CHAPTER 56 CRYOPATHIC HEMOLYTIC SYNDROMES
CHAPTER 56 CRYOPATHIC HEMOLYTIC SYNDROMES
CHARLES H. PACKMAN
Cold-Agglutinin–Mediated Autoimmune Hemolytic Anemia
Definition and History
Etiology and Pathogenesis
Course and Prognosis
Paroxysmal Cold Hemoglobinuria
Definitions and History
Etiology and Pathogenesis
Course and Prognosis
Cryopathic hemolytic syndromes are caused by autoantibodies that bind optimally to red blood cells (RBC) at temperatures below body temperature. The ability of these antibodies to injure RBC is directly related to their ability to fix complement. Two types of cold-reactive autoantibodies to RBC are recognized: cold agglutinins and cold hemolysins. Both may be idiopathic, without an underlying disease, or may occur as a secondary form, usually associated with B-lymphoproliferative disorders or with certain infections. With both types of cold-reactive autoantibody, there is potential for intravascular hemolysis. Warm autoantibodies, on the other hand, usually cause extravascular hemolysis. Cold agglutinins are generally of IgM isotype, while cold hemolysins are usually of IgG isotype. In both types, the direct antiglobulin test result is positive for complement. Cold-agglutinin disease is associated with high-titer RBC agglutinating activity in the serum, more active at 4°C (39.2°F) than at 37°C (98.6°F). Cold hemolysins are detected by the biphasic Donath-Landsteiner test. Therapy consists mainly of keeping the patient warm and controlling the underlying disorder in secondary forms.
Acronyms and abbreviations that appear in this chapter include: DAF, decay-accelerating factor; HRF, homologous restriction factor; RBC, red blood cell.
Cryopathic hemolytic syndromes are autoimmune disorders caused by autoantibodies that bind RBC optimally at temperatures below 37°C (98.6°F) and usually below 31°C (87.8°F). There are two major types of “cold antibody” that may produce autoimmune hemolytic anemia (Table 56-1). One is mediated by cold agglutinins. The other, paroxysmal cold hemoglobinuria, is mediated by an autoantibody (the Donath-Landsteiner antibody) that is not an agglutinin but a potent hemolysin (for discussion of these terms, see the introductory section of Chap. 55). Chronic cold-agglutinin–mediated autoimmune hemolytic anemia is extremely rare in children. Conversely, acute hemolytic anemia due to Donath-Landsteiner antibody accounts for a substantial proportion of autoimmune hemolytic anemia in children but is very rare in adults. Either of these disorders is encountered less commonly than autoimmune hemolytic anemia due to warm autoantibodies. In both cryopathic syndromes, the complement system plays a major role in RBC injury, and there is a much greater potential for direct intravascular hemolysis than in warm-antibody–mediated autoimmune hemolytic anemia.
TABLE 56-1 CRYOPATHIC HEMOLYTIC SYNDROME
COLD-AGGLUTININ–MEDIATED AUTOIMMUNE HEMOLYTIC ANEMIA
DEFINITION AND HISTORY
Cold agglutinins were first described by Landsteiner in 1903.1 However, recognition of the connection among cold agglutinins, hemolytic anemia, and Raynaud-like peripheral vascular phenomena evolved slowly. In 1918, Clough and Richter detected cold agglutinins in a patient with pneumonia.2 In 1925 and 1926, Iwai and Mei-Sai3,4 reported two patients with cold agglutinins and Raynaud’s phenomenon and showed that flow of blood through capillary tubes in vitro or in superficial capillaries in vivo was impeded at low temperatures. During the late 1940s and early 1950s, the observations of many workers gradually established the pathogenic importance of cold agglutinins in RBC injury. Schubothe introduced the term cold-agglutinin disease in 1953 and clearly distinguished this disorder from other acquired hemolytic syndromes.5
In current usage, cold-agglutinin disease pertains to patients with chronic autoimmune hemolytic anemia in which the autoantibody directly agglutinates human RBC at temperatures below body temperature, maximally at 0 to 5°C (32 to 41°F). Fixation of complement to a patient’s RBC by cold agglutinins in vivo occurs at higher temperatures, but generally below 37°C (98.6°F). Cold agglutinins typically are IgM, although occasionally they may be globulins of other isotypes. Those occurring in chronic cold-agglutinin disease generally are monoclonal. Most cold agglutinins have specificity for oligosaccharide antigens (I or i) of the RBC (see “Origin of Cold Agglutinins,” below).
