Trombocitopenia neonatal: Revisión. I. Definiciones, diagnóstico diferencial, causas, trombocitopenias inmunes / Neonatal thrombocytopenia: A review. I. Definitions, differential diagnosis, causes, immune thrombocytopenia

La trombocitopenia, definida como recuento plaquetario inferior a 100 x 109/l, es un hallazgo muy frecuente en el período neonatal, que ocurre, en especial, en niños críticamente enfermos y en prematuros. Sus causas son múltiples: puede deberse tanto a enfermedades del niño como a otros factores involucrados en la interrelación niño-placenta-madre. En este primer artículo, se enumeran las causas de trombocitopenia; se plantea el enfoque diagnóstico frente a un neonato trombocitopénico y se describen detalladamente las distintas entidades correspondientes a trombocitopenias de etiología inmune. Se presentan los diferentes mecanismos causales y se revisan las distintas características de la trombocitopenia secundaria a trombocitopenia inmune materna y de la trombocitopenia neonatal aloinmune. Se describen las diversas estrategias terapéuticas disponibles para cada una de ellas, tanto para su manejo posnatal como para el prenatal. Se enfatiza sobre la gravedad de la enfermedad y las serias complicaciones y secuelas asociadas a la trombocitopenia neonatal aloinmune

Thrombocytopenia, defined as a platelet count below 100 x 109/L, is a very common finding in the neonatal period, especially in critically ill infants and preterm newborns. Its causes are multiple: it may be due both to pediatric conditions and to other factors involved in the fetal-placental-maternal interface. This initial article describes the causes of thrombocytopenia, proposes a diagnostic approach to manage a thrombocytopenic newborn infant, and provides a detailed description of the different conditions corresponding to thrombocytopenia of immune etiology. It also describes the different causative mechanisms and reviews the varying characteristics of thrombocytopenia secondary to maternal immune thrombocytopenia and neonatal alloimmune thrombocytopenia. The different treatment approaches to each of the different conditions are described both for their pre- as well as their postnatal management. The severity of thrombocytopenia and the serious complications and sequelae associated with the neonatal alloimmune thrombocytopenia are highlighted.

Conocimientos actuales sobre la patogénesis, presentación clínica, diagnóstico y manejo de la trombocitopenia neonatal aloinmune / Current knowledge on neonatal alloimmune thrombocytopenia's pathogenesis, clinical presentation, diagnostic and management

Introducción: La trombocitopenia neonatal aloinmune es una enfermedad producida por anticuerpos maternos contra antígenos plaquetarios fetales heredados del padre. Puede ser causa de hemorragia intracraneal y conducir a la muerte o discapacidad en el feto/neonato. Aunque es la causa más grave de trombocitopenia en el neonato y la más común en los recién nacidos a término, en general ha sido poco investigada. Objetivos: Exponer los conocimientos actuales sobre la patogénesis, presentación clínica, diagnóstico y del manejo pre- y posnatal de la trombocitopenia neonatal aloinmune, Métodos: Se realizó una revisión de la literatura, en inglés y español, a través del sitio web PubMed y el motor de búsqueda Google académico de artículos publicados en los últimos 10 años. Se hizo un análisis y resumen de la bibliografía revisada. Resultados: Los anticuerpos IgG maternos son transportados a través de la placenta a la circulación fetal, opsonizan las plaquetas fetales que son removidas por fagocitosis. Los antígenos más implicados son el HPA-1a y HPA-4a. La fisiopatología de la enfermedad es muy similar a la enfermedad hemolítica perinatal, pero aún no se han implementado programas de pesquisa y el diagnóstico se realiza después del nacimiento del niño afectado de trombocitopenia, hemorragia intracraneal o muerte in útero de causa no explicada. Consideraciones finales: El impacto clínico de la trombocitopenia neonatal aloinmune y las oportunidades de tratamiento potencian la necesidad de implantar programas de pesquisa para la detección de fetos en riesgo de padecer esta enfermedad(AU)

Introduction: Neonatal alloimmune thrombocytopenia is a disease produced by maternal antibodies against fetal platelet antigens inherited from the father. It can be a cause of intracranial hemorrhage and lead to death or disability in the fetus / neonate. Although it is the most serious cause of thrombocytopenia in newborns and the most common in full-term infants, it has generally been poorly investigated. Objectives: To approximate to current knowledge about the pathogenesis, clinical presentation, diagnosis and pre- and post-natal management of neonatal alloimmune thrombocytopenia. Methods: A review of literature, in English and Spanish, through PubMed website and Google scholar search engine of articles published in the last 10 years was conducted. An analysis and summary of the reviewed bibliography was made. Results: Maternal IgG antibodies are transported through the placenta to the fetal circulation, opsonizing fetal platelets that are removed by phagocytosis. The most involved antigens are HPA-1a and HPA-4a. The pathophysiology of this disease is very similar to perinatal hemolytic disease, but research programs have not been implemented yet and diagnosis is made after birth of children affected by thrombocytopenia, intracranial hemorrhage or in uterus death by unexplained causes. Final considerations: Clinical impacts of neonatal alloimmune thrombocytopenia and treatment opportunities enhance the need to implement screening programs for the detection of fetuses at risk of suffering from this disease(AU)

