1. Alloimmune Thrombocytopenia Sokołowska Małgorzata Pomorska Akademia Medyczna Szczecin

2. Neonatal alloimmune thrombocytopenia (NAIT) This is the platelet equivalent of HDN Thrombocytopenia is caused by immune destruction of fetal/neonatal platelets IgG maternal HPA antibodies cross the placenta Platelet destruction invariably starts before birth Placental transfer stops at birth, but platelet destruction continues into neonatal life Not recognised in the antenatal period in women not investigated before

3. 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

4. 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:

5. Introduction Maternal circulation Fetal circulation Placenta platelet IgG platelet Immune System Recognizes As foreign 1 2 3 Alloimmune thrombocytopenia

6. HPA alloimmunisation 1. Pregnancy eg. HPA-1a neg mother carrying HPA-1a pos baby cc 2. Blood Transfusion eg. HPA-1a neg person receiving HPA-1a pos blood transfusion Antigen pos platelets enter person’s circulation Production of platelet antibody (anti-HPA-1a)

7. Incidence AIT : Platelet count < 150,000 ⅹ 10 9 /L  (1% of unselecte neonates) Severe : <50,000 ⅹ 10 9 /L (25% of neonates with thrombocytopenia) 1:1500 deliveries

8. 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

9. Pathophysiology Definition :  fetal/neonatal platelet count < 150 ⅹ 10 9 /L  maternal platelet alloantibodies Manifestations  Concentration of maternal IgG  Density of the target antigen on the fetal platelets  Phagocytic activity  Compensatory ability of the fetal bone marrow

10. Platelet surface antigen HLA class I HPA (human platelet antigen) ABO antigen

12. Frequency of HPA-1a Most common alloantigen in white population : HPA-1a  2 nd common alloantigen: HPA-5b Serologic frequency : HPA-1a positive : 98% HPA-1a negative : 2% In Asian : HPA-4b 1,7% (+)

13. HLA and immune response to HPA-1a There is a strong link between HLA- DRB3*0101(DR52a) & HPA-1a alloimmunisation In an HPA-1a neg, DRB3*0101 pos woman, likelihood of anti-HPA-1a formation is 33% The chances of anti-HPA-1a developing in a woman negative for DRB3*0101 is < 1% This HLA Class II molecule seems to play an important role in antigen presentation

14. Listen up! They say, that the maternal platet count is normal and alloimmunization is not suspected until after the birth of the affected child. Even in the first affected infant, is frequently severe and usually develops before the third trimester. It can thus cause fetal intracranial hemorrhage, even as early as 20 weeks!!!!!!!!!!!!!!!!!!!!!!!!!

15. Clinical features of NAIT: Mild disease: asymptomatic only sl. reduction of platelet count Moderate: superficial bleeding e.g.purpura, petechie, ecchymoses etc. Severe:platelet count <30-50x109/l internal bleeding intracranial haemorrhage (ICT)-cysts hydrocephalus & ventriculomegaly Mortality up to 14%

16. Clinical features

17. Laboratory Studies Antiplatelet antibody testing  PSIFT (Platelet Suspension Immunofluorescence Test)  MAIPA (Monoclonal Antibody Immobilization of Platet Antigens) Platelet antigen typing  MAIPA  ELISA  DNA-based test (PCR-)SPP

18. Management of NAIT Treatment is required for symptomatic & severe cases Should be started if there is strong clinical suspicion Treatment of NAIT without waiting for laboratory diagnosis HPA compatible platelet transfusions (most effective) Intravenous immunoglobulin (IVIg) Steroids (dexamethasone, prednizone) Steroids / immunoglobulin iv Cranial ultrasound for all severe cases

19. Management Medical  Iv immunoglobulin / steroids Surgical (favor in Europe)  Uterofetal platelet transfusion Goal : Prevent antenatal / perinatal ICH  ICH : mental retardation, fetal /neonatal death

21. Pre-natal management of cases with severe NAIT Most Fetal Medicine specialists start with intravenous immunoglobulin (IVIg) injections to mother from about 12 - 14 wk Dose: 1g/kg b.w. every week Around 20 - 22 wk, first fetal blood sampling (FBS) and intrauterine transfusion (IUT) if thrombocytopenic Repeat IUTs as necessary

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

23. Future pregnancies In a mother who has had an affected baby, the chances of having another affected child is high if the implicated Ag is inherited Severe thrombocytopenia may occur as early as 20 - 24 weeks of gestation Chances of inheriting the paternal antigen depends on the zygosity of the father Both parents should be counselled All ‘at risk’ pregnancies should be managed in FMUs

24. Summary NAIT is a serious condition with significant morbidity & mortality (ICH: 11% {34/305}; Deaths : 7.2% {22/305}) Most cases are caused by anti-HPA-1a or anti-HPA-5b or both In severe cases, treatment should be given ASAP before test results There must be good communication between FMUs and local hospitals when known cases are referred for delivery BB staff, Haematologist & Neonatal team must be alerted by the Obstetricians

