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Rho(D) Immune Globulin


Rho(D) Immune Globulin

Article Author:
Athina Yoham
Article Editor:
Damian Casadesus
Updated:
5/30/2020 2:33:39 PM
For CME on this topic:
Rho(D) Immune Globulin CME
PubMed Link:
Rho(D) Immune Globulin

Indications

Rho(D) immune globulin (Anti-D immune globulin or RhIG) is a commercial biological antibody derived from human plasma that targets red blood cells (RBCs) positive for the Rh(D) antigen (also referred to as the D antigen).  When a blood type is described as being positive (A+, B+, AB+, O+), this indicates that the individual has RBCs that are positive for the D antigen and are thus Rh-positive.

RhIG is most known for its use in the prevention of hemolytic disease of the fetus and neonate, which is the result of the mother's immune system forming transplacental passage of anti-D antibodies due to previous exposure to an incompatible Rh blood type of either a previous pregnancy or received blood products. If the Rh-negative mother forms anti-D antibodies, this is known as Rhesus (Rh) isoimmunization.  These maternally-derived anti-D antibodies may then cross the placenta and target Rh-positive fetal RBCs for destruction resulting in hemolysis. This hemolytic disease may have devastating effects on the fetus, depending on the severity of the immune response.     

Several trademark names for RhIG products exist in the United States.  Although RhoGAM is a specific brand name, it is the common parlance used to refer to all RhIG products. Careful examination of the product insert is necessary to establish the associated indications and other unique characteristics. 

Indications for RhIG vary by manufacturer. An FDA-approved RhIG product exists for each of the following indications:

  1. Immune Thrombocytopenia Purpura (ITP)
    • Rh(D)-positive, non-splenectomized
      • Chronic ITP in children and adults
      • Acute ITP in children
      • Improving platelet counts secondary to HIV infection
  2. Rh Isoimmunization Suppression 
    • Rh(D)-negative, non-sensitized patient with Rh-incompatible fetus
      • Prophylaxis in the following clinical situations: 
        • Routine antepartum and postpartum mothers
        • Obstetric complications (ectopic pregnancy, threatened abortion, fetal demise in second or third trimesters)
        • Spontaneous or induced abortions
        • Following invasive obstetric procedures [1]
      • Abdominal traumas involving fetal-maternal hemorrhage 
    • Incompatible transfusions of Rh(D)-positive RBCs in Rh(D)-negative individuals [2]

Possible non-FDA-approved uses of RhIG:

  1. Anti-D alloimmunization prophylaxis after platelet transfusion of Rh-positive individuals to Rh-negative patients with acute leukemia due to possible RBC residual in platelet concentrates.[3] [Level 3]

Mechanism of Action

The mechanism of action for patients receiving RhIG in ITP treatment is not entirely understood. Prevention of Rh isoimmunization appears to be an immunologic blockade of Fc receptors (RcR) within the reticuloendothelial system (RES); other immunomodulatory effects are also possible. Intravenous (IV) infusion of anti-D into an Rh-positive recipient leads to antibody coating of the circulating erythrocytes, which are eventually cleared primarily by the spleen. Clearance of sensitized erythrocytes by RES results in increased platelet counts and reduced bleeding.[4][5]

The mechanism by which RhIG prevents isoimmunization is not completely understood but is likely to suppress the immune response and antibody formation in Rh-incompatible individuals (Rh-negative exposed to Rh-positive RBCs). If administration occurs within 72 hours of full-term delivery, the incidence decreases from 12% to 13% to 1% to 2%. The chances of isoimmunization drops to <1% with the administration schedule at 28 weeks gestation and within 72-hours postpartum.[2][6] 

Administration

Administration of RhIG for prevention of Rh isoimmunization achieved by either intramuscular (IM) or intravenous (IV) injection, depending on the indication and manufacturer recommendations. During pregnancy, a single dose should be given prophylactically at weeks 26 to 28 and again within 72 hours of delivery of an Rh-positive infant.

