RESUMEN
Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a disease that causes thrombocytopenia and a risk of bleeding in the (unborn) child that result from maternal alloantibodies directed against fetal, paternally inherited, human platelet antigens (HPA). It is hypothesized that these alloantibodies can also bind to the placenta, causing placental damage. This study aims to explore signs of antibody-mediated placental damage in FNAIT. We performed a retrospective study that included pregnant women, their newborns, and placentas. It comprised 23 FNAIT cases, of which nine were newly diagnosed (14 samples) and 14 were antenatally treated with intravenous immune globulins (IVIg) (21 samples), and 20 controls, of which 10 had anti-HLA-class I antibodies. Clinical information was collected from medical records. Placental samples were stained for complement activation markers (C1q, C4d, SC5b-9, and mannose-binding lectin) using immunohistochemistry. Histopathology was examined according to the Amsterdam criteria. A higher degree of C4d deposition was present in the newly diagnosed FNAIT cases (10/14 samples), as compared to the IVIg-treated FNAIT cases (2/21 samples, p = 0.002) and anti-HLA-negative controls (3/20 samples, p = 0.006). A histopathological examination showed delayed maturation in four (44%) placentas in the newly diagnosed FNAIT cases, five (36%) in the IVIg-treated FNAIT cases, and one in the controls (NS). C4d deposition at the syncytiotrophoblast was present in combination with low-grade villitis of unknown etiology in three newly diagnosed FNAIT cases that were born SGA. We conclude that a higher degree of classical pathway-induced complement activation is present in placentas from pregnancies with untreated FNAIT. This may affect placental function and fetal growth.
Asunto(s)
Activación de Complemento/inmunología , Feto/patología , Antígenos de Histocompatibilidad Clase I/inmunología , Inmunoglobulinas Intravenosas/inmunología , Placenta/patología , Trombocitopenia Neonatal Aloinmune/patología , Adulto , Anticuerpos/inmunología , Estudios de Casos y Controles , Femenino , Feto/inmunología , Humanos , Recién Nacido , Masculino , Placenta/inmunología , Embarazo , Estudios Retrospectivos , Trombocitopenia Neonatal Aloinmune/inmunologíaRESUMEN
INTRODUCTION: Maternal alloimmunization against human platelet antigen (HPA)-1a has been implied to mediate both reduced birth weight and chronic placental inflammation. Fetal growth restriction is associated with different types of chronic inflammation in the placenta, mainly chronic histiocytic intervillositis and chronic villitis. The aim of this prospective study was to do a systematic examination of placentas from HPA-1a alloimmunized pregnancies, with focus on the histopathological and immunohistochemical diagnosis of variants of chronic inflammation. MATERIAL AND METHODS: In a Polish-Norwegian study, 48 placentas were examined. The histopathology of placentas from 27 HPA-1a immunized women was compared with 21 placentas from non-immunized HPA-1a negative women (controls). In the group of alloimmunized women, ten received antenatal intravenous immunoglobulin G (IVIg). Tissue sections from formalin fixed paraffin embedded placental tissue were stained with hematoxylin and eosin and microscopically examined with focus on various types of chronic placental inflammations. RESULTS: Chronic histiocytic intervillositis was observed in 40.7% of placentas from HPA-1a alloimmunized pregnancies, compared to none in the control group (p = 0.001). Chronic villitis of unknown etiology was more frequently found in the alloimmunized group, however this difference was not statistically significant. Maternal administration of IVIg did not seem to protect against chronic inflammatory lesions. DISCUSSION: Placentas with detectable maternal anti-HPA-1a antibodies are associated with highly increased risk of low-grade chronic histiocytic intervillositis.
