Rho(D) Immune Globulin
   HOME

TheInfoList



OR:

Rho(D) immune globulin (RhIG) is a medication used to prevent RhD isoimmunization in mothers who are RhD negative and to treat idiopathic thrombocytopenic purpura (ITP) in people who are Rh positive. It is often given both during and following
pregnancy Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ca ...
. It may also be used when RhD-negative people are given RhD-positive blood. It is given by injection into muscle or a
vein Veins are blood vessels in humans and most other animals that carry blood towards the heart. Most veins carry deoxygenated blood from the tissues back to the heart; exceptions are the pulmonary and umbilical veins, both of which carry oxygenated b ...
. A single dose lasts 12 weeks. It is made from human blood plasma. Common side effects include
fever Fever, also referred to as pyrexia, is defined as having a body temperature, temperature above the human body temperature, normal range due to an increase in the body's temperature Human body temperature#Fever, set point. There is not a single ...
, headache, pain at the site of injection, and red blood cell breakdown. Other side effects include
allergic reactions Allergies, also known as allergic diseases, refer a number of conditions caused by the hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic derma ...
,
kidney problems Kidney failure, also known as end-stage kidney disease, is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney failure is classified as eit ...
, and a very small risk of viral infections. In those with ITP, the amount of red blood cell breakdown may be significant. Use is safe with
breastfeeding Breastfeeding, or nursing, is the process by which human breast milk is fed to a child. Breast milk may be from the breast, or may be expressed by hand or pumped and fed to the infant. The World Health Organization (WHO) recommends that br ...
. Rho(D) immune globulin is made up of
antibodies An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...
to the
antigen In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...
Rho(D) present on some
red blood cells Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek language, Greek ''erythros'' for "red" and ''k ...
. It is believed to work by blocking a person's immune system from recognizing this antigen. Rho(D) immune globulin came into medical use in the 1960s, following the pioneering work of
John G. Gorman John G. Gorman is an Australian born physician and medical researcher. In 1980, Gorman shared the Lasker-DeBakey Clinical Medical Research Award for pioneering work on the rhesus blood group system, the role of rhesus D antibodies in the causation ...
. In 1980, Gorman shared the
Lasker-DeBakey Clinical Medical Research Award Lasker-DeBakey Clinical Medical Research Award is one of four annual awards presented by the Lasker Foundation. The Lasker-DeBakey award is given to honor outstanding work for the understanding, diagnosis, prevention, treatment, and cure of diseas ...
for pioneering work on the
rhesus blood group system The Rh blood group system is a human blood group system. It contains proteins on the surface of red blood cells. After the ABO blood group system, it is the most likely to be involved in transfusion reactions. The Rh blood group system consists ...
. RhIG is on the
World Health Organization's List of Essential Medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health ...
.


