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CHAPTER 55 ACQUIRED HEMOLYTIC ANEMIA DUE TO WARM-REACTING AUTOANTIBODIES

CHAPTER 55 ACQUIRED HEMOLYTIC ANEMIA DUE TO WARM-REACTING AUTOANTIBODIES
Williams Hematology

CHAPTER 55 ACQUIRED HEMOLYTIC ANEMIA DUE TO WARM-REACTING AUTOANTIBODIES

CHARLES H. PACKMAN

Definition and History

Classification

Epidemiology
Etiology and Pathogenesis

Etiology

Pathogenesis
Clinical Features
Laboratory Features

General Features

Serologic Features
Differential Diagnosis
Therapy, Course, and Prognosis

Therapy

Course and Prognosis
Chapter References

Autoimmune hemolytic anemia (AHA) is characterized by shortened red cell survival and the presence of autoantibodies directed against autologous red blood cells (RBC). A positive direct antiglobulin reaction (Coombs’ test) is important for the diagnosis. Most patients with AHA (80 percent) exhibit warm-reactive antibodies of the IgG isotype. Most of the remainder exhibit cold-reactive autoantibodies of the IgM class, labeled cold agglutinins because they directly agglutinate RBC in vitro. The direct antiglobulin reaction may detect IgG, proteolytic fragments of complement (mainly C3), or both on the RBC of patients with warm-antibody AHA. In cold-antibody AHA, only complement is detected because the antibody dissociates from the RBC during washing of the cells. About half of patients with AHA have no underlying associated disease; these cases are termed idiopathic. Secondary cases are associated with underlying autoimmune, malignant, or infectious diseases or with ingestion of certain drugs. The etiology of AHA is unknown.
The symptoms of AHA are those of anemia. The usual laboratory features include anemia, reticulocytosis, and a positive direct antiglobulin reaction. The blood film exhibits polychromasia and spherocytosis, the latter a hallmark of the disease. Indirect hyperbilirubinemia, increased urinary urobilinogen and serum lactate dehydrogenase (LDH), and decreased serum haptoglobin are variably present but not necessary for the diagnosis.
Although most patients do not require transfusion of RBC, transfusion should not be withheld from those with symptomatic anemia. Glucocorticoids are effective in slowing the rate of hemolysis. Splenectomy is indicated for patients who require an unacceptably high maintenance dose or prolonged administration of glucocorticoids. Intravenous immunoglobulin may provide short-term control of hemolysis, and immunosuppressive drugs and danazol have been used with success in refractory cases.

Acronyms and abbreviations that appear in this chapter include: AHA, autoimmune hemolytic anemia; CLL, chronic lymphocytic leukemia; DAT, direct antiglobulin test; HIV, human immunodeficiency virus; HLA, human leukocyte antigen; HS, hereditary spherocytosis; IAT, indirect antiglobulin test; LDH, lactate dehydrogenase; PNH, paroxysmal nocturnal hemoglobinuria; RBC, red blood cells; SLE, systemic lupus erythematosus.

DEFINITION AND HISTORY
The two main features of AHA are (1) shortened RBC survival in vivo and (2) evidence of host antibodies reactive with autologous RBC, most frequently demonstrated by a positive direct antiglobulin reaction (Coombs’ test).
The antiglobulin test was introduced in 1945. Previously, it was recognized that the sera of some patients with AHA could directly agglutinate saline suspensions of normal or autologous human RBC. These serum factors, later shown to be specific antibodies (largely of the IgM class), were termed direct or saline agglutinins. In a smaller proportion of cases, the patients’ sera could mediate lysis of the test RBC in the presence of fresh serum as a complement source. The heat-stable factors (antibodies) necessary for such in vitro complement-mediated lysis were called hemolysins. However, in the majority of cases of AHA, neither direct agglutinins nor hemolysins could be demonstrated in the patients’ sera. In 1945, Coombs, Mourant, and Race1 reported that RBC coated with nonagglutinating Rh antibodies (now known to be of the IgG isotype) could be agglutinated by rabbit antiserum to human g-globulin. That is, the rabbit antiglobulin serum cross-linked IgG antibody–coated RBC to produce visible agglutination. Subsequently, it was found that addition of rabbit antiglobulin serum to a suspension of washed RBC isolated from patients with suspected AHA produced agglutination in many cases, including those lacking saline agglutinins or hemolysins.2,3 This procedure is now termed the direct antiglobulin (Coombs’) test. Subsequent studies established that positive direct antiglobulin reactions in AHA are attributable to coating of the RBC with immunoglobulins (mainly IgG) and/or complement proteins. When the RBC are coated chiefly with complement proteins, a positive direct antiglobulin test is dependent upon the presence of anticomplement (principally anti-C3) in the antiglobulin reagent.
CLASSIFICATION
Autoimmune hemolytic anemia may be classified in two complementary ways (Table 55-1). The majority of cases (80 to 90 percent in adults) are mediated by warm-reactive autoantibodies4,5 and 6 or antibodies displaying optimal reactivity with human RBC at 37°C (98.6°F). A smaller proportion is attributable to autoantibodies exhibiting greater affinity for RBC at temperatures below 37°C (cold-reactive autoantibodies; see Chap. 56). This distinction is important, not only because of differences in the pathophysiology of RBC injury, but also in the therapeutic approaches required. An even smaller proportion of patients with AHA exhibit both cold-reactive and warm-reactive autoantibodies,7,8 which apparently recognize different antigens on the RBC membrane.9 Red blood cell destruction is generally more severe in such mixed cases.

