Blood Abnormalities- ABO Incompatibility

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Blood Abnormalities- ABO Incompatibility
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• Isoimmune hemolytic anemia may result when ABO
  incompatibility occurs between the mother and the
  newborn infant. This disorder is most common with
  blood type A or B infants born to type O mothers.
  The hemolytic process begins in utero and is the
  result of active placental transport of maternal
  isoantibody.
• In type O mothers, isoantibody is predominantly
  IgG is capable of crossing the placental
  membranes. Because of its larger size, the mostly
  IgM isoantibody found in type A or B mothers
  cannot cross.
• Symptomatic clinical disease, which usually does
  not present until after birth, is a compensated
  mild hemolytic anemia with reticulocytosis,
  microspherocytosis, and early-onset unconjugated
  hyperbilirubinemia.

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• Incidence. Risk factors for ABO incompatibility
  are present in 12-15 of pregnancies, but
  evidence of fetal sensitization (positive direct
  Coombs' test) occurs in only 3-4.
• Symptomatic ABO hemolytic disease occurs in lt1
  of all newborn infants but accounts for
  approximately 2\3 of observed cases of hemolytic
  disease in the newborn.

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Pathophysiology

• Bilirubin is formed from the breakdown of
  hemoglobin in red blood cells. Red blood cells
  (RBC) only live for 70-90 days in the newborn
  period, unlike the older child whose cells live
  120 days. Increased RBC destruction, decreased
  hepatic blood flow, and immature systems for
  breakdown of bilirubin causes jaundice in the
  newborn.
• The (GIT) in the newborn lacks the necessary
  bacteria to break down waste, increasing the
  reuptake of bilirubin. Jaundice results from
  liver immaturity, obstruction of bile ducts, and
  excessive hemolysis.

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Bilirubin production

• Bilirubin is a product of heme catabolism.
  Approximately 80 to 90 of bilirubin is produced
  during the breakdown of hemoglobin from (RBCs).
• Hemoglobin globin heme co
  biliverdine
• Bilirubin albumin hepatocyte
  (glucuronic acid)
• bilirubin diglucuronides bilirubin
  monoglucuronides. Conjugated bilirubin
• Conjugated bilirubin is secreted into the bile,
  and then excreted into the digestive tract.
  conjugated bilirubin is reduced to urobilin.
• Un conjugated bilirubin lipid soluble can cross
  blood brain barrier and its neurotoxic.
• Conjugated bilirubin water soluble not
  neurotoxic it indicates serious liver disorder .

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Methods of Diagnosis

• A complete diagnostic evaluation
• Determination of direct and indirect bilirubin
  fractions
• Determination of hemoglobin
• Reticulocyte count
• Blood type
• Coombs test
• Examination of the peripheral blood smear

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Management

• Antepartum treatment. Because of the low
  incidence of moderate to severe ABO hemolytic
  disease, invasive maneuvers before term is
  reached (eg, amniocentesis or early delivery) are
  usually not indicated.
• Postpartum treatment
• General measures. The maintenance of adequate
  hydration and evaluation for potentially
  aggravating factors (e.g., sepsis, drug exposure,
  or metabolic disturbance) should be considered.

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• 2. Phototherapy. Once a diagnosis of ABO
  incompatibility is established, phototherapy may
  be initiated before exchange transfusion is
  given. Because of the usual mild to moderate
  hemolysis, phototherapy may entirely obviate the
  need for exchange transfusion or may reduce the
  number of transfusions required.
• 3. Exchange transfusion.
• 4. Intravenous immunoglobulin (IVIG). By blocking
  neonatal reticuloendothelial Fc receptors, and
  thus decrease hemolysis of the antibody-coated
  RBCs, high-dose IVIG (1 g/kg over 4 h) has been
  shown to reduce serum bilirubin levels and the
  need for blood exchange transfusion with ABO or
  Rh hemolytic diseases.

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• Prognosis. For infants with ABO incompatibility,
  the overall prognosis is excellent.
• Timely recognition and appropriate management of
  the rare infant with aggressive ABO hemolytic
  disease may avoid any potential morbidity or
  severe hemolytic anemia and secondary
  hyperbilirubinemia and the inherent risks
  associated with exchange transfusion and with the
  use of blood products.

