coombs’ test temperature of 37°C. The major diagnostic procedure for paroxysmal cold hemoglobinuria is the Donath-Landsteiner test, in which the development of hemolysis in patient and normal blood is compared at cold temperature.
Secondary acquired autoimmune hemolytic anemia
The causes of acquired hemolytic anemia of the secondary type, either warm or cold variety, can be divided into three main groups. The first group in order of frequency is leukemia and lymphoma; most often chronic lymphocytic leukemia, to a lesser extent lymphocytic lymphoma, and occasionally Hodgkin’s disease. The second group in order of frequency is collagen disease, notably lupus erythematosus. The third group is a miscellaneous collection of systemic diseases in which overtly hemolytic anemia rarely develops but may do so from time to time. These diseases include viral infections, severe liver disease, ovarian tumors, and carcinomatosis. It should be emphasized that in all three disease groups, anemia is a common or even frequent finding, but the anemia is usually not hemolytic, at least not of the overt or symptomatic type.
Drug-induced hemolytic anemia
Drug-induced hemolytic anemia is sometimes included with the autoimmune hemolytic anemias. However, in most cases antibodies are formed primarily against the drug, and action against the RBC is secondary to presence of the drug on the RBC surface. These cause about 10%-20% of Coombs’-positive autoantibodies. There are four basic mechanisms proposed, as follows:
1.
Combination of the drug with antidrug antibody to form an immune complex that is adsorbed onto RBCs, often activating complement. Quinidine is the best-known drug of this type. The antiquinidine antibody is of the IgM class.
2.
Binding of the drug to the RBC membrane and acting as a hapten. Penicillin (in very large doses, і10 million units/day for 7 days or more) is the major drug of this type, although abnormality develops in fewer than 3% of these cases.
3.
Nonspecific coating of RBC by drug with absorption of various proteins. The antibiotic cephalothin has been shown to act by this mechanism. A positive direct Coombs’ test result is produced by antibodies against proteins absorbed onto the cell or onto cephalothin. There is no hemolysis, however. Cephalothin may occasionally act as a hapten and in these cases may be associated with hemolytic anemia.
4.
Unknown mechanism. a-Methyldopa is the predominant drug of this type and may be the most common agent associated with drug-induced hemolytic anemia. The antimethyldopa antibody is of the IgG class and usually has Rh group specificity. Besides coating of RBCs, a-methyldopa–treated patients may have circulating autoantibodies demonstrated by an indirect Coombs’ test, which is unusual for other drugs. Patients taking a-methyldopa may also develop a syndrome resembling systemic lupus erythematosus, with antinuclear antibodies and lupus erythematosus cells (Chapter 23). Up to 25% of patients (literature range 10%-36%) develop a positive direct Coombs’ test, and about 1% (literature range 0%-5%) develop hemolytic anemia. The direct Coombs’ test result remains positive 1-24 months after the end of therapy.Laboratory investigation of possible drug-induced hemolytic anemia is usually difficult for the ordinary laboratory. The procedure usually involves washing off (eluting) the antibody from the RBC, if possible, and trying to determine whether the antibody has specificity against drug-coated RBCs rather than normal RBCs.
Traumatic (microangiopathic) hemolytic anemia
This category includes several diseases that produce hemolytic anemia with many schistocytes, the schistocytes being formed through some kind of trauma. Representative conditions are disseminated intravascular coagulation and thrombotic thrombocytopenic purpura (in which RBCs strike fibrin clots in small vessels), the hemolytic-uremic syndrome (thrombi in renal glomerular capillaries and small vessels), the cardiac prosthesis syndrome (in which RBCs are damaged while passing through the artificial heart valve), and hemolytic anemia associated with vascular grafts and some long-term indwelling catheters. The same type of hemolytic anemia may be found in a few patients with malignancy (most commonly gastric carcinoma), in Zieve’s syndrome associated with cirrhosis, in the first few hours after extensive severe burns, and in Clostridium welchii septicemia. As noted in Chapter 2, schistocytes can be found in smaller numbers in other conditions. Microangiopathic hemolytic anemia is discussed in greater length in Chapter 8.