Cold-agglutinin disease traditionally has been classified as being either primary (idiopathic) or secondary (see Table 56-1). The latter is most commonly seen in adolescents or young adults as a self-limited process associated with Mycoplasma pneumoniae infections or infectious mononucleosis and, rarely, in children with chickenpox. The term also has been used to describe a chronic disorder occurring in older patients with known malignant lymphoproliferative diseases. On the other hand, idiopathic (primary) chronic cold-agglutinin disease has its peak incidence after age 50. This disorder, with its characteristic monoclonal IgM cold agglutinins, may be considered a special form of monoclonal gammopathy. As with other “essential” or idiopathic monoclonal gammopathies, some cases in this group gradually develop features of a B-cell lymphoproliferative disorder that resembles Waldenström’s macroglobulinemia. Thus, the distinction between primary and secondary types of chronic cold-agglutinin disease is not absolute.
ETIOLOGY AND PATHOGENESIS
ORIGIN OF COLD AGGLUTININS
A high proportion of monoclonal IgM cold agglutinins with either anti-I or anti-i specificity have heavy-chain variable regions encoded by VH4–34, formerly designated VH4.21.6,7 and 8 This VH gene encodes a distinct idiotype identified by a rat monoclonal antibody, 9G4. This idiotype is expressed both by the cold agglutinins themselves and on the surface immunoglobulin of B cells synthesizing cold agglutinins or related immunoglobulins possessing VH4–34 sequences.9 Using the 9G4 monoclonal antibody as a probe, this idiotype was found, not only in a very high proportion of circulating B cells and marrow lymphoplasmacytoid cells of patients with lymphoma-associated chronic cold-agglutinin disease, but also in a smaller proportion of B cells in the blood and lymphoid tissues of normal adult donors and in the spleens of 15-week human fetuses.9 These data suggest that B cells expressing the VH4–34 gene (or a closely related sequence) are present throughout ontogeny. Chronic cold-agglutinin disease, therefore, may represent a marked, unregulated expansion of a subset (clone) of such B cells.
Light-chain V-region gene use in anti-I cold agglutinins is also highly selective; there is a strong bias toward use of the kappa III variable region subgroup (Vk-III).7,10 Light-chain selection among anti-i cold agglutinins, however, is much more variable and includes those of type lambda.7,11
These observations that pathologic cold agglutinins are synthesized with distinct and highly selected V-region sequences must be viewed against the background of two other subsequent observations. First, VH4–34 or related VH genes also may encode the heavy-chain variable regions of other types of antibodies, such as rheumatoid factor autoantibodies and alloantibodies to a variety of blood group antigens, including polypeptide determinants such as Rh.12 Second, normal human antibodies to an exogenous carbohydrate antigen, Haemophilus influenzae type b capsular polysaccharide, also are encoded by a restricted set of VH genes13 and Ig light-chain V genes.14 Thus, the regulation of Ig gene use for the production of anti-I or anti-i cold agglutinins may not differ fundamentally from normal antibody formation to other carbohydrate antigens.
In the setting of B-cell lymphoma or Waldenström’s macroglobulinemia, cold agglutinins may be produced by the malignant clone itself. Two patients with lymphoma and monoclonal cold agglutinin were each identified to have a karyotypically abnormal B-cell clone that produced a cold agglutinin identical to that found in their sera.15,16 Trisomy 3 has been the most frequently observed karyotypic abnormality in patients with non-Hodgkin’s lymphoma and cold agglutinins.15,16 and 17
Normal human sera generally have naturally occurring cold agglutinins in low titer (usually 1/32 or less). Otherwise healthy persons may develop elevated titers of cold agglutinins specific for I/i antigens during certain infections (e.g., M. pneumoniae, Epstein-Barr virus, or cytomegalovirus). In contrast to other forms of cold-agglutinin disease, the hyperproduction of these postinfectious cold agglutinins is transient. There is some evidence that such postinfectious cold agglutinins may be less clonally restricted than those occurring in chronic cold-agglutinin disease,18 but this is not a universal finding.19 Whether VH4–34 also encodes most heavy-chain variable regions of all naturally occurring or postinfectious cold agglutinins remains to be determined.
