neonatal alloimmune thrombocytopenia: diagnosis, management, investigations
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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. - PowerPoint PPT PresentationTRANSCRIPT
Neonatal Alloimmune Thrombocytopenia:Diagnosis, Management, Investigations
Donald M. Arnold, MD MScMedical Director, Platelet Immunology Laboratory
McMaster University
Transfusion Medicine Residency TeachingJune 11, 2008
Neonatal Alloimmune Neonatal Alloimmune ThrombocytopniaThrombocytopnia
Thrombocytopenia in a fetus or neonate Thrombocytopenia in a fetus or neonate caused by maternal antiplatelet caused by maternal antiplatelet alloantibodies, directed against a fetal alloantibodies, directed against a fetal platelet alloantigen, inherited from the platelet alloantigen, inherited from the father. father.
Definition:
NeonatalNeonatalAlloimmuneAlloimmune
ThrombocytopeniaThrombocytopenia
Most common cause of Most common cause of severe TCPsevere TCP in infant in infant Most common cause of Most common cause of ICHICH in term in term
newbornsnewborns First pregnancies, First pregnancies, without warningwithout warning Otherwise healthyOtherwise healthy babies babies
NATNAT Fetus inherits platelet antigens from fatherFetus inherits platelet antigens from father
Transplacental passage of fetal platelet Transplacental passage of fetal platelet antigensantigens
Mother forms IgG alloAbs that cross placentaMother forms IgG alloAbs that cross placenta
Maternal alloAb react with fetal plateletsMaternal alloAb react with fetal platelets
AlloAb-sensitized platelets are cleared in RE AlloAb-sensitized platelets are cleared in RE systemsystem
NAT and HDNNAT and HDNNAT HDN
Affected cells
Most common antigen
Affected pregnancy
Timing of sensitization
Affected Infant
Affected fetus
Main risk factor
Treatment
Prevention
Efficacy of prevention
NAT and HDNNAT and HDNNAT HDN
Affected cells Platelets Red blood cells
Most common antigen
Affected pregnancy
Timing of sensitization
Affected Infant
Affected fetus
Main risk factor
Treatment
Prevention
Efficacy of prevention
NAT and HDNNAT and HDNNAT 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 HDNNAT and HDNNAT 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 HDNNAT and HDNNAT 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 HDNNAT and HDNNAT 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 HDNNAT and HDNNAT 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 HDNNAT and HDNNAT 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 HDNNAT and HDNNAT 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 HDNNAT and HDNNAT 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 HDNNAT and HDNNAT 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%
Incidence: 1 in 1,000 to 1 in 2,000 births
NN IncidenceIncidence
Burrows and KeltonBurrows and Kelton, 1993, 1993 15,93215,932 1 in 1,7001 in 1,700
UhrynowskaUhrynowska, 2000, 2000 24,10124,101 1 in 2,4001 in 2,400
Turner,Turner, 2005 2005 26,00026,000 1 in 5,0001 in 5,000
Kjeldsen-Kragh,Kjeldsen-Kragh, 2007 2007 100,448100,448 1 in 1,7001 in 1,700
NATNAT
<150,000 - 1 in 100<150,000 - 1 in 100 < 50,000 - 1 in 400< 50,000 - 1 in 400 <20,000 - NAT<20,000 - NAT
Severity of Severity of thrombocytopenia thrombocytopenia
Burrows, Kelton 1993
Predictors of Severity of Predictors of Severity of NATNAT
• History of NAT in a siblingHistory of NAT in a sibling Murphy, Murphy, 20062006
• Worse with subsequent pregnancies Worse with subsequent pregnancies Bussel, Bussel, 19971997
• Worse with increased gestational ageWorse with increased gestational age Kaplan, Kaplan, 19881988
• ICH in a previous sibling – greater severityICH in a previous sibling – greater severityBussel, 1997Bussel, 1997
Treatment of affected Treatment of affected neonatesneonates
Without warningWithout warning Prompt recognitionPrompt recognition IVIg (2g/kg); Effective in 75% of IVIg (2g/kg); Effective in 75% of
