Blackwell Science, LtdOxford, UKTRFTransfusion0041-11322003 American Association of Blood BanksDecember 2003431215031507CommentaryEDITORIALEDITORIAL

EDITORIAL

“Least incompatible” units for transfusion in autoimmune

hemolytic anemia: should we eliminate this meaningless term? A
commentary for clinicians and transfusion medicine professionals

M
uch has been written about the detailed transfusion reaction. Compatible blood will not react with
serologic approaches that are available to RBC antibodies in the patient’s serum. The most impor-
select the optimal unit of RBCs for patients tant antibodies are anti-A and anti-B because these cause
whose autoimmune hemolytic anemia the most severe hemolytic reactions. Hemolysis caused by
(AIHA) makes necessary more complex compatibility test anti-A and anti-B is easily avoided by providing blood of
procedures than usual.1-6 These must appear baffling to identical or compatible ABO type. Determining the correct
clinicians who have not had detailed training in the labo- ABO type of the patient is not a major problem in patients
ratory aspects of transfusion medicine. Compounding the with AIHA.
problem is the fact that, when clinicians do seek consul- The most important technical problem faced by the
tation with the transfusion service, they are sometimes transfusion service regarding patients with AIHA relates to
merely informed that a “least incompatible” unit is avail- other RBC alloantibodies, which are capable of causing
able. This term, devoid of a scientific definition and hemolytic transfusion reactions. These alloantibodies are
cloaked in mystery, merely adds to the confusion. developed as a result of previous transfusions or pregnan-
This commentary outlines for the clinician the labo- cies and may be directed against antigens of a number of
ratory procedures used by transfusion services for select- blood group systems, such as Rh, Kell, Kidd, and Duffy.
ing RBCs for transfusion of patients with AIHA and offers Published data indicate that alloantibodies were detected
suggestions for both clinicians and transfusion service in 209 of 647 sera (32%) of patients with AIHA,4 clearly
professionals about appropriate communication between indicating the need for a method to detect these antibod-
clinical and laboratory services. The fundamental mes- ies to prevent alloantibody-induced hemolytic transfusion
sage offered is that clinicians have a responsibility to reactions. Indeed, undetected alloantibodies may be the
understand the principles of compatibility test procedures cause of increased hemolysis following transfusion, which
in patients with AIHA, and transfusion services have an may be falsely attributed to an increase in the severity of
obligation to provide to the clinician information con- AIHA.5
cerning the extent and effectiveness of the compatibility These alloantibodies are ordinarily detected and
test procedures employed. identified by testing the patient’s serum against a panel of
RBCs of known phenotypes. For example, anti-Jka (an anti-
body in the Kidd blood group system that can causes seri-
COMPATIBILITY TESTING IN AIHA:
ous hemolytic transfusion reactions) is identified by the
A GUIDE FOR THE CLINICIAN
fact that the patient’s serum will react with Jk(a+) RBCs
Physicians who are responsible for the care of patients and will not react with Jk(a–) RBCs. However, in warm
with AIHA should be familiar with the following aspects of antibody AIHA, the autoantibody in the patient’s serum
compatibility testing in patients with AIHA so that they will generally react with all RBCs tested, thus masking the
may communicate effectively with the transfusion service presence of the anti-Jka.
personnel.1-6
APPROACHES TO SELECTING DONOR
UNITS OF RBCs FOR TRANSFUSION OF
GENERAL PRINCIPLES
PATIENTS WITH WARM ANTIBODIES
In the day-to-day operation of a hospital’s transfusion ser-
A number of approaches are available for selecting donor
vice, compatibility testing is performed to select units of
RBC units for transfusion of patients who have warm
RBCs that can be transfused without risk of a hemolytic
autoantibodies.1-6 These include routine testing of the
patient’s serum against a RBC panel; diluting the patient’s
serum before doing compatibility testing; performing
adsorption tests, which will remove the autoantibody but
ABBREVIATION: AIHA = autoimmune hemolytic anemia.
not alloantibodies from the patient’s serum; and supply-
TRANSFUSION 2003;43:1503-1507. ing phenotypically matched RBC units.