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Neonatal Hyperbilirubinemia
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• Neonatal jaundice is a common finding in general
  pediatrics. Many babies 3050 of normal term
  newborns, have transient jaundice 35days after
  birth.
• This unconjugated hyperbilirubinaemia is due to
  immaturity of the hepatic enzyme glucuronosyl
  transferase, which is responsible for
  glucuronidation of bilirubin.
• Unconjugated hyperbilirubinaemia occurring later
  in the perinatal period may be associated with
  breast feeding, so-called breast-milk jaundice.
  Elevated blood levels of unconjugated bilirubin
  can be due to haemolysis, sepsis, hypothyroidism
  or pyloric stenosis.

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• In contrast, conjugated hyperbilirubinaemia
  nearly always reflects hepatic dysfunction, which
  may be due to many different disorders, such as
  the neonatal hepatitis syndrome, biliary atresia
  or duct paucity syndromes, all of which have
  different long-term outcomes.
• The nature of the liver disease must be
  determined as early as possible in order to start
  appropriate treatment or provide supportive
  therapies.
• The best current practice is to investigate
  jaundice in any infant who is 14 days old, to
  determine whether unconjugated or conjugated
  hyperbilirubinaemia is present.

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Unconjugated hyperbilirubinemia

• Bilirubin, a breakdown product of heme, is
  extremely toxic. When it binds to cellular
  macromolecules, as in neural tissue, it causes
  damage, disrupts metabolic processes and leads to
  cell death.
• As bilirubin is normally tightly bound to albumin
  in the vascular compartment, concentrations of
  free bilirubin, which is capable of diffusing
  into brain tissue, are extremely low.
• Several parameters influence the level of free
  bilirubin production of unconjugated bilirubin,
  the serum albumin concentration, and the
  concentration of bilirubin competitors that also
  bind to albumin.

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• These include commonly used drugs such as
  sulphonamides, frusemide and benzoate free fatty
  acids, including lipid infusions for total
  parenteral nutrition and other breakdown
  products from red cell haemolysis.
• Premature infants are more vulnerable to
  bilirubin neurotoxicity than term infants, a
  tendency that may be potentiated by dehydration,
  which causes hyperosmolality, acidosis hypoxia.
  
• Kernicterus is the most serious consequence of
  severe unconjugated hyperbilirubinaemia, and
  develops secondary to binding of bilirubin in
  specific areas of the brain such as the basal
  ganglia. It may be fatal or cause severe movement
  disorders (choreoathetosis), mental retardation
  and deafness.

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Physiological jaundice

• As hepatic bilirubin glucuronosyl transferase
  activity is low at the time of birth, nearly all
  newborn babies have hyperbilirubinaemia in the
  first week of life. Unconjugated bilirubin
  predominates whereas serum conjugated bilirubin
  is low or undetectable.
• Approximately half of term babies are jaundiced
  more severe jaundice (serum bilirubin 200mmol/l)
  occurs in 820 in the first week of life.
  Factors associated with severe jaundice include
  breast feeding, exaggerated perinatal weight loss
  (gt7 of birth weight), maternal DM, bruising,
  induction of labour with oxytocin. The severity
  and duration of jaundice may be increased in
  infants born prematurely.

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• The mechanism(s) of such severe physiological
  jaundice remain uncertain, while environmental
  factors cannot be entirely excluded, genetic
  control of bilirubin production clearance
  appears to be most important
• There may be increased bilirubin load due to
  shortened RBC lifespan, increased activity of the
  enterohepatic circulation, and inefficient uptake
  of bilirubin by hepatocytes due to relatively
  immature expression of ligandin, which mediates
  uptake of organic anions, in addition to
  immaturity of hepatic bilirubin glucuronosyl
  transferase.

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Treatment

• Treatment may not be necessary in most cases.
  Phototherapy should be initiated for normal term
  infants only when serum total bilirubin is
  gt300mmol/l. The decision is complex and depends
  not only on the bilirubin concentration and its
  rate of increase, but also on the weight and
  gestational age of the infant, postnatal age, the
  rate at which bilirubin is generated and the
  adequacy of bilirubin albumin binding.
• Numerous clinical trials have demonstrated the
  effectiveness of phototherapy for decreasing
  unconjugated hyperbilirubinaemia (bilirubin
  gt300mmol/l) in term infants and in premature
  babies with serum bilirubin gt200mmol/l.