Paroxysmal nocturnal hemoglobinuria (PNH)
Patients with paroxysmal nocturnal hemoglobinuria (PNH) develop an acquired blood cell membrane defect in which RBCs, WBCs, and platelets demonstrate abnormal sensitivity to the effect of activated serum complement. This is manifest by hemolytic anemia, granulocytopenia, and thrombocytopenia. Not all patient RBCs have the same degree of abnormality, and resistance to lysis varies from relatively normal to markedly abnormal. It is often associated with aplastic anemia and is said to develop in 5%-10% of these patients without regard to the cause of the marrow depression (with the exception that PNH is not associated with radiation marrow damage). It may appear either at the beginning of aplasia, during the aplastic period, or during recovery. About 50% of cases develop without prior evidence of aplastic marrow. It may also develop in some patients with erythroleukemia, myelofibrosis, or refractory anemia.
RBCs that are abnormally sensitive to complement have markedly decreased acetylcholinesterase levels, but this is not thought to be the cause of the defect in PNH.
Paroxysmal nocturnal hemoglobinuria most often affects young or middle-aged adults, with the usual age range being 10-60 years. The disease presents as hypoplastic anemia in about 25% of cases, as an episode of abdominal pain in about 10%, and with hemoglobinuria in about 50%. Clinically, there is a chronic hemolytic anemia, with crisis episodes of hemoglobinuria occurring most often at night. However, hemoglobinuria is present at disease onset only in about 50% of cases. Another 20% develop it within 1 year, and eventually it occurs in more than 90% of patients. Anemia is usually of moderate degree except during crisis, when it may be severe. A crisis is reflected by all the usual laboratory parameters of severe hemolysis, including elevated plasma hemoglobin levels. No spherocytosis or demonstrable antibodies are present. The disease gets its name because hemoglobinuric episodes turn urine collected during or just after sleep to red or brown due to large amounts of hemoglobin. Urine formed during the day is clear. Stimuli known to precipitate attacks in some patients include infections, surgery, and blood transfusion.
Laboratory findings. In addition to anemia, leukopenia (granulocytopenia) is present in about 50% of patients, and some degree of thrombocytopenia is present in about 70%. This is in contrast to most other hemolytic anemias, in which hemolysis usually provokes leukocytosis. The MCV is elevated in about 83%, normal in about 13%, and decreased in about 5%. The reticulocyte count is elevated in about 90%. Loss of iron in the urine (in the form of hemoglobin and hemosiderin) leads to chronic iron deficiency in some patients. For some reason the kidney in PNH is not damaged by the hemoglobin or by renal tubular cell deposition of hemosiderin.
Venous thrombosis is frequent in PNH, and patients have a considerably increased tendency toward infection (predominantly lung and urinary tract). There may be episodes of abdominal pain related to venous thrombosis.
Tests for paroxysmal nocturnal hemoglobinuria. A good screening test is a urine hemosiderin examination. However, a positive urine hemosiderin value may be obtained in many patients with chronic hemolytic anemia of various types and also may be produced by frequent blood transfusions, especially if these are given over periods of weeks or months. A much more specific test is the acid hemolysis (Ham) test. The RBCs of PNH are more susceptible to hemolysis in acid pH. Therefore, serum is acidified to a certain point that does not affect normal RBCs but will hemolyze the RBCs of PNH. Another widely used procedure is the sugar-water (sucrose hemolysis) test, which is easier to perform than the Ham test and may be more sensitive. It is based on evidence that RBCs in PNH are more susceptible to hemolysis in low ionic strength media than normal RBCs. Many laboratories screen with the sugar-water test and confirm a positive result with the Ham test. The sugar-water test is apt to produce more weak positive reactions in patients who do not have verifiable PND than does the Ham test. In my experience (also reported by others) there occasionally is discrepancy between results of the sugar-water test and the Ham test in the same patient, resulting in diagnostic problems.
