Transcript Alloimmunization disorders

Alloimmunization disorders
Steven R. Allen, MD
Scott & White Hosp & Clinic
Temple, TX
Educational objectives
• Review fetal & neonatal consequences
of alloimmunization disorders
• Update genetics of Rh blood group
• Discuss strategies for prevention of Rh
alloimmunization
• Develop management strategies for
alloimmunization disorders
Immune responses
Ab against Ag from:
• Autoimmunity:
Self
• Isoimmunity:
MZ twin; inbred strain
• Alloimmunity:
another member, same
species
• Heteroimmunity: another species
Alloimmunization Disorders
• Rhesus blood group
• Atypical blood groups
• Platelet
Rh alloimmunization
Historic landmarks
1940: Rhesus
& similar human
RBC Ag
(Landsteiner &
1932: hemolysis Weiner)
1963: IP
assoc’d with
trans
hydrops (Diamond)
(Liley)
1992:
RhD
& non-D
cloned
*
1600’s:
hydrops, jaundice;
unknown etiology
1938: a-fetal
Hgb Ab
postulated
(Darrow)
1961: AF
bili predicts
HDN
severity
(Liley)
1985:
PUBS
trans
(Daffos)
*1967: RhIG
Rh alloimmunization
Historic landmarks
1940: Rhesus
& similar human
RBC Ag
(Landsteiner &
1932: hemolysis Weiner)
1963: IP
assoc’d with
trans
hydrops (Diamond)
(Liley)
1992:
RhD
& non-D
cloned
*
1600’s:
hydrops, jaundice;
unknown etiology
1938: a-fetal
Hgb Ab
postulated
(Darrow)
1961: AF
bili predicts
HDN
severity
(Liley)
1985:
PUBS
trans
(Daffos)
*1967: RhIG
Rh genetics & biochemistry
• Rh = D … and more
• 2 homologous structural genes on
1p36-p34, RHD (encoding D) & RHCE
(encoding CcEe polypeptides), with
92% sequence identity
• Alternative mRNA splicing of single
gene produces CcEe Ag variability
Rh genetics & biochemistry
• Gene product: 417 AA non-glycosylated
hydrophobic transmembrane protein,
expressed only on erythrocytes
(unknown function, and no shared
sequence homology with any other
known protein)
• Other blood groups encoded on
chromosome # 1 and other
chromsomes
Rhesus blood group
Rh pos
RhD
gene
Rh D
Ag
X
X
RhCE
gene
Rh CE
Ag
X
X
X
X
(= 2 Rh
genes)
Rh neg
(=1 Rh
gene)
What is Du?
• Present in 0.2-1% of caucasians
• Prior Du designation has been changed
to “weak D positive”
• Created by a variety of mutations in
RhD gene
• Manage as if “D positive”
Incidence of Rh negativity*
30
25
20
%
15
10
5
0
Native Eurasia Afro-Am
N
Am
Europe
* a caucasian trait
US
Basque
Development of
Rh alloimmunization
• Rh neg mother
• Maternal exposure to Rh pos RBCs
– non-pregnant: transfusion, including
RBC contaminated plts or WBCs
– pregnant: transplacental hemorrhage
(dose dependent; incidence follows:)
• 75% overall
• 60%  0.1 mL (0.1 mL sufficient for
alloimmunization)
• 0.25% > 30 mL
Maternal immune response
D alloimmunization
Primary
• weak
• IgM (IgG wks later)
• develops over 8 wks
to 6 mos
Secondary
• rapid response of
IgG
• higher avidity than
primary response
Maternal response modulated by ABO status:
ABO incompatibility is protective
(alloimmunization risk decreased by 75%)
Risk of Rh alloimmunization
P0, Rh neg mom, Rh pos fetus, ABO compatible
no RhIG
18
*
16
14
12
% 10
8
6
4
2
0
Term preg
Termination
Sab
Amnio (US)
* 90% due to peripartum feto-maternal hemorrhage
Risk of Rh alloimmunization
P0, term preg, Rh incompatible, ABO compatible
Effect of RhIG
18
16
14
12
% 10
8
6
4
0.1%
2
0
No RhIG
p/p RhIG
p/p + 28 wk RhIG
Mechanism of hemolytic disease
of the newborn (HDN)
• Fetal RBCs destroyed by mat -D (IgG)
– non-complement mediated
– -D coated RBCs adhere to macrophages,
form rosettes, & are trapped in spleen
– RBC membrane fragments removed, with
RBC fragility & lysis
• Fetal anemia
Mechanism of hemolytic disease
of the newborn (HDN)…cont
• Extramedullary erythropoiesis
– erythroblastosis
– hepatosplenomegaly
– hep dysfxn, including hypoproteinemia
– portal hypertension
• Hydrops
Rh Immune Globulin
• 300 g dose neutralizes exposure risk of up
to 30 mL fetal blood if given within 72 h
• AABB recommends screen before each dose
(to r/o greater exposure volume or prior
alloimmunizaiton)
• t 1/2 = 24 d…generally effective for 12 wk
(if
given @ 28 wks, 15-20% will have low titer @
term)
• risk of viral infxn minimal (Hep C) to absent
(HIV)
Prevention of Rh Alloimmunization
ACOG RhIG recommendations (Level A)
Rh neg women not Rh alloimmunized
should receive RhIG:
• At approx 28 wks (unless FOB Rh neg)
• Within 72 h of del of Rh pos infant *
• After a 1st TM pregnancy loss
• After invasive procedures, such as
amniocentesis
* cost-effective
Prac Bull #4, 5/99
Prevention of Rh Alloimmunization
ACOG RhIG recommendations (Level C)
RhIG prophylaxis should be considered if
a patient experiences:
• threatened abortion
• 2nd or 3rd TM bleeding
• External cephalic version
• Abdominal trauma
Prac Bull #4, 5/99
Advantage to Rh immunoglobulin
admin after BTL?
