Module 6 Ics

Front 1

What are the two models explaining the hematopoietic stem cell ontogeny in the embro and fetus?

Back 1

1. Single stem cell model
-- hematopoietic stem cells arise from the yolk sac
-- migrate to the fetal liver and later to BM

2. Dual stem cell model
-- hematopoietic stem cells arise during the mesoderm formation
-- migrate both to the yolk sac and to intraembryonic sites (aorta, gonad, mesonephros)
-- capable of self-renewal and diff in absence of growth factors as opposed to progenitor cells found in adult marrow
-- shown to give rise to several mature cell types (erythrocytes, megakaryocytes, granulocytes, monocytes, anc cells of immune system)
-- present in cord at birth and been shown to engraft and sustain long-term hematopoiesis in transplanted individuals

Front 2

What are the periods that divide hematopoiesis from coception to birth?

Back 2

mesoblastic

hepatic

myeloid

Front 3

Describe the process of hematopoiesis.

Back 3

Foci of primitive erythropoiesis are identified by the 3rd to 4th week in the area vasculosa of the yolk sac
-- give rise to the blood vessels and to the primitive blood cells, hematocytoblasts

First blood cells produced by the embryo are RBC series and can be seen 4-5wks post-conception. Characterized by:
1. intravasc differentiation and embryonic Hb content
2. persistence of the nucleus as they mature
3. increased sensitivity to erythropoietin: more rapid differentiation and shortened lifespan
4. megaloblastic appearance w/ MCV of 250fl/cell

Normoblastic erythropoiesis begins around 6th week of gestation in the liver and by 10th week development accounts for >90% of circulating RBCs
-- liver remains major site of hematopoiesis from 3rd to 6th month

By second trimester, gradually shifts from liver to BM

Front 4

What about hematopoiesis following birth?

Back 4

Amount of marrow tissue continues to grow w/o increase in cellular concentration.

To increase production:
-- increase cell turnover OR
-- increase volume of hematopoietic tissue producing marrow expansion mostly seen in the calveria

Front 5

Erythropoiesis is primarily under the influence of...?

Back 5

The fetus; only partially affected by maternal factors

Erythropoietin, produced by fetal liver plays increasing role in
-- hepatic and myeloid phase
-- will be detectible in cord blood at birth

Front 6

Erythropoietin levels after birth?

Back 6

Becomes almost undetectible w/in the first week of life
-- Hb synth and RBC production decline abruptly in first week of life

Front 7

Hb content in newborns?

Back 7

Content changes composition throughout embryonic/fetal development and continues through the first few months of life

ε chain --> embryonic Hb
-- declines in first trimester (by second month)

γ-chain --> fetal Hb
-- begins in first trimester
-- peak levels 2nd and 3rd trimesters
-- levels decline after birth for "Hb switch"

β chain --> adult Hb
-- low levels throughout gestation
-- levels increase after birth for "Hb switch"

(See pg 144 for chart)

Front 8

Normal blood values for a fetus at gestational age?

Back 8

↑ Hb and Hct during pregnancy w/ stabilization at ~33wks

↓ MCV and ↓ retic count throughout pregnancy

Front 9

Normal blood values at time of cord clamping?

Back 9

Placental vessels:
-- 75-125mL of blood (25-33% of fetal blood volume)
-- delayed clamping (30-40sec after birth) ↑ both blood volume (up to 60%) and Hb level

Front 10

Normal blood values at a sampling site?

Back 10

At birth, the cap/venous ratio is >1.0 and inversely correlates w/ gestational age
-- >1.2 in premature infants <30 wks gestation

This difference disappears by 5 days life

Front 11

List causes of anemia in neonates.

Back 11

Hemorrhage
Hemolysis
Impaired RBC production

Front 12

Causes of hemorrhage in a neonate?

Back 12

1. feto-maternal or fetal-fetal occult hemorrhage

2. obstetrical complications/malformation of placenta and cord

3. internal hemorrhage

4. iatrogenic (blood draws)

Front 13

Causes of feto-maternal hemorrhage?

Back 13

Most common:
-- traumatic amniocentesis
-- external cephalic version prior to delivery

Other causes:
-- traumatic injury to mother during pregnancy
-- third trimester amniocentesis
-- placental abnormalities
-- manual removal of placenta

Front 14

Incidence of feto-maternal hemorrhage?

Back 14

documented in 3/1000 women

Fetal cells will be present in ~50% of all pregnancies
-- when present, account for less than 2mL in 98% of those pregnancies


Hemorrhage ≥ 30mL have been documented in ~3/1000 women

Front 15

Dx of feto-maternal hemorrhage?

Back 15

Depends upon the demonstration of fetal cells in the maternal circulation.

