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How to Prevent Alloimmunization

Rough Draft. Written to parents, not medical professionals, in a simple, easy-to-understand manner.Review of preventative options and considerations for patients undecided on receiving RhD prophylaxis

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Alloimmunization is when a person makes antibodies as a result of foreign blood mixing. When this happens in women due to exposure to fetal blood, it is called maternal alloimmunization. These antibodies cross the placenta and attack the unborn child; a disease called hemolytic disease of the fetus and newborn or HDFN for short. HDFN can have devastating consequences ranging from anemia, hyperbilirubinemia, and even death. One of the common questions people ask is, how can I prevent antibodies from forming? How can we alloimmunization? There are 3 key ways that an average person can prevent alloimmunization: receive RhoD immune globulin in a timely manner, avoid donating blood if you are Kell +, and ask for phenotypically matched blood if you are already alloimmunized. 



Preventing Anti-D Alloimmunization with Rh D Immune Globulin aka Rhogam


RhoD immune globulin goes by many names - Rhogam, WinRho, BayRho, and RhD prophylaxis just to name a few. Rhogam is an injection of anti-D antibodies. It is not a vaccine or a treatment for alloimmunization; it is a preventative only. When a woman is pregnant, it is normal for some of the baby’s blood to enter her system. If the woman is Rh- and her baby Rh+, this is a blood mismatch. Up to 70% of Rh- women who are exposed to Rh+ blood will have an immune response (created anti-D if not given Rhogam). (https://www.dovepress.com/prevention-and-management-of-transfusion-induced-alloimmunization-curr-peer-reviewed-fulltext-article-IJCTM).  A mother’s body will recognize a foreign antigen, create antibodies to defend against the foreign antigen, and send them to attack the foreign cells. This is exactly what happens when a person has a cold or virus, and is how our immune system is supposed to work. Unfortunately the immune system doesn’t recognize the difference between a virus that that a person wants to get rid of, and a baby that a mother wants to keep. 


There are two ways that Rhogam may work. Rhogam will neutralize any fetal cells in mom’s blood circulation. Rhogam also tricks the immune system into thinking that it has already made anti-D antibodies, so the body will never learn how to make the anti-D antibodies. The mother’s body will see the baby's blood cells, but it will also see the anti-D antibodies from the Rhogam and think that it has enough antibodies already. If the immune system thinks that there are enough antibodies already, it will not make any. Since the mother’s immune system has never learned how to make anti-D antibodies, alloimmunization has not happened, and the baby is safe. Rhogam does not cross the placenta and will never get into the baby.  Rhogam does not cause HDFN. 


Rhogam has been safely given to millions of pregnant women and prevents them from developing anti-D alloimmunization only. Rhogam is never given to the infant, only to the mother. Rhogam should be given to Rh- women with any antibodies other than anti-D. Women with anti-D should not receive Rhogam. Rhogam will cause a positive antibody screen for up to 6 months after administration. This is not dangerous, but it can make monitoring for the development of anti-D difficult. Rhogam will not titer over 1:16, and any higher titers are the result of true anti-D alloimmunization. Rhogam should not be used if you are Rh+ or if you have had a severe allergic reaction to human immune globulin. 


Since the RhD antigen is present on baby’s blood cells as early as 8 weeks gestation, an early miscarriage or abortion can sensitize a woman. Women should receive a low dose of Rhogam at early sensitizing events (bleeding, miscarriage, threatened abortion, ectopic pregnancy). Women should receive a higher dose of Rhogam at 13 weeks and later in pregnancy whenever there are any potentially sensitizing events (invasive procedures, amniocentesis, external cephalic version, fetal maternal hemorrhage, trauma, loss, delivery, etc). A single dose of RhoGAM has enough anti-D to suppress the immune response to 15 mL (or less) of Rh-positive red blood cells. https://www.rxlist.com/rhogam-drug.htm In the United States, Rhogam is commonly given at 28 weeks and within 72 hours of birth. This will prevent anti-D alloimmunization in the majority of women. Rhogam must be given on time, every time.