Neonatal Alloimmune Thrombocytopenia Caused by Anti-HLA-A2 Alloantibodies Determined by Luminex Single Antigen Bead Assay

Neonatal alloimmune thrombocytopenia (NAIT) occurs when maternal alloantibodies react to antigens expressed on fetal platelets, which is mainly platelet-specific alloantigen or HLA, resulting in their immune destruction. Here, we described a patient who suffered from NAIT caused by anti-HLA-A2 antibody. Sera from the mother and the newborn were screened for human platelet antigen-specific antibodies and HLA antibodies by ELISA, and HLA antibodies were detected in both of them. The antibody specificity was identified as anti-HLA-A2 by Luminex single antigen bead assay. HLA typing results showed that patient's father descended HLA-A2 antigen on the patient and the mother was HLA-A2 negative. It is most conceivable that anti-HLA-A2 alloantibody in the mother's sera crossed the placenta and subsequently caused NAIT in the case presented. The patient received platelet concentrates, oral steroid and intravenous globulin and platelet count increased to 120x10(9)/L on the 90th day of life. The Luminex single antigen bead assay used in this case is highly sensitive and specific assay to determine antibody specificity and it is faster and more convenient for routine use in clinical laboratory so that this assay could be useful to diagnose NAIT caused by HLA antibodies and treat such NAIT patients with HLA matched platelet transfusion.

A Case of Neonatal Alloimmune Thrombocytopenia due to Anti-HLA-B35

Neonatal alloimmune thrombocytopenia (NAIT) is induced by maternal antibodies to fetal platelet alloantigens. Because the main cause of NAIT is incompatibility to platelet specific antibodies, NAIT due to HLA antibodies are relatively rare. We managed a case of NAIT induced by maternal anti-HLA-B35 antibodies. The patient was a second born male. He had no petechiae or purpura at birth. He was admitted to the hospital due to fever for 5 days and a platelet count of 106x10(9)/L. The fever subsided after admission but on the 2nd day of admission, petechiae developed on the chest wall and the platelet count decreased to 25x10(9)/L. Other laboratory findings included C-reactive protein, prothrombin time, and partial thromboplastin time were normal. His mother's platelet count was normal and she had no history of bleeding. Anti-HLA-B35, B52, B56, C3, and C14 were identified in the mother's serum by a panel reactive antibody test and HLA-B35 antigen was identified in the father's and patient's sera. These finding suggested that maternal Anti-HLA-B35 antibody was a response to neonatal HLA-B35 antigen inherited from the father. The patient received concentrated platelet and intravenous immunoglobulin. The platelet count rose to 248x10(9)/L and was maintained thereafter.

A Case of Neonatal Alloimmune Thrombocytopenia due to Anti-HLA-B62+B75 / 대한수혈학회지

We encountered a case of neonatal alloimmune thrombocytopenia (NAIT) due to anti-HLA-B62+B75. We incidentally find thrombocytopenia (14,000/uL at birth and decreased to 4,000/uL at 12 hours after birth) in a female fullterm neonate. Petechial skin lesions are developed on her back and buttock at second day of birth. Her mother suffered from preeclamsia during her last trimester, but her platelet count was 167,000/uL and she had no history of abnormal bleeding. Anti-HLA-B62+B75 antibody was identified in mother's serum by panel reactive antibody test and was reactive with father's platelet by mixed passive hemagglutination assay. Platelet concentrate was transfused at the second and 5th days and patient's platelet count rose up to 58,000/uL just after transfusion but decreased to 21,000/uL eventually. From the 8th day, gamma globulin (1g/kg/day) was started intravenously for 3 days and platelet count rose up to 128,000/uL at 13th day and remained within normal limit thereafter.

A Case of Neonatal Alloimmune Thrombocytopenia Related to HLA Antibody

Neonatal alloimmune thrombocytopenia(NAIT) is a very rare disease caused by maternal alloantibodies' response to neonatal platelet antigens. Because the most common cause of NAIT is incompatibility for platelet-specific antigens, NAIT cases due to anti-HLA antibodies are very exceptional. The patient was a second born female. She had no petechia or purpura at birth. But her platelet count was 55,000/mm3 and other laboratory findings were normal. On family history, the first baby had thrombocytopenia at birth too without petechia or other abnormal symptoms and his platelet count became spontaneously normal later. The mother's platelet count was normal and she had no history of idiopathic thrombocytopenic purpura(ITP) or bleeding tendency. Platelet crossmatching test showed positive between citric acid untreated paternal platelets and maternal serum, but negative to citric acid treated paternal platelets. These findings suggest maternal serum which contain anti-HLA antibodies to attack neonatal platelets and paternal platelets. Therefore this report documents a patient with neonatal thrombocytopenia induced by maternal anti HLA antibody.