In the presence of HbF producing hemoglobinopathies in the mother and ABO incompatibility:

Kleinhauer and Betke acid elucidation technique is most commonly used test
-- based on the resistance of the fetal Hb to elute from intact red cells in acid medium

Front 16

Incidence of fetal-fetal hemorrhage?

Back 16

Observed only in monozygotic multiple births w/ monochorial placentas

13-33% twin-twin transfusion in twin pregnancies
-- difference in Hb btwn recipient and donor can be as high as 5g/dL

Front 17

Result of fetal-fetal hemorrhage?

Back 17

DONOR: Severe anemia

RECIPIENT: Polycythemia w/ symptoms of hyperviscosity, DIC, and hyperbilirubinemia

Front 18

Causes of obstetrical complications/malformations of placenta and cord?

Back 18

Rupture of cord can occur:
-- during rapid delivery
-- in normal delivery when it is too short
-- if entangled around fetus
-- if forceps are used in difficult deliveries

Velamentous insertion of umbilical cord
-- rare
-- 1-2% of pregnancies assoc w/ this malformation result in severe hemorrhage and perinatal death rate ranging from 58% - 80%

Other causes:
-- accidential incision of placenta during C-section
-- placenta previa or abrupto

Front 19

What can cause internal hemorrhage?

Back 19

traumatic delivery
vacuum extraction
breech delivery
VitK deficiency
neonatal infection (CMV, adenovirus)
hemangioma
BW <1500g
maternal intake of meds interfering w/ normal hemostasis
maternal platelet Ab directed against fetus' platelets

**anemia occurs in first 24 to 72 hours of life w/o assoc jaundice

Front 20

Iatrogenic blood draws and anemia?

Back 20

Number of draws is inversely proportional to birth weight and gestational age
-- more premature will be sickest and require greatest magnitude of interventions

Neonates <1500g lose btwn 5 and 45% of their blood volume during the first 4 weeks in the hospital

Need increased number of transfusions

Front 21

Clinical manifestations of acute blood loss in a newborn?

Back 21

acute distress
pallor
shallow, rapid, irregular respiration
weak or absent pulses
NO hepatosplenomegaly

Front 22

Venous pressure of acute blood loss in a newborn?

Back 22

LOW

Front 23

Lab values of acute blood loss in a newborn?

Back 23

Hb CONCENTRATION:
-- may be normal initially
-- drops rapidly during first 24h of life

RBC MORPHOLOGY:
normochromic, macrocytic

SERUM IRON:
-- normal at birth

COURSE:
-- rapid treatment of anemia and shock to prevent death

TX:
-- IV fluids and blood
-- iron therapy later

Front 24

Clinical manifestations of chronic blood loss in a newborn?

Back 24

-- marked pallor disproportionate to evidence of distress
-- occasional CHF, including hepatosplenomegaly

Front 25

Venous pressure of chronic blood loss in a newborn?

Back 25

Normal or elevated

Front 26

Lab values of chronic blood loss in a newborn?

Back 26

Hb CONCENTRATION:
-- low at birth

RBC MORPHOLOGY:
-- hypochromic, microcytic
-- anisocytosis
-- poikilocytosis

SERUM IRON:
-- low at birth

COURSE:
-- generally uneventful

TX:
-- iron therapy
-- PRBCs occasionally necessary

Front 27

How does hemolysis manifest?

Back 27

1. persistent increase in reticulocytes w/ or w/o anemia in the absence of hemorrhage

2. rapidly declining Hb w/o increase of reticulocytes and in the absence of hemorrhage

Front 28

Neonates and bilirubin levels?

Back 28

For same degree of hemolysis, normal neonates will have higher rates of indirect hyperbilirubinemia (lipid soluble) than an adult counterpart

Seen in 60% of tern infants, 80% premature infants

Normal newborns exhibit a mild elevation of bilirubin in the cord blood w/ a:
-- gradual rise to ~8mg/dl by day 3 to 5 (5-7 in premies)
-- normalization in the second week of life (second month in premies)

Front 29

Contributing factors to higher bilirubin levels in neonates?

Back 29

1. increased production or destrucion of RBCs
-- fetal RBC has shorter life than adult RBCs

2. Physiologic hepatic immaturity in performing glucoronidation
-- transferase level at birth is ~1% of adult level and reaches 5% by 3 to 4 days old

3. Overactive enterohepatic recirculation

Front 30

Possible implications of increased bilirubin levels?

Back 30

When bili production increases perinatally:
-- rapid rise of indirect bilirubinemia --> most often in 1st 24h of life
-- increased risk of developing kernicterus if not managed rapidly and aggressively

Front 31

Describe mild hemolytic disease in a newborn/fetus.

Back 31

Indirect bili: <16-20mg/dL

No anemia

No treatment required

Incidence: 45-60%

Front 32

Describe moderate hemolytic disease in a newborn/fetus.

