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Neonatal Alloimmune Thrombocytopenia: Diagnosis, Management, Investigations

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.

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Neonatal Alloimmune Thrombocytopenia: Diagnosis, Management, Investigations

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  1. 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

  2. Neonatal Alloimmune Thrombocytopnia Thrombocytopenia in a fetus or neonate caused by maternal antiplatelet alloantibodies, directed against a fetal platelet alloantigen, inherited from the father. Definition:

  3. Neonatal Alloimmune Thrombocytopenia • Most common cause of severe TCP in infant • Most common cause of ICH in term newborns • First pregnancies, without warning • Otherwise healthy babies

  4. NAT • Fetus inherits platelet antigens from father • Transplacental passage of fetal platelet antigens • Mother forms IgG alloAbs that cross placenta • Maternal alloAb react with fetal platelets • AlloAb-sensitized platelets are cleared in RE system

  5. NAT and HDN

  6. NAT and HDN

  7. NAT and HDN

  8. NAT and HDN

  9. NAT and HDN

  10. NAT and HDN

  11. NAT and HDN

  12. NAT and HDN

  13. NAT and HDN

  14. NAT and HDN

  15. NAT and HDN

  16. NAT Incidence: 1 in 1,000 to 1 in 2,000 births

  17. Severity of thrombocytopenia • <150,000 - 1 in 100 • < 50,000 - 1 in 400 • <20,000 - NAT Burrows, Kelton 1993

  18. 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

  19. Treatment of affected neonates • Without warning • Prompt recognition • IVIg (2g/kg); Effective in 75% of cases • Platelet transfusions: • Antigen-negative (maternal) platelets • Random-donor platelets

  20. = unmatched PLTs; = matched PLT; ∆ = IVIg; □= steroids Kiefel Blood, 2006

  21. Antenatal treatment (prevention) • IVIg 1g/kg/wk (2g/kg/wk for refractory) • IVIg + corticosteroids • Intrauterine platelet transfusions • Fetal blood sampling (FBS)

  22. Risk-based treatment 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

  23. 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

  24. 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

  25. Risk-based treatment • 11 SERIOUS COMPLICATIONS OF 175 PUBS (6%) - 1 Fetal Death - 9 Emergency C-Sections (14%)

  26. Testing for NAT

  27. Antigens on Platelets • Blood group antigens (ABO) • Common antigens (HLA) • Platelet specific antigens

  28. Platelet Specific Antigens • Chosen name, or name related to individual with antigen (PlA1,Zav, Gov). • Current recommendation: All antigens designated as HUMAN PLATELET ANTIGENS (HPA). • Antigens numbered in order of discovery. Higher frequency allele is “a”. Example: PLA1 = HPA-1a; PLA2 = HPA-1b Nomenclature

  29. 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.

  30. 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 PLA2 HPA-3b Bak-b

  31. Key Message Gene discrepancy is not NAT! “Genetic NAT” is 10 times more common than actual NAT”.

  32. Testing

  33. Platelet Phenotyping

  34. Phenotyping and Antibody Identification Radioimmunoprecipitation

  35. 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

  36. Phenotype, antibody detection (RIP) Mom: HPA-1a neg Dad: HPA-1a pos Mom: Anti-1a

  37. Genotype (PCR)

  38. Genotype (SSP)

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