Medical uses

In a pregnancy where the mother is RhD negative and the father is RhD positive, the probability of the fetus having RhD positive blood is dependent on whether the father is
homozygous Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mo ...
for RhD (i.e., both RhD alleles are present) or
heterozygous Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mo ...
(i.e., only one RhD allele is present). If the father is homozygous, the fetus will necessarily be RhD positive, as the father will necessarily pass on a Rh D positive allele. If the father is heterozygous, there is a 50% chance that the fetus will be RhD positive, as he will randomly pass on either the RhD positive allele or not. If a fetus is RhD positive and the mother is RhD negative, the mother is at risk of RhD alloimmunization, where the mother mounts an immune response (develops
antibodies An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...
) to fetal red blood cells. This usually has minimal effect on the first such pregnancy; but, in a second such pregnancy, pre-existing maternal antibodies to RhD antigens on fetal red blood cells often leads to
erythroblastosis fetalis Hemolytic disease of the newborn, also known as hemolytic disease of the fetus and newborn, HDN, HDFN, or erythroblastosis foetalis, is an alloimmune condition that develops in a fetus at or around birth, when the IgG molecules (one of the five ...
, a condition which can be fatal to the fetus. In countries without Rh immune globulin (RhIG) protocols, as many as 14% of affected fetuses are stillborn and 50% of live births result in neonatal death or brain injury. Because of this severe complication, the
American College of Obstetricians and Gynecologists The American College of Obstetricians and Gynecologists (ACOG) is a professional association of physicians specializing in obstetrics and gynecology in the United States. Several Latin American countries are also represented within Districts of ...
(ACOG) recommends that all RhD negative mothers, regardless of fetal blood type, receive RhIG at about 28 weeks gestation, and again shortly after delivery in the case of an RhD positive or RhD unknown baby. It should be given within 3 days of a potential exposure to Rh positive blood from the baby such as may occur during second or third trimester miscarriage, amniocentesis, cordocentesis, chorionic villus sampling, external cephalic version, trauma, or delivery. It should be considered after first trimester miscarriage. The '28 weeks' recommendation comes from the fact that 92% of women who develop an anti-D during pregnancy do so at or after 28 weeks gestation.Roback et al. AABB Technical Manual, 16th Ed. Bethesda, AABB Press, 2008.Prevention of Rh D Alloimmunization. ACOG Practice Bulletin Number 4. Washington, DC: American College of Obstetricians and Gynecologists, 1999. It is given by intramuscular injection as part of modern routine
antenatal Prenatal development () includes the embryonic development, development of the embryo and of the fetus during a viviparity, viviparous animal's gestation. Prenatal development starts with fertilization, in the germinal stage of embryonic developm ...
care. Despite excellent results, the medication retains an FDA
Pregnancy Category The pregnancy category of a medication is an assessment of the risk of fetal injury due to the pharmaceutical, if it is used as directed by the mother during pregnancy. It does ''not'' include any risks conferred by pharmaceutical agents or their ...
C. RhIG is recommended in the UK after antenatal pathological events that are likely to cause a feto–maternal hemorrhage. Applicable 'pathologic events' include accidents which may induce fetomaternal hemorrhage (motor vehicle accidents, falls, abdominal trauma), following obstetric/gynecologic procedures during pregnancy, and at the time of threatened- or spontaneous-/elective
abortion Abortion is the termination of a pregnancy by removal or expulsion of an embryo or fetus. An abortion that occurs without intervention is known as a miscarriage or "spontaneous abortion"; these occur in approximately 30% to 40% of pregn ...
s, regardless of gestational age. There is insufficient evidence that the use of Rho(D) immune globulin after a spontaneous miscarriage is needed and a
Cochrane review Cochrane (previously known as the Cochrane Collaboration) is a British international charitable organisation formed to organise medical research findings to facilitate evidence-based choices about health interventions involving health professi ...
recommends that local practices be followed. In an RhD negative mother, RhIG can prevent temporary sensitization of the maternal immune system to RhD
antigen In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...
s, which can cause rhesus disease in the current or in subsequent pregnancies. With the widespread use of RhIG,
Rh disease Rh disease (also known as rhesus isoimmunization, Rh (D) disease, and blue baby disease) is a type of hemolytic disease of the fetus and newborn (HDFN). HDFN due to anti-D antibodies is the proper and currently used name for this disease as the ...
of the
fetus A fetus or foetus (; plural fetuses, feti, foetuses, or foeti) is the unborn offspring that develops from an animal embryo. Following embryonic development the fetal stage of development takes place. In human prenatal development, fetal deve ...
and
newborn An infant or baby is the very young offspring of human beings. ''Infant'' (from the Latin word ''infans'', meaning 'unable to speak' or 'speechless') is a formal or specialised synonym for the common term ''baby''. The terms may also be used to ...
has almost disappeared in the developed world. The risk that an RhD negative mother can be alloimmunized by a RhD positive fetus can be reduced from approximately 16% to less than 0.1% by the appropriate administration of RhIG. Rh immune globulin is composed of IgG antibodies and therefore is able to cross the placenta. In rare cases this can cause a baby to have a weakly positive direct antiglobulin test (DAT) due to sensitization of fetal cells from mothers who have received multiple doses of RhIG. However, no treatment is necessary as the clinical course is benign.