TABLE 55-1 CLASSIFICATION OF AUTOIMMUNE HEMOLYTIC ANEMIA

It is also useful to classify AHA based on the presence or absence of underlying diseases (see Table 55-1). When no recognizable underlying disease is present, the AHA is termed primary or idiopathic. When AHA appears to be a manifestation or complication of an underlying disorder, the term secondary AHA is applied. Lymphocytic malignancies, particularly chronic lymphocytic leukemia (CLL) and lymphomas, account for about half of secondary AHA cases (see Chap. 98 and Chap. 103). Systemic lupus erythematosus (SLE) and other autoimmune diseases account for a lesser but considerable proportion of secondary AHA cases. A large proportion of patients with mixed cold and warm autoantibodies have SLE.7,8 Infectious mononucleosis and Mycoplasma pneumoniae occasionally are associated with cryopathic AHA (see Chap. 90). In spite of the frequent occurrence of immune thrombocytopenia in patients infected with the human immunodeficiency virus (HIV), AHA is relatively rare in these patients (see Chap. 89).10,11 Other associated diseases, less commonly reported, are listed in Table 55-1. The etiologic and pathogenic significance of these associations is poorly understood, but most of these associated diseases are recognized to involve components of the immune system, either by neoplasia or by aberrant immunopathologic responses.
EPIDEMIOLOGY
Estimates of the frequency of primary (idiopathic) AHA vary from 20 to 80 percent of all types of AHA, depending on the referral patterns of the reporting center.4,6,12,13 In general, AHA may be considered secondary (1) when AHA and the underlying disease occur together with greater frequency than can be accounted for by chance alone; (2) when the AHA reverses simultaneously with correction of the associated disease; or (3) when AHA and the associated disease are related by evidence of immunologic aberration.4 Using these criteria, the frequency of primary AHA is probably closer to 50 percent of all cases. Careful follow-up of patients with “primary” AHA is essential, since hemolytic anemia may be the presenting finding in a patient who subsequently develops overt evidence of underlying lymphoproliferative disorder or SLE.
ETIOLOGY AND PATHOGENESIS
ETIOLOGY
The etiology of warm-antibody AHA is unknown. Warm-antibody AHA is the most common type of AHA and is the focus of the remainder of this chapter. The autoantibodies that mediate RBC destruction are predominantly (but not exclusively) IgG globulins possessing relatively high binding affinity for human RBC at 37°C. As a result, the major share of autoantibodies is commonly bound to the patient’s circulating erythrocytes. Eluates prepared from the patient’s washed, autoantibody-coated RBC constitute a very important source of purified autoantibody for investigation of specificity, immunoglobulin structure, or other properties. In addition, sera from patients with warm AHA often are used in blood banks for cross-matching and for general screening of antibody specificity. The quantity of such autoantibody in serum may be low and in some cases may not reflect the full spectrum of anti-RBC specificity revealed in concurrently prepared RBC eluates.14
Autoimmune hemolytic anemia has been diagnosed in people of all ages, from infants to the elderly. The majority of patients are over age 40, with peak incidence around the seventh decade. This age distribution probably reflects, in part, the increased frequency of lymphoproliferative malignancies in the elderly, resulting in an age-related increase in the frequency of secondary AHA. Although multiple cases occasionally are observed in families,15,16 and 17 most cases of primary AHA arise sporadically. Development of AHA does not have an apparent association with any particular HLA haplotype or other genetic factor.
In patients with primary AHA, erythrocyte autoantibodies are the only recognizable immunologic aberration. Furthermore, the autoantibodies of any one patient often are specific for only a single RBC membrane protein (see “Serologic Features”). The narrow spectrum of autoreactivity suggests that the mechanism underlying the development of AHA in such patients is not secondary to a generalized defect in immune regulation. Rather, it appears that these patients may develop warm-antibody AHA through an aberrant immune response to a self-antigen or to an immunogen that mimics a self-antigen.
In patients with secondary AHA, the disease may be associated with a fundamental disturbance in the immune system; for example, when it appears in the setting of lymphoma, CLL, SLE, primary agammaglobulinemia (common variable immunodeficiency), or hyper-IgM immunodeficiency syndrome. In these settings, warm-antibody AHA most likely arises through an underlying defect in immune regulation, although the contribution of an aberrant immune response to self-antigen cannot be excluded. Autoimmune hemolytic anemia seems especially frequent in patients with low-grade lymphoma or CLL treated with fludarabine18 or 2-chlorodeoxyadenosine (cladribine).19 The T lymphocytopenia induced by these drugs may exacerbate the preexisting tendency of these patients to form autoantibodies.
A still unexplained observation is that certain drugs, such as a-methyldopa, can induce warm-reacting IgG anti-RBC autoantibodies in otherwise normal persons. The autoantibodies induced by a-methyldopa have Rh-related serologic20 and immunochemical21 specificity similar to that of autoantibodies arising in many patients with “spontaneous” AHA (see below and Chap. 57). A critical difference is that the drug-associated autoantibodies subside when the drug is discontinued, suggesting (1) that the latent potential to form this type of anti-RBC autoantibody is present in many immunologically normal individuals and (2) that the steps required to generate such autoantibodies do not necessarily create a sustained autoimmune state. The maintenance of chronic idiopathic AHA, on the other hand, either may be secondary to a continuing (but unknown) stimulus or may be induced by a short stimulus to which the patient continues to respond.
