Case Study
Anti-c (Little c) IgM: An Uncommonly
Observed but Expected Phenomenon
Alan A. George, DO,1 Clayton D. Simon, MD1*
Lab Med Fall 2014;45:e142-e145
DOI: 10.1309/LME8U8K5GVGWBAOY
ABSTRACT
The c-antigen (little c) is part of the Rh blood group system and is
found in approximately 80% of the United States population. Anti-c
antibody develops in individuals sensitized through previous exposure
and is associated with acute and delayed hemolytic transfusion
reactions as well as hemolytic disease of the newborn (HDN). Most
antibodies produced against Rh antigens are of the immunoglobulin (Ig)
Clinical History and Laboratory
Workup
A 30-year-old, otherwise-healthy white woman who was
gravida 2 para 1 (G2P1) was admitted for delivery in active
labor at approximately 39 weeks and 6 days into her
pregnancy. Her medical history was unremarkable, and
there was no history of prior blood transfusions. Her first
pregnancy 2 years previously had progressed normally.
She had experienced spontaneous vaginal delivery (SVD);
however, manual placental extraction was required.
During her current admission for delivery of her second
pregnancy, we noted a positive antibody screen result,
prompting further evaluation. Results of an initial antibody
Abbreviations
G2P1, gravida 2 para 1; SVD, spontaneous vaginal delivery; DAT, direct
antiglobulin test; Ig, immunoglobulin; HDN, hemolytic disease of the
newborn
Department of Pathology, Brooke Army Medical Center, Houston, Texas
1
*To whom correspondence should be addressed.
[email protected]
e142 Lab Medicine Fall 2014 | Volume 45, Number 4
G type. We present a case of anti-c in a 30-year-old white woman who
was gravida 2 para 1 (G2P1), whose laboratory workup at the time of
admission for delivery suggests recent exposure and seroconversion
in the latter part of her pregnancy, with evidence of the expected but
rarely demonstrated presence of anti-c IgM and IgG.
Keywords: anti-c, little c, IgM, pregnancy, hemolytic, seroconversion
screen, approximately 6 months before admission,
had been negative. Her pregnancy course was notable
for anemia, with a hemoglobin level of 11.2 g/dL and
hematocrit of 33.4%; otherwise, the pregnancy course
was uneventful. On admission, vital signs and the results
of a complete blood count and a chemistry panel were
unremarkable. The patient was taking prenatal vitamins
and iron supplements.
Our laboratory workup revealed an A+ blood type and a
positive result via antibody screening (not shown), with
2 of 3 cells showing 3+ and 4+ reactivity, respectively.
Results of an antibody panel showed an anti-c antibody
reacting in all 3 phases of tube testing (enhanced with
low ionic strength saline), with a negative autocontrol; the
patient’s phenotype was negative for the c-antigen (Figure
1). Additional test cells excluded antibodies to N, Jka, and
Fya (not shown). The patient delivered a healthy neonate
via SVD; delivery was complicated by cord avulsion, and
the mother again required manual placental extraction. No
blood products were transfused.
Our workup continued with a direct antiglobulin test (DAT)
on the blood of the neonate; the results were negative.
The phenotype of the infant was positive for the c-antigen,
showing 4+ reactivity. An antibody titration further showed
an immunoglobulin IgM titer of 64 and an IgG titer of 8
(Figure 2). The mother and neonate had an otherwise
uneventful hospital course and were discharged after
routine observation.
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Case Study
Figure 1
Antibody panel results for the patient, a 30-year-old white woman who was gravida 2 para 1 (G2P1).
Discussion
The Rh blood group system is one of the most complex
human blood groups identified. It is highly polymorphic
and immunogenic; second to the ABO group, it is the
most clinically significant in transfusion medicine.1-3 It is
comprised of at least 45 independent antigens, the most
important of which are D, C, c, E, and e.1,2 These antigens
are encoded by the RHD and RHCE genes, located
together on chromosome 1.1 The Rh system is one of the
most immunogenic blood groups in humans and is wellknown for its role in hemolytic disease of the newborn
(HDN), in which mothers with Rh negativity are sensitized
to the D antigen during their first Rh-positive pregnancy
or exposure to Rh-positive blood and subsequently
mount a severe immune response to the D antigen
during subsequent Rh-positive pregnancies, producing
a hemolytic reaction that is life threatening to the fetus.1,2
The alloantibodies produced are primarily IgG and react
optimally at warm temperatures, with obvious clinical
significance.
Approximately 85% of the United States population test
positive for the D antigen, whereas the remaining 15%
test negative.3 However, the introduction of anti-D IgG
(anti-RhD; Rho[D] immune globulin) in 19684 significantly
and effectively altered the development of HDN, reducing
the risk to 0.1%-0.2%.5,6 Despite this success, hemolytic
reactions associated with other antigens in the Rh system,
such as c-antigen, remain problematic.7
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The c-antigen (little c) which is found in approximately 80%
of the United States population, is considered the most
clinically significant Rh antigen after D and is associated
with severe HDN.3 Anti-c antibodies arise through
previous exposure, such as fetomaternal hemorrhage or
transfusion, and can produce acute and delayed hemolytic
reactions. As with the D antigen, pregnant women and
girls are usually sensitized to the c-antigen during an initial
pregnancy, and complications occur with repeat exposure
during subsequent pregnancies. Pregnancies complicated
by anti-c are not extremely common; however, one may
gather an idea of their incidence from the retrospective
review by Hackney and colleagues8 (102 cases over a 34year period at one United States institution and dozens
of other cases at various institutions worldwide). Two
relatively recent cases9,10 can also be found in the literature.
