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Vox Sang 1991;60:244-245
Neonatal Alloimmune Thrombocytopenia due to Anti-Brb(HPA-Sa) Report of Three Cases in ltvo Families' V Kiefel", Y. Shechterb, D. Atiasb, H.KrolP, S. Santoso', C. Mueller-EckhardP "Institute for Clinical Immunology and Transfusion Medicine, Justus Liebig University, Giessen, FRG; bRambam Medical Center, Blood Bank, Haifa, Israel
Neonatal alloimmune thrombocytopenia (NAIT) due to platelet-specific Bra (HPA-5b) antibodies, as first described by Kiefel et al. [l,21, is the second most frequent type of NAIT in the European population [3]. Anti-Bra ranks first in Japanese [Y. Shibata, pers. commun]. Fetomaternal Brb (HPA-5a) incompatibilities are expected to be very rare on account of the high phenotype frequency of Brb (about 99%) and the resulting very low number of Brahomozygous mothers (about 1%).To the first case of Brb-NAITreported in this issue of the Journal by Bierling et al. we can add three additional cases, one observed in Israel and two siblings in Germany.
Case Reports Case 1 The 32 year-old Jewish woman (gravida 3, para 2) suffered from gestosis occumng in the 25th week of her 3rd pregnancy. Both previous children had been healthy at birth without documented signs of purpura. Since the fetus of the present pregnancy showed signs of intrauterine growth retardation, delivery was induced at week 30 of gestation. The premature neonate was asphyctic at birth and required artifical respiration for 4 days because of idopathic respiratory distress syndrome. Purpura was noted immediately postpartum associated with a platelet count of lO,OoO/pl; other values (hemoglobin, white blood cells) were normal. No signs of intracranial hemorrhage (ICH) were found by sonography. A random platelet transfusion was administered followed by an increase of the platelet count to 44,OOO/pl. In the next 4 days the platelet count gradually declined again, but rose spontaneously on day 5 and normalized after day 12. The child was discharged in the 7th week of life and has since then developed normally.
I These studies were supported by the Deutsche Forschungsgemeinschaft (27719-7).
Maternal serum contained strong polyspecific HLA antibodies
(100% panel lymphocytotoxicity) and, in addition, a Brb alloantibody recognized by the MAIPA assay [4]. Family typing showed that the mother was Br(a+b-), the father Br(a-b+) and all 3 children were heterozygous Br(a+b+). HLA type of the mother: Al, -; B17,44; Bw4; DRw6,7; DRw52,w53; DQwl, DQw2. Cases 2.1 and 2.2 This gravida 1, para 0, otherwise healthy white woman (born 1957) developed at week 24 of gestation hypertension and signs of gestosis, abnormalities of placenta and oligohydramnios. A male child was delivered by cesarean section at week 35 in April, 1987, because of pathological cardiotocogramfindings. The neonate (2.1) was dystrophic and showed several anomalies (Clinodactyly, anal atresia, genital abnormalities, hemivertebra of sacrum and others). Sonography of the skull revealed slight ventricular dilatation, but no signs of ICH. There was moderate thrombocytopenia (41,OOO/pl), leukocytopenia and anemia, symptoms of a hemorrhagic diathesis were not noted. Thrombocytopenia persisted for approximately 3 weeks and remitted without specific therapy. The second child (2.2), a girl, was born by vaginal delivery after an uneventful pregnancy in June, 1990. The neonate was normal without any signs of a hemorrhagic tendency. On day 4, slight fever developed and a mild thrombocytopenia (76,OOO/pl) was registered which normalized until day 8 without treatment. The maternal serum contained weak lymphocytotoxic HLA antibodies and a Brb (HPA-5a)-specific platelet alloantibody, detected in the MAIPA assay. Only weak reactions without clear specificity were observed in immunofluorescence. Family typing for platelet antigens: mother Zw(a+b-), Bak(a+), Br(a+b-); father Zw(a+b+), Bak(a-); Br(a-b+); child 2.1 Zw(a+b+), Br(a+b+); child 2.2 Zw(a+b-), Br (a+b+). HLA typing of mother: A3,32(w19); B35 w64(14); Bw6; Cw5,w8; DR1,7; DRw53; DQwl,w2.