Volume 43, December 2003 TRANSFUSION 1503

EDITORIAL
Testing the patient’s serum against a RBC panel
If a weakly reactive autoantibody and a strongly reactive
alloantibody are present, the differences in the strength of
the reaction of various cells of the panel will make this
evident. Nevertheless, there is no assurance that a
patient’s alloantibody will react more strongly than the
autoantibody, so additional tests are necessary.
Dilution technique
A serum dilution, such as 1 in 5, may be selected arbitrarily
for compatibility testing in the hope that this will dilute
out the autoantibody but not the alloantibody.7 Although
the procedure will detect some alloantibodies, Leger and
Garratty6 reported that only 19 percent of potentially clin-
ically significant alloantibodies were identifiable without
further testing. It appears preferable to select a dilution of
the patient’s serum that reacts 1+ against donor RBCs and
then test that dilution against a panel of RBCs.8 The dilu-
tion techniques are easy and rapid. Nevertheless, they are
unreliable so other, more effective procedures should be
performed except in very urgent situations.
Adsorption procedures
Warm autoadsorption technique. The optimal
adsorption technique for detecting alloantibodies in the
presence of a broadly reactive autoantibody is the warm
autoadsorption procedure. In this technique, some of the
autoantibody is eluted from the patient’s RBCs, and then
these cells are used to adsorb the autoantibody from the
patient’s serum at 37∞C. The serum can then be tested
for alloantibodies, because alloantibodies will not be
adsorbed onto the patient’s own RBCs.
A problem faced by transfusion services is that the
patient’s severe anemia may preclude obtaining a large
enough volume of RBCs for the autoadsorption proce-
dure. Physicians should provide as many RBCs as may be
reasonable because the autoadsorption procedure is the
most effective method for detecting alloantibodies in
patients with warm autoantibodies. The warm autoad-
sorption test is not useful in patients who have been trans-
fused recently (within about the past 3 months) because
even a small percentage of transfused cells may adsorb the
alloantibody during the in vitro adsorption procedure,
thus invalidating the results.9
Allogeneic adsorption. When autoadsorption tests
are not feasible, the optimal procedure is the allogeneic
adsorption technique, that is, adsorption of autoantibody
from the patient’s serum with several samples of alloge-
neic RBCs of varying phenotypes.
For example, performing an adsorption with a Jk(a–)
cell of a serum sample containing a warm autoantibody
and an anti-Jka alloantibody will remove the autoanti-
body but not the anti-Jka. By selecting two or three sam-
1504 TRANSFUSION Volume 43, December 2003
ples of RBCs of various phenotypes for the alloadsorption
procedure, alloantibodies that are responsible for almost
all clinically important hemolytic transfusion reactions
can be detected. Nevertheless, the technique is labor-
intensive and is unpopular in transfusion service
laboratories.
Transfusion of phenotypically matched RBC. When
extended phenotyping of the patient’s RBCs is performed,
it is possible to determine which alloantibodies a patient
could develop as a result of previous transfusions or preg-
nancies. For example, if a patient is Jk(a+), it is impossible
to develop an anti-Jka alloantibody. Transfusion of RBCs
that are selected on the basis of the patient’s extended
phenotype can provide a significant measure of safety,10
but some caveats and precautions must be stressed.3
To provide adequate safety, typing must be performed
for numerous RBC antigens (e.g., D, C, E, c, e, K, Jka, Jkb,
Fya, Fyb, S, and s). However, determining the extended
phenotype is technically difficult when the patient has a
positive DAT and may be impossible in a significant per-
centage of patients with warm antibody AIHA even when
attempted by the most skilled technologists. Those trans-
fusion services that may prefer to select blood for transfu-
sion on the basis of extended phenotyping rather than
adsorption tests must keep in mind that adsorption tests
will be necessary for those patients for whom an extended
phenotype cannot be determined. Partial phenotyping,
for example, for Rh, K, and Jka antigens, would only pro-
vide protection against a limited number of alloantibodies
that can cause hemolytic transfusion reactions,11-13 and
therefore would not preclude the necessity of pretransfu-
sion adsorption studies.
Whether implementation of this approach is cost-
effective and feasible at many hospitals and blood centers
has not been determined. If the intention is to emphasize
providing phenotype-matched units, it must be deter-
mined that the blood supplier could readily provide such
units, and it must be recognized that adsorption studies
will be required in cases were the patient’s RBCs cannot
be phenotyped.
COMPATIBILITY TESTING IN COLD
ANTIBODY AIHAs
Compatibility testing in cold antibody AIHAs is less labor-
intensive than in warm antibody AIHA. In cold agglutinin
syndrome, the autoantibody does not often react up to a
temperature of 37∞C, whereas clinically significant RBC
alloantibodies will react at this temperature. Accordingly,
the compatibility test can be performed strictly at 37∞C. If
the transfusion service is not able to perform testing
strictly at 37∞C, one or two cold autoadsorptions should
be performed, which will not remove a high-titer cold
agglutinin completely, but are likely to eliminate reactions
that occur at 37∞C. Even though the specificity of cold

