Hemolytic Disease
Hemolytic Disease
Hemolytic Disease
C2
Physiology Laboratory
Small Group Discussion
Output
A French midwife was the first to report hemolytic disease of the newborn (HDN)
in a set of twins in 1609. In 1932, Diamond and colleagues described the relationship
among fetal hydrops, jaundice, anemia, and erythroblasts in the circulation, a condition
later called erythroblastosisfetalis. Levine later determined the cause after Landsteiner
and Weiner discovered the Rh blood group system in 1940. In 1953, Chown
subsequently confirmed the pathogenesis of Rh alloimmunization to be the result of
passage of Rh-positive fetal RBCs after transplacental hemorrhage into maternal
circulation that lacked this antigen.
In 1966, 2 groups from the United Kingdom and the United States demonstrated,
in a combined study, that anti-D immunoglobulin G (IgG) prophylaxis soon after delivery
prevented sensitization in Rh-negative women. The World Health Organization (WHO)
technical report in 1971 recommended that a dose of 25 mcg (125 IU) of anti-D
immunoglobulin G (IgG) should be given intramuscularly for every 1 mL of fetomaternal
hemorrhage of Rh-positive packed RBCs or 2 mL of whole blood.
Diagnosis:
Physiology Laboratory Small Group Discussion Output |Hemolytic Disease of the Newborn 2
Peripheral blood morphology shows increased reticulocytes .Erythroblasts (also
known as nucleated red blood cells) occur in moderate and severe disease.
Positive direct Coombs test (might be negative after fetal interuterine blood
transfusion)
Blood tests done on the mother
During the prenatal period, an indirect Coombs test can show previous exposure to
Rh-positive antigens. If there are indications that the mother is Rh-sensitized,
amniocentesis can be done to detect bilirubin levels in the amniotic fluid.
Anemia
Jaundice
Kernicterus
Enlargement of liver and spleen
If the infants survive, the condition is marked by:
Heart failure
Edema
Pulmonary congestion
Lethargy seizures
Mental retardation
Treatment:
• Red Blood Cells (RBCs) are infused into abdominal cavity of fetus and then
absorbed into fetal circulation to avoid hydropsfetalis and fetal death.
- Selection of Blood for IUT: - Most IUTs are accomplished using group O. - Rh-
negative RBCs that are less than 7 days from collection
- RBCs are usually dry packed to remove residual anti-A and anti-B and
reconstituted with group AB fresh frozen plasma t provide coagulation factors.
Physiology Laboratory Small Group Discussion Output |Hemolytic Disease of the Newborn 3
- The risk of these procedures is now largely dependent on the prior condition of
the fetus and the gestational age at which transfusion is commenced.
- Titer greater than 32 for anti-D and 8 for anti-K OR four fold increase in titer
indicates need for analysis of amniotic fluid.
• Amniocentesis - Perform at 28 weeks if HDN in previous child
- Perform at 22 weeks if previous child severely affected • Perform if maternal
antibody increases before 34th wk.
- High values of bilirubin in amniotic fluid analyses by the Liley method or a
hemoglobin concentration of cord blood below 10.0 g/mL.
Immunomodulators
Class Summary
These agents normalize antibody levels in patients with primary defective
antibody synthesis. They prevent and treat certain bacterial and viral infections and
reduce the immune-mediated hemolysis and phagocytosis.
Intravenous immunoglobulin (Gamimune, Gammagard, Sandoglobulin, Gammar-P)
Several studies have reported success in minimizing the need for exchange
transfusion in severe HDN with IVIG. Effective adjunct to phototherapy. Mechanism of
action appears to be related to blockage of Fc receptors in the neonatal
reticuloendothelial system. Studies have also documented decreased hemolysis after
administration of IVIG using carboxyhemoglobin levels. Administration in doses of 500-
1000 mg/kg in the first few hours of life to a newborn with severe hemolysis should be
considered. However, efficacy depends on timing of administration, duration of
treatment, and severity of hemolysis. Should be prepared by and dispensed from
pharmacy and should not be mixed with normal saline. Dispensed as either 3% or 6%
solution.