Most neonates were not severely affected; however,
reports of fetal hydrops and death exists in the literature.8
Similar to the other Rh antibodies, anti-c is also primarily
of the IgG type. IgM anti-c, however, has been reported,
as well as other Rh IgM antibodies.11,12 As IgM antibodies
are the first immunoglobulins to be produced during
any humoral immune response followed by IgG13, it is
not unexpected that the process of sensitization and
seroconversion after c-antigen exposure (and exposure
to other Rh antigens) involves the same course of anti-c
IgM production before anti-c IgG is formed. The fact that
a MEDLINE search we performed using the keywords
“anti-c IgM,” “anti little c IgM,” “anti small c IgM,” and “Rh
IgM antibodies” proved difficult to locate relevant hits that
Fall 2014 | Volume 45, Number 4 Lab Medicine e143
Case Study
Phase
Cell
Dilution
Titer
1
2
4
8
16
32
64
128
256
512
Albacyte
Lot: v147943
Exp: 8/11/2014
3+
3+
2+
1+
1+
W+
=
=
=
=
=
=
=
1:32
RT
Albacyte CC
30 minutes Lot: v147946
Exp: 8/11/2014
3+
3+
3+
2+
2+
1+
W+
=
=
=
=
=
=
1:64
37
4+
3+
3+
2+
1+
W+
=
=
=
=
=
=
=
1:32
2+
2+
1+
W+
IS
Cell #2
IgG (AHG)
1,024 2,048 4,096
=/
=/
=/
=/
=/
=/
=/
=/
=/
CC 2+ CC 2+ CC 2+ CC 2+ CC 2+ CC 2+ CC 2+ CC 2+ CC 2+
1:8
Figure 2
Antibody titration results for the patient, a 30-year-old white woman who was gravida 2 para 1 (G2P1).
specifically referred to instances of anti-c IgM-associated
HDN is also unsurprising. It is possible that the IgM
component of the antibody does not remain very long in
that phase and is difficult to capture, or it is also possible
(and more likely) that the existence of the IgM component
is known and therefore unlikely to garner much interest in
demonstrating it even when observed.
Nevertheless, our laboratory workup provides evidence
supportive of a mother with Rh positivity who had recent
in-utero exposure to the c-antigen late in pregnancy,
followed by seroconversion with the development of IgM
anti-c, observed in the immediate spin phase of tube
testing (Figure 1), and on the antibody titer (Figure 2). The
negative DAT results of the neonate indicate that IgG levels
were not high enough, such that crossing the placenta
still in the early phase. Although an anti-E (big E) antibody
could not be excluded on the panel (Figure 1) due to
a lack of donor test cells, the pattern of reactivity and
maternal/fetal phenotypes were most consistent with an
anti-c antibody. The reason for the underlying fetomaternal
hemorrhage remains unidentified; however, leakage of
fetal red blood cells into the maternal circulation can
occur late in pregnancy.1 Although we used tube testing
in this instance, it would not be unusual to also encounter
difficulty detecting an IgM anti-c antibody using gel
technology; however, the sensitivity of antibody detection
with gel testing is reportedly higher.14
Management of pregnant women and girls who harbor
an anti-c entity is not currently defined; however, the
e144 Lab Medicine Fall 2014 | Volume 45, Number 4
conditions of such patients are often managed in a manner
similar to that for individuals who harbor anti-D antibodies.8
Most Rh-negative blood contains the c-antigen (due to the
genetic mechanisms of the Rh system; the explanation for
these is beyond the scope of this article). Hence, sensitized
mothers requiring transfusions should be given Rh-positive
blood due to the scarcity of Rh-negative units that are
c-antigen negative.15
In summary, this case demonstrates the formation of
anti-c IgM and IgG in a pregnant 30-year-old white
woman, which we discovered as labor commenced.
Fetomaternal hemorrhage was the likely cause of
sensitization; complications associated with the antibody
did not occur. This case may be of educational interest to
blood bank physicians and health care professionals alike
and highlights the importance of antibody screening in
pregnant women and girls who are approaching delivery.
Acknowledgements
The authors of this article are employees of the United
States Federal Government and/or the U.S. Army. The
opinion(s) or assertion(s) contained herein are the private
views of the author(s) and do not reflect the official policy
or position of Brooke Army Medical Center, the U.S. Army
Medical Department, the U.S. Army Office of the Surgeon
General, the Department of the Army, Department of
Defense, or the U.S. government.
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Case Study
Financial Disclosures and
Conflicts of Interest
None reported. LM
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