agglutinins is frequently anti-I, providing RBCs negative
for the I antigen is not practical because of their rarity, and
their use may not be beneficial.
Similarly, in paroxysmal cold hemoglobinuria, the
autoantibody will not react at 37∞C. In this disorder, the
autoantibody is unusual among AIHAs in that it very often
has specificity for a RBC antigen, almost always the P anti-
gen. Although the routine crossmatch test may appear to
be compatible with P+ RBCs because the antibody reacts
only in the cold (usually < 15∞C), there are some sugges-
tions that p or Pk red cells (lacking the P antigen) will
survive better.14,15 Nevertheless, these RBCs are only avail-
able from rare donor files, and patients are likely to require
transfusion before the RBCs can be obtained. Generally,
transfusion of RBCs of common P types should be pro-
vided because patients with PCH often have severe
hemolysis, and waiting for p or Pk RBCs is likely to delay a
needed transfusion. Successful transfusion of patients
with PCH has been reported by numerous authors and,
almost certainly, the transfusions were of P+ blood.16
SELECTING LEAST INCOMPATIBLE UNITS
AS THE ONLY COMPATIBILITY TEST
PROCEDURE FOR A PATIENT WITH AIHA
The term least incompatible unit seems to be used very
frequently, although it is not defined in the medical liter-
ature and is used differently by different transfusion med-
icine professionals. It is probably true that the term lingers
on from decades ago before techniques for detecting
alloantibodies in the presence of autoantibodies had been
introduced. Adsorption procedures, as reviewed above,
were not described until the 1960s17-19 and were not widely
implemented until later.8,20,21 Before this time, when a
patient with AIHA had a serum autoantibody that reacted
with all cells in the crossmatch test, the transfusion service
would merely select a number of ABO-compatible units,
test the reactivity of the patient’s autoantibody against
them, and select the unit that reacted least strongly.22
Such a procedure for selecting least incompatible
units must not be considered an acceptable alternative to
the techniques described above for selecting donor units
for transfusion of patients with AIHA. This process as the
sole means of selecting RBCs for transfusion of such
patients will not reliably detect alloantibodies and is unac-
ceptable in modern day transfusion medicine. This is a
dangerous practice and should be abandoned, except in
extremely urgent settings in which there is not time to
perform adequate serologic tests.
SELECTING LEAST INCOMPATIBLE UNITS
AFTER TESTING FOR ALLOANTIBODIES
Some transfusion services appear to use least incompati-
ble unit in another context. They perform adequate sero-
EDITORIAL
logic studies as reviewed above and select donor units for
transfusion on that basis and then go on to crossmatch
the selected units with the patient’s serum. Although all
such crossmatches will be incompatible because of the
patient’s autoantibody, the transfusion service may
choose the least incompatible unit even if no specificity of
the reactions can be ascertained.
Others may crossmatch with adsorbed serum and, if
residual reactions still occur following adsorption, least
incompatible units are chosen, although a preferable
approach is to perform additional adsorptions until
removal of the autoantibody is complete.1
In either of these settings, there is no disadvantage to
selecting the unit that reacts least strongly. This may seem
to provide some additional assurance that an alloantibody
has not been missed, although this is unlikely after an
appropriate search for alloantibodies, as described above,
has been carried out. One may also argue that the patient’s
autoantibody may react more strongly with some uniden-
tified RBC antigen(s) than others. However, some variabil-
ity in reactivity caused by an autoantibody can be
expected to occur when a number of units are cross-
matched simply because of the limitations of precision of
serologic reactions. If no specificity of the autoantibody
can be determined, modest differences in the variability
in reactivity are not likely to be of significance. Indeed,
even if some specificity of the autoantibody can be deter-
mined, data indicate that this is not always an important
factor in RBC survival after transfusion in AIHA.1 There-
fore, although it is conceivable that some benefit may
ensue by selecting a least incompatible unit, one should
not deceive oneself about the likely significance of that
process.
Because the term least incompatible unit is not for-
mally defined and does not represent the critical aspect
of compatibility testing in AIHA, use of the term in dis-
cussion with clinicians can lead only to confusion and a
lack of confidence in the safety of units selected by the
transfusion service for transfusion to a patient with
AIHA.
COMMUNICATION BETWEEN CLINICIANS
AND THE TRANSFUSION SERVICE
Responsibilities of the clinician
A discussion between the attending physician and the
transfusion service should take place as soon as it is evi-
dent that a patient with AIHA is being considered for
transfusion. The clinician should indicate the urgency of