Colony-stimulating Factor
Purified glycoprotein produced from mammalian cells modified with gene coding
for human erythropoietin (EPO). Amino acid sequence is identical to that of endogenous
EPO. Biological activity mimics human urinary EPO, which stimulates division and
differentiation of committed erythroid progenitor cells and induces release of
reticulocytes from bone marrow into the blood stream.
Physiology Laboratory Small Group Discussion Output |Hemolytic Disease of the Newborn 4
Stannsoporfin (SnMP, Stanate)
Also inhibits nitric oxide synthase and soluble guanylyl cyclase. Repeated doses
lead to inhibition of intestinal hemeoxygenase involved in iron absorption and may lead
to anemia. It also stimulates HO-1 transcription and protein levels. The half-life as
measured in healthy adult volunteers is 3.8 h.
The following may be indicated in patients with hemolytic disease of newborn (HDN):
These neonates have normal blood volume but elevated central venous pressure.
Despite of the first use of phototherapy by Cremer and associates more than 40 years
ago, no standard method for delivering phototherapy is yet available.
Phototherapy units differ widely with respect to the type and size of lamps used.
The efficacy of phototherapy depends on the spectrum of light delivered, the blue-
green region (425-490 nm) of visible light being the most effective; irradiance
(µW/cm2/nm); and surface area of the infant exposed.
Physiology Laboratory Small Group Discussion Output |Hemolytic Disease of the Newborn 5
High-intensity phototherapy first described by Tan in 1977 uses irradiance greater
than 25 µW/cm2/nm up to 40 µW/cm2/nm when a dose-response relationship to
bilirubin degradation reaches a plateau.
The structural isomer lumirubin is slowly formed, and its formation is irreversible and
is directly proportional to the irradiance and surface area of skin exposed to
phototherapy. Lumirubin is the predominant isomer formed during high-intensity
phototherapy.Decrease in bilirubin is mainly the result of excretion of these
photoproducts in bile and removal via stool. In the absence of conjugation, these
photoisomers can be reabsorbed by way of the enterohepatic circulation and
diminish the effectiveness of phototherapy.
The guidelines are based on total serum bilirubin levels and the direct fraction
should not be subtracted from the total unless it is more than 50% of the total serum
bilirubin level.
Intensive phototherapy should be started for babies with hemolytic disease. This
implies the use of irradiance in the 430-490 nm band of more than 30 µW/cm2/nm
delivered to as much of the infant's surface area as possible. This can be
accomplished using special blue fluorescent tubes that are labeled F20T12/BB
(General Electric, Westinghouse, Sylvania) or TL52/20W (Phillips, Eindhoven, The
Netherlands) and positioning them 10-15 cm above the infant. When fluorescent
tubes are used, they should be brought as close to the infant as possible to
increase irradiance. However, when halogen spotlights are used, the distance
above the infant should be as per the manufacturer's instructions because
spotlights can cause burns. Phototherapy lights emit minimal UV radiation that does
not cause erythema and is completely absorbed by the acrylic Plexiglas covering of
the tubes.
The infant should be in the bassinet, and the sides should be lined with white cloth
or aluminum foil to expose more surface area. The exposed surface area is
increased by the use of 1-2 fiberoptic pads that should be placed under the infant or
Physiology Laboratory Small Group Discussion Output |Hemolytic Disease of the Newborn 6
by the use of BiliBed (MedelaInc; McHenry, Ill) or Bili-Bassinet (Olympic Medical;
Seattle, Wash), which provides phototherapy from above and below. The diaper
should be removed if bilirubin is approaching exchange levels.
The serum bilirubin declines by 0.5-1 mg/dL in the first 4-8 hours on intensive
phototherapy and should be measured in 2-3 hours to document the effectiveness.