To be sure, normal subjects may be found to be Coombs-positive when they volunteer to donate blood.22,23 and 24 The positive direct antiglobulin test in these normal donors often is due to warm-reacting IgG autoantibodies, similar in serologic specificity14 and in IgG subclass23 to those occurring in AHA. Although many of these donors remain Coombs-positive without developing overt hemolytic anemia, a few have been documented to develop AHA.23,24 The incidence of positive direct antiglobulin tests in normal blood donors is roughly 1 in 10,000.22,23 This figure is higher than the reported incidence of AHA itself (1 to 2 cases per 100,000).4,5 Since blood donation per se is not likely to contribute to an increased risk of developing autoantibodies, the 1-in-10,000 proportion may be the approximate frequency of positive direct antiglobulin tests in the entire population. It may be that a substantial proportion of patients who present with clinically overt primary AHA are from a subset of those asymptomatic individuals who are innately Coombs-positive. This concept, however, is not established.
Several concepts have been developed to explain immunologic tolerance to self-antigens.25,26 and 27 Relevant to AHA, membrane-bound antigens expressed in a multivalent array at high concentration may induce tolerance by effecting clonal deletion of autoreactive B cells.28 Both the Rh-related and the non-Rh types of RBC antigens that are targeted by AHA autoantibodies (see “Serologic Features”) are expressed normally by human fetal erythrocytes, as early as 10 to 12 weeks of life.29 However, because new B cells develop daily in the marrow throughout life and because B cells may somatically mutate their Ig receptors (see Chap. 83), self-tolerance in the B-cell compartment is never assured. It has been suggested by analogy to observations in NZB mice30,31 that the peritoneal cavity may be a privileged compartment that could shelter autoreactive B cells from host RBC, allowing them to escape deletion, later to produce anti-RBC autoantibodies with appropriate T-cell help.32 The strong predominance of IgG antibodies in AHA suggests B-cell isotype switching, which is consistent with the idea of an antigen-driven process. Moreover, since T-cell help is necessary for inducing B-cell isotype switching, the pathway or pathways to autoantibody induction in AHA also may involve an abnormal or unique mode of antigen presentation to T cells.33
PATHOGENESIS
Erythrocyte autoantibodies in AHA are pathogenic. In contrast to autologous RBC, labeled RBC lacking the antigen targeted by the autoantibodies may survive normally in patients with warm-antibody AHA.5,34,35 On the other hand, transplacental passage of IgG anti-RBC autoantibodies from a mother with AHA to the fetus can induce intrauterine or neonatal hemolytic anemia.36 Finally, despite notable exceptions and differences relating to IgG subclass of the autoantibody, there is, in general, an inverse relationship between the quantity of RBC-bound IgG antibody and RBC survival when serial studies are made on a given patient.37,38,39,40,41 and 42
In AHA, the patient’s RBC typically are coated with IgG autoantibodies with or without complement proteins. Autoantibody-coated RBC are trapped by macrophages in the Billroth cords of the spleen and, to a lesser extent, by Kupffer cells in the liver (see Chap. 5).34,37,38,40,41,42,43 and 44 This process leads to sphering, fragmentation, and ingestion of the antibody-coated RBC.45,46 The macrophage has surface receptors for the Fc region of IgG, with preference for the IgG1 and IgG3 subclasses,47,48 and surface receptors for opsonic fragments of C3 (C3b and C3bi) and C4b.49,50 and 51 When present together on the RBC surface, IgG and C3b/C3bi appear to act cooperatively as opsonins to enhance trapping and phagocytosis.40,41,50,51,52,53 and 54 Although RBC sequestration in warm-antibody AHA occurs primarily in the spleen,34,41,42 and 43 very large quantities of RBC-bound IgG37,39,44 or the concurrent presence of C3b on the RBC37,40,41 may favor trapping in the liver as well.
Interaction of a trapped RBC with splenic macrophages may result in phagocytosis of the entire cell. More commonly, a type of partial phagocytosis occurs that results in the formation of spherocytes. As RBC adhere to macrophages via the Fc receptors, portions of RBC membrane are internalized by the macrophage. Since membrane is lost in excess of contents, the noningested portion of the RBC assumes a spherical shape, the shape with the lowest ratio of surface area to volume.45,46,55 Spherical RBC are more rigid and less deformable than normal RBC. As such, spherical RBC are fragmented further and/or destroyed in future passages through the spleen. Spherocytosis is a consistent and diagnostically important hallmark of AHA,56 and the degree of spherocytosis correlates well with the severity of hemolysis.5
Direct complement-mediated hemolysis with hemoglobinuria is unusual in warm-antibody AHA, despite the fact that many warm autoantibodies fix complement. The failure of C3b-coated RBC to be hemolyzed by the terminal complement cascade (C5–C9) has been attributed, at least in part, to the ability of complement regulatory proteins (factors I and H) in plasma and C3b receptors on the RBC surface to alter the hemolytic function of cell-bound C3b and C4b.57 Glycosylphosphatidylinositol-linked erythrocyte membrane proteins, such as decay-accelerating factor (CD55)58 and homologous restriction factor,59 may limit the action of autologous complement on autoantibody-coated RBC.
In addition, cytotoxic activities of macrophages and lymphocytes may play a role in the destruction of RBC in warm-antibody AHA. Monocytes can lyse IgG-coated RBC in vitro independently of phagocytosis.60,61 Cell-bound complement is neither necessary nor sufficient for such cytotoxicity, but bound C3b/C3d can potentiate the effects of IgG.61 In one study,60 cytotoxicity, but not phagocytosis, was inhibited by hydrocortisone in vitro. Lymphocytes also are able to lyse IgG antibody–coated RBC in vitro.62,63 and 64 The relative contribution of antibody-dependent monocyte- and lymphocyte-mediated cytotoxicity to RBC destruction in patients with warm-antibody AHA is not known.
CLINICAL FEATURES
Presenting complaints of warm-antibody AHA usually are referable to the anemia itself, although occasionally jaundice is the immediate cause for seeking medical advice. Symptoms are usually slow and insidious in onset over several months, but occasionally a patient may have sudden onset of symptoms of severe anemia and jaundice over a period of a few days. In secondary AHA, the symptoms and signs of the underlying disease may overshadow the hemolytic anemia and associated features.
In idiopathic AHA with only mild anemia, the physical examination may be normal. Even patients with relatively severe hemolytic anemia may have only modest splenomegaly. However, in very severe cases, particularly those of acute onset, patients may present with fever, pallor, jaundice, hepatosplenomegaly, hyperpnea, tachycardia, angina, or heart failure.