Asunto(s)
Histiocitosis/patología , Integrina beta3/inmunología , Placenta/patología , Trombocitopenia Neonatal Aloinmune/patología , Adulto , Estudios de Casos y Controles , Femenino , Humanos , Inmunoglobulinas Intravenosas , Placenta/inmunología , EmbarazoRESUMEN
BACKGROUND: CD36 isoantibodies are capable of inducing neonatal alloimmune thrombocytopenia (NAIT) and platelet refractoriness. As to now the CD36 type I deficiency has been reported in East Asian and African individuals. However, it is virtually unknown in Caucasians. The aim of this study was to display the prevalence of the CD36 deficiency within parts of the Arabian population in Germany. Secondly, we are presenting the case of a newborn suffering from NAIT which was induced by CD36 antibody. METHODS: Platelet (p) CD36 was determined by flow cytometry on 1328 samples mainly from individuals of Arabian origin and a family with a neonate affected by NAIT. DNA sequencing was performed on all pCD36-negative samples. RESULTS: Thirty-five (2.64%) of all donor samples were pCD36 negative, 19 (1.43%) had a weak expression. Including only individuals from the Arabian peninsula, frequencies were 3.39% and 1.75%, respectively. CD36 type I deficiency on both platelets and monocytes combined with a CD36 isoantibody were detected in the mother of the NAIT baby. The baby was successfully transfused with two HPA-unselected platelet concentrates. In case of need, two platelet units with a weak pCD36 expression were on hand. A total of 45 different CD36 mutations were detected within pCD36-negative individuals, some being homozygous, most of them only present on one allele. CONCLUSION: The CD36-negative phenotype is present in a significant number of individuals of Arabian origin and enables CD36 isoimmunization in NAIT or refractoriness. Blood transfusion services should be aware of such cases.
Asunto(s)
Plaquetas/patología , Antígenos CD36/genética , Trombocitopenia Neonatal Aloinmune/genética , Plaquetas/metabolismo , Antígenos CD36/deficiencia , Femenino , Eliminación de Gen , Expresión Génica , Alemania/epidemiología , Humanos , Recién Nacido , Masculino , Mutación , Linaje , Polimorfismo de Nucleótido Simple , Trombocitopenia Neonatal Aloinmune/epidemiología , Trombocitopenia Neonatal Aloinmune/patologíaRESUMEN
BACKGROUND: Neonatal thrombocytopenia is common in preterm and term neonates admitted to neonatal intensive care units. The etiology behind neonatal thrombocytopenia is complex. Inherited thrombocytopenia is rare and usually results from genetic mutations. CASE PRESENTATION: Here we report a case of twins with severe inherited thrombocytopenia presented in the neonatal period who were shown to be compound heterozygotes for 2 UDP-N-acetylglucosamine 2-epimerase (GNE) gene mutations, c.1351C > T and c.1330G > T, of which c.1330G > T is a novel mutation. CONCLUSION: These two GNE mutations may help in the diagnosis and management of thrombocytopenia diagnosed in neonates.
Asunto(s)
Heterocigoto , Complejos Multienzimáticos/genética , Mutación , Trombocitopenia Neonatal Aloinmune/genética , Gemelos/genética , Secuencia de Bases , Femenino , Expresión Génica , Estudio de Asociación del Genoma Completo , Humanos , Lactante , Unidades de Cuidado Intensivo Neonatal , Modelos Moleculares , Complejos Multienzimáticos/deficiencia , Estructura Secundaria de Proteína , Trombocitopenia Neonatal Aloinmune/diagnóstico , Trombocitopenia Neonatal Aloinmune/patologíaRESUMEN
Alloimmunization against human platelet antigen (HPA)-1a during pregnancy can cause foetal/neonatal alloimmune thrombocytopenia (FNAIT) and severe bleeding in the foetus or newborn and likely depends on several factors. HPA-1a alloimmunization is associated with DRB3*01:01, which is associated with several DR-DQ haplotypes. However, it is not known to what extent these haplotypes contribute to the prevalence of HPA-1a alloimmunization. HPA-1a-alloimmunized women, identified in a prospective study, and random donors were typed for selected DRB3, DRB4, DRB1, DQA1 and DQB1 alleles to determine allele and DR-DQ haplotype frequencies. DRB3*01:01 was carried by 94% HPA-1a-immunized women compared to 27% in the general population. In the first population, the DR3-DQ2 haplotype was overrepresented (P < .003). The prevalence of HPA-1a alloimmunization was estimated to be about twice as frequent with DR3-DQ2 compared to DR13-DQ6, together accounting for about 90% of DRB3*01:01-positive individuals. Further, we examined DQB1*02 and DRB4*01:01 alleles for their reported association with HPA-1a alloimmunization, in the context of DR-DQ haplotypes. Since ~ 80% of DQB1*02 alleles are linked to the DR3-DQ2 haplotype, the association might be coincidental. However, the DQB1*02:02-associated DR7-DQ2 haplotype was also overrepresented in alloimmunized women, suggesting a role for this allele or haplotype in HPA-1a alloimmunization. As DRB4*01:01 is predominantly associated with the DR7-DQ2 haplotype in HPA-1a-alloimmunized individuals, the reported association with FNAIT may be coincidental. Typing for DR-DQ haplotypes revealed important genetic associations with HPA-1a alloimmunization not evident from typing individual alleles, and the presence of different DRB3-associated DR-DQ haplotypes showed different prevalence of HPA-1a alloimmunization.
