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Can Alloimmunization Be Prevented?

When it comes to alloimmunization, we commonly think of moms and the effects on their babies, but thousands of people develop alloimmunization each year due to blood transfusions. For these people, their antibodies may be detected when they need another blood transfusion or during pregnancy. In addition to asking, how did I develop these antibodies, people also ask, can alloimmunization be prevented? Alloimmunization is preventable in some cases, but not all cases. There is currently only one option for preventing alloimmunization during pregnancy. It is much easier to prevent alloimmunization due to blood transfusions by using phenotypically matched blood for patients who receive multiple transfusions, women of childbearing age, or for those who are already producing alloantibodies.

Prevent Anti-D Alloimmunization with Rh D Immune Globulin aka RhoGAM©️

The amount of women forming anti-D antibodies has been greatly reduced by receiving RhoD immune globulin on time every time. 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. As little as 1.0 mL of blood can sensitize a woman and stimulate antibody production. Up to 70% of Rh- women who are exposed to Rh+ blood will produce anti-D antibodies if RhoGAM©️ is not administered 1.

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 a person wants to get rid of, and a baby that a mother wants to keep.

There are two ways that RhoGAM©️ may work. 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 2. RhoGAM©️ may also trick the immune system into thinking that it has already made anti-D antibodies. The mother’s body will see the fetal 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 cause HDFN.

RhoGAM©️ has been safely given to millions of pregnant women and prevents them from developing anti-D alloimmunization only. It cannot prevent alloimmunization to any of the 250+ other antigens. RhoGAM©️ is never given to the infant, only to the mother. 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©️ or MicRhoGAM©️ 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). 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©️ may 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.

Who should receive RhoGAM©️?

Rh- women at any gestation who:

  • do not have anti-D.
  • have any other alloantibody besides anti-D.
  • have had bleeding, miscarriage, threatened abortion, or an ectopic pregnancy.
  • have had any potentially sensitizing events such as invasive procedures, amniocentesis, CVS, external cephalic version, fetal maternal hemorrhage, trauma, loss, delivery, etc.

Who should NOT receive RhoGAM©️>

Rh- women at any gestation who:

  • have anti-D antibodies.
  • have had an allergic reaction to RhoGAM©️ in the past.

 

What Exactly Is Rhogam? Can I Have RhoGAM©️ If My Religion Prohibits The Use of Blood Products?

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.” 3

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.” 4

Key Points

  • RhoGAM©️ DOES NOT cause HDFN.
  • RhoGAM©️ DOES NOT treat HDFN.
  • RhoGAM©️ CAN be used by those with religious objections to blood products.
  • RhoGAM©️ DOES prevent anti-D alloimmunization 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.

Prevent Kell Alloimmunization with Kell- blood

One of the most dangerous antibodies that a woman can make is anti-K. Anti-K antibodies can cause fetal anemia at any titer and suppress bone marrow production of new red blood cells. The K antigen is highly immunogenic and is the third most potent antigen at causing a woman to produce antibodies 5. Luckily only 2% of Blacks and 9% of Caucasians have the K antigen so most women will have a K- partner and are unlikely to develop anti-K from pregnancy 5. This means that the majority of anti-K alloimmunization comes from blood transfusions and is easily preventable.

Multiple articles suggest matching a patient’s Kell status prior to transfusion 6, 7, 8, 9. Matching both the RhD and Kell status can reduce alloimmunization rates by 63.5% 7. 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-K alloimmunization. If there is less K+ blood in circulation, then there will be less people developing anti-Kell alloimmunization.

Key Points

  • Most cases of anti-K come from blood transfusions.
  • Kell - women should ask that any transfused blood be Kell- as well.
  • Kell + people should not donate blood.

Prevent Alloimmunization to Other Antigens with Phenotypically Matched Blood

While there are some ways to reduce alloimmunization to the D and K antigens, there is no universally accepted way to prevent alloimmunization to more than 300 other antigens. There are no shots to prevent alloimmunization to other antigens, and options are extremely limited for those patients who are already alloimmunized. Once a patient has developed one alloantibody, they are more likely to develop another 1. Up to 75% of alloantibodies can be prevented by matching the patient’s antigen status to the Rh (c, C, e, E) and MNS antigens 11, 12. Since antigen frequencies vary by ethnicity, it is vital to increase the amount of non-caucasian blood donors to allow for closer blood matching 13. 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). These patients are very high risk for hemolytic transfusion reactions, one of the leading causes of transfusion-related fatalities 10, 13. 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, Kidd, and MNS antigens because these are some of the most immunogenic antigens 8. 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 14. Another key way to locate phenotypically matched blood is to create a database of blood donors with alloantibodies and rare blood types.

