Transcript Neonatal Alloimmune Thrombocytopenia

Neonatal Alloimmune Thrombocytopenia:
Diagnosis, Management, Investigations
Donald M. Arnold, MD MSc
Medical Director, Platelet Immunology Laboratory
McMaster University
Transfusion Medicine Residency Teaching
June 11, 2008
Neonatal Alloimmune
Thrombocytopnia
Definition:
Thrombocytopenia in a fetus or neonate caused by
maternal antiplatelet alloantibodies, directed against a
fetal platelet alloantigen, inherited from the father.
Neonatal
Alloimmune
Thrombocytopenia
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Most common cause of severe TCP in infant
Most common cause of ICH in term newborns
First pregnancies, without warning
Otherwise healthy babies
NAT
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Fetus inherits platelet antigens from father
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Transplacental passage of fetal platelet antigens
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Mother forms IgG alloAbs that cross placenta
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Maternal alloAb react with fetal platelets
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AlloAb-sensitized platelets are cleared in RE system
NAT and HDN
NAT
Affected cells
Most common antigen
Affected pregnancy
Timing of sensitization
Affected Infant
Affected fetus
Main risk factor
Treatment
Prevention
Efficacy of prevention
HDN
NAT and HDN
Affected cells
Most common antigen
Affected pregnancy
Timing of sensitization
Affected Infant
Affected fetus
Main risk factor
Treatment
Prevention
Efficacy of prevention
NAT
HDN
Platelets
Red blood cells
NAT and HDN
NAT
HDN
Affected cells
Platelets
Red blood cells
Most common antigen
HPA-1a
Rh-D
Affected pregnancy
Timing of sensitization
Affected Infant
Affected fetus
Main risk factor
Treatment
Prevention
Efficacy of prevention
NAT and HDN
NAT
HDN
Affected cells
Platelets
Red blood cells
Most common antigen
HPA-1a
Rh-D
Affected pregnancy
First
Second +
Timing of sensitization
Affected Infant
Affected fetus
Main risk factor
Treatment
Prevention
Efficacy of prevention
NAT and HDN
NAT
HDN
Affected cells
Platelets
Red blood cells
Most common antigen
HPA-1a
Rh-D
Affected pregnancy
First
Second +
Timing of sensitization
16 weeks onwards
At birth, or during a procedure
Affected Infant
Affected fetus
Main risk factor
Treatment
Prevention
Efficacy of prevention
NAT and HDN
NAT
HDN
Affected cells
Platelets
Red blood cells
Most common antigen
HPA-1a
Rh-D
Affected pregnancy
First
Second +
Timing of sensitization
16 weeks onwards
At birth, or during a procedure
Affected Infant
TCP, bleeding
Hemolysis, jaundice, kernicterus
Affected fetus
Main risk factor
Treatment
Prevention
Efficacy of prevention
NAT and HDN
NAT
HDN
Affected cells
Platelets
Red blood cells
Most common antigen
HPA-1a
Rh-D
Affected pregnancy
First
Second +
Timing of sensitization
16 weeks onwards
At birth, or during a procedure
Affected Infant
TCP, bleeding
Hemolysis, jaundice, kernicterus
Affected fetus
ICH
Hydrops fetalis
Main risk factor
Treatment
Prevention
Efficacy of prevention
NAT and HDN
NAT
HDN
Affected cells
Platelets
Red blood cells
Most common antigen
HPA-1a
Rh-D
Affected pregnancy
First
Second +
Timing of sensitization
16 weeks onwards
At birth, or during a procedure
Affected Infant
TCP, bleeding
Hemolysis, jaundice, kernicterus
Affected fetus
ICH
Hydrops fetalis
Main risk factor
Previously affected infant
Rh-negative mothers
Treatment
Prevention
Efficacy of prevention
NAT and HDN
NAT
HDN
Affected cells
Platelets
Red blood cells
Most common antigen
HPA-1a
Rh-D
Affected pregnancy
First
Second +
Timing of sensitization
16 weeks onwards
At birth, or during a procedure
Affected Infant
TCP, bleeding
Hemolysis, jaundice, kernicterus
Affected fetus
ICH
Hydrops fetalis
Main risk factor
Previously affected infant
Rh-negative mothers
Treatment
Supportive
Supportive
Prevention
Efficacy of prevention
NAT and HDN
NAT
HDN
Affected cells
Platelets
Red blood cells
Most common antigen
HPA-1a
Rh-D
Affected pregnancy
First
Second +
Timing of sensitization
16 weeks onwards
At birth, or during a procedure
Affected Infant
TCP, bleeding
Hemolysis, jaundice, kernicterus
Affected fetus
ICH
Hydrops fetalis
Main risk factor
Previously affected infant
Rh-negative mothers
Treatment
Supportive
Supportive
Prevention
IVIG
Anti-D
Efficacy of prevention
NAT and HDN
NAT
HDN
Affected cells
Platelets
Red blood cells
Most common antigen
HPA-1a
Rh-D
Affected pregnancy
First
Second +
Timing of sensitization
16 weeks onwards
At birth, or during a procedure
Affected Infant
TCP, bleeding
Hemolysis, jaundice, kernicterus
Affected fetus
ICH
Hydrops fetalis
Main risk factor
Previously affected infant
Rh-negative mothers
Treatment
Supportive
Supportive
Prevention
IVIG
Anti-D
Efficacy of prevention
?
