The Not So Legendary Chimera

In the Iliad, Homer described the chimera as “a thing of immortal make, not human, lion-fronted and snake behind, a goat in the middle, and snorting out the breath of the terrible flame of bright fire (1).” This mythical creature has a lion’s head, a goat’s middle and the tail of a serpent, and the siting of a chimera was considered to be an omen for disaster! Thankfully, not so much in blood bank. Though ABO discrepancies can be a challenge, even most chimeras can easily be resolved with a few additional steps and a patient history.

Figure 1. The mythical chimera.

To review, an ABO discrepancy occurs when unexpected reactions occur in the forward or reverse grouping, or the forward typing does not match the reverse typing. Some weak subgroups of A (notably A3) are known for giving mixed field reactions. Weak activity with anti-A, anti-B or anti-D can also in result mixed field reactions in leukemia patients. In these examples, the mixed field reactions are due to the weakened expression of the corresponding antigens.

Chimerism is the presence of 2 cell populations in a single individual. There are scenarios where ABO discrepancies causing mixed field reactions indicate an apparent chimera. A group A positive patient who received several units of O negative blood will have mixed field reactions due to the presence of two blood types in their peripheral blood. This would be a temporary situation. A patient who received a bone marrow or stem cell transplant from a non-group identical donor will have 2 populations of red blood cells until the new type is established. We refer to these as artificial chimera cases, as the second blood type is not naturally occurring, but present due to the introduction of a different blood type via transfusion or transplantation.

Table 1. Group A pos patient who received several units of group O neg red cells

Like the mythical beast, a chimera in biology describes an organism that has cells from two or more zygotes. When chimerism exhibits only in the blood, the phenomenon can be termed an artificial chimerism, as described above, as dispermic chimerism or as twin chimerism. Dispermic chimerism occurs in other animal species but is a rarity in humans. It occurs when 2 eggs are fertilized by 2 sperm and these products are fused into one body. In this case, the chimerism is not limited to blood, but may also result in hermaphroditism, or two different skin colors or eye colors.

Twin chimerism occurs when, in utero, one twin transfuses blood cells, including stem cells,  to the other. Sine the fetal immune system is immature, the host does not see these transfused blood cells as foreign antigens.  The stem cells can proliferate and this results in the production of cells from both the donor and the host for the rest of the individual’s life. Two non-compatible blood groups can co-exist in one individual! This phenomenon is usually discovered by coincidence during a routine type and screen. This patient could be found to have mixed field or weak reactions on ABO typing, or could have missing reactions in the back type, all with no history of transfusion, transplantation and no disorder that could explain the findings. What is a tech to do? An important step in resolving all ABO discrepancies is to review patient history.

In 1953 a human chimera was reported in the British Medical Journal. A woman was found to have blood containing two different blood types. Apparently this resulted from her twin brother’s cells living in her body (2). More recently, in 2014, a case described in Blood Transfusion describes a 70 year old female who was found to have mixed field reactions with ABO and RhD typing during routine testing before surgery. She had no history of transfusion or transplantation, and a history of seven pregnancies. Repeat testing by other methods and with different reagents gave the same results. On further questioning, the patient affirmed that she had been born a twin, but her twin brother had died as an infant. Since chimerism was suspected, molecular typing and flow cytometry were performed. The presence of male DNA was found by PCR testing and flow cytometry confirmed two distinct populations of red blood cells (3).

Twin chimeras with mixed blood types of 50%/50% or 75%/25% are easily picked up in ABO typing as mixed field reactions. A twin chimera with 95% group O blood and 5% group A may show a front type of a group O and a back type that lacks anti-A . Because there is immune tolerance to A cells from the twin, the expected naturally occurring anti-A is not present. On the other hand, a twin chimera who is primarily group A with 5% O cells would not be recognized as a chimera in routine ABO typing.

Table 2. Group O chimera with 5% minor cell population A cells
Table 3. Group A chimera with 5% O cells

How common is blood group chimerism?  A 1996 study found that such blood group chimerism is not rare. Though we do not often encounter this in blood bank, their study of 600 twin pairs and 24 triplet pairs showed that this occurs more often than was originally thought, with a higher incidence in triplets than in twins. Because it does not cause any symptoms or medical issues, many such chimeras go undetected. In addition, the study found that many of these chimeras had very minor second populations, making them undetectable in serological testing. In blood bank, we generally test for ABO/RH  and do not test for other antigens in routine testing. The study used 849 marker antigens. They also used a very sensitive fluorescent technique which they developed for detecting these very subtle minor populations. This study showed that while chimeras are not rare, they are something that, with present testing methods, we will not encounter too often (4).

Dual cell populations induced by chimeras have been the subject of many studies. Historically, most chimeras were naturally occurring. With newer medical interventions and therapies, we may see more situations that lead to mixed cell populations. Transfusion, stem cell transplants, kidney transplantation, IVF and artificial insemination can all lead to temporary and sometimes permanent chimeras. These can present challenges in the blood bank laboratory in interpreting results and for patient management. A question of chimera presentation can usually be solved by putting on our detective hats and investigating patient history. Further testing can be done with flow cytometry and molecular methods, if needed. Modern medicine may have given us more blood bank challenges but modern technology has equipped us with newer methods to solve them. A chimera is no longer a sign of impending trouble!

References

  1. Homer, Iliad.  In Richmond Lattimore’s Translation.
  2. Bowley, C. C.; Ann M. Hutchison; Joan S. Thompson; Ruth Sanger (July 11, 1953). “A human blood-group chimera” (PDF). British Medical Journal: 8
  3. Sharpe, C.; Lane, D.; Cote J.; Hosseini-Maaf, B.; Goldman, M; Olsson, M.; Hull, A. (2014 Oct ). “Mixed Field reactions in ABO and Rh typing chimerism likely resulting from twin hematopoiesis”, Blood Transfusion:12(4): 608-610
  4. Van Dijk, B. A.; Boomsma, D. I.; De Man, A. J. (1996). “Blood group chimerism in human multiple births is not rare”. American Journal of Medical Genetics. 61(3): 264–8 

-Becky Socha, MS, MLS(ASCP)CM BB CM graduated from Merrimack College in N. Andover, Massachusetts with a BS in Medical Technology and completed her MS in Clinical Laboratory Sciences at the University of Massachusetts, Lowell. She has worked as a Medical Technologist for over 30 years. She’s worked in all areas of the clinical laboratory, but has a special interest in Hematology and Blood Banking. When she’s not busy being a mad scientist, she can be found outside riding her bicycle.

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