The increased production of cold agglutinins in response to infection with M. pneumoniae may be secondary to the fact that the oligosaccharide antigens of the I/i type serve as specific Mycoplasma receptors.20 This may lead to altered antigen presentation involving a complex between a self-antigen (I/i) and a non–self-antigen (Mycoplasma). Alternatively, the anti-i cold agglutinins may arise as a consequence of polyclonal B-cell activation, as occurs in infectious mononucleosis (see Chap. 90).
PATHOGENIC EFFECTS OF COLD AGGLUTININS
Most cold agglutinins are unable to agglutinate RBC at temperatures above 30°C (86°F). The highest temperature at which these antibodies cause detectable agglutination is termed the thermal amplitude. This value may vary considerably from one patient to another. Generally, patients with cold agglutinins of higher thermal amplitudes have a greater risk for cold-agglutinin disease.5 Active hemolytic anemia, for example, has been observed in patients with cold agglutinins of modest titer (e.g., 1:256) that have high thermal amplitudes.21
The pathogenicity of a cold agglutinin is dependent upon its ability to bind host RBC and to activate complement.22,23,24,25,26,27 and 28 This process is called complement fixation. Although in vitro agglutination of the RBC may be maximal at 0 to 5°C (32 to 41°F), complement fixation by these antibodies may occur optimally at 20 to 25°C (68 to 77°F) and may be significant at even higher physiologic temperatures.21,22 and 23 Agglutination is not required for this process. The great preponderance of cold-agglutinin molecules are IgM pentamers, but small numbers of IgM hexamers with cold-agglutinin activity are found in patients with cold-agglutinin disease. Hexamers fix complement and lyse RBC more efficiently than do pentamers, suggesting that hexameric IgM may play a role in the pathogenesis of hemolysis in these patients.29
Cold agglutinins may bind to RBC in superficial vessels of the extremities, where the temperature generally ranges between 28 and 31°C (82.4 and 87.8°F), depending upon ambient temperature.24 Cold agglutinins of high thermal amplitude may cause RBC to aggregate at this temperature, thereby impeding RBC flow and producing acrocyanosis. In addition, the RBC-bound cold agglutinin may activate complement via the classical pathway. Once activated complement proteins are deposited onto the RBC surface, it is no longer necessary for the cold agglutinin to remain bound to the RBC for hemolysis to occur. Instead, the cold agglutinin may dissociate from the RBC at the higher temperatures in the body core and again be able to bind another RBC at the lower temperatures in the superficial vessels. As a result, patients with high–thermal-amplitude cold agglutinins tend to have a sustained hemolytic process and acrocyanosis.30
Patients with antibodies of lower thermal amplitude require significant chilling to initiate complement-mediated injury of RBC. This sequence may result in a burst of hemolysis with hemoglobinuria.30 Combinations of these clinical patterns also occur. Cold agglutinins of the IgA isotype, an isotype that does not fix complement, may cause acrocyanosis but not hemolysis.31 Thus, the relative degree of hemolysis or impeded RBC flow is influenced significantly by the properties and quantity of the cold agglutinins in a given patient.
Complement fixation may effect RBC injury by two major mechanisms: (1) direct lysis and (2) opsonization for hepatic and splenic macrophages. Both mechanisms probably operate to varying degrees in any one patient. Direct lysis requires propagation of the full C1-to-C9 sequence on the RBC membrane. If this occurs to a significant degree, the patient may experience intravascular hemolysis leading to hemoglobinemia and hemoglobinuria. Intravascular hemolysis of this severity is relatively rare. More commonly, the complement sequence on many RBC is completed only through the early steps, leaving opsonic fragments of C3 (C3b/C3bi) and C4 (C4b) on the cell surface. These fragments provide only a weak stimulus for phagocytosis by monocytes in vitro.32,33 However, activated macrophages may ingest C3b-coated particles avidly.34 Accordingly, a RBC heavily coated with C3b (and/or C3bi) may be removed from the circulation by macrophages either in the liver or, to a lesser extent, the spleen.23,26,35,36 The trapped RBC may be ingested entirely or released back into the circulation as a spherocyte after losing some of its plasma membrane.