Following delivery

A D-negative mother who is not alloimmunized to D should also receive an appropriate dose of RhIG after delivery of a D-positive infant. After delivery, a cord blood sample from infants born to D-negative mothers should be tested for the D antigen. If the neonate is D-negative, no further RhIG is needed. However, if the infant is D-positive, the mother should have a postpartum blood sample screened for fetomaternal hemorrhage in order to determine the appropriate dosage of RhIG to be administered. (The presence of residual anti-D from antepartum RhIG administration does not indicate ongoing protection from alloimmunization- repeat administration of RhIG is necessary.) The rosette test is a sensitive method to detect fetomaternal hemorrhage of 10 cc or more. This qualitative (not quantitative) test will be positive if fetal D-positive cells are present in the maternal sample, indicating a significantly large fetomaternal hemorrhage has occurred. A rosette test may be falsely positive if the mother is positive for the
weak D The Rh blood group system is a human blood group system. It contains proteins on the surface of red blood cells. After the ABO blood group system, it is the most likely to be involved in transfusion reactions. The Rh blood group system consists ...
phenotype and falsely negative if the neonate is weak D. If the mother is positive for the weak D phenotype, the rosette test should not be used; instead, a quantitative test such as the
Kleihauer–Betke test The Kleihauer–Betke ("KB") test, Kleihauer–Betke ("KB") stain, Kleihauer test or acid elution test is a blood test used to measure the amount of fetal hemoglobin transferred from a fetus to a mother's bloodstream. It is usually performed on ...
or flow cytometry should be utilized. If the rosette test is negative, then a dose of 300 micrograms of RhIG is given (sufficient to prevent alloimmunization after delivery in 99% of cases). The RhIG dose suppresses the immune response to up to 30 cc of whole fetal blood (15 cc of red blood cells). If a fetomaternal hemorrhage in excess of 30 cc has occurred, additional testing is mandatory in order to determine the appropriate dosage of RhIG to prevent alloimmunization. A positive rosette test should be followed by a quantitative test such as the Kleihauer–Betke test or an alternative approach such as
flow cytometry Flow cytometry (FC) is a technique used to detect and measure physical and chemical characteristics of a population of cells or particles. In this process, a sample containing cells or particles is suspended in a fluid and injected into the flo ...
. See the article on Kleihauer–Betke test for details on how the volume of fetomaternal hemorrhage is calculated. The dosage of RhIG is calculated from the volume of fetal hemorrhage (in mL). Ex: 50 mL fetal hemorrhage / 30 mL = 1.667 (round up to 2) then add 1 = 3 vials of RhIG. Postpartum RhIG should be administered within 72 hours of delivery. If prophylaxis is delayed, the likelihood that alloimmunization will be prevented is decreased. However, ACOG still recommends that RhIG be administered because partial protection still occurs. If the D-type of a newborn or stillborn is unknown or cannot be determined, RhIG should be administered.