All three children presented with typical signs of NAIT. Child 1 had a moderate purpura with severe thrombocytopenia, while the platelet counts in cases 2.1 and 2.2 were only slightly decreased with no evidence of augmented bleeding tendency. A usually mild clinical course is rather typical for Bra-NAIT, as recently shown in a large series of 39
245
NAIT due to Anti-Brb(HPA-5a)
such cases [5]. However, visceral hemorrhages and even ICH may eventually occur [5]. Serological detection of antibodies is best accomplished by the glycoprotein-specificMAIPA assay, while conventional binding assays usually yield only weak or equivocal results, particularly if HLA antibodies are simultaneously present. Treatment of choice in Brb-NAITis transfusion of maternal platelets which have been resuspended in plasma of a blood group AB donor, since random donor platelets will be incompatible in 99%. This contrasts to an 80% compatibilitychance of random platelets in Bf-NAIT. The insufficient effect of random platelets is exemplified in case 1. Interestingly,one of the immunized mothers of Jewish descent was HLA-DRw6positive, an ‘immune-response’marker, which is also significantly associated with BP immunization in the European population [6]. Further studies are required studies to analyze this phenomenon for other ethnic groups.
3 Mueller-Eckhardt C, Kiefel V, Grubert A, Kroll H, Weisheit M, Schmidt S,MueUer-Eckhardt G, Santoso S: 348 cases of suspected neonatal alloimmune thrombocytopenia. Lancet 1989;i:363-366. 4 Kiefel V, Santoso S, Weisheit M, Mueller-Eckhardt C: Monoclonal antibody-specificimmobilization of platelet antigens (MAIPA): A new tool for the identificationof platelet-reactive antibodies. Blood 1987;70:1722-1726. 5 Kaplan C, Morel MC, Kroll H, Kiefel V, Schlegel N, Chesnel N, Mueller-Eckhardt C: Neonatal alloimmune thrombocytopenia due to anti-BP: Clinical and immunological analysis of 39 cases. Submitted for publication. 6 Mueller-Eckhardt C, Kiefel V, b o l l H, Mueller-Eckhardt G: HLA-DRw6, a new immune response marker for immunization against the platelet alloantigen Bra. Vox Sang 1989;57:90-91.
References 1 Kiefel V, Santoso S , Katzmann B, Mueller-Eckhardt C: A new platelet-specificalloantigen BP. Report of four cases with neonatal alloimmune thrombocytopenia. Vox Sang 1988;54:101-106. 2 Kiefel V, Santoso S , Katzmann B, Mueller-Eckhardt C: The BrV Brballoantigen system on platelets. Blood 1989;73:2219-2223.
V. Kiefel, Institute for Clinical Immunology and Transfusion Medicine, Justus Liebig University, Langhansstr. 7 D-W-6300 Giessen (FRG)
Vox Sang 1991;60:244-245
Neonatal Alloimmune Thrombocytopenia due to Anti-Brb(HPA-Sa) Report of Three Cases in ltvo Families' V Kiefel", Y. Shechterb, D. Atiasb, H.KrolP, S. Santoso', C. Mueller-EckhardP "Institute for Clinical Immunology and Transfusion Medicine, Justus Liebig University, Giessen, FRG; bRambam Medical Center, Blood Bank, Haifa, Israel
Neonatal alloimmune thrombocytopenia (NAIT) due to platelet-specific Bra (HPA-5b) antibodies, as first described by Kiefel et al. [l,21, is the second most frequent type of NAIT in the European population [3]. Anti-Bra ranks first in Japanese [Y. Shibata, pers. commun]. Fetomaternal Brb (HPA-5a) incompatibilities are expected to be very rare on account of the high phenotype frequency of Brb (about 99%) and the resulting very low number of Brahomozygous mothers (about 1%).To the first case of Brb-NAITreported in this issue of the Journal by Bierling et al. we can add three additional cases, one observed in Israel and two siblings in Germany.
Case Reports Case 1 The 32 year-old Jewish woman (gravida 3, para 2) suffered from gestosis occumng in the 25th week of her 3rd pregnancy. Both previous children had been healthy at birth without documented signs of purpura. Since the fetus of the present pregnancy showed signs of intrauterine growth retardation, delivery was induced at week 30 of gestation. The premature neonate was asphyctic at birth and required artifical respiration for 4 days because of idopathic respiratory distress syndrome. Purpura was noted immediately postpartum associated with a platelet count of lO,OoO/pl; other values (hemoglobin, white blood cells) were normal. No signs of intracranial hemorrhage (ICH) were found by sonography. A random platelet transfusion was administered followed by an increase of the platelet count to 44,OOO/pl. In the next 4 days the platelet count gradually declined again, but rose spontaneously on day 5 and normalized after day 12. The child was discharged in the 7th week of life and has since then developed normally.
I These studies were supported by the Deutsche Forschungsgemeinschaft (27719-7).