In vivo studies of the fate of 51Cr-labeled C3b-coated RBC23,26,27,37 indicate that many of the erythrocytes trapped in the liver or spleen gradually may reenter the circulation. Such released cells generally are coated with the opsonically inactive C3 fragment, C3dg. Conversion of cell-bound C3b or C3bi to C3dg results from the action of the naturally occurring complement inhibitor, factor I, in concert with factor H or CR1 receptors.38 These surviving C3dg-coated RBC circulate with a near-normal life span23,26,27,37,39 and are resistant to further uptake of cold agglutinins or complement.23,26,40 However, C3dg-coated RBC also may react in vitro with anticomplement (anti-C3) serum in the direct antiglobulin test. In fact, most of the antiglobulin-positive RBC of patients with cold agglutinin disease are coated with C3dg.
Progression of the complement cascade on many RBC generally does not go beyond the formation of C3b. Phosphatidylinositol-linked RBC membrane proteins protect against injury by autologous complement components. These proteins include decay-accelerating factor (DAF, or CD55; see Chap. 13) and homologous restriction factors (HRF). DAF inhibits the formation and function of cell-bound C3-converting enzyme,41 thus indirectly limiting formation of C5-converting enzyme. HRF, on the other hand, impedes C9 binding and formation of the C5b–9 membrane attack complex.42
Cold-agglutinin disease is less common than warm-antibody autoimmune hemolytic anemia, accounting for only 10 to 20 percent of all cases of autoimmune hemolytic anemia.22,43,44 Women are affected more commonly than men.22,43 No genetic or racial factors are known to contribute to the pathogenesis of this disease.
Although the majority of patients with mycoplasma pneumonia have significant cold-agglutinin titers, they only infrequently develop clinical hemolytic anemia.45,46 and 47 However, subclinical RBC injury may occur. In one series of M. pneumoniae infections, weakly positive direct antiglobulin reactions and/or mild reticulocytosis were noted in the absence of anemia in a substantial number of cases.45 Cold agglutinins occur in over 60 percent of patients with infectious mononucleosis but, again, hemolytic anemia is rare.48,49 and 50
Most patients with cold-agglutinin hemolytic anemia have chronic hemolytic anemia with or without jaundice. In others, the principal feature is episodic, acute hemolysis with hemoglobinuria induced by chilling (see the discussion of thermal amplitude under “Pathogenic Effects of Cold Agglutinins,” above.) Combinations of these clinical features may occur. Acrocyanosis and other cold-mediated vasoocclusive phenomena affecting the fingers, toes, nose, and ears are associated with sludging of RBC in the cutaneous microvasculature. Skin ulceration and necrosis are distinctly unusual. Hemolysis occurring in M. pneumoniae infections is acute in onset, typically appearing as the patient is recovering from pneumonia and coincident with peak titers of cold agglutinins. The hemolysis is self-limited, lasting 1 to 3 weeks.43 Hemolytic anemia in infectious mononucleosis develops either at the onset of symptoms or within the first 3 weeks of illness.49
Other physical findings are variable, depending upon the presence of an underlying disease. Splenomegaly, a characteristic finding in lymphoproliferative diseases or infectious mononucleosis, also may be observed in idiopathic cold-agglutinin disease.
In classic chronic cold-agglutinin disease, the anemia is mild to moderate and fairly stable. However, patients may develop hemoglobin levels as low as 5 to 6 g/dl. In addition to polychromasia, the blood film also may show spherocytosis. However, these features are generally less marked than in typical cases of warm-antibody autoimmune hemolytic anemia. RBC autoagglutination may be noted on the blood film. Autoagglutination also may be evident in anticoagulated blood at room temperature. This phenomenon may be intensified by cooling the blood to 4°C (39.2°F) and reversed by warming to 37°C (98.6°F). This property distinguishes cold autoagglutination from rouleaux formation. Mild to moderate leukocytosis is often seen during active hemolysis, for example, following exposure of the patient to chilling. The platelet count is usually normal. Mild hyperbilirubinemia is common.
Cold agglutinins are distinguished by their ability to agglutinate saline-suspended human RBC at low temperature, maximally at 0 to 5°C (32 to 41°F). This reaction is reversible by warming. In chronic cold-agglutinin disease, the serum titers are commonly 1:10,000 or higher and may reach 1:1,000,000 or more. As noted above, cold agglutinins are characteristically IgM. IgA or IgG cold agglutinins have been reported in a few cases,31,43,51 sometimes in combination with IgM.52 Occasionally, warm-reactive IgG autoantibodies are found in association with IgM cold agglutinins.53 Mixed warm- and cold-antibody autoimmune hemolytic anemia is discussed in Chap. 55.