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• Body temperature and fluid status must be
  monitored closely fluid loss may be excessive,
  mainly because of increased insensible loss and
  additionally due to frequent watery stools. Eye
  patches are required. The baby may be more
  irritable, especially as normal parental
  interaction is often interrupted.
• For babies of ethnic extraction in whom severe
  unconjugated hyperbilirubinaemia may commonly
  occur even in the absence of haemolysis, exchange
  transfusion remains a viable therapy to prevent
  kernicters.
• Exchange transfusion may be required to prevent
  possible kernicterus in any baby with severe
  unconjugated hyperbilirubinaemia.

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Breast-milk jaundice

• Moderately severe unconjugated hyperbilirubinaemia
  associated with breast feeding is common,
  occurring in 0.52 of healthy newborn babies.
  Jaundice may develop after the fourth day of life
  (early pattern) or towards the end of the first
  week of life (late pattern) and usually peaks
  around the end of the second week of life.
  Jaundice may overlap with physiological jaundice
  or be protracted and last 12months.
• The etiology remains uncertain. Contamination of
  breast milk with steroids such as pregnanediols
  appears unlikely. Breast milk may contain
  endogenous substances, such as free fatty acids,
  which displace bilirubin in the intestinal
  contents enhance the enterohepatic circulation
  of bilirubin, although increased free fatty acids
  were not found in freshly expressed breast milk
  from mothers of infants with breast-milk
  jaundice.

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• Breast-fed babies have less frequent stools and
  eliminate less bile in faeces than bottle-fed
  babies, which may increase bilirubin reabsorption
  and contribute to hyperbilirubinaemia. More
  frequent breast feeding may enhance gut motility
  stool output.

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• The diagnosis is clinical an exclusively
  breast-fed infant with unconjugated
  hyperbilirubinaemia, normal conjugated bilirubin,
  haemoglobin and reticulocyte counts, no maternal
  blood group incompatibility, and a normal
  physical examination except for jaundice. The
  diagnosis is supported by a drop in serum
  bilirubin (50 in 13 days) if breast feeding is
  interrupted for 48h
• Breast-milk jaundice lasting 12months requires
  surveillance by the physician to exclude liver
  disease, although pale stools, if noted, are
  highly suggestive of important liver disease.

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Systemic disease

• Unconjugated hyperbilirubinaemia is frequently
  associated with systemic disease. Haemolysis of
  any etiology increases the bilirubin load and
  includes rhesus and ABO incompatibility with
  Coombs positivity G-6-PD deficiency
  erythrocyte membrane defects.
• Severe haemolytic disease of any aetiology can
  result in severe jaundice associated with
  kernicterus and requires aggressive treatment
  with phototherapy and/or exchange transfusion.
• Bruising, haemorrhage into brain or lung tissue,
  and neonatal polycythaemia also increase the
  bilirubin load. The association of unconjugated
  hyperbilirubinaemia with congenital
  hypothyroidism is based on early observations

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• The mechanism of jaundice is not known, but
  thyroid function should be evaluated in any
  neonate with jaundice. Unconjugated
  hyperbilirubinaemia is also found with pyloric
  stenosis and other forms of upper intestinal
  obstruction, which resolves rapidly after pyloric
  myotomy
• The mechanism remains uncertain. Alikely
  explanation is that these infants have Gilbert
  syndrome and develop unconjugated
  hyperbilirubinaemia due to reduced oral intake.
• Other pathological conditions associated with
  unconjugated hyperbilirubinaemia include sepsis,
  hypoxia, hypoglycaemia, galactosaemia and
  fructose intolerance.

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Inherited disordersCriglerNajjar syndromes

• CriglerNajjar syndromes type 1 and 2 are
  autosomal recessive conditions which lead to
  unconjugated hyperbilirubinaemia due to a
  deficiency of the enzyme bilirubin uridine
  diphosphate glucuronosyl transferase (UDPGT).
• In CriglerNajjar type 1 there is effectively no
  UDPGT present in type 2 the defect is partial.
  The genetic basis for these diseases has been
  elucidated since the structure of the human
  bilirubin glucuronosyl transferase gene has been
  established

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• Clinical features and diagnosis Both conditions
  present early in the perinatal period with a
  rapid rise in bilirubin despite phototherapy.
  Kernicterus may develop in the perinatal period,
  particularly if treatment is delayed or if
  associated with dehydration or sepsis.
• Liver function tests, including conjugated
  bilirubin, are normal. Liver histology is normal
  except for occasional bile plugs.
• Confirmation of the diagnosis may be obtained by
  detection of the enzyme deficiency in liver or
  estimation of bilirubin mono- and diglucuronides
  in bile aspirates. Bilirubin diglucuronides are
  not present in bile in type 1 but can be found in
  type 2.