Rhogam is made from ultra-purified human blood plasma. They take plasma (not blood cells) from people who already have anti-D. After carefully screening the donors, the manufacturers chill this plasma, separate out the antibodies, and filter it multiple times. “The final product contains 5 ± 1% IgG, 2.9 mg/mL sodium chloride, 0.01% Polysorbate 80 (non-animal derived) and 15 mg/mL glycine. Small amounts of IgA, typically less than 15 μg per dose, are present. 3 The pH range is 6.20 - 7.00 and IgG purity is > 98%. The product contains no added human serum albumin (HSA), no thimerosal or other preservatives and utilizes a latex-free delivery system.” (Source: Rhogam package insert)


Because Rhogam does not contain any blood cells, Jehova’s Witnesses and other blood-abstaining religions are not absolutely prohibited from receiving Rhogam. Witnesses are taught that the use of fractions of blood that do not contain blood cells or platelets, such as immunoglobulins and albumin, are "not absolutely prohibited", and are instead a matter of personal choice. The Watchtower has consistently said that it is a matter of choice for each Christian couple, but pointed out that since antibodies cross the placenta normally, it does not seem like a violation of the Old Testament prohibition on the misuse of blood to take a shot of just antibodies. The Watchtower further goes on to say, “The decision whether to take RhIG remains finally, though, a matter for each Christian couple to decide conscientiously. However, if a husband and wife facing the Rh issue decide not to take the RhIG when medically indicated, they need to be willing to accept the risk of having a future child seriously affected by an illness that could possibly have been prevented. In this situation they might even decide that the course of wisdom is to take extra precautions so they do not have more children and expose themselves to the possibility of such a tragedy. Concerned Christian parents should prayerfully consider all aspects before making such weighty decisions.” https://wol.jw.org/en/wol/d/r1/lp-e/101994890#h=43



Infographic of Key Points

  • Rhogam DOES NOT cause HDFN.

  • Rhogam DOES NOT treat HDFN.

  • Rhogam DOES NOT cross the placenta.


  • Rhogam DOES prevent anti-D alloimmunization in 99.8% of women (or should we say 99.8% of the time).

  • Rhogam DOES need to be given at early gestations (before 12 weeks).

  • Rhogam DOES need to be given On Time, Every Time. (within 72 hours of any potential exposure to fetal cells). 

  • Rhogam DOES allow a woman to safely have more pregnancies.



Contradiction: Rhogam’s manufacturer’s website says that Rhogam does not cross the placenta, but another site says that infants whose mother had Rhogam have a weakly positive direct coombs at birth. Some babies born of women given Rho(D) Immune Globulin (Human) antepartum have weakly positive direct antiglobulin (Coombs) tests at birth. https://www.rxlist.com/rhogam-drug.htm#precautions



Preventing anti-Kell Alloimmunization


Rhogam prevents anti-D alloimmunization, but what about other antibodies? There are over 250 different red blood cell antibodies that can be made. One of the most dangerous antibodies that a woman can make is anti-Kell. Anti-Kell antibodies attack the K antigen. K antigens are highly immunogenic - this means that they are very good at irritating the immune system and triggering antibody production. In fact, Kell antigens are the third most potent antigens at causing a women to produce antibodies (https://www.ncbi.nlm.nih.gov/books/NBK2270/). Luckily only 2% of Blacks and 9% of Caucasians have the K antigen on their blood, this means that most women will have a K- partner and are unlikely to develop anti-Kell from pregnancy. The majority of anti-Kell alloimmunization comes from blood transfusions. This makes anti-Kell alloimmunization easy to prevent. If a patient knows that a blood transfusion is needed, she can request that any blood given be Kell negative. Hospitals, laboratories, and transfusion services can choose to match patients on their Kell phenotype (antigen status). On the other end of the blood transfusion cycle, blood donors can have their K antigen status checked with a test called a K/k antigen phenotype. Kell positive people can choose to abstain from donating blood to reduce the incidence of transfusion-related anti-Kell alloimmunization. (Too technical and wordy?)  If there is less K+ blood in circulation, then there will be less people developing anti-Kell alloimmunization.