Clinical warm-antibody AHA may be aggravated or first become apparent during pregnancy.36,65,66 Most cases are mild, however, and the prognosis for the fetus is generally good, provided the mother is treated early.65
LABORATORY FEATURES
GENERAL FEATURES
By definition, patients with AHA present with anemia, the severity of which can range from life-threatening to very mild. Patients with AHA may present with hematocrit levels below 10 percent. On the other hand, some AHA patients may have compensated hemolytic anemia and a near-normal hematocrit. For these patients, the predominant laboratory features are an increased reticulocyte count and a positive direct Coombs’ test. Occasionally, however, the patient may have leukopenia and neutropenia.5,72 Platelet counts are typically normal. Rarely, severe immune thrombocytopenia is associated with warm-antibody AHA. This constellation is termed Evans syndrome.73 In this syndrome, the RBC and platelet antibodies are apparently distinct.74
Evaluation of the blood film can reveal several features related to AHA. Polychromasia indicates a reticulocytosis, reflecting an increased rate of reticulocyte egress from the marrow. Spherocytes are seen in patients with moderate to severe hemolytic anemia (see Color Plate II-8). Unless hereditary spherocytosis cannot be excluded, this finding suggests an immune hemolytic process. Red blood cell fragments, nucleated RBC, and, occasionally, erythrophagocytosis by monocytes may be seen in severe cases. Most patients have mild leukocytosis and neutrophilia.
The reticulocyte count usually is elevated. Nevertheless, early in the course of the disease, over one-third of all patients may have transient reticulocytopenia despite having a normal or hyperplastic erythroid marrow.67,68,69 and 70 The mechanism for this is unknown, although it has been speculated that autoantibodies reactive against antigens on reticulocytes may lead to their selective destruction.71 One unusual patient with AHA, reticulocytopenia, and marrow erythroid aplasia had a serum antibody that inhibited erythroid colony formation in vitro.71 The aplastic crisis remitted after the serum IgG level was lowered by immunoadsorption. Reticulocytopenia also may be seen in patients with marrow function compromised by an underlying disease, parvovirus infection, toxic chemicals, or nutritional deficiency. Marrow examination usually reveals erythroid hyperplasia and also may provide evidence of an underlying lymphoproliferative disorder.
Hyperbilirubinemia (chiefly unconjugated) is highly suggestive of hemolytic anemia, although its absence does not exclude the diagnosis. Total bilirubin is only modestly increased, up to 5 mg/dl, and, with rare exceptions, the conjugated (direct) fraction constitutes less than 15 percent of the total. Urinary urobilinogen is increased regularly, but bile is not detected in the urine unless serum conjugated bilirubin is increased. Usually, serum haptoglobin levels are low, and LDH levels are elevated. Hemoglobinuria is encountered in rare patients with hyperacute hemolysis who develop significant hemoglobinemia.
SEROLOGIC FEATURES
DIRECT ANTIGLOBULIN TEST PATTERN
The diagnosis of AHA requires the demonstration of immunoglobulin and/or complement bound to the patient’s RBC. As a screening procedure, it is customary to use a “broad-spectrum” antiglobulin (Coombs’) reagent, that is, one that contains antibodies directed against human immunoglobulin as well as complement components (principally C3). If agglutination is noted with a broad-spectrum reagent, antisera reacting selectively with IgG (the “gamma” Coombs’) or with C3 (the “nongamma” Coombs’) are used to define the specific pattern of RBC sensitization. Monospecific antisera to IgM or IgA also have been used in selected cases.
There are three major patterns of direct antiglobulin reaction in warm-antibody AHA: (1) RBC coated with only IgG, (2) RBC coated with IgG and complement components, and (3) RBC coated with complement components without detectable immunoglobulin.5,75,76 and 77 In patterns 2 and 3, the complement components most readily detected are C3 fragments (mainly C3dg). Each pattern has been associated with accelerated RBC destruction. Positive antiglobulin reactions with anti-IgA or anti-IgM are encountered less commonly, often in association with bound IgG and/or complement.78,79,80,81,82,83 and 84
FREE VERSUS BOUND AUTOANTIBODY
The autoantibody molecules in patients with warm-antibody AHA exist in a reversible, dynamic equilibrium between RBC and plasma.85,86 In addition to the major portion of autoantibody bound to the patient’s RBC (detected by the direct antiglobulin test, DAT), “free” autoantibody may be detected in the plasma or serum of these patients by means of the indirect antiglobulin test (IAT). In the IAT, the patient’s serum or plasma is incubated with normal donor erythrocytes at the appropriate temperature (in this case, 37°C). The cells are washed, suspended in saline solution, and then tested for agglutination by antiglobulin serum. The presence of such unbound autoantibody in plasma depends upon the total amount of antibody being produced and the binding affinity of the antibody for RBC antigens. In general, patients with heavily sensitized RBC are more likely to exhibit plasma autoantibody. Protease-modified RBC are more sensitive than native RBC in detecting plasma autoantibody, but such data must be interpreted with caution, since alloantibodies, naturally occurring antibodies to cryptic antigens, and other serum components may interact with enzyme-modified RBC. Patients with a positive IAT due to a warm-reactive autoantibody should also have a positive DAT. A patient with a serum anti-RBC antibody (positive IAT) and a negative DAT probably has, not an autoimmune process, but, rather, an alloantibody stimulated by prior transfusion or pregnancy.
QUANTITY OF RBC-BOUND AUTOANTIBODY
Figure 55-1 relates the intensity of the direct antiglobulin reaction, using specific anti-IgG serum, to the number of IgG molecules bound per RBC. The latter was determined by a sensitive antibody-consumption method.87 A trace-positive antiglobulin reaction (read macroscopically) detects 300 to 400 molecules of IgG per cell.87,88 In another laboratory, a trace-positive antiglobulin reaction with anti-C3 was obtained with 60 to 115 molecules C3 per cell.87