• Some women later want a pregnancy
• Improves availability of blood if a
transfusion ever needed
Screening for Rh Alloimmunization
1st TM Rh & IDC
– If Rh pos, no further testing indicated
– If Rh neg & IDC neg, give RhIG at 28 wks
(and rpt IDC per AABB recommendation)
– If Rh neg & IDC pos, check titer serially,
q 2-4 wks (mgmt based in part on titer)
Predictors of severity of HDN
•
•
•
•
Rhesus genotype of father of baby
History of HDN
Maternal Ab titer
Amniotic fluid spectrophotometric
measurements
• Ultrasonographic findings
– MCA peak velocity
– hydrops
• Invasive fetal testing
Rhesus genotype of father of baby
• Rh neg: NO RISK - routine prenatal care (regardless
of maternal -D titer)
• Rh positive:
– Zygosity for D can be predicted based on CcEe
phenotype or genotype, ethnicity, and number of
prior D-positive offspring
– if homozygous (45%), then fetus at risk
– if heterozygous (55%), fetus has 50% chance of
being vulnerable
• Assume Rh pos (& fetus at risk) if unable to confirm
otherwise
History of HDN
• Subsequent pregnancies generally have
similar or > degree of alloimmunization
• Risk of recurrent hydrops = 90%
• Hydrops generally recurs at similar or
earlier (not later) gestational age
• Risk of hydrops in 1st affected
pregnancy = 10%
Maternal -D titer
• -D titer is a crude predictor
• Critical titer indicates the need for
additional evaluation
• Critical titer generally 16
(altho may vary, 8-32, between labs
and by technique)
Ultrasonography to assess for
fetal anemia
• Hydrops is a late sign of significant
anemia
• Doppler velocimetry predicts anemia best studied in MCA*
– peak velocity > 1.5 MoM for gest age
predicts anemia (sensitivity  86%;
false pos rate 12%)
* NEJM 2000;342:9-14
Invasive fetal testing
• Amniocentesis
– OD 450
– fetal Rhesus genotype
• Umbilical blood sampling
– reserved for those at risk for
severe anemia (based on noninvasive testing)
OD 450
(correlates with bilirubin concentration)
Wavelength (nm)
1
650
550
500
450
*
OD
0.1
0.01
* OD =0.21
365
350
Liley graph
Gest age (wks)
1
28
OD 450
0.1
Potential for fetal death in 7-10 d
3
2
1
Low risk of significant anemia
0.01
40
Limitations to OD 450
interpretation
• Original Liley graph limited to
gestational ages  28 wks
• Physiologic (nl) fetal bilirubin production
peaks at 23-25 wks
• Poor correlation between OD 450 and
fetal Hct < 28 wks
• Betamethasone may artifactually lower
OD 450
Fetal blood analysis
• Direct: degree of anemia
– lowest normal Hct 30% (18 wks) to 33%
(30 wks)
– hydrops rarely occurs above 15% Hct
• Indirect correlates of anemia
– reticulocyte count
– Direct Coombs titer
In utero transfusion
• Rationale for therapy
– suppression of abnormal erythropoiesis
– improvement of O2 carrying capacity
– prevention of hydrops
– opportunity for pulmonary maturation
• Blood for transfusion
– O negative, compatible with mother
– washed, irradiated, CMV negative
– tightly packed (Hct approx 85%)
Intraperitoneal transfusion
• EGA >18 wks
• RBCs absorbed into fetal circulation,
12% per day
• larger transfusion volumes allow longer
intervals between transfusions
• generally replaced by IVT
Intravascular transfusion
• EGA > 18 wks
• transfuse max of 30-50 mL/kg
• repeat at intervals based on fetal status,
final Hct, and expected decline of Hct
(1% per day)
• better results than IPT if anterior
placenta or fetus hydropic
Prognosis for survival
following transfusion
Intraperitoneal