For any known or suspected maternal exposure to Rh-positive RBCs or any incompatible Rh-positive blood product received, RhIG should be administered within 72 hours and dosed accordingly to the amount of RBC exposure per manufacturer guidelines. In pregnant women, RhIG should be administered every 12 weeks from the first injection to maintain a sufficient quantity of passively acquired anti-D antibodies.  

Administration for ITP is via IV infusion only.[7] There is a risk of complement system activation when IM-only preparations are given IV and should always be avoided in patients with ITP. Peak serum levels are achieved faster with IV administration; however, the half-life is approximately the same (24 days) for IV and IM administration. Dosages are expressed in micrograms or international units (IUs). The conversion scale is 1 microgram = 5 IUs. The presence of RhIG can persist for months after administration and varies by the individual immune response.[8]

Adverse Effects

According to the drug label, the following adverse effects have occurred. 

The most common adverse effects include[9]:

  • Chills
  • Headache
  • Asthenia
  • Fever
  • Dizziness
  • Infection
  • Hypertension
  • Vasodilation
  • Drowsiness
  • Shivering
  • Diaphoresis 
  • Pallor
  • Decreased hemoglobin in patients with ITP
  • Increased lactate dehydrogenase  
  • Decreased haptoglobins
  • Increased serum bilirubin
  • Abdominal and back pain
  • Antibody development (positive anti-C antibody test)
  • Injection site reaction - erythema, discomfort, mild pain 
  • Hyperkinetic muscle activity 

The most serious adverse interactions include[10]:

  • Disseminated intravascular coagulation
  • Intravascular hemolysis (ITP patients)
  • Acute renal insufficiency
  • Clinically compromising anemia
  • Death

Contraindications

The FDA-labeled contraindications for RhIG vary by the manufacturer but include the following:

  1. A hemolytic reaction may result if given to Rh-positive patients; RhIG should be avoided in these individuals. 
  2. Patients with a history of severe hypersensitivity or anaphylaxis to any human immune globulin product
  3. Patients with preexisting hemolysis, autoimmune hemolytic anemia or high risk for hemolysis
  4. RhIG products may contain a small quantity of IgA and therefore, should be avoided in IgA deficient individuals with antibodies against IgA.

Monitoring

According to published monitoring parameters on Rh(D) immune globulin, if indicated for the alloimmunization prophylaxis, after administration patients should be monitored for at least 20 minutes to watch for any signs of systemic reactions.  

If using RhIG for the treatment of ITP, the black-box warning recommends closely monitoring patients for at least 8 hours to rule out any evidence of intravascular hemolysis. While a majority of patients will be asymptomatic, signs and symptoms to be mindful of in a minority of patients include fever, back pain, shaking chills, and discolored urine or hematuria and may indicate hemolysis.[10]

Recommended labs for monitoring before treatment initiation include:

CBC (baseline anemia assessment and degree of hemolysis), differential and PBS review (evidence of hemolysis, infection), DAT and antibody screen, reticulocyte count, Urinalysis, serum creatinine, BUN. [10]

Recommended labs for monitoring following treatment include:

CBC (1 to 3 days after infusion if first administration), urinalysis 1 to 2 hours after treatment (dipstick only, unless positive for blood), serum creatinine (only if posttreatment hemoglobin decreased >1 g/dL) and BUN (only if posttreatment hemoglobin decreased >1 g/dL).[10]

If intravascular hemolysis is suspected, monitor plasma hemoglobin, LDH, haptoglobin, and plasma bilirubin (direct and indirect).  

Toxicity

Severe and life-threatening toxicities are rare with RhIG treatments. In the event of an overdose in ITP, patients should receive close monitoring for hemoglobin decrease of more than 1.2g/dL.[11]

In the suppression of Rh Isoimmunization, hemolytic reactions can occur in the case of incompatible blood transfusions after very large doses of RhIG have been given.

Patients should be monitored closely for signs and symptoms of hemolysis with the initiation of supportive treatment at the start of symptoms.

Enhancing Healthcare Team Outcomes

Several RhIG products are currently available in the United States. Although there are multiple brand names, they all have similar clinical indications and dosing but differ significantly in specific attributes. Pharmacists can play an essential role in ensuring the safe administration of these products by guiding clinicians on the use and timing of RhIG therapy.

