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Platelet Allo-Antibody Syndromes

Donald M. Arnold MDCM, FRCPC Assist professor, McMaster University McMaster Platelet immunology Laboratory CBS Hamilton. Platelet Allo-Antibody Syndromes. 1. Troubles with this talk. “Difficulties with Platelet Transfusion, HLA Serology & Management of NAIT & PTT” Nomenclature

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Platelet Allo-Antibody Syndromes

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  1. Donald M. Arnold MDCM, FRCPC Assist professor, McMaster University McMaster Platelet immunology Laboratory CBS Hamilton Platelet Allo-Antibody Syndromes 1

  2. Troubles with this talk • “Difficulties with Platelet Transfusion, HLA Serology & Management of NAIT & PTT” • Nomenclature • Limited evidence • Variability in practice • Serious illnesses • Costly, potentially dangerous treatments 2

  3. Learning Objectives • Understand the mechanism of platelet antigen sensitization 2. Explore pathophysiology of: • platelet refractoriness • fetal or neonatal alloimmune thrombocytopenia • post-transfusion purpura 3. Discuss management of PLT refractoriness, FNAT and PTP

  4. Human Leukocyte Antigens (HLA) 4

  5. Human Platelet Antigens (HPA) 5

  6. Human Platelet Antigens (HPA) 6

  7. Antigens on Platelets • Blood group antigens (ABO) • Common tissue antigens (HLA) • Platelet specific antigens (HPA) 7

  8. Platelet Specific Antigens • Chosen name, or name related to individual with antigen (PlA1,Zav, Gov). • Currently all antigens are designated as human platelet antigen(HPA). • Antigens numbered in order of discovery. Higher frequency allele is “a”. e.g. PLA1 = HPA-1a, PLA2 = HPA-1b Nomenclature 8

  9. Platelet Specific Antigens • To date, more than 22 platelet specific alloantigens identified, with 6 diallelic system (HPA-1, 2, 3, 4, 5, 15). Almost all are associated with a single amino acid substitution (SNP). • Antibodies against HPA-1a are most commonly implicated in NAT, PTP. 9

  10. Platelet Transfusion Refractoriness

  11. Platelet Refractoriness Definition • 1h corrected count incr < 5 – 10 x109/L • Percent PLT recovery <20% • 1h CCI < 5 x109/L x2 using ABO-identical fresh platelets • A post-transfusion platelet count that is less than expected 11

  12. Causes of PLT refractoriness • Immune • Anti-HLA, anti-ABO, anti-HPA • Non-immune • Fever • Sepsis • Splenomegaly • DIC • Bleeding • VOD • GVHD 12

  13. Immune • Alloimmunization occurs after transfusion, pregnancy, transplantation. • Alloimmunization does not mean refractory • Strategies to reduce refractoriness: • Leukoreduction • Platelet dose? • Apheresis vs. whole blood derived platelets 13

  14. TRAP (Slichter 1997) 14

  15. TRAP (Slichter 1997) 15

  16. Slichter Blood 2005 16

  17. Decline in PLT responsiveness A: In all patients (n=6334 transfusions; 533 patients) B: In HLA-antibody-negative patients (n= 5484 transfusions; 477 patients) Slichter Blood 2005 17

  18. Apheresis vs. Whole blood PLTs Heddle, Transfusion 2008 18

  19. Management AlgorithmHod BMJ 2008 19

  20. Hod BMJ 2008 20

  21. Fetal/ Neonatal Alloimmune Thrombocytopenia 21

  22. 22

  23. 23

  24. FNAT Low platelets and bleeding in a fetus or neonate caused by maternal antibodies directed against fetal platelet antigens inherited from the father. Definition: 24

  25. FNAT Incidence: 1 in 1,000 to 1 in 2,000 births 25

  26. FNAT • Most common cause of severe TCP in infant • Most common cause of ICH in term newborns • First pregnancies, without warning • Otherwise healthy babies 26

  27. NFNATAT • Fetal platelet antigen: Inherited from father • Sensitization: Transplacental • Immunization: Mother forms IgG allo-antibodies • Maternal antibodies: React with fetal platelets • Fetal platelet destruction: Spleen and RES 27

  28. Arnold et al, Trans Med Rev 2008 28

  29. Incidence of TCP at birth • <150,000 - 1 in 100 • < 50,000 - 1 in 400 • Infection • Immune mediated • Chromosomal abnormalities • <20,000 - NAT Burrows, Kelton 1993 29

  30. NAT and HDN Arnold et al, Trans Med Rev 2008 30

  31. Treatment of affected neonates • Present without warning • Require prompt recognition and treatment • IVIg (2g/kg) • Effective in 75% of affected neonates Mueller-Eckhardt C, Blut 1989 • Platelet transfusions: • Antigen-negative (maternal) platelets Allen, Blood 2007 • Random-donor platelets Kiefel et al Blood 2006 31

  32. Antenatal treatment • IVIg 1g/kg/wk (2g/kg/wk for refractory) • IVIg + corticosteroids • Intrauterine platelet transfusions • Fetal blood sampling (FBS) 32

  33. Risk-based treatment High Risk (n= 40)Standard Risk (n= 39) (previous ICH or PLT<20) (neither) IVIg vs. IVIg + predIVIg 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 33

  34. 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 34

  35. 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 35

  36. Risk-based treatment • 11 SERIOUS COMPLICATIONS OF 175 PUBS (6%) - 1 Fetal Death - 9 Emergency C-Sections (14%) 36

  37. What is the optimal management of mothers at-risk of NAT? • IVIG Cochrane collaboration 2006 • Corticosteroids Berkowitz, Bussel, 2006 • Invasive vs. non-invasive approach? • Fetal blood sampling • FBS + intrauterine PLT transfusions • Cesarean section • No FBS • Empiric treatment • Vaginal delivery 37

  38. Is there a role for screening? • N= 100,448 pregnancies screened (for HPA-1a) • Offered early c/s with compatible platelets. • 3 of 161 (6%) screen-positive infants died or had ICH; versus 10 of 51 (20%) unscreened infants. Kjeldsen-Kragh J, Blood, 2007 38

  39. Post Transfusion Purpura

  40. PTP: Clinical • Frequency: uncertain • 1 per 2 million RBCs (2008, SHOT) • Adults (~50 years); females (5x) • PLT <15 x109/L, Bleeding ++ • Onset: 9 days post blood transfusion • Recovery: 7 – 48 days after onset • Mortality ~10% (intracerebral hemorrhage)

  41. Sensitization • Sensitization by previous transfusions, pregnancy • Usually HPA-1bb recipients • Other at risk HPA genotypes

  42. SHOT(www.shotuk.org)

  43. PTP Pathogenesis • Transfusion of incompatible PLTs • Typically, anti-HPA-1a Abs • Destroy transfused and autologous PLTs • Theories: • Immune complexes • Adsorbed PLT antigens • Concomitant auto-Abs • Further research needed

  44. PTP: Treatment • Supportive: Ag-negative platelet transfusions • IVIG • Plasma exchange • Corticosteroids

  45. Summary • Platelet sensitization • HLA antibodies are ubiquitous, transient • Example: PLT refractoriness • HPA antibodies are rare, persistent • Examples: FNAT, PTP

  46. Summary • PLT refractoriness: • Consider HLA matched, XM compatible PLTs • FNAT: • Newborn PLT <20; FNAT until proven otherwise • PTP: • Severe thrombocytopenia (PLT <15) and bleeding

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