casescases Platelet transfusions:Platelet transfusions:
Antigen-negative (maternal) Antigen-negative (maternal) plateletsplatelets
Random-donor plateletsRandom-donor platelets
= unmatched PLTs; = matched PLT; ∆ = IVIg; □= steroids
Kiefel Blood, 2006
Antenatal treatment Antenatal treatment (prevention)(prevention)
IVIg 1g/kg/wk (2g/kg/wk for refractory)IVIg 1g/kg/wk (2g/kg/wk for refractory) IVIg + corticosteroidsIVIg + corticosteroids Intrauterine platelet transfusionsIntrauterine platelet transfusions Fetal blood sampling (FBS)Fetal blood sampling (FBS)
High Risk (n= 40) Standard Risk (n= 39)
(previous ICH or PLT<20) (neither)
IVIg vs. IVIg + pred IVIg vs. pred
(1g/kg/wk) (1mg/kg) (1g/kg/wk) (0.5mg/kg)
PUBS (20 wks, repeat 3-8 wks)
Outcome: increase in fetal platelet count
Berkowitz, Bussel, 2006
Risk-based treatmentRisk-based treatment
HIGH RISK MothersHIGH RISK Mothers(platelet count)(platelet count)
PrePre 2-8 wks2-8 wks BirthBirth
IVIg alone*IVIg alone* 7,0007,000 17,00017,00067,00067,000
IVIg + pred IVIg + pred 8,0008,000 67,00067,00099,00099,000
* One ICH* One ICH Berkowitz, Bussel, 2006
Risk-based treatmentRisk-based treatment
STANDARD RISK Mothers*STANDARD RISK Mothers*(platelet count)(platelet count)
PrePre 3-8 wks3-8 wks
IVIg aloneIVIg alone >20,000>20,000 31,00031,000
Pred alone Pred alone >20,000>20,000 26,00026,000
* 2 fetal deaths, 2 ICH* 2 fetal deaths, 2 ICH Berkowitz, Bussel, 2006
Risk-based treatmentRisk-based treatment
11 SERIOUS COMPLICATIONS OF 175 11 SERIOUS COMPLICATIONS OF 175 PUBS (6%)PUBS (6%)
- 1 Fetal Death - 1 Fetal Death
- 9 Emergency C-Sections (14%) - 9 Emergency C-Sections (14%)
Risk-based treatmentRisk-based treatment
Testing for NATTesting for NAT
Antigens on PlateletsAntigens on Platelets
Blood group antigens (ABO) Blood group antigens (ABO) Common antigens (HLA)Common antigens (HLA) Platelet specific antigens Platelet specific antigens
Chosen name, or name related to Chosen name, or name related to individual with antigen (Plindividual with antigen (PlA1A1,Zav, Gov).,Zav, Gov).
Current recommendation: All antigens Current recommendation: All antigens designated as HUMAN PLATELET designated as HUMAN PLATELET ANTIGENS (HPA).ANTIGENS (HPA).
Antigens numbered in order of Antigens numbered in order of discovery. discovery.
Higher frequency allele is “a”.Higher frequency allele is “a”. Example: PLA1 = HPA-1a; PLA2 = Example: PLA1 = HPA-1a; PLA2 =
HPA-1bHPA-1b
Platelet Specific AntigensPlatelet Specific Antigens
Nomenclature
To date, 22 platelet specific To date, 22 platelet specific alloantigens identified, with 6 diallelic alloantigens identified, with 6 diallelic system (HPA-1, 2, 3, 4, 5, 15). Almost system (HPA-1, 2, 3, 4, 5, 15). Almost all are associated with a all are associated with a single single nucleotide substitution.nucleotide substitution.
Platelet Specific AntigensPlatelet Specific Antigens
Major clinically important platelet antigens in NATHPA-1a PLA1HPA-5a Br-b, Zav-bHPA-5b Br-a, Zav-aHPA-15a Gov-bHPA-15b Gov-aHPA-4a (Asian population) Pen-a
Associated with up to 5% of all NATHPA-3a Bak-aHPA-2a Ko-bHPA-2b Ko-a
Implicated in NAT, but occur rarely in the populationHPA-6b Ca-a, Tu-aHPA-8b Sr-aHPA-9b Max-aHPA-13b Sit-a
Rarely implicated in NATHPA-1b PLA2HPA-3b Bak-b
Key MessageKey Message
Gene discrepancy is Gene discrepancy is notnot NAT! NAT!
““Genetic NAT” is 10 times more Genetic NAT” is 10 times more common than common than
actual NAT”.actual NAT”.
TestingTesting
Platelet PhenotypingPlatelet Phenotyping
RadioimmunoprecipitationRadioimmunoprecipitation
Phenotyping and Phenotyping and Antibody Identification Antibody Identification
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
Mom: HPA-1a negDad: HPA-1a pos
Mom: Anti-1a
Phenotype, antibody Phenotype, antibody detection (RIP)detection (RIP)
Genotype (PCR)Genotype (PCR)
Genotype (SSP)