Immune thrombocytopenia

Primary
immune thrombocytopenia Immune thrombocytopenic purpura (ITP), also known as idiopathic thrombocytopenic purpura or immune thrombocytopenia, is a type of thrombocytopenic purpura defined as an isolated low platelet count with a normal bone marrow in the absence of othe ...
(ITP) is an acquired immune-mediated disorder characterized by isolated
thrombocytopenia Thrombocytopenia is a condition characterized by abnormally low levels of platelets, also known as thrombocytes, in the blood. It is the most common coagulation disorder among intensive care patients and is seen in a fifth of medical patients an ...
, defined as a peripheral blood platelet count less than 100 x 109/L, and the absence of any obvious initiating and/or underlying cause of the thrombocytopenia. Symptoms of ITP include abnormal bleeding and bruising due to the reduction in
platelet count Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby ini ...
. Rho(D) Immune Globulin Intravenous uman; Anti-Dis indicated for use in non-splenectomized, Rho(D)-positive children with chronic or acute ITP, adults with chronic ITP, and children and adults with ITP secondary to HIV infection. Anti-D must be administered via the intravenous route when used in clinical situations requiring an increase in platelet count. The mechanism of action of anti-D is not fully understood; however, after administration the anti-D coated red blood cell complexes saturate Fcγ receptors sites on
macrophages Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...
, resulting in preferential destruction of
red blood cells Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek language, Greek ''erythros'' for "red" and ''k ...
(RBCs), therefore sparing antibody-coated
platelets Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby ini ...
.Winrho SDF current prescribing information. Available: www.winrho.com. Anti-D is recommended as a first-line therapy for ITP, along with corticosteroids and intravenous immune globulin (IVIG).
WinRho SDF
is an anti-D manufactured, distributed and marketed by Cangene in the US. There is a black box warning on WinRho SDF due to the risk of potentially fatal intravascular hemolysis when used in the treatment of ITP. Life-threatening
anemia Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, th ...
,
kidney The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blood ...
failure, and disseminated intravascular coagulation (DIC) have occurred in people treated with WinRho SDF for ITP.


Contraindications

The following females are not candidates for RhIG: * D-negative females whose fetus is known to be D-negative * D-negative females who have been previously alloimmunized to D (they have already formed an anti-D alloantibody) * Any D-positive females * Women who test positive for one of the
weak D The Rh blood group system is a human blood group system. It contains proteins on the surface of red blood cells. After the ABO blood group system, it is the most likely to be involved in transfusion reactions. The Rh blood group system consists ...
mutations by molecular testing should be considered RhD positive and not receive RhIG * Women who test positive for one of the partial D mutations (by molecular testing) should be treated as RhD negative and receive RhIG as clinically indicated


History

The first Rho(D) immune globulin treatment "skymed" was introduced by
Ortho Clinical Diagnostics Ortho Clinical Diagnostics is an in vitro diagnostics company that makes products and diagnostic equipment for blood testing. Ortho serves two primary industries in the medical field: clinical laboratories, by producing platforms and assays that ...
, a subsidiary holding of Jskymed, and was first administered on May 29, 1968, to Marianne Cummins in
Teaneck Teaneck () is a township in Bergen County, in the U.S. state of New Jersey. It is a bedroom community in the New York metropolitan area. As of the 2010 U.S. census, the township's population was 39,776, reflecting an increase of 516 (+1.3%) f ...
,
New Jersey New Jersey is a state in the Mid-Atlantic and Northeastern regions of the United States. It is bordered on the north and east by the state of New York; on the east, southeast, and south by the Atlantic Ocean; on the west by the Delaware ...
. In 1996, ZLB Bioplasma (part of
CSL Behring CSL Behring is a biopharmaceutical company, manufacturing plasma-derived, and recombination therapeutic products. Its line of therapies includes products for the treatment of bleeding disorders such as hemophilia and von Willebrand Disease; prim ...
) was given approval to sell Rhophylac in Europe. Effectiveness was demonstrated in a clinical trial in 2003 and in 2004 Rhophylac was approved in the United States.