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• Treatment for CriglerNajjar type 1 consists of
  aggressive use of measures to remove bilirubin
  with either phototherapy or exchange transfusion.
  Effective phototherapy depends on delivering
  radiant energy from light of wavelength 400500
  nm to the skin.
• Irradiance is not related to the brightness of
  the lights the quantity of irradiation is
  inversely related to the distance between the
  lights and the infant. Skin pigmentation does not
  influence effectiveness of treatment. The
  development of lighted mattresses has facilitated
  treatment permitted early discharge from
  hospital.

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• Outcome Sudden late neurological deterioration in
  CriglerNajjar type 1 may occur even if
  management of hyperbilirubinaemia has been
  meticulous. Late intrahepatic cholestasis has
  been reported. The outcome following liver
  transplantation is excellent.

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Conjugated hyperbilirubinaemia

• Conjugated hyperbilirubinaemia nearly always
  indicates liver disease, which may be due to the
  neonatal hepatitis syndrome, biliary atresia or
  duct paucity syndromes. The nomenclature for
  neonatal liver disease is problematic.
• The term neonatal jaundice causes confusion
  with physiological jaundice, while neonatal
  cholestasis is imprecise. In the first 34
  months of life every infant ha some degree of
  neonatal cholestasis on a physiological basis,
  which is multifactorial.

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Conjugated hyperbilirubinaemia

• Hepatocellular pathways of bile acid conjugation
  and biliary secretion are immature, and uptake of
  bile acids and other organic anions by
  hepatocytes is inefficient, leading to high
  concentrations of bile acids in blood the
  circulating bile acid pool is contracted, ileal
  uptake of bile acids is underdeveloped
• The term neonatal hepatitis is inadequate
  because hepatic inflammation is not prominent in
  every condition. The term neonatal hepatitis
  syndrome (NHS) is now used as it conveys the
  similarity of the clinical illness in infants and
  suggests a broad spectrum of causative disease
  processes.

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• How common is hyperbilirubinemia? How do we
  define its severity?
• For infants in the first week of life
• 90 of healthy term newborns have (TSB) levels
  above 2.0 mg/dL
• 50 have levels greater than 6.0 mg/dL
• 5 have levels above 13 mg/dL
• By the fourth day of life, approximately 95 of
  TSB values were 17 mg/dL, a value they
  considered indicative of severe neonatal
  hyperbilirubinemia.

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• Primary causes of neonatal hyperbilirubinemia
• Increased bilirubin production from enhanced red
  cell turnover
• Decreased bilirubin clearance, due to decreased
  hepatic clearance or increased enterohepatic
  circulation

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• Usual causes of increased bilirubin production
• Bilirubin is the end product of heme catabolism.
  In newborns, bilirubin production is distributed
  as follows
• 75 from normal destruction of senescent (RBCs)
• 25 from the breakdown products of ineffective
  erythropoiesis and from nonhemoglobin sources
  such as cytochromes and catalyses

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• Factors associated with increased bilirubin
  production
• Normally elevated hemoglobin levels (15-20 gm/dL)
  
• Prematurity
• Blood group incompatibility
• Breakdown of extravascular blood
• Maternal diabetes
• RBC enzyme defects, such as (G6PD) deficiency
• RBC membrane defects (e.g., hereditary
  spherocytosis)
• Other hemolytic processes, such as sepsis

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• Causes of delayed clearance of bilirubin
• Bilirubin clearance from the body requires
  hepatic processing (conjugation), biliary
  excretion, and fecal or urinary elimination of
  intestinally metabolized bilirubin products.
  Conditions that may interfere with or delay this
  process include
• Diminished uptake of bilirubin by the hepatocyte
• Decreased glucuronyl transferase enzyme
  conjugating activity
• Familial disorders of bilirubin excretion
• Sluggish or obstructed biliary excretion This
  causes an increase in serum direct bilirubin.
• Active enterohepatic circulation (e.g., with
  antibiotic treatment, prolonged gut transit time,
  delayed passage of meconium, and inadequate
  enteral intake). This increases the level of
  unconjugated bilirubin.
• Prematurity All of the systems noted are even
  less mature

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• Hematologic manifestations of neonatal hemolysis
• Decrease in hemoglobin concentration
• Reticulocytosis gt8 at birth, gt5 in first 2-3
  days, and gt2 after first week
• Changes in the peripheral smear
  microspherocytosis, anisocytosis, target cells
  Elevated carboxyhemoglobin levels