Hemolytic anemia due to toxins
Chemical. Lead poisoning is the most frequent cause in this group. Ingestion of paint containing lead used to be frequent in children and still happens occasionally. Auto battery lead, gasoline fumes, and homemade whiskey distilled in lead-containing apparatus are the most common causes in adults. It takes several weeks of chronic exposure to develop symptoms unless a large dose is ingested. The anemia produced is most often mild to moderate, and the usual reason for seeking medical treatment is development of other systemic symptoms, such as convulsions from lead encephalopathy, abdominal pain, or paresthesias of hands and feet. The anemia is more often hypochromic but may be normochromic; it is usually normocytic. Basophilic stippling of RBCs is often very pronounced and is a classic diagnostic clue to this condition. Basophilic stippling may occur in any severe anemia, especially the hemolytic anemias, but when present to an unusual degree should suggest lead poisoning unless the cause is already obvious. The stippled cells are reticulocytes, which, for some unknown reason, appear in this form in these patients. However, in some patients, basophilic stippling is minimal or absent. Tests useful in lead poisoning for screening purposes or for diagnosis are discussed in Chapter 35.
Other chemicals were mentioned in the discussion of G-6-PD deficiency anemia. Benzene toxicity was discussed in the section on hypoplastic bone marrow anemias. Other chemicals that often produce a hemolytic anemia if taken in sufficient dose include naphthalene, toluene, phenacetin, and distilled water given intravenously. Severe extensive burns often produce acute hemolysis to varying degrees.
Bacterial. Clostridium welchii septicemia often produces a severe hemolytic anemia with spherocytes. Hemolytic anemia is rarely seen with tuberculosis. The anemia of infection is usually not overtly hemolytic, although there may be a minor hemolytic component (not demonstrable by the usual laboratory tests).
Hemolytic anemia due to parasites
Among hemolytic anemias due to parasites, malaria is by far the most frequent. It must be considered in persons who have visited endemic areas and who have suggestive symptoms or no other cause for their anemia. The diagnosis is made from peripheral blood, best obtained morning and afternoon for 3 days. Organisms within parasitized RBCs may be few and often are missed unless the laboratory is notified that malaria is suspected. A thick-drop special preparation is the method of choice for diagnosis. With heavy infection, the parasites may be identified on an ordinary (thin) peripheral blood smear. A hemolytic anemia is produced with the usual reticulocytosis and other laboratory abnormalities of hemolysis. Most patients have splenomegaly. Bartonella infection occurs in South America, most often in Peru. This is actually a bacterium rather than a parasite, but in many textbooks it is discussed in the parasite category. The organisms infect RBCs and cause hemolytic anemia clinically similar to malaria. Babesiosis is an uncommon protozoan infection of RBC similar in some respects to malaria. This condition is discussed in Chapter 18.
Hypersplenism
Hypersplenism is a poorly understood entity whose main feature is an enlarged spleen associated with a deficiency in one or more blood cell elements. The most common abnormality is thrombocytopenia, but there may be a pancytopenia or any combination of anemia, leukopenia, and thrombocytopenia. Hypersplenism may be primary or, more commonly, secondary to any disease that causes splenic enlargement. However, splenic enlargement in many cases does not produce hypersplenism effects. Portal hypertension with secondary splenic congestion is the most common etiology; the usual cause is cirrhosis. If anemia is produced in hypersplenism, it is normocytic and normochromic without reticulocytosis. Bone marrow examination in hypersplenism shows either mild hyperplasia of the deficient peripheral blood element precursors or normal marrow.
Several mechanisms have been proposed to explain the various effects of hypersplenism. To date, the weight of evidence favors sequestration in the spleen. In some cases, the spleen may destroy blood cells already damaged by immunologic or congenital agents. In some cases, the action of the spleen cannot be completely explained.