Asunto(s)
Antígenos de Plaqueta Humana/inmunología , Predisposición Genética a la Enfermedad/genética , Antígenos HLA-DQ/genética , Cadenas HLA-DRB3/genética , Trombocitopenia Neonatal Aloinmune/genética , Femenino , Frecuencia de los Genes/genética , Técnicas de Genotipaje , Haplotipos/genética , Humanos , Recién Nacido , Integrina beta3 , Embarazo , Trombocitopenia Neonatal Aloinmune/inmunología , Trombocitopenia Neonatal Aloinmune/patologíaRESUMEN
Maternal alloimmunization to paternally inherited antigens on fetal/neonatal platelets can cause fetal/neonatal alloimmune thrombocytopenia (FNAIT) after antibody-mediated removal of platelets from the fetal circulation. The complications vary from mild bleeding symptoms to severe intracranial hemorrhage and subsequent neurological impairment or death. Studies on in vivo mechanisms are challenging to measure directly in pregnant women, rendering murine models as valuable and attractive alternatives, despite some critical differences between mice and men affecting the translational value. Here we present and discuss, the different murine models that substantially have increased our knowledge and understanding of FNAIT pathogenesis - as well as pre-clinical evaluation of therapeutic and preventive strategies.
Asunto(s)
Trombocitopenia Neonatal Aloinmune/prevención & control , Trombocitopenia Neonatal Aloinmune/terapia , Animales , Modelos Animales de Enfermedad , Femenino , Humanos , Recién Nacido , Masculino , Ratones , Trombocitopenia Neonatal Aloinmune/patologíaRESUMEN
Maternal antibodies against human platelet antigen (HPA) and/or human leukocyte antigen (HLA) cause fetal and neonatal alloimmune thrombocytopenia (FNAIT) in 0.09-0.15% of live births. Severe cases account for 5-31% and the frequency of multiple kinds of alloantibodies is 6.9-9% of FNAIT. We present a case of severe FNAIT associated with anti-HPA-5b, anti-HLA-A31, and anti-HLA-B55 antibodies, successfully treated with immunoglobulin and platelet transfusion. The anti-HLA-B55 antibody was detected in the newborn's serum, but disappeared on the 20th day, which was followed by an increase of the platelet count. These findings suggested the potential involvement of an anti-HLA antibody in the pathogenesis of FNAIT.
Asunto(s)
Antígenos de Plaqueta Humana/inmunología , Antígenos HLA-A/inmunología , Antígenos HLA-B/inmunología , Inmunidad Materno-Adquirida/inmunología , Isoanticuerpos/inmunología , Trombocitopenia Neonatal Aloinmune/inmunología , Adulto , Femenino , Humanos , Inmunoglobulinas/administración & dosificación , Recién Nacido , Masculino , Transfusión de Plaquetas/métodos , Pronóstico , Trombocitopenia Neonatal Aloinmune/patología , Trombocitopenia Neonatal Aloinmune/terapiaRESUMEN
BACKGROUND: Neonatal alloimmune thrombocytopenia (NAIT) commonly arises due to antibodies against a small number of well-defined human platelet antigens (HPAs). A minority of NAIT cases occur due to maternal immunization against low-frequency polymorphisms in platelet glycoprotein that result in new immunogenic epitopes. Antibodies to these novel epitopes can be detected by the incubation of maternal serum with paternal platelets and is usually performed after initial investigation using HPA-typed panel platelets has failed to provide evidence of NAIT. STUDY DESIGN AND METHODS: The propositus and the parents from a case of suspected neonatal alloimmune thrombocytopenia (NAIT) were investigated using serologic and molecular techniques to detect and identify relevant platelet-specific antibodies and for HPA typing. Calculations of molecular dynamics were undertaken to explore potential variations in the molecular structure. RESULTS: Maternal antibodies were detected that were reactive only in crossmatch with paternal platelets using the platelet immunofluorescence test (PIFT) and a GPIIb/IIIa monoclonal antibody immobilization of platelet antigen (MAIPA) assay. In the propositus and father, a novel mutation c.1373 A > G was found in exon 10 of ITGB3 resulting in the substitution of an aspartic acid for a glycine (p.Asp458Gly). Recombinant GPIIIa glycoprotein mutated to contain the novel mutation and expressed in HEK293 cells with GPIIb was also specifically recognized by maternal antibodies. Calculations of molecular dynamics identified that the mutation was in a structurally constrained site. CONCLUSION: This case describes a low-frequency platelet antigen (Asp458Gly) that defines a further alloantigenic target in NAIT. The case emphasizes the role of the platelet crossmatch as the single most useful tool to establish evidence of immunization of low-frequency platelet glycoprotein polymorphisms. A crossmatch should always be performed where there is strong clinical evidence of NAIT but initial laboratory investigations are not confirmatory.