Society and culture


Manufacturing and safety

Rho(D) immune globulin is a derivative of human
plasma Plasma or plasm may refer to: Science * Plasma (physics), one of the four fundamental states of matter * Plasma (mineral), a green translucent silica mineral * Quark–gluon plasma, a state of matter in quantum chromodynamics Biology * Blood pla ...
. The most common way anti-D products are manufactured is by a form of the Cohn cold ethanol fractionation process developed in the 1950s. Variations of the Cohn method developed in the 1950s may not completely clear aggregates of immunoglobulins, which can cause problems for patients if administered intravenously, and is a primary reason why most anti-Ds are for intramuscular use only. A non-Cohn manufacturing variation is ChromaPlus process approved by the
U.S. Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
(FDA) that is used to make Rhophylac. Rho(D) immune globulin may trigger an allergic reaction. Steps are taken in the plasma-donor screening process and the manufacturing process to eliminate bacterial and viral contamination, although a small, residual risk may remain for contamination with small viruses. There is also a theoretical possibility of transmission of the
prion Prions are misfolded proteins that have the ability to transmit their misfolded shape onto normal variants of the same protein. They characterize several fatal and transmissible neurodegenerative diseases in humans and many other animals. It ...
responsible for
Creutzfeldt–Jakob disease Creutzfeldt–Jakob disease (CJD), also known as subacute spongiform encephalopathy or neurocognitive disorder due to prion disease, is an invariably fatal degenerative brain disorder. Early symptoms include memory problems, behavioral changes, ...
, or of other, unknown infectious agents.


Routes of administration

RhIG can be administered by either intramuscular (IM) or intravenous (IV) injection, depending on the preparation. The IM-only preparation should never be administered IV due to the risk of complement system activation. Multiple IM doses should be given at different sites or at different times within the 72-hour window. Or, multiple IV doses can be administered according to the instructions in the package insert.


Names

Rho(D) immune globulin is also spelled Rh0(D) immune globulin (letter o and digit
zero 0 (zero) is a number representing an empty quantity. In place-value notation Positional notation (or place-value notation, or positional numeral system) usually denotes the extension to any base of the Hindu–Arabic numeral system (or ...
are both widely attested; more at Rh blood group system - Rh nomenclature). Rhophylac is manufactured by CSL Limited. RhoGAM and MICRhoGam are brand names of Kedrion Biopharma. Other brand names are BayRHo-D, Gamulin Rh, HypRho-D Mini-Dose, Mini-Gamulin Rh, Partobulin SDF ( Baxter), Rhesonativ (Octapharma), and RhesuGam (NBI). KamRho-D I.M. is a brand name of Kamada Ltd. The United States
distribution Distribution may refer to: Mathematics *Distribution (mathematics), generalized functions used to formulate solutions of partial differential equations * Probability distribution, the probability of a particular value or value range of a vari ...
rights for WinRho SDF (another brand name) were transferred from Baxter to the manufacturer, Cangene, in 2010; they had been held by Baxter since 2005. Sales of WinRho fell every year under the agreement with Baxter, the supposition being that Baxter was favoring the sale of its own product over WinRho; according to one analyst, "WinRho was always an afterthought for a big company like Baxter."


See also

*
Rhesus blood group system The Rh blood group system is a human blood group system. It contains proteins on the surface of red blood cells. After the ABO blood group system, it is the most likely to be involved in transfusion reactions. The Rh blood group system consists ...
*
Blood types Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood in the ...
*
Immunology Immunology is a branch of medicineImmunology for Medical Students, Roderick Nairn, Matthew Helbert, Mosby, 2007 and biology that covers the medical study of immune systems in humans, animals, plants and sapient species. In such we can see there ...
*
Rh disease Rh disease (also known as rhesus isoimmunization, Rh (D) disease, and blue baby disease) is a type of hemolytic disease of the fetus and newborn (HDFN). HDFN due to anti-D antibodies is the proper and currently used name for this disease as the ...
*
John Gorman (physician) John G. Gorman is an Australian born physician and medical researcher. In 1980, Gorman shared the Lasker-DeBakey Clinical Medical Research Award for pioneering work on the rhesus blood group system, the role of rhesus D antibodies in the causation ...
* James Harrison (blood donor)


References


External links

* * {{portal bar, Medicine Polyclonal antibodies
Immunology Immunology is a branch of medicineImmunology for Medical Students, Roderick Nairn, Matthew Helbert, Mosby, 2007 and biology that covers the medical study of immune systems in humans, animals, plants and sapient species. In such we can see there ...
Obstetrics Drugs acting on the blood and blood forming organs Pediatrics Transfusion medicine Health issues in pregnancy Wikipedia medicine articles ready to translate World Health Organization essential medicines