Back 32

No fetal hydrops

Moderate anemia

Severe jaundice -- risk of kernicterus

Treat w/ exchange transfusion

Incidence: 25-30%

Front 33

Describe severe hemolytic disease in a newborn/fetus.

Back 33

IN UTERO fetal hydrops
-- incidence of 20-25%

Before 34 weeks 10-12%
After 34 weeks 10-12%

Treat w/ intrauterine transfusion

Front 34

Name two hemolytic diseases.

Back 34

1. Rh Hemolytic disease

2. ABO Hemolytic disease

Front 35

Prevalence of Rh hemolytic disease?

Back 35

Prevalence w/in 6mos of delivery of the first Rh+ ABO compatible infant is 16%

Front 36

Immune response of Rh hemolytic disease?

Back 36

PRIMARY:
-- slow, 8-9wks
-- weak
-- produces IgM

SECONDARY:
-- rapid
-- intense
-- produces IgG --> crosses placenta

Front 37

Pathogenesis of Rh hemolytic disease?

Back 37

Maternal anti-D IgG Ab (IgG1 and/or IgG3) coats fetal RBCs --> destruction

Persistent extramedullary erythropoiesis
-- spleen, liver
-- kidney, adrenal glands
-- hepatosplenomegaly --> hepatic and cardiac failure

Front 38

Tx of Rh hemolytic disease for the mother?

Back 38

1. Prevention of Rh immunization w/ anti-D IgG
-- 300μg after full-term delivery
-- ≥100μg after 2nd trimester abortion
-- 50μg after 1st trimester abortion

2. Suppression of alloimmunization
-- intensive plasma exchange
-- high dose IGIV

Front 39

Tx of Rh hemolytic disease for the fetus and infant?

Back 39

1. Intrauterine transfusion
-- blood <96 hrs old irradiated to produce GVHD
-- 40-50mL/kg admin in umbilical vein under ultrasound guidance

2. Exchange transfusion (prevents further hemolysis)
-- Group O or ABO compatible blood used
-- 1.5 - 2 infant blood volues are exchanged (130-170 mL/kg)
-- 90% of RBCs are removed after 2 volumes and 70% after 1 volume
-- not as good in removing bilirubin and IgG

3. phototherapy

Front 40

Prevalence of ABO hemolytic disease?

Back 40

--Milder thatn Rh hemolytic disase and ABO incompatibility in adults

-- hydrops fetalis is extremely rare

Front 41

Pathogenesis of ABO hemolytic disease?

Back 41

-- fewer A and B Ag on fetal RBCs

-- Anti-A and Anti-B do not bind complement on the fetal RBC mbrn

-- Most Anti-A and Anti-B are IgM and do not cross the placenta

-- IgG Anti-A and Anti-B cross the placenta binding to several other tissues and secretions

Front 42

Labs of ABO hemolytic disease?

Back 42

25-30% of ABO-incompatible babies will have a weakly positive DAT on cord blood at delivery
-- often negative on capillary blood 2-3 days later

Front 43

Tx of ABO hemolytic disease?

Back 43

Less that 2% of ABO incompatible babies will have disease severe enough to require exchange transfusion

Front 44

Do any other antibodies cayse fetal hemolytic disease?

Back 44

Striking reduction in Rh hemolytic disease has been accompanied by an increase in non-D alloimmunization

Ab associated w/ hydrops fetalis are:
-- Anti-Kell
-- Anti-c
-- Anti-Fya

Front 45

What are the causes of impaired RBC production in a fetus/neonate?

Back 45

1. physiologic anemia of prematurity

2. Diamond-Blackfan syndrome

3. Others:
-- Pearson's syndrome, Leigh disease, Kearns-Sayre syndrome
-- Congenital infections --> CMV, rubella, adenovirus, parvovirus
-- Congenital leukemia, Down's syndrome, etc.

Front 46

Describe physiologic anemia of prematurity.

Back 46

1. ↓↓ RBC mass > expanding plasma volume

2. Combination of physiologic shutdown of hematopoietic activity soon after birth and accelerated destruction of immature RBCs
-- Hb as low as 11.4g/dL in full-term infang at 8-12wks (normal)
-- Hb of 8.0g/dL at 4-8 wks for premature infants <1500g

Front 47

Treatment for physiologic anemia of prematurity?

Back 47

Erythropoietin (r-HuEPO) is as effective as allogeneic blood transfusion in increasing Hb level, but much more costly

Front 48

Describe Diamond-Blackfan Syndrome.

Back 48

25% of affected patients are anemic at birth
-- Hb <10g/dL
-- reticulocytopenia

Physical anomalies in 30%
-- short stature is most common
-- others: microcephaly, cleft palate, triphalangeal thumb, eye anomalies

Inheritance is uncertain