FIGURE 55-1 Comparison of direct antiglobulin reactions (with anti-IgG serum) with molecules of red cell–bound IgG determined by a quantitative antibody consumption assay (method in Ref. 87). The two assays were conducted concurrently on the same blood specimen. The antiglobulin reactions were performed manually and read macroscopically.

More sensitive methods of quantifying RBC-bound IgG allow the identification of AHA patients who have all the usual hallmarks of warm-antibody AHA but a negative DAT with anti-immunoglobulin and anticomplement reagents.87,88 and 89 In many such patients, the RBC are coated with quantities of IgG autoantibody that are too low to give a positive antiglobulin reaction (subthreshold IgG). However, the specialized methods (e.g., anti-IgG consumption assays, automated enhanced agglutination techniques, enzyme-linked and radioimmunoassays) do detect very small quantities of cell-bound IgG. In such cases, studies with highly concentrated RBC eluates confirm that these IgG molecules are warm-reacting anti-RBC autoantibodies.87 These patients generally have relatively mild hemolysis and often respond favorably to glucocorticoid therapy. By these specialized methods, subthreshold IgG also may be detected in a significant number of patients who exhibit the “complement alone” pattern of direct antiglobulin reaction in the absence of drug sensitivity or cold agglutinins. In such cases, studies with concentrated RBC eluates have suggested that these subthreshold quantities of bound IgG antibodies are capable of fixing much larger quantities of C3 to the cell membrane.87
NATURE OF THE AUTOANTIBODIES AND RBC TARGET ANTIGENS
In any series of warm-antibody AHA patients, the correlation between the strength of the antiglobulin reaction (IgG molecules per RBC) and the rate of RBC destruction is variable. The IgG subclass of warm autoantibodies apparently influences the degree to which these antibodies shorten RBC survival. IgG1 is the most commonly encountered subclass, either alone or in combination with other IgG subclasses.78,90 IgG1 and IgG3 autoantibodies appear to be more effective in decreasing RBC life span than do those of the IgG2 or IgG4 subclass.78,91 This difference may be due to the greater affinity of macrophage Fc receptors for IgG1 and IgG3 47,48 and the higher complement-fixing activity of IgG1 or IgG3 antibodies relative to that of IgG2 or IgG4 antibodies.57
The autoantibodies eluted from patients’ RBC or present in their plasma typically bind to all the common types of human RBC represented in test panels used by blood banks and thus might appear to be nonspecific. However, the antibodies of any one patient typically recognize one or more antigenic determinants (epitopes) that are common to virtually all human RBC, that is, “public” antigens. These antibodies have been useful for evaluating RBC membrane structures and for identifying rare RBC phenotypes, namely, RBC that lack a common blood group antigen or antigens. Nearly half of all AHA patients have autoantibodies specific for epitopes on Rh proteins.4,5,14,92,93 and 94 The autoantibodies of such patients commonly do not react with human RBC of the rare Rhnull phenotype, lacking expression of the Rh complex. Occasionally, the anti-Rh autoantibodies have anti-e, anti-E, or anti-c (or, more rarely, anti-D) specificity. Patients who have autoantibodies with selective specificity (e.g., anti-e) nearly always have other autoantibodies reactive with all human RBC, except Rhnull. Autoantibodies with such specificity have been designated collectively as Rh related.21,94
The remaining patients with warm-antibody AHA have IgG autoantibodies that are fully reactive with Rhnull RBC.4,5,14,92,93 and 94 The exact specificity of the autoantibodies for many of these patients is undefined. In other instances, autoantibody specificity for serologically defined blood group antigens outside the Rh system have been defined using RBC of appropriate antigen-deficient phenotype: anti-Wrb,14 anti-Ena,95 anti-LW,96 anti-U,97 anti-Ge,83,98 anti-Sc1,99 or antibodies to Kell blood group antigens.100 For ease of reference, this entire group of autoantibodies is designated non–Rh related.21,94
Immunochemical studies indicate that the autoantibodies from almost any AHA patient react with individual membrane proteins. The major target of the Rh-related autoantibodies is a 32- to 34-kDa nonglycosylated polypeptide lacking on Rhnull RBC.21,101 This polypeptide is similar, if not identical, to the polypeptide expressing the Rh(e) alloantigen. Many a-methyldopa–induced autoantibodies also react with this polypeptide.21 Autoantibodies with non-Rh serologic specificity have been found that react with the band 3 anion transporter21,102 or with both band 3 and glycophorin A.21 The latter autoantibodies may react with an epitope formed through the interaction of these two proteins on the RBC membrane.103 It is interesting to note that anti-RBC autoantibodies in NZB mice exhibit anti–band 3 specificity.104 Furthermore, naturally occurring anti–band 3 IgG autoantibodies are found in essentially all humans.105,106 and 107 These autoantibodies may play a role in the clearance of senescent RBC by reacting with neoantigens formed on these cells by proteolytic alteration105 or aggregation106 of band 3 proteins. Such neoantigens are not found on younger RBC. An important but unanswered question concerns the possible relationship between the naturally occurring and pathologic anti–band 3 autoantibodies.