Maternal serum contained strong polyspecific HLA antibodies
(100% panel lymphocytotoxicity) and, in addition, a Brb alloantibody recognized by the MAIPA assay [4]. Family typing showed that the mother was Br(a+b-), the father Br(a-b+) and all 3 children were heterozygous Br(a+b+). HLA type of the mother: Al, -; B17,44; Bw4; DRw6,7; DRw52,w53; DQwl, DQw2. Cases 2.1 and 2.2 This gravida 1, para 0, otherwise healthy white woman (born 1957) developed at week 24 of gestation hypertension and signs of gestosis, abnormalities of placenta and oligohydramnios. A male child was delivered by cesarean section at week 35 in April, 1987, because of pathological cardiotocogramfindings. The neonate (2.1) was dystrophic and showed several anomalies (Clinodactyly, anal atresia, genital abnormalities, hemivertebra of sacrum and others). Sonography of the skull revealed slight ventricular dilatation, but no signs of ICH. There was moderate thrombocytopenia (41,OOO/pl), leukocytopenia and anemia, symptoms of a hemorrhagic diathesis were not noted. Thrombocytopenia persisted for approximately 3 weeks and remitted without specific therapy. The second child (2.2), a girl, was born by vaginal delivery after an uneventful pregnancy in June, 1990. The neonate was normal without any signs of a hemorrhagic tendency. On day 4, slight fever developed and a mild thrombocytopenia (76,OOO/pl) was registered which normalized until day 8 without treatment. The maternal serum contained weak lymphocytotoxic HLA antibodies and a Brb (HPA-5a)-specific platelet alloantibody, detected in the MAIPA assay. Only weak reactions without clear specificity were observed in immunofluorescence. Family typing for platelet antigens: mother Zw(a+b-), Bak(a+), Br(a+b-); father Zw(a+b+), Bak(a-); Br(a-b+); child 2.1 Zw(a+b+), Br(a+b+); child 2.2 Zw(a+b-), Br (a+b+). HLA typing of mother: A3,32(w19); B35 w64(14); Bw6; Cw5,w8; DR1,7; DRw53; DQwl,w2.
All three children presented with typical signs of NAIT. Child 1 had a moderate purpura with severe thrombocytopenia, while the platelet counts in cases 2.1 and 2.2 were only slightly decreased with no evidence of augmented bleeding tendency. A usually mild clinical course is rather typical for Bra-NAIT, as recently shown in a large series of 39
245
NAIT due to Anti-Brb(HPA-5a)
such cases [5]. However, visceral hemorrhages and even ICH may eventually occur [5]. Serological detection of antibodies is best accomplished by the glycoprotein-specificMAIPA assay, while conventional binding assays usually yield only weak or equivocal results, particularly if HLA antibodies are simultaneously present. Treatment of choice in Brb-NAITis transfusion of maternal platelets which have been resuspended in plasma of a blood group AB donor, since random donor platelets will be incompatible in 99%. This contrasts to an 80% compatibilitychance of random platelets in Bf-NAIT. The insufficient effect of random platelets is exemplified in case 1. Interestingly,one of the immunized mothers of Jewish descent was HLA-DRw6positive, an ‘immune-response’marker, which is also significantly associated with BP immunization in the European population [6]. Further studies are required studies to analyze this phenomenon for other ethnic groups.
3 Mueller-Eckhardt C, Kiefel V, Grubert A, Kroll H, Weisheit M, Schmidt S,MueUer-Eckhardt G, Santoso S: 348 cases of suspected neonatal alloimmune thrombocytopenia. Lancet 1989;i:363-366. 4 Kiefel V, Santoso S, Weisheit M, Mueller-Eckhardt C: Monoclonal antibody-specificimmobilization of platelet antigens (MAIPA): A new tool for the identificationof platelet-reactive antibodies. Blood 1987;70:1722-1726. 5 Kaplan C, Morel MC, Kroll H, Kiefel V, Schlegel N, Chesnel N, Mueller-Eckhardt C: Neonatal alloimmune thrombocytopenia due to anti-BP: Clinical and immunological analysis of 39 cases. Submitted for publication. 6 Mueller-Eckhardt C, Kiefel V, b o l l H, Mueller-Eckhardt G: HLA-DRw6, a new immune response marker for immunization against the platelet alloantigen Bra. Vox Sang 1989;57:90-91.
References 1 Kiefel V, Santoso S , Katzmann B, Mueller-Eckhardt C: A new platelet-specificalloantigen BP. Report of four cases with neonatal alloimmune thrombocytopenia. Vox Sang 1988;54:101-106. 2 Kiefel V, Santoso S , Katzmann B, Mueller-Eckhardt C: The BrV Brballoantigen system on platelets. Blood 1989;73:2219-2223.
V. Kiefel, Institute for Clinical Immunology and Transfusion Medicine, Justus Liebig University, Langhansstr. 7 D-W-6300 Giessen (FRG)