99%
NAT
Incidence:
1 in 1,000 to 1 in 2,000 births
N
Incidence
Burrows and Kelton, 1993
15,932
1 in 1,700
Uhrynowska, 2000
24,101
1 in 2,400
Turner, 2005
26,000
1 in 5,000
100,448
1 in 1,700
Kjeldsen-Kragh, 2007
Severity of thrombocytopenia
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<150,000 - 1 in 100
< 50,000 - 1 in 400
<20,000 - NAT
Burrows, Kelton 1993
Predictors of Severity of NAT
•
History of NAT in a sibling
Murphy, 2006
•
Worse with subsequent pregnancies
Bussel, 1997
•
Worse with increased gestational age
Kaplan, 1988
•
ICH in a previous sibling – greater severity
Bussel, 1997
Treatment of affected neonates
Without warning
 Prompt recognition
 IVIg (2g/kg); Effective in 75% of cases
 Platelet transfusions:
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 Antigen-negative
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(maternal) platelets
Random-donor platelets
= unmatched PLTs;
= matched PLT;
∆ = IVIg; □= steroids
Kiefel Blood, 2006
Antenatal treatment (prevention)
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IVIg 1g/kg/wk (2g/kg/wk for refractory)
IVIg + corticosteroids
Intrauterine platelet transfusions
Fetal blood sampling (FBS)
Risk-based treatment
High Risk (n= 40)
Standard Risk (n= 39)
(previous ICH or PLT<20)
IVIg
vs.
(1g/kg/wk)
(neither)
IVIg + pred
(1mg/kg)
IVIg
vs.
(1g/kg/wk)
pred
(0.5mg/kg)
PUBS (20 wks, repeat 3-8 wks)
Outcome: increase in fetal platelet count
Berkowitz, Bussel, 2006
Risk-based treatment
HIGH RISK Mothers
(platelet count)
Pre
2-8 wks
Birth
IVIg alone*
7,000
17,000
67,000
IVIg + pred
8,000
67,000
99,000
* One ICH
Berkowitz, Bussel, 2006
Risk-based treatment
STANDARD RISK Mothers*
(platelet count)
Pre
3-8 wks
IVIg alone
>20,000
31,000
Pred alone
>20,000
26,000
* 2 fetal deaths, 2 ICH
Berkowitz, Bussel, 2006
Risk-based treatment
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11 SERIOUS COMPLICATIONS OF 175 PUBS (6%)
- 1 Fetal Death
- 9 Emergency C-Sections (14%)
Testing for NAT
Antigens on Platelets
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Blood group antigens (ABO)
Common antigens (HLA)
Platelet specific antigens
Platelet Specific Antigens
Nomenclature
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Chosen name, or name related to individual
with antigen (PlA1,Zav, Gov).
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Current recommendation: All antigens
designated as HUMAN PLATELET
ANTIGENS (HPA).
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Antigens numbered in order of discovery.
Higher frequency allele is “a”.
Example: PLA1 = HPA-1a; PLA2 = HPA-1b
Platelet Specific Antigens
To date, 22 platelet specific alloantigens identified,
with 6 diallelic system (HPA-1, 2, 3, 4, 5, 15).
Almost all are associated with a single nucleotide
substitution.
Major clinically important platelet antigens in NAT
HPA-1a
PLA1
HPA-5a
Br-b, Zav-b
HPA-5b
Br-a, Zav-a
HPA-15a
Gov-b
HPA-15b
Gov-a
HPA-4a (Asian population)
Pen-a
Associated with up to 5% of all NAT
HPA-3a
Bak-a
HPA-2a
Ko-b
HPA-2b
Ko-a
Implicated in NAT, but occur rarely in the population
HPA-6b
Ca-a, Tu-a
HPA-8b
Sr-a
HPA-9b
Max-a
HPA-13b
Sit-a
Rarely implicated in NAT
HPA-1b
HPA-3b
PLA2
Bak-b
Key Message
Gene discrepancy is not NAT!
“Genetic NAT” is 10 times more common than
actual NAT”.
Testing
Platelet Phenotyping
Phenotyping and Antibody
Identification
Radioimmunoprecipitation
Investigation of Neonatal Alloimmune Thrombocytopenia
Platelet Antigen Typing:
Genotyping
– Maternal and Paternal blood samples
Genotyping
– Direct and Cultured amniocytes
Phenotyping
– Maternal and Paternal samples
Platelet Antibody Investigation:
Radioimmunoprecipitation
Antigen Capture ElA
Flow Cytometry
Phenotype, antibody detection (RIP)
Mom: HPA-1a neg
Dad: HPA-1a pos
Mom: Anti-1a
Genotype (PCR)
Genotype (SSP)