DIFFERENTIAL DIAGNOSIS
Several nonautoimmune diseases also may result in spherocytic anemia, such as hereditary spherocytosis (HS), Zieve’s syndrome, clostridial sepsis, and the hemolytic anemia that precedes Wilson’s disease. Among the hereditary hemolytic anemias, HS can resemble acquired AHA most closely. This is because the spherocytic anemia associated with HS may be detected first in adulthood (see Chap. 43). In addition, splenomegaly may be prominent in both HS and AHA. Family studies of patients with HS, however, usually can identify other affected individuals. Most important, the RBC of patients with congenital hemolytic anemia do not have a positive DAT.
In hemolytic anemia accompanied by a positive DAT, serologic characterization of the autoantibody may distinguish warm-antibody AHA from cold-reacting autoantibody syndromes (see Chap. 56). Diagnosis of a drug-related immune hemolytic anemia depends upon a history of appropriate drug intake supported by compatible serologic findings (see Chap. 57). In patients who recently have been transfused, a positive direct antiglobulin reaction may in reality reflect the binding of a newly formed alloantibody to donor RBC in the patient’s circulation. This could lead to a false impression of an autoimmune process.
Recent recipients of organ transplants may develop an alloimmune hemolytic anemia that mimics AHA. The problem is seen in kidney, liver, or marrow transplants and usually occurs when an organ from a blood group O donor is transplanted into a blood group A recipient. It is thought that B lymphocytes present in the donated organ or marrow form alloantibodies against recipient RBC.108,109,110,111 and 112 Patients of blood group O who receive a marrow transplant from a donor of blood group A or B may develop a transiently positive DAT and hemolysis of RBC made by the marrow graft, due to temporary persistence of previously synthesized host anti-A or anti-B.113 Furthermore, some group O marrow transplant recipients exhibit mixed hematopoietic chimerism with persistence of host B lymphocytes that can make alloantibodies directed against RBC made by the marrow graft.113 In these settings, the findings of hemolysis and a positive DAT due to anti-A and anti-B are probably diagnostic of an alloimmune process, since autoantibodies directed against the major blood group antigens A and B are extremely rare.
Other acquired types of hemolytic anemia are less easily confused with AHA because spherocytes are not prominent on the blood film and the DAT is negative. Patients with paroxysmal nocturnal hemoglobinuria (PNH) may complain of dark urine (hemoglobinuria). This finding is unusual in patients with warm-antibody AHA but can occur in patients with the cold-antibody syndromes (see Chap. 56). Both the acidified serum test and the sucrose hemolysis test are usually positive in PNH but negative in AHA. Microangiopathic hemolytic disorders, such as thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, can be distinguished from AHA by examining the blood film. In the former diseases, the blood smear displays marked RBC fragmentation and minimal spherocytosis. In addition, microangiopathic hemolytic anemia more frequently is associated with thrombocytopenia than is warm-antibody AHA.
THERAPY, COURSE, AND PROGNOSIS
THERAPY
TRANSFUSION
The clinical consequences of AHA are related to the severity of the anemia and acuity of its onset. Most patients with AHA develop anemia over a period sufficient to allow for cardiovascular compensation and hence do not require RBC transfusions. However, RBC transfusions may be necessary for an AHA patient who has an underlying disease complicating the anemia, such as symptomatic coronary artery disease, or who rapidly develops severe anemia with signs and/or symptoms of circulatory failure.
Transfusion of RBC in AHA presents two difficulties: one is the problem of cross-matching, and the other is the short half-life of the transfused RBC. It is nearly always impossible to find truly serocompatible donor blood except in rare cases when the autoantibody is found specific for a defined blood group antigen (see “Serologic Features”). Otherwise, one must choose donor RBC that are least incompatible with the patient’s serum in cross-match testing. Before transfusing an incompatible unit, it is important to test the patient’s serum carefully for an alloantibody that could cause a severe hemolytic transfusion reaction against donor RBC, especially in patients with a history of pregnancy or prior transfusion.94,114,115