25. NAT and HDN NATHDN Affected cells Most common antigen Affected pregnancy Timing of sensitization Affected Infant Affected fetus Main risk factor Treatment Prevention Efficacy of prevention

26. NAT and HDN NATHDN Affected cellsPlateletsRed blood cells Most common antigen Affected pregnancy Timing of sensitization Affected Infant Affected fetus Main risk factor Treatment Prevention Efficacy of prevention

27. NAT and HDN NATHDN Affected cellsPlateletsRed blood cells Most common antigenHPA-1aRh-D Affected pregnancy Timing of sensitization Affected Infant Affected fetus Main risk factor Treatment Prevention Efficacy of prevention

28. NAT and HDN NATHDN Affected cellsPlateletsRed blood cells Most common antigenHPA-1aRh-D Affected pregnancyFirstSecond + Timing of sensitization Affected Infant Affected fetus Main risk factor Treatment Prevention Efficacy of prevention

29. NAT and HDN NATHDN Affected cellsPlateletsRed blood cells Most common antigenHPA-1aRh-D Affected pregnancyFirstSecond + Timing of sensitization16 weeks onwardsAt birth, or during a procedure Affected Infant Affected fetus Main risk factor Treatment Prevention Efficacy of prevention

30. NAT and HDN NATHDN Affected cellsPlateletsRed blood cells Most common antigenHPA-1aRh-D Affected pregnancyFirstSecond + Timing of sensitization16 weeks onwardsAt birth, or during a procedure Affected InfantTCP, bleedingHemolysis, jaundice, kernicterus Affected fetus Main risk factor Treatment Prevention Efficacy of prevention

31. NAT and HDN NATHDN Affected cellsPlateletsRed blood cells Most common antigenHPA-1aRh-D Affected pregnancyFirstSecond + Timing of sensitization16 weeks onwardsAt birth, or during a procedure Affected InfantTCP, bleedingHemolysis, jaundice, kernicterus Affected fetusICHHydrops fetalis Main risk factor Treatment Prevention Efficacy of prevention

32. NAT and HDN NATHDN Affected cellsPlateletsRed blood cells Most common antigenHPA-1aRh-D Affected pregnancyFirstSecond + Timing of sensitization16 weeks onwardsAt birth, or during a procedure Affected InfantTCP, bleedingHemolysis, jaundice, kernicterus Affected fetusICHHydrops fetalis Main risk factorPreviously affected infantRh-negative mothers Treatment Prevention Efficacy of prevention

33. NAT and HDN NATHDN Affected cellsPlateletsRed blood cells Most common antigenHPA-1aRh-D Affected pregnancyFirstSecond + Timing of sensitization16 weeks onwardsAt birth, or during a procedure Affected InfantTCP, bleedingHemolysis, jaundice, kernicterus Affected fetusICHHydrops fetalis Main risk factorPreviously affected infantRh-negative mothers TreatmentSupportive Prevention Efficacy of prevention

34. NAT and HDN NATHDN Affected cellsPlateletsRed blood cells Most common antigenHPA-1aRh-D Affected pregnancyFirstSecond + Timing of sensitization16 weeks onwardsAt birth, or during a procedure Affected InfantTCP, bleedingHemolysis, jaundice, kernicterus Affected fetusICHHydrops fetalis Main risk factorPreviously affected infantRh-negative mothers TreatmentSupportive PreventionIVIGAnti-D Efficacy of prevention

35. NAT and HDN NATHDN Affected cellsPlateletsRed blood cells Most common antigenHPA-1aRh-D Affected pregnancyFirstSecond + Timing of sensitization16 weeks onwardsAt birth, or during a procedure Affected InfantTCP, bleedingHemolysis, jaundice, kernicterus Affected fetusICHHydrops fetalis Main risk factorPreviously affected infantRh-negative mothers TreatmentSupportive PreventionIVIGAnti-D Efficacy of prevention?99%

37. AIT The diagnosis can be made on clinical grounds if the mother has normal platelet count and there is no evidence of any immunological disorder, and her infant has thrombocytopenia without evidence of other disease. Recurs in 70-90 % of subsequent pregnancies,is ofen severe, and usually develops eariel in with each successive pregnancy.

38. AIT ( Isoimmune thrombocytopenia) It is caused by maternal isoimmunisation to fetal platet antigens in a manner similar to D-antigen isoimmunization. Thus, the maternal platet count is normal and alloimmunization is not suspected until after the birth of the affected child. Even in the first affected infant, is frequentlysevere and usually develops before the third trimester. It can thus cause fetal intracranial hemorrhage, even as early as 20 weeks

39. Questions?