Asunto(s)
Integrina beta3/genética , Polimorfismo Genético/genética , Trombocitopenia Neonatal Aloinmune/genética , Animales , Animales Recién Nacidos , Antígenos de Plaqueta Humana/genética , Células HEK293 , Humanos , Recién Nacido , Isoantígenos/genética , Glicoproteínas de Membrana Plaquetaria/genética , Trombocitopenia Neonatal Aloinmune/patologíaRESUMEN
Fetal and neonatal alloimmune thrombocytopenia (FNAIT) and neonatal alloimmune neutropenia (NAN) are two rare complications of newborns caused by antibodies against paternal inherited antigens. Human platelet (HPA) and neutrophil antigens (HNA) are the common targets. Human leukocyte antigen (HLA) class I proteins are also expressed on platelets and neutrophils and anti-HLA antibodies have occasionally been implicated in these complications. We report a premature twin infant who presented with severe thrombocytopenia and neutropenia clinically compatible with FNAIT and NAN, from a mother with no identifiable HPA or HNA antibodies, but with very high levels of complement-fixing antibodies against paternal inherited HLA. These antibodies were also detected in the infant. HLA antibodies are commonly present in multiparous women who deliver healthy infants. They can, however, be cytotoxic and cause clinical complications after blood products transfusion (TRALI and becoming refractory to platelets transfusion) and after organ transplantation (allogeneic organ rejection).
Asunto(s)
Anticuerpos/inmunología , Feto/patología , Antígenos HLA/inmunología , Neutropenia/inmunología , Trombocitopenia Neonatal Aloinmune/inmunología , Plaquetas/inmunología , Femenino , Humanos , Recién Nacido , Masculino , Neutropenia/patología , Neutrófilos/inmunología , Placenta/patología , Embarazo , Trombocitopenia Neonatal Aloinmune/patologíaRESUMEN
Neonatal alloimmune thrombocytopenia (NAIT) is a common but significant challenge for neonatologists and a potentially devastating disease that may lead to intracranial bleeding. The underlying mechanism of thrombocytopenia is expected to be mediated by accelerated clearance of antibody-opsonized fetal platelets. We report severe recurrent NAIT related to human platelet antigen (HPA)-15 systems in 2 consecutive siblings. The first child presented with intracranial hemorrhage at birth and subsequently died. The diagnosis of NAIT, although initially suspected, was ruled out after negative investigation of only HPA-1, HPA-3, and HPA-5 systems. The second child experienced a clinically milder presentation but a profound thrombocytopenia. In both siblings, NAIT was unexpectedly associated with amegakaryocytosis, suggesting that alloimmunization could extend at the megakaryocyte level. In addition, both siblings presented with drastic abnormalities in the B-cell compartment, which led to broad investigations for an immune-deficiency syndrome and provided a novel pathophysiologic hypothesis. Both placental examinations revealed major lymphoid infiltration involving the villous placenta, which is consistent with the diagnosis of villitis of unknown etiology. Severe thrombocytopenia in an otherwise healthy newborn should raise high the suspicion of NAIT. The diagnosis of NAIT should not be ruled out until extensive human platelet antigen systems have been investigated to screen for fetal-maternal antigen incompatibility. This is crucial not only for the newborn to allow optimal lifesaving treatments but also for effective management of future pregnancies. Interestingly, antibodies to HPA-15 have previously been reported with severe NAIT-related thrombocytopenia, but we are the first to report associated in vivo amegakaryocytosis.