Infographic

Most cases of anti-Kell come from blood transfusions.

Kell - women should ask that any transfused blood be Kell- as well.
Kell + people should not donate blood.




Preventing Alloimmunization to Other Antigens


While there are some ways to reduce alloimmunization to the D and K antigens, there is no universally accepted way to prevent alloimmunization to other antigens. There are no shots to prevent alloimmunization to other antigens, and options are limited for those patients who are already alloimmunized. Once a patient has developed one alloantibody, they are more likely to develop another https://www.dovepress.com/prevention-and-management-of-transfusion-induced-alloimmunization-curr-peer-reviewed-fulltext-article-IJCTM . One way to prevent the development of additional antibodies is have an RBC antigen phenotype run and to know your antigen status. All patients with antibodies should have a medical alert card with their current antibodies listed, and if known, their red blood cell antigen type (see figure below). If a blood transfusion is required, patients with one antibody should be given blood that is matched phenotypically for at least the C, E, and K antigens. In some cases, transfusion centers may match blood for the C, E, K, Duffy, and Kidd antigens because these are five of the most immunogenic antigens. In patients who have received multiple transfusions, antigen matched transfusions result in a much lower alloimmunization rate of 1-5% compared with an alloimmunization rate of 30% when blood is not phenotypically matched (https://www.sciencedirect.com/topics/medicine-and-dentistry/alloimmunization). 



[Medical Alert Card Sample showing Transfusion Alert: Anti-E antibodies. Phenotype: ee CC]



Additional Facts/references
Currently, in many centers, all children with SCD undergo extensive RBC antigen phenotyping at the time of diagnosis, a policy supported by most experts (Rosse et al. 1990). When and if RBC transfusion is required, these SCD patients routinely receive RBC units phenotypically matched for (at least) C, E, and K antigens.

Once an SCD patient has made an RBC alloantibody, he or she may benefit from RBC units matched for C, E, K, Fya, and Jkb antigens, the five most common and most clinically significant antibodies made by SCD patients. https://www.sciencedirect.com/topics/medicine-and-dentistry/alloimmunization

Which are the most immunogenic antibodies? ABO, D, Kell, Rh, Duffy, Kidd, MNS


Maternal alloimmunization is preventable in many cases. The amount of women forming anti-D antibodies is greatly reduced by receiving Rhogam on time every time. Anti-Kell alloimmunization can be reduced if Kell+ people would abstain from donating blood. Alloimmunization rates to other antigens can be reduced by using phenotypically matched blood for women with antibodies who need additional transfusions. Alloimmunization is something that can be partially prevented. The number of children suffering from Hemolytic Disease of the Fetus and Newborn can be reduced. Do something today [link to Ways You Can Help].

I’m not hugely thrilled with this last paragraph. I wanted it to be both a wrap up, and inspire people to action. Perhaps it is not needed if we ditch the essay format for the current Headlines and Info format. 




https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4794441/

Objectives The objective is to present a pregnancy complication associated with intravenous drug use, namely, that of red blood cell alloimmunization and hemolytic disease of the fetus and newborn.

Methods An observational case series is presented including women with red blood cell alloimmunization most likely secondary to intravenous drug abuse

Results Five pregnancies were identified that were complicated by red blood cell alloimmunization and significant hemolytic disease of the fetus and newborn, necessitating intrauterine transfusion, an indicated preterm birth, or neonatal therapy.

Conclusions As opioid abuse continues to increase in the United States, clinicians should be aware of the potential for alloimmunization to red blood cell antibodies as yet another negative outcome from intravenous drug abuse.