The recommendation is to delay live vaccine administration until at least 12 weeks after the last dose of RhIG. However, according to CDC Guidelines on General Recommendations on Immunization and Pink Book on Immunology and Disease Preventable Illness on Rubella, postpartum vaccination of rubella-susceptible women with rubella or MMR vaccine should not be delayed during the last trimester or at delivery. It should be serologically tested 6 to 8 weeks post-vaccination to ensure that seroconversion has occurred.

If RhIG is inadvertently omitted after delivery, it should be given as soon as possible within the first 72 hours. Partial protection can be achieved when administered with 13 days of birth and may provide some type of benefit up to as much as 28 days after delivery; the longer the delay, the less protective.[12][13] [Level 2] [Level 3]


References

[1] Kim YA,Makar RS, Detection of fetomaternal hemorrhage. American journal of hematology. 2012 Apr;     [PubMed PMID: 22231030]
[2] Bowman JM, The prevention of rh-immunization. Canadian family physician Medecin de famille canadien. 1977 Dec;     [PubMed PMID: 20469282]
[3] Villalba A,Santiago M,Freiria C,Montesinos P,Gomez I,Fuentes C,Rodriguez-Veiga R,Fernandez JM,Sanz G,Sanz MA,Carpio N,Solves P, Anti-D Alloimmunization after RhD-Positive Platelet Transfusion in RhD-Negative Women under 55 Years Diagnosed with Acute Leukemia: Results of a Retrospective Study. Transfusion medicine and hemotherapy : offizielles Organ der Deutschen Gesellschaft fur Transfusionsmedizin und Immunhamatologie. 2018 May;     [PubMed PMID: 29928170]
[4] Ware RE,Zimmerman SA, Anti-D: mechanisms of action. Seminars in hematology. 1998 Jan;     [PubMed PMID: 9523745]
[5] Crow AR,Lazarus AH, The mechanisms of action of intravenous immunoglobulin and polyclonal anti-d immunoglobulin in the amelioration of immune thrombocytopenic purpura: what do we really know? Transfusion medicine reviews. 2008 Apr;     [PubMed PMID: 18353251]
[6] Crowther C,Middleton P, Anti-D administration after childbirth for preventing Rhesus alloimmunisation. The Cochrane database of systematic reviews. 2000;     [PubMed PMID: 10796089]
[7] Costumbrado J,Mansour T,Ghassemzadeh S, Rh Incompatibility 2020 Jan;     [PubMed PMID: 29083656]
[8] Bussel JB,Graziano JN,Kimberly RP,Pahwa S,Aledort LM, Intravenous anti-D treatment of immune thrombocytopenic purpura: analysis of efficacy, toxicity, and mechanism of effect. Blood. 1991 May 1;     [PubMed PMID: 1850307]
[9] Hong F,Ruiz R,Price H,Griffiths A,Malinoski F,Woloski M, Safety profile of WinRho anti-D. Seminars in hematology. 1998 Jan;     [PubMed PMID: 9523744]
[10] Despotovic JM,Lambert MP,Herman JH,Gernsheimer TB,McCrae KR,Tarantino MD,Bussel JB, RhIG for the treatment of immune thrombocytopenia: consensus and controversy (CME). Transfusion. 2012 May;     [PubMed PMID: 21981825]
[11] Cheung E,Liebman HA, Anti-RhD immunoglobulin in the treatment of immune thrombocytopenia. Biologics : targets     [PubMed PMID: 19707396]
[12] Samson D,Mollison PL, Effect on primary Rh immunization of delayed administration of anti-Rh. Immunology. 1975 Feb;     [PubMed PMID: 804437]
[13] Fung Kee Fung K,Eason E,Crane J,Armson A,De La Ronde S,Farine D,Keenan-Lindsay L,Leduc L,Reid GJ,Aerde JV,Wilson RD,Davies G,Désilets VA,Summers A,Wyatt P,Young DC, Prevention of Rh alloimmunization. Journal of obstetrics and gynaecology Canada : JOGC = Journal d'obstetrique et gynecologie du Canada : JOGC. 2003 Sep;     [PubMed PMID: 12970812]