Asunto(s)
Linfocitos B , Vellosidades Coriónicas/patología , Linfopenia/diagnóstico , Linfopenia/patología , Megacariocitos/patología , Trombocitopenia Neonatal Aloinmune/diagnóstico , Trombocitopenia Neonatal Aloinmune/patología , Antígenos de Plaqueta Humana/sangre , Hemorragia Cerebral/etiología , Femenino , Humanos , Recién Nacido , Inflamación/patología , Linfopenia/complicaciones , Linfopenia/inmunología , Embarazo , Recurrencia , Trombocitopenia Neonatal Aloinmune/inmunologíaRESUMEN
MYH9-related disease is a rare cause of thrombocytopenia. We report an infant girl who presented with severe thrombocytopenia at birth and was initially diagnosed with and treated for neonatal alloimmune thrombocytopenia. However, persistent thrombocytopenia led to the suspicion of congenital thrombocytopenia and subsequent identification of a novel variant in MYH9 (E1421K). In silico analysis strongly predicts that this is a disruptive substitution. Immunofluorescent analysis of neutrophils demonstrates abnormal aggregates of MYH9 protein. This case also suggests that a very high immature platelet fraction (≥40%) may be useful for rapidly differentiating MYH9-related disease from other causes of neonatal thrombocytopenia.
Asunto(s)
Proteínas Motoras Moleculares , Mutación Missense , Cadenas Pesadas de Miosina , Agregación Patológica de Proteínas , Trombocitopenia Neonatal Aloinmune , Sustitución de Aminoácidos , Plaquetas/metabolismo , Plaquetas/patología , Femenino , Enfermedades Genéticas Congénitas/sangre , Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Congénitas/patología , Enfermedades Genéticas Congénitas/terapia , Humanos , Recién Nacido , Proteínas Motoras Moleculares/genética , Proteínas Motoras Moleculares/metabolismo , Cadenas Pesadas de Miosina/genética , Cadenas Pesadas de Miosina/metabolismo , Neutrófilos/metabolismo , Neutrófilos/patología , Agregación Patológica de Proteínas/genética , Agregación Patológica de Proteínas/metabolismo , Agregación Patológica de Proteínas/patología , Agregación Patológica de Proteínas/terapia , Trombocitopenia Neonatal Aloinmune/sangre , Trombocitopenia Neonatal Aloinmune/genética , Trombocitopenia Neonatal Aloinmune/patología , Trombocitopenia Neonatal Aloinmune/terapiaRESUMEN
In fetal/neonatal alloimmune thrombocytopenia (FNAIT), platelets are destroyed by maternal antibodies directed against fetal/neonate antigens. Thrombocytopenia can be severe and lead to intracranial hemorrhage (ICH) in about 10% of cases. Although three types of antigen groups, presented on platelets [ABO blood group antigens, human leukocyte antigens (HLA) and human platelet antigens (HPA)] are known to be implicated in immune platelet destruction, antibodies against HPA are most commonly involved in FNAIT and hence are the target of extensive research. Awareness of FNAIT by physicians as well as the availability of the most sensitive diagnostic methods capable of detecting a wide range of antibodies are crucial for the diagnosis of FNAIT and the prevention of severe thrombocytopenia and its bleeding risks in subsequent pregnancies.
Asunto(s)
Antígenos de Plaqueta Humana/inmunología , Plaquetas/patología , Trombocitopenia Neonatal Aloinmune/diagnóstico , Trombocitopenia Neonatal Aloinmune/inmunología , Sistema del Grupo Sanguíneo ABO/análisis , Sistema del Grupo Sanguíneo ABO/inmunología , Anticuerpos/análisis , Anticuerpos/inmunología , Antígenos de Plaqueta Humana/análisis , Plaquetas/inmunología , Antígenos HLA/análisis , Antígenos HLA/inmunología , Humanos , Recién Nacido , Trombocitopenia Neonatal Aloinmune/patologíaRESUMEN
Lack of reliable laboratory parameters is the main challenge in the management of fetal and neonatal alloimmune thrombocytopenia (FNAIT). Despite the long-known association between the HLA-DRB3*01:01 allele and human platelet antigen 1a (HPA-1a) alloimmunisation, maternal human leucocyte antigen (HLA) typing has been of little clinical value. Recently, other DRB3 allele variants have been suggested to predict the severity of FNAIT. In this nationwide population-based retrospective cohort study, we performed extensive HLA typing of 96 women, accounting for 87% of our cohort of 110 families with confirmed or possible HPA-1a-immunisation. The HLA type was compared with anti-HPA-1a levels, severity of neonatal disease and responsiveness to maternally administrated intravenous gammaglobulin (IVIG). HLA haplotypes were constructed to investigate further HLA associations. Despite significantly lower anti-HPA-1a levels in DRB3*01:01-negative women, the carrier status of this particular allele could not be used to confirm or rule out FNAIT in the absence of detectable antibodies. In the haplotype analysis, the DRB3*01:01 allele was the actual factor associated with FNAIT. No other HLA allele was shown to be of additional value as a predictor of severe FNAIT or non-responsiveness to IVIG treatment. Thus, HLA genotyping was not found useful in differentiating high- and low-risk pregnancies or in guiding antenatal treatment in affected families.
Asunto(s)
Prueba de Histocompatibilidad , Valor Predictivo de las Pruebas , Trombocitopenia Neonatal Aloinmune/inmunología , Adulto , Alelos , Estudios de Cohortes , Femenino , Genotipo , Glucuronidasa/inmunología , Cadenas HLA-DRB3/inmunología , Humanos , Recién Nacido , Madres , Embarazo , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Trombocitopenia Neonatal Aloinmune/diagnóstico , Trombocitopenia Neonatal Aloinmune/patología , Adulto JovenRESUMEN
The most frequently involved antigen in severe fetal and neonatal alloimmune thrombocytopenia (FNAIT) is the human platelet antigen 1a. Platelets express the HLA-A and B antigens on their membrane and some studies report that maternal anti-HLA class I antibody can also cause FNAIT. We report here a very unusual case of a first twin pregnancy produced in vitro by oocyte and semen donation where the mother developed markedly elevated HLA antibodies, in the absence of anti-platelet or anti-neutrophil antibodies, that provoked in one of the twins a profound thrombocytopenia and intracranial hemorrhage and a mild thrombocytopenia and neutropenia in the second twin lasting until the fourth month of life. In addition, anti-D alloimmunization provoked hemolytic disease of the newborn with intrauterus anemia detected in the first twin and post-natal anemia in the second twin that required red blood cell transfusion and phototherapy. We hypothesize that the complete HLA-incompatible twin pregnancy due to the oocyte donation might have contributed to the severity of the clinical manifestations.
Asunto(s)
Antígenos HLA/inmunología , Embarazo Gemelar , Trombocitopenia Neonatal Aloinmune/inmunología , Resultado Fatal , Femenino , Fertilización In Vitro , Humanos , Persona de Mediana Edad , Embarazo , Trombocitopenia Neonatal Aloinmune/patología , Trombocitopenia Neonatal Aloinmune/fisiopatologíaRESUMEN
BACKGROUND: Alloimmunization against human platelet antigens (HPAs) can occur prenatally and induce fetal/neonatal alloimmune thrombocytopenia (FNAIT). The aim of this study was to identify placental histological features associated with platelet alloimmunization and their clinical significance. METHODS: This study examined 21 placentas from FNAIT-affected pregnancies and 42 age-matched control cases, all collected from pathology departments in the Rhône-Alpes region. Clinical and laboratory findings were collected for each FNAIT case. Two pathologists reviewed the placental slides of each FNAIT and control case. Histological features, with special emphasis on chronic inflammatory lesions, were evaluated. Differences between the two groups were calculated with odds ratios (ORs) and assessed with Wald's chi-square. RESULTS: FNAIT was associated with a significantly higher frequency of chronic chorioamnionitis (CC) (OR 14, 95%CI 1.7-113.8), basal chronic villitis (BCV) (OR 17, 95%CI 2-145.6) and chronic intervillositis (CIV). Chronic villitis (CV) (OR 3.7, 95%CI 0.9-15.2) and chronic deciduitis (CD) (OR 4.7, 95%CI 0.79-28.2) were also more frequent in the FNAIT than the control group, but these differences were not statistically significant. CONCLUSIONS: FNAIT is significantly associated with CC, BCV, and CIV. This chronic inflammatory reaction is preferentially localized on the maternofetal interface. Anti-HPA alloimmunization may trigger an immunological conflict similar to graft-versus-host disease.
Asunto(s)
Placenta/patología , Trombocitopenia Neonatal Aloinmune/patología , Adulto , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Humanos , Recién Nacido , Embarazo , Estudios RetrospectivosRESUMEN
OBJECTIVE: Fetal/neonatal alloimmune thrombocytopenia is a severe bleeding disorder, which can result in intracranial hemorrhage (ICH), leading to death or neurological sequelae. In whites, maternal anti-human platelet antigen-1a (HPA-1a) antibodies are responsible for the majority of cases. No predictive factors for ICH are available to guide prophylactic treatment during pregnancy. In this study, we investigated antibodies from mothers with ICH-positive fetal/neonatal alloimmune thrombocytopenia and with ICH-negative fetal/neonatal alloimmune thrombocytopenia to identify serological and functional differences between the groups. APPROACH AND RESULTS: In an antigen capture assay, we observed a stronger binding of +ICH antibodies to endothelial cell (EC)-derived αvß3. By absorption experiments, we subsequently identified anti-HPA-1a antibodies of anti-αvß3 specificity in the +ICH but not in the -ICH cohort. Only the anti-αvß3 subtype, but not the anti-ß3 subtype, induced EC apoptosis of HPA-1a-positive ECs by caspase-3/7 activation, and mediated by reactive oxygen species. In addition, only the anti-αvß3 subtype, but not the anti-ß3 subtype, interfered with EC adhesion to vitronectin and with EC tube formation. CONCLUSIONS: We conclude that the composition of the anti-HPA-1a antibody subtype(s) of the mother may determine whether ICH occurs. Analysis of anti-HPA-1a antibodies of the anti-αvß3 subtype in maternal serum has potential in the diagnostic prediction of ICH development and may allow for modification of prophylactic treatment in fetal/neonatal alloimmune thrombocytopenia.
Asunto(s)
Autoanticuerpos/inmunología , Células Endoteliales/inmunología , Integrina alfaVbeta3/inmunología , Hemorragias Intracraneales/inmunología , Trombocitopenia Neonatal Aloinmune/inmunología , Animales , Especificidad de Anticuerpos , Antígenos de Plaqueta Humana/inmunología , Antígenos de Plaqueta Humana/metabolismo , Apoptosis , Autoanticuerpos/metabolismo , Células CHO , Estudios de Casos y Controles , Caspasa 3/metabolismo , Caspasa 7/metabolismo , Adhesión Celular , Cricetulus , Células Endoteliales/metabolismo , Células Endoteliales/patología , Femenino , Edad Gestacional , Células Endoteliales de la Vena Umbilical Humana/inmunología , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Células Endoteliales de la Vena Umbilical Humana/patología , Humanos , Recién Nacido , Integrina alfaVbeta3/genética , Integrina alfaVbeta3/metabolismo , Integrina beta3 , Hemorragias Intracraneales/metabolismo , Hemorragias Intracraneales/patología , Masculino , Intercambio Materno-Fetal , Neovascularización Fisiológica , Embarazo , Especies Reactivas de Oxígeno/metabolismo , Trombocitopenia Neonatal Aloinmune/metabolismo , Trombocitopenia Neonatal Aloinmune/patología , TransfecciónRESUMEN
BACKGROUND: The most feared bleeding complication in fetal and neonatal alloimmune thrombocytopenia (FNAIT) is an intracranial hemorrhage (ICH). However, FNAIT may also lead to other severe bleeding problems. The aim was to analyze this spectrum and evaluate the occurrence of severe hemorrhages other than ICH in fetuses or neonates with FNAIT. STUDY DESIGN AND METHODS: A retrospective chart analysis of cases of FNAIT presenting with severe bleeding complications other than ICH at our institution from 1990 to 2015 was conducted. Additionally, a review of the literature was performed to identify case reports and case series on FNAIT presenting with extracranial hemorrhage. RESULTS: Of 25 fetuses or neonates with severe bleeding due to FNAIT, three had isolated severe internal organ hemorrhage other than ICH, two pulmonary hemorrhages and one gastrointestinal hemorrhage. Two of these three neonates died due to this bleeding. Eighteen cases of extracranial bleeding complications as a first presentation of FNAIT were found in the literature, including ocular, gastrointestinal, spinal cord, pulmonary, renal, subgaleal, and genitourinary hemorrhages. CONCLUSION: Bleeding complications other than ICH may be more extensive, and the presentation of FNAIT may have a greater spectrum than previously described. A high index of suspicion on the possible diagnosis of FNAIT with any bleeding complication in a fetus or neonate may enable adequate diagnostics, adequate treatment, and appropriate follow-up in future pregnancies, as is especially relevant for FNAIT.
Asunto(s)
Hemorragia/etiología , Trombocitopenia Neonatal Aloinmune/patología , Adulto , Femenino , Enfermedades Fetales , Hemorragia/patología , Humanos , Incidencia , Recién Nacido , Embarazo , Estudios Retrospectivos , Trombocitopenia Neonatal Aloinmune/epidemiologíaRESUMEN
The thrombocytopenia is found in 1%-5% of newborns. Depending on mechanisms of pathogenesis of thrombocytopenia is divided on immune and non-immune one. The reaction of of interaction between antibodies and antigens of superficial structures of cells are in the basis of immune destruction of thrombocytes. During intrauterine period and period of newborness auto-, trans- and alloimmune alternatives of development of thrombocytopenia can be observed. The neonatal alloimmune thrombocytopenia is registered with rate of 1 case per 800-1000 newborns. The study was targeted to developing algorithm of diagnostic of immune thrombocytopenia, detecting main diagnostic criteria, exploring clinical significance of results of laboratory tests. The methods of study included typing of genes of HPA system using polymerase chain reaction with detection of results in real-time mode, detection of compatibility of HPA-genotypes of mother and child using flow cytometry technique. The following criteria of diagnostic of neonatal alloimmune thrombocytopenia: 1. detection of incompatible combination of HPA genes in mother and child (HPA-1bb/HPA-1ab; HPA-5aa/HPA-5ab; HPA-15ab/HPA- 15ab); 2. detection in blood serum of mother antibodies adsorbing more than on 3% of thrombocytes of child; 3. absence of antithrombocyte antibodies in mother and child (coefficient of auto-sensitization is less than 5%). The immune genesis of thrombocytopenia is established in 40% 0f children with low number of thrombocytes at birth. In 50% of cases the cause was determined as anti-thrombocyte alloantibodies with diagnosis neonatal alloimmune thrombocytopenia. Also in 50% of cases decreasing of number of thrombocytes in children occurred as result of impact of autoantibodies of mother with diagnosis "transimmune thrombocytopenia". The considered laboratory methods have high specificity and permit to properly diagnose immune causes of thrombocytopenia in newborns.
Asunto(s)
Antígenos de Plaqueta Humana/inmunología , Autoanticuerpos/sangre , Relaciones Materno-Fetales , Trombocitopenia Neonatal Aloinmune/sangre , Antígenos de Plaqueta Humana/sangre , Antígenos de Plaqueta Humana/genética , Autoanticuerpos/genética , Autoanticuerpos/inmunología , Plaquetas/inmunología , Plaquetas/patología , Femenino , Genotipo , Humanos , Recién Nacido , Integrina beta3 , Masculino , Trombocitopenia Neonatal Aloinmune/genética , Trombocitopenia Neonatal Aloinmune/inmunología , Trombocitopenia Neonatal Aloinmune/patologíaRESUMEN
Neonatal alloimmune thrombocytopaenia (NAIT) results from a fetomaternal incompatibility with maternal sensitisation against a fetal human platelet antigen (HPA) and antibodies transfer to the fetal circulation, leading to platelet destruction. The clinical presentation is variable and isolated intraocular haemorrhage is rare. We present the case of a male newborn, with intrauterine growth restriction, born at 29â weeks due to pre-eclampsia. He presented proptosis of the left eye, hyphaema and elevated intraocular pressure, with no other signs of haemorrhage. Severe thrombocytopaenia was found (27×10(9)/L). Perinatal infection and maternal thrombocytopaenia were excluded. Positive anti-HPA-1a and antihuman leucocyte antigen class I alloantibodies were found in the mother. Platelet crossmatch between the father's platelets and mother's plasma was positive. Platelet transfusions and intravenous immunoglobulin were given with favourable response. This case highlights an unusual presentation of NAIT, which should be suspected in the presence of severe thrombocytopaenia in the first 24-72â h of life.