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

transplant from a donor of blood group A or B may develop a tran- immune hemolytic anemia have a positive DAT that distinguishes this
siently positive DAT and hemolysis of RBCs made by the marrow graft group from patients with inherited RBC defects.
because of temporary persistence of previously synthesized host anti-A
or anti-B. Furthermore, some group O stem cell transplantation recip- THERAPY
300
ients exhibit mixed hematopoietic chimerism with persistence of host B
lymphocytes that can make alloantibodies directed against RBCs made GENERAL
300
by the stem cell graft. In these settings, the findings of hemolysis and
a positive DAT as a result of anti-A and anti-B probably are diagnostic Transfusion
of an alloimmune process, because autoantibodies directed against the The clinical consequences of AHA or drug-induced immune hemo-
major blood group antigens A and B are extremely rare. lytic anemia are related to the severity of the anemia and acuity of its
Other acquired types of hemolytic anemia are less easily confused onset. Many patients develop anemia over a period sufficient to allow
with either warm- or cold-antibody AHA because spherocytes are not for cardiovascular compensation and hence do not require RBC trans-
prominent on the blood film and the DAT is negative. Patients with fusions. However, RBC transfusions may be necessary and should not
paroxysmal nocturnal hemoglobinuria (PNH) may complain of dark be withheld from a patient with an underlying disease complicating the
urine (hemoglobinuria). This finding is unusual in patients with warm- anemia, such as symptomatic coronary artery disease, or a patient who
antibody AHA but can occur in patients with the cold-antibody syn- rapidly develops severe anemia with signs and/or symptoms of circula-
dromes. Decreased levels of CD55 and CD59 on blood cells, detected tory failure, as in paroxysmal cold hemoglobinuria or ternary complex
by flow analysis, are characteristic of PNH but not AHA (Chap. 40). drug-induced immune hemolysis.
Microangiopathic hemolytic disorders, such as thrombotic thrombocy- Transfusion of RBCs in immune hemolytic anemia presents two
topenic purpura and hemolytic uremic syndrome, can be distinguished difficulties: (1) crossmatching and (2) the short half-life of the trans-
from AHA by examining the blood film. In the microangiopathic fused RBCs (Chap. 138). Finding truly serocompatible donor blood is
hemolytic diseases, the blood film displays marked RBC fragmentation nearly always impossible except in rare cases when the autoantibody
and minimal spherocytosis. In addition, microangiopathic hemolytic is specific for a defined blood group antigen (see “Serologic Features”
anemias more frequently are associated with thrombocytopenia than is above).
either warm- or cold-antibody AHA. It is most important to identify the patient’s ABO type so as to avoid
The clinical and laboratory features of chronic cold agglutinin dis- a hemolytic transfusion reaction mediated by anti-A or anti-B. This part
ease are sufficiently distinctive so that the diagnostic possibilities are of the matching process allows for selection of either ABO-identical
limited. In general, a high-titer cold agglutinin (>1:512) and a positive or -compatible blood for transfusion. With respect to compatibility, the
DAT with anticomplement serum (but not with anti-IgG) are consis- more difficult technical issue relates to the detection of RBC alloanti-
tent with cold agglutinin disease. In many instances of drug-induced bodies which may be masked by the presence of the autoantibody.
immune hemolytic anemia, the DAT result also is positive only for com- Clinicians often speak of “least incompatible” blood for transfu-
plement. The drug history and a low (or absent) cold agglutinin titer, sion, but this term has lately fallen into disrepute because it lacks a pre-
however, help to distinguish drug-induced immune hemolytic anemia cise definition. 301,302 In fact all units will be serologically incompatible
from cold agglutinin disease. If the patient has an elevated cold aggluti- but units that are incompatible because of the presence of autoantibody
nin level and a positive DAT result with both anti-IgG and anti-C3, then are less dangerous to transfuse than those units that are incompatible
the patient may have a mixed-type AHA. Warm-antibody AHA, hered- because of an alloantibody.
itary hemolytic disorders, and PNH should be excluded in cases exhib- Before transfusing an incompatible unit, the patient’s serum must
iting primarily a chronic hemolytic anemia. The pattern of antiglobulin be tested carefully for an alloantibody that could cause a severe hemo-
reaction, family history, the result of analysis of CD55/CD59 on blood lytic transfusion reaction against donor RBCs, especially in patients with
cells provide additional help in difficult cases. When the hemolysis is a history of pregnancy, abortion or prior transfusion. 264,303–305 Patients
episodic, paroxysmal cold hemoglobinuria, march hemoglobinuria, who have been neither pregnant nor transfused with blood products
and PNH also should be considered. When cold-induced peripheral are unlikely to harbor an alloantibody. Early consultation between the
vasoocclusive symptoms are predominant, the differential diagnosis clinician and the blood bank physician is essential. An understanding
should include cryoglobulinemia and Raynaud phenomenon, with or of the basic aspects of blood compatibility testing, coupled with the
without an associated rheumatic disease. Infectious mononucleosis, knowledge of a patient’s pregnancy and transfusion history allow for
M. pneumoniae infection, and lymphoma can be considered in appro- informed discussion and confident transfusion of mismatched blood if
priate clinical settings. the situation demands.
Paroxysmal cold hemoglobinuria must be distinguished from Once selected, the packed RBCs should be administered slowly
the subset of cases of chronic cold agglutinin disease manifesting epi- and in the case of cold hemolysis syndromes should be brought at least
sodic hemolysis and hemoglobinuria. This distinction is made pri- to room temperature. During the transfusion, the patient should be
marily in the laboratory. In general, patients with paroxysmal cold monitored for signs of a hemolytic transfusion reaction (Chap. 138).
hemoglobinuria lack high titers of cold agglutinins. Furthermore, the The transfused cells may be destroyed as fast as or perhaps even faster
Donath-Landsteiner antibody is a potent in vitro hemolysin, in contrast than the patient’s own cells. However, the increased oxygen-carrying
to most cold agglutinins, which are weak hemolysins. Warm-antibody capacity provided by the transfused cells may be sufficient to maintain
AHA, march hemoglobinuria, myoglobinuria, and PNH can be distin- the patient during the acute interval required for other modes of ther-
guished through the history and appropriate laboratory studies. apy to become effective.
Immune hemolysis caused by drugs should be distinguished from For patients with AHA who require chronic transfusion support,
(1) the warm- or cold-antibody types of idiopathic AHA, (2) congen- use of prophylactic antigen-matched donor RBCs for transfusion has
306
ital hemolytic anemias such as HS, and (3) drug-mediated hemolysis been proposed as a means of preventing alloimmunization. This pro-
resulting from disorders of red cell metabolism, such as glucose-6- cess is feasible only in institutions with access to a good selection of
phosphate dehydrogenase deficiency. Patients with drug-induced phenotyped RBC units and a reference laboratory. 307

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