High-dose IVIG 1 g/kg given early in high-risk neonates with rapid rise of bilirubin
level (>0.5 mg/kg/h) and worsening anemia (Hb< 12 g/dL) despite intensive
phototherapy, is be able to eliminate the need for exchange transfusion and to
reduce duration of phototherapy. The number needed to treat (NNT) is 6.
Phototherapy is indicated in the term infant with hemolytic disease of the newborn
immediately after birth due to Rh disease and due to ABO incompatibility as follows:
Unborn (cord blood) - Total serum bilirubin level of more than 3.5 mg/dL
Age less than 12 hours - Total serum bilirubin level of more than 10 mg/dL
Age less than 18 hours - Total serum bilirubin level of more than 12 mg/dL
Age less than 24 hours - Total serum bilirubin level of more than 14 mg/dL
Age 2-3 days - Total serum bilirubin level of more than 15 mg/dL
Immediately after birth in all preterms who weigh less than 2500 g
This process removes approximately 70-90% of fetal RBCs. The amount of bilirubin
removed directly varies with the pretransfusion bilirubin level and amount of blood
exchanged. Because most of the bilirubin is in the extravascular space, only about
25% of the total bilirubin is removed by an exchange transfusion. A rapid rebound of
serum bilirubin level is common after equilibration and frequently requires additional
exchange transfusions.
The indications for exchange transfusion are controversial, except for the fact that
severe anemia and the presence of a rapidly worsening jaundice despite optimal
phototherapy in the first 12 hours of life indicate the need for exchange transfusion. In
Physiology Laboratory Small Group Discussion Output |Hemolytic Disease of the Newborn 7
addition, the presence of conditions that increase the risk of bilirubin encephalopathy
lowers the threshold of safe bilirubin levels.
IVIG has been shown to reduce the need for exchange transfusion in hemolytic
disease of the newborn due to Rh or ABO incompatibility. The number needed to treat
to prevent one exchange transfusion was noted to be 2.7 and was estimated to be 10,
if all the infants with strongly positive direct Coombs test were to receive the
medication.In addition, it also reduced the duration of hospital stay and
phototherapy.Although it was very effective as a single dose, multiple doses were
more effective in stopping the ongoing hemolysis and reducing the incidence of late
anemia.
Physiology Laboratory Small Group Discussion Output |Hemolytic Disease of the Newborn 8
Tin-mesoporphyrin in a dose of 4.5 mg/kg (6 µmole/kg) was used in an infant with
persistent hemolysis due to Rh alloimmunization to prevent need for further
phototherapy, without any adverse effects.
Prognosis:
The severity of this condition can vary. Some babies have no symptoms. In other
cases, problems such as hydrops can cause the baby to die before, or shortly after
birth. Severe HDN may be treated before birth by intrauterine blood transfusion.
Prevention:
The most severe form of this disease, which is caused by Rh incompatibility, can
be prevented if the mother is given a shot of a medicine called RhoGAM at certain times
during and after her pregnancy. If you have had a baby with this disease, talk with your
doctor if you plan to have another baby.
References:
3.Fasano RM. Hemolytic disease of the fetus and newborn in the molecular
era. Semin Fetal Neonatal Med. 2015 Nov 14.
4.van der Schoot CE, Tax GH, Rijnders RJ, de Haas M, Christiaens GC. Prenatal
typing of Rh and Kell blood group system antigens: the edge of a
watershed. Transfus Med Rev. 2003 Jan. 17(1):31-44.
5.Singleton BK, Green CA, Avent ND, et al. The presence of an RHD
pseudogene containing a 37 base pair duplication and a nonsense mutation in
africans with the Rh D-negative blood group phenotype. Blood. 2000 Jan 1.
95(1):12-8.
Physiology Laboratory Small Group Discussion Output |Hemolytic Disease of the Newborn 9
Physiology Laboratory Small Group Discussion Output |Hemolytic Disease of the Newborn 10