Once selected, the packed RBC should be administered slowly. During the transfusion, the patient should be monitored for signs of a hemolytic transfusion reaction (see Chap. 140). The transfused cells may be destroyed as fast as the patient’s own cells or perhaps even faster. However, the increased oxygen-carrying capacity provided by the transfused cells may be sufficient to maintain the patient during the acute interval required for other modes of therapy to become effective.
GLUCOCORTICOIDS
Therapy with glucocorticoids has reduced the mortality associated with severe idiopathic warm-antibody AHA. First used for this disorder almost 50 years ago,116 glucocorticoids can cause dramatic cessation or marked slowing of hemolysis in about two-thirds of patients.4,5,76,117,118 About 20 percent of treated patients with warm-antibody AHA achieve complete remission. About 10 percent show minimal or no response to glucocorticoids. The best responses are seen in idiopathic cases or in those related to SLE.
Most patients should be treated with oral prednisone at an initial daily dose of 60 to 100 mg. Critically ill patients with rapid hemolysis may receive intravenous methylprednisolone, 100 to 200 mg in divided doses over the first 24 h. High doses of prednisone may be required for 10 to 14 days. When the hematocrit stabilizes or begins to increase, the prednisone dose may be decreased in rapid-step dose reductions to approximately 30 mg/day. With continued improvement, the prednisone dose may be further decreased at a rate of 5 mg/day every week, to a dose of 15 to 20 mg/day. These doses should be administered for 2 to 3 months after the acute hemolytic episode has subsided, after which the patient may be weaned from the drug over 1 to 2 months or treatment switched to an alternate-day therapy schedule (e.g., 20 to 40 mg every other day). Alternate-day therapy reduces glucocorticoid side effects but should be attempted only after the patient has achieved stable remission on daily prednisone in the range of 15 to 20 mg/day. Therapy should not be stopped until the DAT becomes negative. Although many patients achieve full remission of their first hemolytic episode, relapses may occur after the glucocorticoids are discontinued. Therefore, these patients should be followed for at least several years after treatment. A relapse may require repeat glucocorticoid therapy, splenectomy, or immunosuppression.
Occasionally, patients who present with only a positive DAT, minimal hemolysis, and stable hematocrit may require no treatment. However, these patients should be observed for clinical deterioration, since the rate of RBC destruction may increase spontaneously.
Glucocorticoids may influence hemolysis in warm-antibody AHA by several mechanisms. Earlier investigators noted that hematologic improvement was often, but not always, accompanied by reduction in the strength of the DAT.5 The subsequent observation of a decrease in cell-bound and/or free serum autoantibody during stable glucocorticoid-induced remission suggested that improved RBC survival following treatment with glucocorticoids resulted from a decrease in synthesis of anti-RBC autoantibodies.39,85 However, this cannot explain why the glucocorticoid-treated patients often improve within 24 to 72 h, a time much shorter than the half-life of anti-RBC autoantibody. Rather, glucocorticoids may suppress RBC sequestration by splenic macrophages.41,42,53,119 A quantitative decrease in one of the three known classes of Fcg receptors47,48 has been observed in the blood monocytes of AHA patients during glucocorticoid therapy.120
SPLENECTOMY
Nearly one-third of patients with warm-antibody AHA may require prednisone chronically in doses greater than 15 mg/day to maintain an acceptable hemoglobin concentration. These patients are candidates for splenectomy.
Splenectomy removes the primary site of RBC trapping. Investigations in human39 and other animal41 subjects confirm that maintenance of a given rate of RBC destruction requires 6 to 10 times as much RBC-bound IgG in splenectomized subjects than in nonsplenectomized subjects. The continuation of hemolysis after splenectomy is partly related to persisting high levels of autoantibody, favoring RBC destruction in the liver by hepatic Kupffer cells.39,41,44
Several investigators have noted the amount of RBC-bound autoantibody to decrease in AHA patients following splenectomy.5,117,121 However, a significant proportion of patients show no change in cell-bound autoantibody following splenectomy. The processes that determine the rate of autoantibody production are poorly understood. The beneficial effect of splenectomy may be related to several factors interacting in complex fashion.122
A patient’s clinical data currently constitute the best selection criteria for splenectomy. Attempts to select potential responders by 51Cr RBC sequestration studies have been disappointing.5,117,123 In most cases, it is reasonable to continue glucocorticoids for 1 to 2 months while waiting for a maximal response. However, if there is no response at all within 3 weeks, the patient’s condition deteriorates, or the anemia is very severe, splenectomy should be done sooner.