A Case of Neonatal Alloimmune Thrombocytopenia dut to Anti-HLA A2

Neonatal alloimmune thrombocytopenia(NAIT) is a rare disease caused by maternal alloimmunization against fetal platelet surface antigen, which is mainly platelet specific alloantigen or human leukocyte antigen(HLA). During routine hemotology, we accidentally discovered thrombocytopenia in a female fullterm newborn admitted due to jaundice. We excluded NAIT due to human platelet alloantigen(HPA), because the HPA of the mother and baby were the same on PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism). Mother's serum was tested for lyrnphocytotoxity against 36 donor lymphocytes, and anti-HLA A2, A24 and B58 were found. HLA typing of the father and baby revealed A2 antigen which was not present on the mothers lymphocytes. The patient received concentrated platelet and intravenous globulin. Her platelet count increased to 222,000/mm from 3,000/mm on the 11th day of life. We described a case of NAIT due to anti-HLA A2 antibody with a detailed clinical feature. (J Korean Pediatr Soc 1999;43:861-865)

Detection of platelet specific antigens by flow cytometry and genotyping method / 대한수혈학회지

BACKGROUND: To identify the human platelet antigens (HPA) associated with neonatal alloimmune thrombocytopenia (NATP), posttransfusion purpura (PTP), and platelet refractoriness, polymerase chain reaction-sequence specific primer (PCR-SSP) method and immunofluorescent method by flow cytometry were used. The frequencies of the genonotypes of HPA systems by PCR-SSP method and those of phenotypes by flow cytometry were determined. Then both types were compared each other and each types were compared with those of established reports. METHOD: Platelet suspensions were prepared from peripheral blood specimens of 200 blood donors and DNA specimens were extracted from those of 160 donors among them. Phenotypes of 200 specimens and genotypes of 160 ones were tested by flow cytometry and PCR-SSP method, respectively. RESLUTS: Frequencies of penotypes of HPA-1a, -3a, -4a, -4b and NaKa were 100.0%, 88.0, 100.0%, 0.5% and 94.0%, respectively. HPA-5 system could not be identified due to a few antigenic sites of HPA-5 systems. The genotype fequencies are of HPA-2 were a+b- 63.75%, a+b+ 35.00%, a-b+ 1.25%; HPA-3, a+b- 38.12%, a+b+ 48.13%, a-b+ 13.75%; HPA-4, a+b- 100.00%, a+b+ 0.00%, a-b+ 0.00%; HPA-5, a+b- 98.12%, a+b+ 1.88%, a-b+ 0.00%. The frequencies of HPA-4 and -5 were almost same as those of other reports but the frequencies of HPA-2 and -3 were somewhat different from others. Concordant rate between phenotype and genotype of HPA-3a,-4a and -4b were 95.6%, 100% and 99.4%, respectively. CONCLUSION: Phenotyping method by flow cytometry was rapid and objective for identifying HPA systems except HPA-5 system which has a few antigenic sites on platelet membrane. Especially it will be useful method for screening HPA-4b as possible cause of NATP in Koreans. But like other serologic methods, phenotyping by flow cytometry also require the highly qualified antiserum and appropriate amount of platelet. PCR-SSP method was also rapid and simple to test of genotypes of HPA-2~5 systems. Because PCR-SSP method is thought to be one of the most simple and economic genotyping methods to overcome the shortages of serologic methods, it is suggested to be the efficient screening method of HPA systems substituting the serologic methods in the cases which HPA sytems can not be identified by flow cytometry.

Genotype Frequencies of Platelet Glycoprotein IIIa-Specific Antigens and Granulocyte Antigens In Korean Pregnant Women* / 대한수혈학회지

BACKROUND: Polymorphism of glycoprotein IIIa on human platelets is one of the factors in alloimmunization that causes neonatal alloimmune thrombocytopenia (NATP), and the granulocyte antigens NA1 and NA2 are often targets of granulocytes antibodies causing neonatal alloimmune neutropenia (NANP). Currently, serotyping relies on the properties of the typing sera or antibodies and technique used. Genotyping circumvents the problems associated with serotyping. METHODS: The genomic DNA of 200 unrelated pregnant women admitted to Taegu Fatima Hospital was typed for three platelet glycoprotein IIIa-specific antigens (HPA-1, HPA-4, and HPA-6w) and granulocyte antigens (NA1 and NA2). Allele specific amplification test using primer designed to study HPA-1 and HPA-4, restriction fragment length polymorphism to study HPA-6w, and sequence specific primers for NA1 and NA2 were used for genotyping. RESULTS: The genotype frequencies were HPA-1(a+b-) 100%, HPA-4 (a+b-) 97.5%, HPA-4(a+b+) 2.5%, HPA-6w(a+b-) 97%, and HPA-6w(a+b+) 3%. These frequencies are similar to Japanese but different from Caucasian. The gene frequencies of NA1 and NA2 were 0.56 and 0.44 respectively. There are no cases of alloimmune thrombocytopenia and neutropenia in newborns from the 200 studied women. CONCLUSIONS: The differences in genotype frequencies among platelet glycoprotein IIIa-specific antigens and in the gene frequencies of NA in Koreans are shown as compared with other ethnic groups. Therefore it is needed to find the proper screening target antigens and antibodies for Korean NATP and NANP patients.