The direct antiglobulin test result, as noted above, is positive with anticomplement reagents. The antibody itself, however, is not detected by the antiglobulin test using antisera to human immunoglobulins. This is because the cold agglutinins readily dissociate from the RBC both in vivo and during the washing steps of the standard antiglobulin procedure. In contrast, C4b and C3b are covalently bound to target RBC via thioester linkages. In one unusual case, it was possible to detect a low-titer IgG cold agglutinin by washing the patient’s RBC in ice-cold saline solution and performing the direct antiglobulin test at 4°C (39.2°F).51
As noted earlier, the majority of cold agglutinins are reactive with oligosaccharide antigens of the I/i system, which are precursors of the ABH and Lewis blood group substances.54,55 and 56 The I/i determinants are bound to erythrocyte membrane glycoprotein (band 3 anion transporter) or to glycolipids.55,56 Anti-I and anti-i have been reported to bind solubilized RBC glycoproteins at 37°C (98.6°F), suggesting that the temperature dependence of cold agglutination of intact RBC may be a function of temperature-induced conformational effects on the cell surface.57,58
I antigens are expressed strongly on adult RBC but weakly on neonatal (cord) RBC. The converse is true of i antigens, indicating that I/i antigen expression is developmentally regulated.55 These differences between adult and cord blood RBC allow evaluation of the serologic specificity of cold agglutinins.22,31,43 I/i antigens, or structurally related analogs, occur in human saliva, milk, amniotic fluid, or hydatid cyst fluid31 and are expressed on human lymphocytes, neutrophils, and monocytes.59
Anti-I is the predominant specificity of cold agglutinins in idiopathic cold-agglutinin disease, in patients with M. pneumoniae, and in some cases of lymphoma. Cold agglutinins with anti-i specificity are found in patients with infectious mononucleosis and in some patients with lymphoma. A small percentage of cold agglutinin–containing sera react equally well with adult and neonatal RBC. These antibodies recognize antigens outside the I/i system, including Pr antigens, consisting of carbohydrate epitopes of glycophorins that are inactivated by protease treatment,31 and, less commonly, the M or P blood group antigens.60,61 Most cold agglutinins associated with chickenpox exhibit anti-Pr specificity; a single case with anti-I specificity has been observed as well.62 Hemolysis due to a cold agglutinin with anti-Pr specificity occurred following an allogeneic marrow transplant.63
In hemolytic anemia associated with infectious mononucleosis, the patient’s serum may contain IgM anti-i cold agglutinins or cold-reactive nonagglutinating IgG anti-i along with IgM cold-reactive anti-IgG antibodies (“rheumatoid factors”) that may cross-link the IgG-coated red cells to produce agglutination.64
The clinical and laboratory features of chronic cold-agglutinin disease are sufficiently distinctive that the diagnostic possibilities are limited. In general, a high-titer cold agglutinin (>1:10,000) together with a direct antiglobulin test result that is positive with anticomplement serum (but not with anti-IgG) is consistent with cold-agglutinin disease. In many instances of drug-induced immune hemolytic anemia, the direct antiglobulin test result is also positive only for complement. The drug history and a low (or absent) cold agglutinin titer, however, help to distinguish this from cold-agglutinin disease. If the patient has elevated cold agglutinins and a positive direct antiglobulin test result with both anti-IgG and anti-C3, then the patient may have a mixed-type autoimmune hemolytic anemia (see Chap. 55). Warm-antibody autoimmune hemolytic anemia, congenital hemolytic disorders, and paroxysmal nocturnal hemoglobinuria should be excluded in cases exhibiting primarily a chronic hemolytic anemia. The pattern of the antiglobulin reaction, family history, and the acid or sucrose hemolysis test provides additional help in difficult cases. When the hemolysis is episodic in nature, one also should consider paroxysmal cold hemoglobinuria (see “Paroxysmal Cold Hemoglobinuria,” below) and march hemoglobinuria, as well as paroxysmal nocturnal hemoglobinuria. When cold-induced peripheral vasoocclusive symptoms are predominant, the differential diagnosis should include cryoglobulinemia and Raynaud’s phenomenon, with or without an associated rheumatic disease. Infectious mononucleosis, M. pneumoniae infection, or lymphoma may be considered in appropriate clinical settings.