• 9% (if transfusion
required before 25
wks) to
• 49% (includes
hydropic fetuses) to
• 84% (best reported)

Intravascular
• 82% (hydropic)
to
• 89% (nonhydropic) to
• 96% (best
reported)
Suppression of Alloimmunization
Not effective
• Promethazine
• Oral Rh+ RBC
membranes
• RhIG
Limited/potential
benefit*
• Plamsapheresis
• IVIG
* begin 1st TM; may
delay need for
invasive testing
Predictors of severity of HDN
•
•
•
•
Rhesus genotype of father of baby
History of HDN
Maternal Ab titer
Amniotic fluid spectrophotometric
measurements
• Ultrasonographic findings
– MCA peak velocity
– hydrops
• Invasive fetal testing
Paternal Rh phenotype
Rh neg
No further testing
Rh positive
Serial Mat Ab titers
Critical anti-D titer
Heterozygous paternal
phenotype
Homozygous paternal
phenotype
Amniocentesis for
fetal genotype
D negative fetus
D positive fetus
No further testing
Serial amnios or
MCA velocity
Abnl amnio or
MCA velocity
PUBS
IUIVT
Deliver
Start here if prior
hydrops & paternal
Rh positive
Case 1
• 28 yo P1001 (uncomplicated prior preg)
• Anti-D titer rising to 16 @ 16 wks
• Husband Rh pos (prior baby Rh pos &
rec’d rhogam @ 28 wks & p/partum; no
hx of transfusion or other exposures)
• Amnio @ 24 wks: fetus D pos (and delta
OD450 extrapolated to mid Zone 2 of
Liley curve)
Liley graph
Gest age (wks)
1
28
OD 450
0.1
40
3
2
1
0.01
Case 2
• 21 P2022
• Anti-D titer 256 @ LOC, 30 wks
• Unmarried; new partner; unaware of
Rhogam given for last preg/EAb
• FOB not available for testing
Liley graph
Gest age (wks)
1
28
OD 450
0.1
40
3
2
1
0.01
Case 3
• 31 yo P3103
• Last pregnancy was delivered @ 34
wks for hydrops (neonatal demise from
HDN)
• Current husband father of all her
children; one prior Rh neg child
• Anti-D titer?
Liley graph
Gest age (wks)
1
28
OD 450
0.1
40
3
2
1
0.01
Atypical Blood Group
Alloimmunization
• Accounts for 2-5% of HDN … increasing
as Rh alloimmunization becomes less
common
• Develops after blood transfusion
– RBCs for transfusion compatible only for
ABO & D
– incidence of sensitization 2% after
transfusion
• Incidence 2% in general Ob population
Examples of atypical
alloimmunization*
Fetal risk
• Kell (K)
• Duffy (Fya)
• Kidd (Jka)
• M
• S
•
•
•
•
Benign
Lewis (Le)
I
P
Duffy (Fyb)
*Extensive list - use reference chart
Management of Atypical
Alloimmunization
Ab capable of HDN?
Routine PNC
(-)
(+)
FOB Ag positive?
Routine PNC
(-)
(+ or unknown)
Rh alloimmunization protocol *
* Kell suppresses erythropoeisis - greater anemia; PUBS sooner
Neonatal alloimmune
thrombocytopemia
• Typical presentation
– intracranial hemorrhage (10-30% of
affected infants)
– 1st pregnancy commonly affected (50%
of cases)
– 12% mortality
• Rare: 1/1000-1/2000 incidence
• Recurrence: 75-90% (same partner)
Neonatal alloimmune
thrombocytopemia
Etiology
• Maternal IgG ab’s directed against fetal
plt Ab
• -HPA-1a most common (HPA-1a
present in 97% of population)
Diagnosing NAT
• Neonatal thrombocytopenia
• Normal maternal platelet count; no ITP
• Discordancy in maternal & paternal
platelet Ab types
• Confirmation of maternal plt Abs
Population screening not practiced
Management of NAT
• Ab titers not predictive of prognosis
• PUBS (x 2-3), 1st @ 24-26 wks
• Treatment options
– Plt transfusions - can use maternal
(weekly!)
– IVIG, maternal administration - most
consistently effective; confirm with PUBS
– Hi dose steroids if IVIG ineffective
• PUBS near term - C/S if severe NAT