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• Level of bilirubin should a premature baby
  receive phototherapy
• The empiric approach has been to apply
  phototherapy early at relatively low TSB values.
  Aggressive use of phototherapy in preterm babies
  (especially those with a birth weight of lt1000
  gm) has been associated with near elimination of
  low-bilirubin kernicterus. Two approaches
  include
• In an at-risk or bruised very-low-birth-weight
  baby, initiate phototherapy by 24 hours of age.
• Initiate phototherapy at 0.5 of body weight. For
  example, in a baby with a birth weight of 800 gm,
  phototherapy might be started when the TSB is 4
  mg/dL.

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• Risk factors for severe hyperbilirubinemia in
  term newborns
• Jaundice within first 24 hours after birth
• A sibling who had jaundice as a neonate
• Unrecognized hemolysis such as ABO
  incompatibility or Rh incompatibility
• Nonoptimal sucking/nursing
• Deficiency in G6PD
• Infection
• Cephalohematomas/bruising
• East Asian or Mediterranean descent
• Maternal diabetes

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• Newborns require a systematic assessment for the
  risk of severe hyperbilirubinemia prior to
  hospital discharge
• Universal predischarge TSB or transcutaneous
  assessment.
• TSB assessment based on a combination of risk
  factor assessment and visual assessment. Note
  that visual assessment alone is inadequate

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How does phototherapy work?

• Light absorption by bilirubin molecule
• In vitro, the unconjugated bilirubin molecule
  absorbs light maximally in the blue portion of
  the visible spectrum, at a wavelength of 450 nm.
• In vivo, because of bilirubin binding to albumin
  and tissue proteins as well as improved skin
  penetration at longer wavelengths, incident light
  in the blue-green spectrum may be more effective.
  
• Excretion of bilirubin
• The photoisomers are principally excreted in the
  bile. When cholestasis is present, the
  photoisomers can be excreted in the urine.
• Excessive serum concentrations of the
  photoisomers (lumirubin) may manifest as bronze
  baby

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• Photoconversion of bilirubin to water-soluble
  isomers
• Absorption of photon energy produces an excited
  state of bilirubin, leading to photoisomerization
  and photo-oxidation.
• Photoisomerization is the main pathway of
  bilirubin elimination.
• Photoisomerization disrupts the internal hydrogen
  bonds of native bilirubin, making it more polar
  and increasing its water solubility.

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Variables control the effectiveness of
phototherapy

1. Spectrum of incident light
2. Irradiance of the phototherapy unit
3. Exposed surface area in the infant
4. Distance of the infant from light source

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• How phototherapy reduce bilirubin levels in the
  first 24 hours of treatment
• Intensive phototherapy Up to 30-50 decline from
  initial TSB in term infants with nonhemolytic
  jaundice
• Standard phototherapy Approximately 6-20 decline

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Side effects of phototherapy

1. Increased IWL, especially in preterm neonates and
   those cared for under radiant warmers. Different
   light sources have variable effects on insensible
   water loss.
2. Reduced gut transit time, probably related to
   increased bilirubin and photoproducts in the gut.
   
3. Decreased platelet counts to lt150,000/mm3.
4. Transient riboflavin deficiency that usually
   resolves within 24 hours of the discontinuation
   of phototherapy.

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• When should phototherapy be stopped in preterm
  infants?
• There is no consensus or adequate clinical data
  to address this issue. Phototherapy may be
  discontinued at the level at which it was
  considered appropriate to initiate the
  intervention, generally 5 mg/dL for infants
  weighing lt1 kg.

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• Causes of death during an exchange transfusion
• Cardiac/vascular
• Arrhythmia
• Vascular perforation by catheter
• Acute hemorrhage
• Thrombus
• Acute volume overload
• Massive air embolism
• Metabolic (especially in preterm infants)
• Severe acidosis
• Hyperkalemia
• Hypocalcemia

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Case analysis

• 24 old male infant, gravida1,para 1.
• Apgar scores 8 at 1 min
• Mother blood type O
• PE icterus appeared on
• face and trunk skin
• liver edge 1cm
• palpable spleen tip

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Case analysis continued

• Lab tests
• Hgb13g/dl, reticulocyte count 7
• Blood smear nucleated RBC
• Blood type A, Rh-positive
• Serum bilirubin 12.9mg/ml
• Direct Coombs test weakly positive
• Question whats the risk factor ?