Key Points

  • Patients with alloantibodies are more likely to develop additional alloantibodies.
  • Phenotypically matched blood reduces the development of additional alloantibodies.
  • We must increase blood donations from non-caucasion blood donors in order to provide the best match.
  • A national database of rare blood donors is needed.
  • Patients with alloantibodies are at high risk for hemolytic transfusion reactions. A medical alert card can help ensure phenotypically matched blood and reduce this risk.
  • Create your own medical alert card here.
 

Maternal alloimmunization is preventable in some cases. The number of children suffering from Hemolytic Disease of the Fetus and Newborn can be reduced. Do something today!

Ways You Can Help

 
 

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  1. Hauck-Dlimi B, Achenbach S, Strobel J, Eckstein R, Zimmermann R. Prevention and management of transfusion-induced alloimmunization: current perspectives. International Journal of Clinical Transfusion Medicine. 2014;2:59-63 https://doi.org/10.2147/IJCTM.S40028.
  2. RhoGAM - Rx List.
  3. Prescribing information for RhoGAM.
  4. The Rh Factor and You. Watchtower.
  5. Dean L. Blood Groups and Red Cell Antigens [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2005. Chapter 8, The Kell blood group. Available from: https://www.ncbi.nlm.nih.gov/books/NBK2270/.
  6. Davies, S.C., Mcwilliam, A.C., Hewitt, P.E., Devenish, A. and Brozovic, M. (1986), Red cell alloimmunization in sickle cell disease. British Journal of Haematology, 63: 241-245. doi:10.1111/j.1365-2141.1986.tb05546.x.
  7. Eiman Hussein, Nermeen Desooky, Abeer Rihan, Abeer Kamal; Predictors of Red Cell Alloimmunization in Multitransfused Egyptian Patients With β-Thalassemia. Arch Pathol Lab Med 1 May 2014; 138 (5): 684–688. doi: https://doi.org/10.5858/arpa.2013-0016-OA.
  8. Alloimmunization on Science Direct.
  9. Lin, Y., Saskin, A., Wells, R.A., Lenis, M., Mamedov, A., Callum, J. and Buckstein, R. (2017), Prophylactic RhCE and Kell antigen matching: impact on alloimmunization in transfusion‐dependent patients with myelodysplastic syndromes. Vox Sang, 112: 79-86. doi:10.1111/vox.12455.
  10. Jeanne E. Hendrickson, Christopher A. Tormey, Beth H. Shaz. Red Blood Cell Alloimmunization Mitigation Strategies. Transfusion Medicine Reviews. Volume 28, Issue 3. 2014. Pages 137-144. ISSN 0887-7963. https://doi.org/10.1016/j.tmrv.2014.04.008..
  11. Harita Gogri, Swati Kulkarni, K. Vasantha, Seema Jadhav, Kanjaksha Ghosh, Ajit Gorakshakar, Partial matching of blood group antigens to reduce alloimmunization in Western India. Transfusion and Apheresis Science. Volume 54, Issue 3. 2016. Pages 390-395. ISSN 1473-0502. https://doi.org/10.1016/j.transci.2016.02.002..
  12. Eiman Hussein, Nermeen Desooky, Abeer Rihan, Abeer Kamal; Predictors of Red Cell Alloimmunization in Multitransfused Egyptian Patients With β-Thalassemia. Arch Pathol Lab Med 1 May 2014; 138 (5): 684–688. doi: https://doi.org/10.5858/arpa.2013-0016-OA.
  13. Karina Yazdanbakhsh, Russell E. Ware, France Noizat-Pirenne; Red blood cell alloimmunization in sickle cell disease: pathophysiology, risk factors, and transfusion management. Blood 2012; 120 (3): 528–537. doi: https://doi.org/10.1182/blood-2011-11-327361.