It is important to keep the patient warm, particularly the extremities. This is moderately effective in providing symptomatic relief. This may be the only measure required in patients with mild chronic hemolysis. Therapy with chlorambucil or cyclophosphamide may be helpful for patients with chronic cold-agglutinin disease of greater severity.5,22,43,65,66 A patient treated with interferon-a experienced rapid resolution of acrocyanosis and hemolytic anemia, associated with a marked decrease in cold agglutinin titer.67 Treatment with interferon-a also has proven beneficial in patients with type II cryoglobulinemia involving monoclonal IgM anti-IgG.68 The results from splenectomy22,43,69 or use of glucocorticoids22,43 generally have been disappointing, although exceptions have been reported,21,22,51,52 particularly in atypical cases. There is experimental35 and clinical21 basis for considering very high doses of glucocorticoids in seriously ill patients. An elderly woman with a B-lymphoproliferative disease and severe refractory hemolysis mediated by cold agglutinins was successfully treated with the anti-CD20 monoclonal antibody, rituximab.70 RBC transfusions generally are reserved for those patients with severe anemia of rapid onset who are in danger of cardiorespiratory complications.51 Washed RBC often are used to avoid replenishing depleted complement components and reactivating the hemolytic process. In critically ill patients, plasma exchange (with replacement by albumin-containing saline solution) may provide transient amelioration of hemolysis.71,72 and 73
COURSE AND PROGNOSIS
Patients with idiopathic cold-agglutinin disease often have a relatively benign course and survive for many years.5,22,43,66 Occasionally, death results from infection or severe anemia or, in the case of secondary cold-agglutinin disease, from an underlying lymphoproliferative process.
The postinfectious forms of cold-agglutinin disease typically are self-limited. Recovery generally occurs in a few weeks. A few cases with massive hemoglobinuria have been complicated by acute renal failure, requiring temporary hemodialysis.
PAROXYSMAL COLD HEMOGLOBINURIA
DEFINITIONS AND HISTORY
Paroxysmal cold hemoglobinuria is a very rare form of autoimmune hemolytic anemia in adults characterized by recurrent episodes of massive hemolysis following cold exposure.22,43 A related form of hemolytic anemia occurs much more commonly in children (or young adults) as an acute, self-limited hemolytic process following several types of viral syndromes (see Table 56-1).22,74,75,76,77 and 78
In 1904, Donath and Landsteiner first described the cold-reactive autoantibody that is responsible for the complement-mediated hemolysis. The disease was recognized during the latter half of the nineteenth century, when it probably was more common because of its association with congenital or tertiary syphilis. With the advent of effective therapy for syphilis, this cause of paroxysmal cold hemoglobinuria has virtually disappeared. Now, recurrent paroxysmal cold hemoglobinuria occurs very rarely in a chronic idiopathic form.22,43 An increasing proportion of Donath-Landsteiner autoantibody–mediated hemolytic anemias occurs as a single postviral episode in children, without recurrent attacks (paroxysms). The prognosis for such cases is excellent. Thus, rather than paroxysmal cold hemoglobinuria, it has been proposed that this entity be termed Donath-Landsteiner hemolytic anemia.75,76 However, this term has not gained widespread acceptance.
ETIOLOGY AND PATHOGENESIS
The mechanism or mechanisms whereby dissimilar infectious agents (e.g., spirochetes and several types of virus) induce the immune system to produce Donath-Landsteiner antibodies with specificity for the human P blood group antigen (see Serologic Features below) is not known. The mechanism of hemolysis, however, probably parallels in vitro events described below. During severe chilling, blood flowing through skin capillaries is exposed to low temperatures. The Donath-Landsteiner antibody and early-acting complement components are presumed to bind to RBC at these lowered temperatures. Upon return of the cells to 37°C (98.6°F) in the central circulation, the cells are lysed by propagation of the terminal complement sequence through C9.
The Donath-Landsteiner antibody itself dissociates from the RBC at 37°C (98.6°F). However, prior to dissociation, it initiates the classical pathway of complement. Erythrocyte membrane proteins that restrict C5b–9 assembly (e.g., homologous restriction factors) may be, for some reason, less effective in controlling Donath-Landsteiner antibody–initiated complement activation than that initiated by cold agglutinins (see section on Cold Agglutinins).
