Table of Contents
Definition / general | Essential features | Terminology | Pathophysiology | Clinical features | Symptoms | Laboratory | Case reports | Treatment | Sample assessment & plan | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Cite this page: Potochny EM, George MR. Rh immune globulin . PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/transfusionmedrhimmuneglobulin.html. Accessed January 17th, 2021.
Definition / general
- Rh (Rhesus) immune globulin (RhIG) is a derivative of pooled human plasma manufactured by cold ethanol fractionation to prevent alloimmunization (antibody formation) to RhD antigen following exposure, such as through a blood transfusion or pregnancy
- Treatment option for immune thrombocytopenia (ITP)
- Available via intramuscular (IM) or intravenous (IV) preparations
Essential features
- RhIG is used to prevent RhD alloimmunization (antibody formation) and as treatment option for ITP
- RhIG is typically administered in 300 μg IM vials as prophylaxis during pregnancy for RhD negative females and at time of delivery if neonate is RhD positive
- In cases of fetal maternal hemorrhage, a fetal screen is indicated and if positive, flow cytometry or Kleihauer-Betke testing is performed to estimate appropriate number of additional vials of RhIG
Terminology
- Rh immune globulin, Rh immunoglobulin, Rh0(D) immunoglobulin
- Trade name preparations of Rh immune globulin include Rhophylac®, RhoGAM®, MICRhoGAM®, WinRho SDF®, HyperRHO S/D®
Pathophysiology
- An RhD negative person exposed to RhD positive red blood cells, either through a blood transfusion or fetal maternal hemorrhage during a pregnancy, is at risk of developing antibodies to RhD
- RhD negative phenotype occurs in roughly 15% of whites
- Predominantly due to RHD gene deletion
- RhD negative phenotype in blacks is ~7 - 8%
- Most due to mutant RHD gene coding for premature stop codon
- RhD negative phenotype in Asians is < 1%
- RhD negative phenotype occurs in roughly 15% of whites
- RhIG can suppress the formation of these antibodies, preventing their development
- References: Shaz: Transfusion Medicine and Hemostasis - Clinical and Laboratory Aspects, 3rd Edition, 2019, Simon: Rossi's Principles of Transfusion Medicine, 5th Edition, 2016
Clinical features
- Consequences of anti-D alloimmunization causing hemolytic disease of the fetus may include:
- Fetal anemia
- Organomegaly from extramedullary hematopoiesis
- Portal hypertension
- Fetal hydrops
- Death from high output cardiac failure
- Consequences of anti-D alloimmunization causing hemolytic disease of the newborn may include:
- Neonatal anemia
- Jaundice
- Kernicterus
Symptoms
- Potential adverse effects following RhIG administration prevention of anti-D formation:
- Nausea, dizziness, headache, pain at injection site, malaise
- Potential adverse effects following RhIG administration for ITP:
- Chills / rigors, fever, headache, hemolysis (rare)
- Reference: PDR: RhoD Immune Globulin Human - Drug Summary [Accessed 11 August 2020]
Laboratory
- Following delivery, an RhD negative female bearing an RhD positive neonate should undergo a fetal blood screen
- Negative fetal screen means only 1 vial RhIG required
- Indicates either no or minimal fetal maternal hemorrhage (< 30 mL)
- Positive fetal screen requires a quantitative test, to dose additional vials of RhIG, such as:
- Flow cytometry
- Kleihauer-Betke test
- Detects fetal red cells in maternal circulation by their pink color
- EDTA (pink / lavender top) specimen required, drawn from the mother following delivery
- Hemoglobin in fetal red cells is resistant to acid treatment (bright pink / red)
- Hemoglobin in maternal red cells is destroyed by acid treatment (clear / light pink “ghost” cells)
- Calculate volume of fetal maternal hemorrhage (FMH):
- [# pink / red (fetal) cells ÷ 2,000 cells counted) x maternal blood volume (5,000 mL is average)
- A 300 µg vial of RhIG will cover 30 mL of whole blood
- Therefore, volume of FMH ÷ 30 = vials of RhIG
- If the number of calculated vials is < 0.5, round down to the nearest whole number and add 1 vial
- If the number of calculated vials is ≥ 0.5, round up to nearest whole number and add 1 vial
- For example, if 1.8 vials is calculated, round up to 2 and add 1 vial = 3 total vials required
- Administration of RhIG will look like an anti-D on antibody identification and is generally called passive anti-D
- Pattern of reactivity is indistinguishable from true alloimmunization; blood bank interpretations may include cautionary statement
- Following administration of RhIG, serologic detection of passive anti-D may occur up to 3 - 4 months by tube testing or gel methodology
- Up to 5 - 6 months by solid phase red cell adherence assay (SPRCA)
- Patients injected with IM RhIG should not develop a positive antibody screen until 7 to 8 hours after administration
- Earlier detection raises concern for true alloimmunization
- Different manufactured brands of RhIG are comparable in strength and duration of reactivity across test methods (Transfusion 2015;55:1444)
- Special circumstance: detection of possible anti-D and anti-C in woman of childbearing age, as this may represent anti-G
- Anti-G is an antibody directed against epitopes on both the C and D antigens
- Antibody titering: anti-G is suspected when the anti-C titer is consistently higher than the anti-D titer (Transfusion 1997;37:493)
- Important to investigate via adsorption studies to determine eligibility for RhIG
- Various combinations of antibodies against C, D and G may be present
- If anti-D is not detected, patient (if woman of childbearing age) is eligible for RhIG
- If anti-D is detected, patient is not eligible to receive RhIG
Case reports
- RhIG for variant RHD:
- 2 cases of variant RHD in pregnant women, misclassified as RhD positive, who did not receive RhIG when indicated and formed anti-D (Immunohematology 2017;33:60)
