Page 873 - Clinical Immunology_ Principles and Practice ( PDFDrive )

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Immunohematological Disorders

Jay N. Lozier, Pierre Noel

Congenital (primary) or acquired (secondary) immunodeficiencies, to cause renal failure from toxicities of hemoglobin to renal
medications, and lymphoproliferative and rheumatological epithelium.
disorders are frequently associated with immune-mediated A second less common mechanism develops primarily in
cytopenias. These processes can affect erythrocytes, leukocytes, patients receiving very high doses of penicillin (rarely used) for
and platelets (individually or in combination). In this chapter, at least 1 week. High-titer antipenicillin IgG develops and binds
we address immune-mediated cytopenias of each hematological to penicillin that is covalently attached to the RBC membranes.
component, discussing pathophysiology, clinical presentation, The resultant hemolysis is less acute than that caused by immune
differential diagnosis, and treatment options. complexes but can be life-threatening.
In a third mechanism, a drug stimulates the production of
IMMUNE-MEDIATED HEMOLYTIC ANEMIA an antibody that reacts with the patient’s RBCs independently
from the drug. Serologically, this antibody is indistinguishable
Immune-mediated hemolysis can be autoimmune, alloimmune, from an idiopathic autoantibody. This has become rare as the
idiopathic, or secondary to drugs or other diseases. Regardless use of the primary causal agent, methyldopa (an antihypertensive
of the underlying cause, immunoglobulin G (IgG) or IgM (rarely medication), has declined. Although these autoantibodies com-
IgA) antibodies are directed against antigens on the red blood monly cause positive clinical antibody tests (see below), they
1,2
cell (RBC) membrane (Table 62.1). These disorders can be rarely cause hemolysis in vivo, and when they do, it usually ceases
categorized on the basis of the underlying cause and the type within 2 weeks of discontinuing the drug.
of antierythrocyte antibody that mediates the process.
Cold Agglutinin Diseases
Autoimmune Hemolysis Mediated by Warm Antibody This type of hemolytic anemia is mediated predominantly by
Although warm-antibody autoimmune hemolytic anemia is rare, anti-I or anti-i IgM that agglutinates red cells at temperatures well
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it increases in prevalence above the age of 50 years and tends to below 37°C. These antibodies engage the complement pathway
be more common in women than in men, as is typical of most resulting in C3b-mediated RBC phagocytosis mainly by Kupffer
autoimmune diseases. In this condition, IgG autoantibodies and cells, whereas membrane-associated complex is a minor mecha-
complement components are present on the RBC surface (see nism at low IgM titers. The severity of the clinical illness depends
below). Although the autoantibody target is most commonly on the concentration of the IgM and its “thermal amplitude.”
the Rh antigen, a variety of other targets are known. The specificity Thermal amplitude describes the temperature range over which
of the antibody, however, does not affect the clinical presentation it binds to RBCs: for example, antibodies that exclusively bind
or management of hemolysis. at 4°C are only active in vitro, whereas those that bind at >30°C
can bind to RBCs as they circulate in the periphery and begin the
Drug-Induced Immune Hemolysis process of complement fixation, which can persist even as the
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Over 125 drugs have been associated with immune hemolysis. cells return to body core temperatures. The activity of the IgM is
Cefotetan, ceftriaxone, and piperacillin currently account for over also determined by its relative affinity for the I- and i-antigens,
80% of cases. The prognosis of drug-related immune hemolysis is which varies from one individual to the next.
much better than that of idiopathic hemolysis because the hemolysis Two general types of cold agglutinin disease are recognized:
stops once the offending drug has been removed. The drugs most a chronic idiopathic disease presenting in patients over age 50
commonly associated with fatal hemolytic anemia are cefotetan years, caused by monoclonal anti-I IgM, and a transient disease
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(8%) and ceftriaxone (6%). Fludarabine and cladribine have been secondary to certain infections (e.g., mycoplasma, Epstein-Barr
associated with immune hemolysis. Following multiple courses virus [EBV], cytomegalovirus [CMV]), caused by polyclonal
of alkylating agents, fludarabine causes autoimmune hemolytic anti-i and anti-I (see Table 62.1). Avoidance of cold environments
anemia in 20% of patients with chronic lymphocytic leukemia is important in both categories of cold agglutinin disease. In
(CLL). The combination of fludarabine and cyclophosphamide addition, cold agglutinin disease can be associated with B-cell
with or without rituximab (FC, FCR) may protect against the lymphoproliferative disorders, and this typically is responsive
development of autoimmune hemolytic anemia. 3,4 to rituximab and/or rituximab combined with fludarabine. 6
Although the biochemical mechanisms of drug-related immune
hemolysis are not completely clear, several hypotheses are generally Paroxysmal Cold Hemoglobinuria
accepted. Most commonly, complexes of drug and IgG and/or Paroxysmal cold hemoglobinuria (PCH) is caused by anti-P IgG
IgM that adsorb to the RBC surface and fix complement. The that is very effective in fixing complement and producing
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resultant intravascular hemolysis is acute and often severe enough intravascular hemolysis. Although rare, it is most common in
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