Page 861 - Williams Hematology ( PDFDrive )

836 Part VI: The Erythrocyte Chapter 54: Hemolytic Anemia Resulting from Immune Injury 837

binds RBCs only in the cold. It readily dissociates from the RBCs at room consistently permits a slow recovery from anemia and a gradual disap-
temperature. In adults subject to recurring episodes in association with pearance of anti-RBC antibodies.
cold exposure, the DAT result remains negative between attacks. The Drugs now not known to cause immune RBC injury will be impli-
antibody is detected by the biphasic Donath-Landsteiner test, in which cated in the future. In any patient with a clinical picture compatible
the patient’s fresh serum is incubated with RBCs initially at 4°C and the with drug-related immune hemolysis, a reasonable approach is stopping
mixture is then warmed to 37°C. Intense hemolysis occurs. Addition of any drug that is suspect while serologic studies are being performed.
11
fresh guinea pig serum or ABO-compatible human serum may be nec- The patient should be monitored for improvement in hematocrit level,
essary to serve as a source of fresh complement if the patient’s serum decrease in reticulocytosis, and gradual disappearance of the positive
has been stored or is complement depleted. Antibody titers rarely exceed DAT. Repeat challenge with the suspected drug may confirm the diag-
1:16. The Donath-Landsteiner antibody typically has specificity for the P nosis, but this measure is seldom necessary in patient management
281
blood group antigen, a glycosphingolipid structure. The P antigen also and may be unsafe. Therefore, rechallenge to exclude a drug-induced
16
occurs on lymphocytes and skin fibroblasts. The finding of P antigen on immune hemolytic anemia should be undertaken only for compel-
skin fibroblasts might be related in some way to the occurrence of cold ling reasons, such as the need to use the specific drug for the patient’s
urticaria in paroxysmal cold hemoglobinuria, a phenomenon that may illness.
10
be transferred passively by serum to normal skin. Antibody specificities
for RBC antigens other than the P blood group have been noted. 290 DIFFERENTIAL DIAGNOSIS
Drug-Induced Immune Hemolytic Anemia Several nonautoimmune diseases may result in spherocytic anemia,
In the hapten/drug adsorption mechanism of immune injury associ- such as hereditary spherocytosis (HS), Zieve syndrome, clostridial sep-
ated with cephalosporins or penicillin, the patient’s drug-coated RBCs sis, and the hemolytic anemia preceding Wilson disease. Among the
bind drug-specific IgG antibody and exhibit positive DAT reactions hereditary hemolytic anemias, HS can resemble acquired AHA most
with anti-IgG. Rarely, both anti-IgG and anti-C3d antisera produce closely because the spherocytic anemia associated with HS may be
positive DAT reactions. Such cases could have superficial resemblance detected first in adulthood (Chap. 46). In addition, splenomegaly may
to warm-antibody AHA. The key serologic difference is that, in this be prominent in both HS and AHA. Family studies of patients with HS,
form of drug-induced immune hemolytic anemia, the antibodies in however, usually can identify other affected individuals. Most impor-
the patient’s serum or eluted from the patient’s RBCs react only with tant, in hereditary hemolytic anemia the DAT is negative.
drug-coated RBCs. In contrast, the IgG antibodies in warm-type AHA In hemolytic anemia accompanied by a positive DAT, serologic
react with unmodified human RBCs and may show preference for cer- characterization of the autoantibody may distinguish warm-antibody
tain known blood groups (e.g., within the Rh complex). Such serologic AHA from cold-reacting autoantibody syndromes. Diagnosis of a
distinction and the history of exposure to high blood levels of penicillin drug-induced immune hemolytic anemia depends upon a history of
or a cephalosporin should be instructive. appropriate drug intake supported by compatible serologic findings. In
In hemolysis mediated by the ternary complex mechanism, the patients who recently received a transfusion, a positive DAT reaction
DAT is positive with anticomplement serum. Immunoglobulins are may reflect the binding of a newly formed alloantibody to donor RBCs
only rarely detectable on the patient’s RBCs. This pattern is similar to in the patient’s circulation (delayed transfusion reaction; Chap. 138).
that encountered in AHA mediated by cold agglutinins. Moreover, the This finding could lead to a false impression of an autoimmune process.
brisk type of hemolysis in the ternary complex mechanism also is seen The venom of the brown recluse spider (Loxosceles recluse) may
in certain cases of cold-antibody AHA. In the drug-induced cases, how- cause severe life-threatening hemolysis. 292,293 The DAT may be positive
ever, the cold agglutinin titer and the Donath-Landsteiner test result are for IgG and or complement 292,293 and spherocytes and RBC fragments
normal, and demonstration of serum antibody acting on human RBCs are present on the blood film. The diagnosis should be considered
293
depends upon the presence of the drug in the test system. Thus, the when there is history or evidence by physical examination of a spider
IAT reaction with anticomplement serum may be positive only if the bite. The role of IgG and complement in hemolysis is unclear, but the
incubation mixture permits interaction of (1) normal RBCs; (2) anti- terminal complement inhibitor, eculizumab, inhibits lysis in vitro. To
drug antibody from the patient’s serum; (3) the relevant drug, either date, the clinical use of eculizumab in this population has not been
still in the patient’s serum or added in vitro in appropriate concentra- reported.
tion; and (4) a source of complement, that is, fresh normal serum or Recent recipients of allogeneic blood stem cell or solid-organ
the patient’s own serum if freshly obtained. A negative result does not transplantations may develop autoimmune hemolysis. In the former,
294
necessarily absolve the suspected drug because the critical determinant antibodies are produced by the stem cell graft against RBCs also pro-
may be a metabolite of the drug in question. In some cases, use of urine duced by the stem cell graft; that is, both antibodies and RBCs are of
or serum (of the patient or a volunteer taking the drug) as a source of donor origin. In the case of solid-organ transplantations, the recipient’s
drug metabolite has permitted successful demonstration of a drug-de- own lymphocytes make antibody against recipient RBCs. In both situ-
pendent mechanism. 61,218,222,291 ations, the autoimmunity is thought to arise from immunosuppressive
In patients with true autoantibodies as a result of α-methyldopa, the therapy causing delayed reconstitution or dysfunction of T-cell immu-
DAT reaction is strongly positive for IgG, but complement only rarely nity, leading to development of antibodies autologous to the offended
is detected on the patient’s RBCs. Autoantibody to RBCs is regularly immune system.
present in the serum of patients and mediates a positive IAT reaction Recipients of transplantations may also develop an alloimmune
with unmodified human RBCs, often showing specificity related to the hemolytic anemia that mimics warm-antibody AHA. The problem is
Rh complex. No presently available specific serologic test can separate seen in kidney, liver, or hematopoietic stem cell transplantations and
idiopathic warm-reacting IgG autoantibodies with Rh-related specifici- usually occurs when an organ from a blood group O donor is trans-
ties from those induced by α-methyldopa administration. The evidence planted into a blood group A or B recipient. B lymphocytes present
must be circumstantial, with the helpful knowledge that discontinua- in the donated organ or stem cell product form alloantibodies against
tion of α-methyldopa, without any form of immunosuppressive therapy, recipient RBCs. 295–299 Patients of blood group O who receive a stem cell

Kaushansky_chapter 54_p0823-0846.indd 836 9/19/15 12:28 AM