- RhIG after fetal maternal hemorrhage (FMH):
- 31 year old woman with large RhIG dose requirement following FMH (Am J Clin Pathol 2016;145:744)
- RhIG after RhD positive red cell transfusion following trauma:
- 25 year old woman involved in car accident (J Clin Apher 2010;25:70)
- RhIG for anti-G when clinically indicated - generally, female children and women with childbearing potential:
- 78 year old man with anti-G (Ann Lab Med 2018;38:280)
- RhIG for immune thrombocytopenia (ITP):
- 5 year old boy with platelet count of 2 x 109/L, a theoretical case for consultation of RhIG for ITP (Hematology Am Soc Hematol Educ Program 2013;2013:283)
Treatment
- Rh immune globulin is given to RhD negative women:
- At approximately 28 weeks estimated gestational age (EGA)
- Again within 72 hours of delivery if the neonate is RhD positive
- Following trauma
- After invasive procedures (amniocentesis, cordocentesis)
- Spontaneous or elective abortions
- Pregnancy inversions
- Pregnant women who are considered D variants (weak or partial D) may be capable of forming an anti-D
- RHD genotyping can distinguish weak from partial D and determine if RhD negative blood or RhIG is indicated
- PCR based test requiring specimen collected in EDTA tube
- Weak D types 1, 2, 3 can be managed as RhD positive
- Recent data suggests types 4.0 and 4.1 can also be managed as RhD positive (Transfusion 2020;60:855)
- Immune thrombocytopenia (ITP)
- Only used when patient is RhD positive
- Anti-D acts like an immune decoy to decrease body's formation of antiplatelet antibodies
- References: Fung: Technical Manual, 19th Edition, 2017, Shaz: Transfusion Medicine and Hemostasis - Clinical and Laboratory Aspects, 3rd Edition, 2019
Sample assessment & plan
- History: 35 year old woman presenting to hospital after motor vehicle accident
- Blood type: O negative
- Laboratory testing:
- Type and screen performed in the blood bank, followed by antibody identification which identifies reactivity consistent with anti-D plus anti-C
- Adsorption studies were performed at an immunohematology reference laboratory, identifying anti-G and anti-C; anti-D not identified
- Clinical significance:
- Anti-G is an antibody formed in almost all cases by Rh negative (D negative), G antigen negative patients. Anti-G reacts with epitopes on both the C antigen and the D antigen. Anti-G typically is seen in a D negative patient who has never knowingly been exposed to Rh positive blood, yet presents with an antibody that looks like a combination of both anti-D and anti-C.
- This antibody can form through previous exposure via pregnancy or transfusion. A patient with anti-G would be transfused in exactly the same way as a patient who has the combination of anti-D and anti-C: with Rh negative (D antigen negative) and C antigen negative blood.
- However, women of childbearing age with anti-G should receive Rh immune globulin during pregnancy to protect against the formation of a true alloimmunization against the D antigen, which could cause severe hemolytic disease of the newborn.
- Difficulty in finding compatible blood:
- This patient can receive O, RhD negative, C antigen negative packed red blood cells, which accounts for approximately 2% of the blood inventory
Board review style question #1
A 31 year old G2P1 woman presents to a new medical center after having moved from out of state. She is 16 weeks pregnant and was referred to maternal fetal medicine for a positive antibody screen. Antibody identification reveals a pattern consistent with anti-D and anti-C. Additional blood samples are requested by the blood bank for adsorption testing at an immunohematology reference laboratory, as anti-G is suspected. In which scenario is RhIG indicated for this patient?
- Anti-G, anti-C and anti-D are identified
- Anti-D and anti-C are identified but anti-G is not identified
- Anti-G and anti-C are identified but anti-D is not identified
- Anti-G and anti-D are identified but anti-C is not identified
Board review style answer #1
C. Anti-G and anti-C are identified but anti-D is not identified. Anti-G is an important consideration in the workup of a woman of childbearing age who appears to have anti-D and anti-C. Adsorption studies to discern the presence or absence of true anti-D should be undertaken to determine eligibility for RhIG in the interest of protecting against severe anti-D hemolytic disease of the newborn. Women of childbearing age who have not formed anti-D are eligible for RhIG. The presence or absence of of anti-G or anti-C does not influence RhIG administration.
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Reference: Rh immune globulin
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Board review style question #2
A 27 year old G1P0 receives 300 μg RhIG at approximately 28 weeks gestational age because her blood type is A, RhD negative. She later delivers a full term healthy boy at 39 weeks gestational age. Cord blood testing of the infant reveals he is O, RhD positive. Additionally, a fetal screen performed on a postpartum sample from the mother is positive, indicating fetal maternal hemorrhage, and a Kleihauer-Betke is reflexively performed in order to properly dose RhIG. How many total vials of 300 μg RhIG are required if 2,000 total cells are counted and 8 fetal cells are identified (and a maternal blood volume of 5,000 mL is presumed)?
- 1 vial RhIG
- 2 vials RhIG
- 3 vials RhIG
- 4 vials RhIG
Board review style answer #2
B. 2 vials. Volume FMH identified by Kleihauer-Betke = (8 fetal cells / 2,000 total cells counted) x 5,000 mL maternal blood volume = 20 mL. 20 mL/30mL = 0.67 vial. In this case, 0.67 vial is rounded up to 1 vial and 1 additional vial is added, making the appropriate RhIG dose 2 vials.
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Reference: Rh immune globulin
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Reference: Rh immune globulin