the transfusion and discuss with the transfusion service
personnel the time required for the more detailed than
usual serologic studies that will be necessary. The clinician
should also discuss the compatibility tests to be under-
taken by the laboratory with the above outline of com-
patibility test procedures as a guide to adequate
Volume 43, December 2003 TRANSFUSION 1505
EDITORIAL
pretransfusion testing. The clinician should seek assur-
ance that appropriate testing is to be performed.
Adequate testing for alloantibodies may take 4 to 6
hours or even longer if testing must be performed at a
referral laboratory. The clinician must balance the risk of
withholding transfusion for that length of time with the
benefit of added safety that complete testing provides
against alloantibody-induced hemolytic transfusion reac-
tions. One should also keep in mind that the probability
that alloantibodies will be present in a person who has not
previously been transfused or pregnant is very low. In fact,
only a few percent of all hospitalized patients have RBC
alloantibodies so that if transfusion is extremely urgent,
the lesser risk may be to transfuse rather than waiting
for completion of the compatibility testing. Even in very
urgent situations, however, there is almost always time to
perform at least some of the recommended compatibility
test procedures such as use of the dilution technique and/
or partial RBC phenotyping, which will provide some
measure of safety.
Responsibilities of the transfusion service
In some instances, it will be the responsibility of the
transfusion service to initiate the communication
because the diagnosis of AIHA may first be made during
compatibility testing for a requested transfusion. In any
case, the transfusion service should feel obligated to
supply the clinician with information about the compat-
ibility test procedures performed. If the transfusion ser-
vice selects RBC units for transfusion after excluding the
presence of alloantibodies by adsorption procedures (or
on the basis of matching the extended RBC phenotype of
the patient), the clinician should be so informed. If the
transfusion service goes on to select a least incompatible
unit from among the selected units, this may possibly
provide some additional measure of safety, but is not the
most important aspect of the compatibility testing.
Merely informing a clinician that a least incompatible
unit was selected fails to provide adequate information
and may result in the clinician avoiding transfusion in a
situation where transfusion is needed. A major objection
to the use of the term least incompatible by transfusion
service personnel when communicating with clinicians
is that the term is not informative. It is understandable
that clinicians may be hesitant to transfuse when they
are only informed that all units are incompatible and
that a least incompatible unit is recommended for
transfusion.
If the transfusion service personnel inform the clini-
cian that appropriate compatibility testing has been per-
formed, the clinician should also be assured that
transfused RBCs are unlikely to cause an acute hemolytic
transfusion reaction even though the RBCs cannot be
expected to survive normally because of the patient’s
1506 TRANSFUSION Volume 43, December 2003
autoantibody. The attending physician can then proceed
to make a decision regarding transfusion on the basis of
the clinical need. The indications for transfusion should
be little different than for other medical patients with ane-
mia and, certainly, no patient should be denied transfu-
sion because all units are incompatible.1,5
In contrast, if the transfusion service merely indicates
to the clinician that least incompatible ABO-matched
units will be supplied, this should be considered
unacceptable.
RECOMMENDATIONS CONCERNING
THE USE OF THE TERM LEAST
INCOMPATIBLE UNIT
Least incompatible unit is a term that should be discarded
for the following reasons: It is not an official term in
immunohematology, it is not defined in transfusion med-
icine nomenclature, it is used differently by various trans-
fusion services, it is not the critical aspect of compatibility
testing in AIHA, and its use does not useful convey
information regarding the extent of compatibility testing
performed. Employing the term may suggest that use of
ABO-matched least incompatible units is an acceptable
alternative to performing an adequate serologic evalua-
tion before transfusion of patients with AIHA, when in fact
it is not an acceptable alternative.
Although least incompatible unit is a term that is
entrenched in “in-house” jargon, it should not be used in
discussions with attending physicians and, if used at all,
should not be permitted outside the confines of the
transfusion service. It is time for transfusion service per-
sonnel and clinicians to discuss issues surrounding trans-
fusion of patients with AIHA in informative, scientific
ways.
Lawrence D. Petz, MD
University of California Los Angeles Medical Center
Los Angeles, CA; and
StemCyte
Arcadia, CA
e-mail: lpetz@stemcyteinc.com
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