Results of splenectomy are variable. Approximately two-thirds of AHA patients will have a partial or complete remission following splenectomy.117,122,124 The relapse rate, however, is disappointingly high. Many patients require further glucocorticoid therapy to maintain acceptable hemoglobin levels, although often at a lower dose than they required prior to splenectomy.5,76,117 Alternate-day therapy is preferable to daily therapy in these cases if adequate control of the anemia can be achieved.
The immediate mortality and morbidity from splenectomy depends upon the presence of underlying disease and the preoperative clinical status. In general it is quite low.125 Following splenectomy, children, more than adults, have an increased risk for developing sepsis due to encapsulated organisms.126 Vaccination against Haemophilus influenzae type b and pneumococcal and meningicoccal organisms is recommended prior to surgery.127
IMMUNOSUPPRESSIVE DRUGS
Cytotoxic drugs such as cyclophosphamide, 6-mercaptopurine, azathioprine, or 6-thioguanine have been given to patients with AHA to suppress synthesis of autoantibody. Direct evidence of such an effect is lacking. Although immunosuppressive therapy has not received universal acceptance, beneficial responses to immunosuppressive drugs have been observed in some patients who failed to respond to glucocorticoids.128,129 It must be emphasized that the majority of patients with warm-antibody AHA respond to glucocorticoids and/or splenectomy and are usually not candidates for immunosuppressive therapy. At present, immunosuppressive therapy should be reserved primarily for those patients who fail to respond to glucocorticoids and splenectomy or for those patients who are poor surgical risks.128
The drugs of choice are cyclophosphamide 60 mg/m2 or azathioprine 80 mg/m2, given daily. If the patient tolerates the drug, it is reasonable to continue treatment for up to 6 months while waiting for a response. When response occurs, the patient may be slowly weaned from the drug. If there is no response, the alternative drug may be tried. Because of the ability of cyclophosphamide or azathioprine to suppress erythropoiesis, blood counts must be monitored with extra care during therapy. Treatment with either agent increases the risk of subsequent neoplasia. In addition, cyclophosphamide may cause severe hemorrhagic cystitis.
OTHER THERAPIES
Plasma exchange or plasmapheresis has been used in patients with warm-antibody AHA. Improvement has been reported in a few cases, but its use is controversial.130,131 Thymectomy has been reported as being useful in a few children who were refractory to glucocorticoids and splenectomy.128 Selective injury to splenic macrophages by administration of vinblastine-loaded, IgG-sensitized platelets has been reported as successful in a few patients.132 There are several anecdotal reports and a case series reporting short-term successful treatment of patients with AHA using high-dose intravenous g-globulin.133,134,135,136 and 137 Danazol, a nonvirilizing androgen, may be useful in patients with AHA, based on uncontrolled studies.138,139 Danazol may eliminate the need for splenectomy when combined with prednisone and may allow for a shorter duration of prednisone therapy.139 Some patients with ulcerative colitis and AHA unresponsive to glucocorticoids and splenectomy may respond to colectomy.140 In patients with AHA associated with an ovarian dermoid cyst, removal of the cyst produced remission of the hemolysis.141 Finally, patients with refractory AHA may be treated effectively with the purine analog 2-chlorodeoxyadenosine (cladribine).142
COURSE AND PROGNOSIS
Patients with idiopathic warm-antibody AHA have unpredictable clinical courses characterized by relapses and remissions. No particular feature of the illness has been a consistent predictor of outcome. In spite of a rather high initial rate of response to glucocorticoids and splenectomy, the overall mortality rate was significant (up to 46 percent) in several older series but much lower in more recent studies.4,5,117,143,144 The actuarial survival at 10 years is reported to be 73 percent.143 Thromboembolic episodes in the form of deep-vein thrombosis or splenic infarcts are relatively common during active phases of the disease.117 Pulmonary emboli, infection, and cardiovascular collapse are causes of death. The prognosis in secondary warm-antibody AHA is largely dependent on the course of the underlying disease.
In children, warm-antibody AHA frequently follows an acute infection or immunization.121,145,146 Most of these patients exhibit a self-limited course and respond rapidly to glucocorticoids. Children with chronic AHA tend to be older.146,147 Those who recover from the initial hemolytic episode have a good prognosis and are unlikely to relapse, although exceptions are known. The overall mortality rate is lower than in adults, ranging from 10 to 30 percent,121,145,146,147,148 and 149 with higher mortality rates in those with chronic AHA121,149 and in those with associated autoimmune thrombocytopenia (Evans syndrome).150
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Books@Ovid
Copyright © 2001 McGraw-Hill
Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn
Williams Hematology

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