Medical centers that receive many referrals report that paroxysmal cold hemoglobinuria constitutes 2 to 5 percent of all cases of autoimmune hemolytic anemia.22,43 Among children, however, Donath-Landsteiner hemolytic anemia accounted for 32.4 percent of 68 immune hemolytic syndromes diagnosed over a 4-year period.77 Most commonly, the diagnosis is missed because of lack of physicians’ awareness or failure to perform the proper serologic studies (see Serologic Features below).74,77 Thus, the true incidence actually may be higher. Although familial occurrence has been reported, there are no known racial or genetic risk factors.22 As noted, most childhood cases follow either specific viral infections or upper respiratory infections of undefined etiology.22,43,74,75,76 and 77
Constitutional symptoms are prominent during a paroxysm. A few minutes to several hours after cold exposure, the patient develops aching pains in the back or legs, abdominal cramps, and perhaps headaches. Chills and fever usually follow. The first urine passed after onset of symptoms typically contains hemoglobin. The constitutional symptoms and hemoglobinuria generally last a few hours. Raynaud’s phenomenon and cold urticaria sometimes occur during an attack, and jaundice may follow.
Hemoglobinuria is an expected finding if the patient is seen early in the attack. The urine may be dark red or brown due to the presence of hemoglobin or methemoglobin, respectively. The blood hemoglobin level often drops rapidly during a severe attack. Reticulocytosis, hemoglobinemia, and hyperbilirubinemia (mainly unconjugated) may be present, depending on when the patient is assessed. Serum complement titers usually are depressed during an acute episode because of rapid consumption. Spherocytosis and erythrophagocytosis by monocytes and neutrophils may be found on the blood film during an attack. Leukopenia often is seen early in the attack, followed by neutrophilic leukocytosis.
The direct antiglobulin reaction is usually positive during and briefly following an acute attack. The positive reaction is due to the coating of surviving RBC with complement, primarily C3dg fragments. The Donath-Landsteiner antibody is a nonagglutinating IgG that binds RBC only in the cold. It readily dissociates from the RBC at room temperature. In those adults subject to recurring episodes in association with cold exposure, the direct antiglobulin test result remains negative between attacks. The antibody is detected by the biphasic Donath-Landsteiner test, in which the patient’s fresh serum is incubated with RBC initially at 4°C (39.2°F) and the mixture is then warmed to 37°C (98.6°F).43 Intense hemolysis occurs. It may be necessary to add fresh guinea pig serum or ABO-compatible human serum to serve as a source of fresh complement if the patient’s serum has been stored or is complement depleted. Antibody titers rarely exceed 1:16. The Donath-Landsteiner antibody typically has specificity for the P blood group antigen, a glycosphingolipid structure.56 The P antigen has been reported to occur also on lymphocytes and skin fibroblasts.78 The latter finding might be related in some way to the occurrence of cold urticaria in paroxysmal cold hemoglobinuria, a phenomenon that may be transferred passively by serum to normal skin.22 Antibody specificities for RBC antigens other than the P blood group also have been noted.79
Paroxysmal cold hemoglobinuria must be distinguished from the subset of cases of chronic cold-agglutinin disease that manifests episodic hemolysis and hemoglobinuria. This distinction is made primarily in the laboratory. In general, patients with paroxysmal cold hemoglobinuria lack high titers of cold agglutinins. Furthermore, the Donath-Landsteiner antibody is a potent in vitro hemolysin, in contrast to most cold agglutinins, which are weak hemolysins. Warm-antibody autoimmune hemolytic anemia, march hemoglobinuria, myoglobinuria, and paroxysmal nocturnal hemoglobinuria may be distinguished through the history and appropriate laboratory studies.
Most contemporary cases of paroxysmal cold hemoglobinuria are self-limited. Acute attacks in both chronic and transient forms of paroxysmal cold hemoglobinuria may be prevented by avoiding exposure to cold. Glucocorticoid therapy and splenectomy have not been useful. When paroxysmal cold hemoglobinuria is associated with syphilis, effective treatment of the infection may result in a complete remission. Antihistaminic and adrenergic agents may relieve symptoms of cold urticaria.
COURSE AND PROGNOSIS
Postinfectious forms of paroxysmal cold hemoglobinuria terminate spontaneously within a few days to weeks after onset,74,75,76 and 77 although the Donath-Landsteiner antibody may persist in low titer for several years.22 Most patients with chronic idiopathic paroxysmal cold hemoglobinuria survive for many years in spite of occasional paroxysms of hemolysis.
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Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn