Elsevier

Blood Reviews

Volume 22, Issue 1, January 2008, Pages 1-15
Blood Reviews

Review
Cold antibody autoimmune hemolytic anemias

https://doi.org/10.1016/j.blre.2007.08.002Get rights and content

Summary

The cold antibody autoimmune hemolytic anemias (AIHAs) are primarily comprised of cold agglutinin syndrome (CAS) and paroxysmal cold hemoglobinuria (PCH) but, in addition, there are unusual instances in which patients satisfy the serologic criteria of both warm antibody AIHA and CAS (“mixed AIHA”). CAS characteristically occurs in middle-aged or elderly persons, often with signs and symptoms exacerbated by cold. The responsible antibody is of the IgM immunoglobulin class, is maximally reactive in the cold but with reactivity up to at least 30 °C. Therapy is often ineffective, but newer agents such as rituximab have been beneficial in some patients. PCH occurs primarily in children, often after an upper respiratory infection. The causative antibody is of the IgG immunoglobulin class and is a biphasic hemolysin that is demonstrated by incubation in the cold followed by incubation at 37 °C in the presence of complement. Acute attacks are frequently severe but the illness characteristically resolves spontaneously within a few days to several weeks after onset and rarely recurs. Treatment consists of supportive care, with transfusions frequently being needed.

Introduction

The immune hemolytic anemias are classified as indicated in Table 1.1 This classification divides these disorders into distinctive categories which have differing clinical manifestations, prognosis and therapy, as indicated in Table 2. The cold antibody autoimmune hemolytic anemias (AIHAs) are primarily comprised of cold agglutinin syndrome (CAS) and paroxysmal cold hemoglobinuria (PCH) but, in addition, there are unusual instances in which patients satisfy the serologic criteria of both warm antibody AIHA and CAS. Such cases are designated as combined cold and warm AIHA or “mixed AIHA.”

These disorders are diagnosed on the basis of characteristic serologic reactions. The majority of cases of AIHA are mediated by warm-reactive autoantibodies, i.e., antibodies displaying optimal reactivity with human RBC at 37 °C and which are usually of the IgG immunoglobulin class. In contrast, CAS is generally caused by IgM autoantibodies which exhibit maximal reactivity at 4 °C.

The causative in PCH antibody is an IgG immunoglobulin with specificity that differs from that found in CAS. The antibody is best detected in vitro by its ability to cause hemolysis of normal RBC in a two-step procedure, which requires incubation in the cold followed by incubation at 37 °C in the presence of complement.

AIHA is designated as “idiopathic” if it is unassociated with any demonstrable underlying disease. In contrast, AIHA is categorized as “secondary” if it is associated with an additional disorder and there is reason to suspect that the association is not merely fortuitous.

The ingestion of some drugs causes hemolytic anemia in which the causative antibody can be shown to have specificity for the drug or its metabolites. Although the antibody reacts with the patient’s own RBCs, these disorders are not autoimmune disorders because the antibody does not have specificity for autoantigens. In other quite remarkable cases, ingestion of a drug causes the development of red cell autoantibodies, i.e., the antibody in the patient’s serum and in an eluate from the patient’s red cells reacts with red cells similarly to autoantibodies in idiopathic AIHAs, and no relationship between the drug and the antibody can be demonstrated in vitro. Such cases are appropriately termed drug-induced AIHAs and can be either of warm antibody or cold antibody type.

Section snippets

Incidence

Cold agglutinin syndrome (CAS) is relatively uncommon compared with warm antibody AIHA (WAIHA), but it occurs much more frequently than PCH. In a series of 347 patients with acquired immune hemolytic anemias (including drug-induced immune hemolytic anemia), 54 patients (15.6%) had CAS.2 Dacie and Worlledge3 reported that 25 percent of their patients with AIHA had CAS, whereas van Loghem et al4 and Dausset and Colombani5 reported an incidence of only 7.7%.

Age and sex

Patients with idiopathic CAS are

Incidence

Many reports emphasize that paroxysmal cold hemoglobinuria (PCH) is an unusual disease. Howard et al64 noted only two occurrences in 38 years and 298,878 admissions at the Montreal Hospital. Becker65 noted that the diagnosis was made in only I patient in 20 years at the University of Chicago clinic, during which time 130,000 patients were admitted to the hospital and 382,799 patients were seen as out-patients. Pirofsky15 encountered only 2 occurrences over a I5-year period at Bellevue Hospital

Diagnostic serologic tests for paroxysmal cold hemoglobinuria

The autoantibody associated with PCH is termed a biphasic hemolysin, that is to say, it sensitizes RBCs in the cold but only hemolyzes them when the RBCs reach 37 °C. The diagnostic test is the Donath Landsteiner (DL) test where normal RBCs are incubated with the patient’s serum at 0 °C (e.g., melting ice) and then moved to 37 °C for a further incubation. No lysis occurs following the incubation at 0 °C, and no lysis occurs if the incubation is carried out only at 37 °C. The thermal amplitude

Combined cold and warm AIHA or “Mixed” AIHA

In unusual instances, a patient will be found who has serologic findings characteristic of warm antibody AIHA while also having a cold agglutinin of high titer and thermal amplitude, thus satisfying the criteria for both warm antibody AIHA and cold agglutinin syndrome.2 Such cases are frequently referred to as “combined cold and warm AIHA” or “mixed” AIHA, and reviews of AIHA generally include such a category.88, 89, 90, 91, 92, 93

Secondary autoimmune hemolytic anemias

Autoimmune hemolytic anemias are classified as secondary for any of several reasons. One reason is the association of AIHA with an underlying disease with a frequency greater than can be explained by chance alone. For example, all authors agree that the incidence of warm antibody AIHA is higher in patients with chronic lymphocytic leukemia (CLL) and systemic lupus erythematosus (SLE) than in the general population.

Another criterion for categorizing a given case of AIHA as secondary is the

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