Transfusion medicine
Red blood cell antigens
Rh system
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PubMed Search: Rh group antigens
Table of Contents
Definition / general | Essential features | Antigens | Antibodies | Terminology | Pathophysiology | Transmission | Laboratory | Case reports | Treatment | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Cite this page: Adkins BD, Booth GS. Rh system. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/transfusionmedrhgroup.html. Accessed April 1st, 2025.
Definition / general
- Most antigenic blood group
- Antibodies are clinically significant
Essential features
- Rh (Rhesus) antigens are widely expressed in the donor population
- Antibodies can cause hemolysis and hemolytic disease of the fetus and newborn (HDFN)
Antigens
- Type: peptide
- RhD is an antigen formed by RHD on chromosome 1 (AABB: Technical Manual, 19th Edition, 2017)
- D antigen has high frequency among all racial groups and products are designated as positive or negative based on its presence
- D variants include individuals who express less D antigen (weak D) and those who express structurally different D antigen (partial D)
- Partial D individuals may form antibodies against a normal D antigen
- RHCcEe are antigens generally coinherited with RhD on chromosome 1 encoded by the RHCE gene
- The D antigen is most immunogenic, though other Rh antigens are very immunogenic and patients who alloimmunize at higher rates, such as individuals with sickle cell disease, are often matched for RhCc and RhEe antigens
- RHAG is a glycoprotein that helps localize Rh antigens to the red cell membrane; absence of this protein leads to RhNull disease
- RhNull disease is characterized by stomatocytosis, enhanced osmotic fragility and mild chronic hemolysis
- Rh antigens form structural epitopes, which may be separately antigenic
- G antigen is formed by 4 shared amino acids between RhD and RhC
- f antigen is a compound antigen found on red cells with Rh antigens ce
- Dce / CE in trans configuration leads to decreased RhD expression due to the Ceppellini effect; the decrease in D expression is most pronounced in the trans configuration but is present to a lesser extent in cis individuals as well (AABB: Technical Manual, 19th Edition, 2017)
Adapted from Transfusion 2004;44:703, AABB: Technical Manual, 19th Edition, 2017Race / Ethnicity RhD+ RhD- C c E e White non-Hispanic 82.7% 17.3% 68% 80% 29% Hispanic 92.7% 7.3% Black non-Hispanic 92.9% 7.1% 27% 96% 22% Asian 98.3% 1.7% Native American 90.3% 9.7% All donors 85.4% 14.6% 98% - RhD is an antigen formed by RHD on chromosome 1 (AABB: Technical Manual, 19th Edition, 2017)
Antibodies
- Majority IgG, fewer IgM (AABB: Technical Manual, 19th Edition, 2017)
- Can cause hemolytic reactions and hemolytic disease of the fetus and newborn
- Occur with exposure to products containing Rh incompatible blood or pregnancy
- Show dosage (not RhD) and improve with enzyme treatment
- Anti-G antibodies will react in a pattern resembling anti-C and anti-D antibodies
- It is important to confirm the presence of anti-G antibodies by differential elution in order to rule out anti-D
- This is meaningful as pregnant patients will still benefit from RhIG to prevent further alloimmunization
Terminology
| DCe | R1 |
| DcE | R2 |
| Dce | R0 |
| DCE | Rz |
| ce | r |
| Ce | r' |
| cE | r" |
| CE | ry |
Pathophysiology
- RhD sensitization occurs during the first pregnancy due to maternal exposure to fetal hemorrhage during gestation or delivery; this leads to an anti-D IgG antibody which can cross the placenta in subsequent pregnancies, leading to hydrops fetalis if not identified by obstetrics teams (AABB: Technical Manual, 19th Edition, 2017)
- Risk of sensitization in an RhD negative mother with an RhD positive fetus is 16%, though this is reduced to < 0.1% with appropriate Rh immunoglobulin administration (AABB: Technical Manual, 19th Edition, 2017)
- 1 vial of RHIg binds 30 mL whole blood or 15 mL red blood cells (RBC)
- Alloimmunization in healthy individuals can be high; however, rates in hospitalized patients and trauma patients tend to be lower
- RhD remains the most immunogenic antigen due to its density on the red blood cell surface and amino acid differences from RhCc / Ee
Transmission
- Exposure to Rh antigens secondary to pregnancy or transfusion
Laboratory
- RhD positivity is determined
- O negative blood is the preferred universal donor blood type in emergency situations; many hospitals will provide RhD positive units in massive transfusion protocols, as RhD alloimmunization is of lower risk in this population; however, women of childbearing age (< 50 years) should always receive RhD negative products
Case reports
- Newborn with D variant implicated in hemolytic disease of the fetus and newborn (Asian J Transfus Sci 2018;12:75)
- 34 year old woman with a case of hydrops fetalis due to Rh alloimmunization (Case Rep Obstet Gynecol 2018;2018:8412139)
- 39 year old Iranian woman with a rare Rh phenotype (Indian J Hematol Blood Transfus 2019;35:402)
- 43 year old Iranian woman was found to be RhNull (Int J Hematol Oncol Stem Cell Res 2018;12:181)
- 58 year old man with passenger lymphocyte syndrome with an anti-D alloantibody (Transfus Med Hemother 2014;41:153)
Treatment
- RhIg dosage may be administered in pregnant patients and in patients after exposure to RhD positive products
- RhD negative mothers with RhD positive partners receive a vial at 28 weeks gestation and after delivery
- In the situation of maternal fetal hemorrhage or other RhD exposure, a Kleihauer-Betke test may be performed in order to calculate RhIg dosing
- 1 vial contains 300 μg and theoretically should bind 30 mL of RhD positive or fetal blood
- Volume in ml of fetal blood = percentage of fetal cells x 50
- Volume of fetal blood/30 ml = number of vials of 300 mcg RhIg
- Number of vials = percentage of fetal cells x 50 / 30
- Round based on the tenth position after the decimal
- < 0.5, round down and add 1 vial
- ≥ 0.5, round up and add 1 vial
- Labs may also determine RhIg dosing using flow cytometry
- Reference: Krywko: Kleihauer Betke Test [Accessed 16 May 2024]
Additional references
Board review style question #1
A 27 year old mother of 2 presents at the OB/GYN. The mother is O- and has never received prenatal care. No heart rate is detected on Doppler and an ultrasound is performed. A hydropic fetus is identified. If no significant fetal maternal hemorrhage occurred in her prior pregnancies, when should this mother have received RhIg to prevent this outcome?
- At 8 weeks and 35 weeks
- At 28 weeks and after delivery
- At 28 weeks and 35 weeks
- Only after delivery
- Only at 28 weeks
Board review style answer #1
B. At 28 weeks and after delivery. Historically, mothers were dosed after delivery to prevent RhD alloimmunization, which still led to some breakthrough alloimmunization (answer D). The addition of dosing at 28 weeks has led to a RhIg failure rate in pregnancy of < 0.01%. Answers A, C and E are incorrect because they are not used in clinical practice.
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Reference: Rh group
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Reference: Rh group
Board review style question #2
A 36 year old man is seen for a viral illness by his primary care physician. A complete blood count is performed and the patient is found to have mild anemia. The physician is concerned and orders a peripheral smear review at a follow up appointment, which is read as mild anemia with anisopoikilocytosis including frequent stomatocytes. What Rh abnormality may this patient have?
- DCe / Ce in trans configuration
- Partial D
- Partial e
- Weak D
- RhNull phenotype
Board review style answer #2
E. RhNull phenotype. This lack of all Rh antigens leads to structural abnormalities (stomatocytes) and chronic mild anemia, which is generally not clinically significant. Answers A, B, C, and D are incorrect because these other Rh types are not classically associated with morphologic changes.
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Reference: Rh group
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Reference: Rh group
