Clinical and diagnostic comparison of neonatal alloimmune thrombocytopenia to non-immune cases of thrombocytopenia

BACKGROUND: Affected patients with neonatal alloimmune thrombocytopenia (AIT) are often severely thrombocytopenic and, if so, may suffer an intracranial hemorrhage (ICH). This study was undertaken to compare the outcome of cases of AIT to cases of neonatal thrombocytopenia shown not to be AIT and to identify clinical features that would facilitate the diagnosis. PROCEDURE: Two hundred twenty two cases of neonatal thrombocytopenia for which serologic testing was obtained by the referring physician were accrued for this study from 11 testing laboratories. The relevant clinical information was pursued. RESULTS: The mean birth platelet count in 110 neonates with AIT was 26,000/mm(3) x 10(9)/L and the rate of ICH was 11% (not all neonates had head sonos). Three criteria distinguished cases of AIT from other causes of neonatal thrombocytopenia (n = 56): (1) severe thrombocytopenia <50,000/mm(3) x 10(9)/L; (2) ICH associated with 1 or more of: a 1-min Apgar score >5, birthweight >2,200 g, grade >1, antenatal occurrence, or signs of bleeding, that is, petechiae, ecchymoses; and (3) no additional, non-hemorrhagic neonatal medical problems. CONCLUSIONS: AIT is a unique type of neonatal thrombocytopenia with significant hemorrhagic consequences. Identification of AIT at the bedside should guide institution of appropriate treatment and lead to serologic testing for confirmation.     

������ͬ��������ѪС�����֢������

??Abstracts?? Neonatal alloimmune thrombocytopenia??NAIT??is a leading cause of neonatalthrombocytopenia andone of the main reasons for thedisease and full-term infantswith intracranial hemorrhage.This paperisfocusedon the NAIT pathogenesis??clinical features??auxiliary examination??diagnosis and intervention and treatment.     

Neonatal alloimmune thrombocytopenia caused by anti‐HLA‐A24 alloantibodies

Neonatal alloimmune thrombocytopenia (NAIT) occurs as a result of maternal alloimmunization against paternally inherited antigens on foetal platelets. Platelets express platelet specific antigens (HPA) along with human leucocyte antigens (HLA) class I. Although anti‐HLA class I antibodies are often detectable in pregnant women, their role in NAIT is considered controversial. We report a case of NAIT where the most sensitive serological analysis and molecular methods could not detect platelet specific antibodies. Only HLA incompatibility and presence of anti‐HLA‐A24 antibodies in both the mother’s and the newborn’s serum were proven. Conclusion: This case supports the idea that some anti‐HLA class I antibodies could cause NAIT.     

MYH9‐macrothrombocytopenia caused by a novel variant (E1421K) initially presenting as apparent neonatal alloimmune thrombocytopenia

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.     

Marked thrombocytopenia in a neonate is associated with anti‐HPA‐5b,anti‐HLA‐A31, and anti‐HLA‐B55 antibodies

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.     

Alloimmune neonatal neutropenia and thrombocytopenia associated with maternal anti HNA-1a, HPA-3b and HLA antibodies.

The incidence of alloimmune neonatal neutropenia combined with neonatal alloimmune thrombocytopenia is very low. We report a case of a neonate who suffered severe neutropenia and thombocytopenia with widespread petechial spots. The presence of alloantibodies in mother's and patient's sera was analyzed by lymphocytotoxicity test, agglutination test, granulocyte indirect immunofluorescence test, platelet immunofluorescence test (PIFT) and solid phase enzyme-linked immunosorbent assay. Human neutrophil antigens (HNA) and human platelet antigen (HPA) genotypes were tested by polymerase chain reaction analyses. The mother's and patient's sera reacted with neutrophils and lymphocytes of the father. PIFT revealed the presence of IgG anti-platelet antibodies in the patient's serum but the test was negative in the maternal serum. Analyses of HNA-1 and HPA genotypes of the family revealed maternal-neonatal HNA-1a and HPA-3b mismatch. The study of the mother's and patient's sera showed the presence of anti HNA1a, HPA-3b and HLA antibodies specific for HLA-A3 and HLA-B38 antigens. These results suggest that the transplacental passage of maternal HNA-1a, HPA-3b and HLA alloantibodies caused neutropenia and thrombocytopenia in this patient.     

Neonatal alloimmune thrombocytopenia due to HPA‐9b incompatibility

Neonatal alloimmune thrombocytopenia (NAIT) is one of the most frequent causes of both severe thrombocytopenia and intracranial hemorrhage (ICH) in fetuses and term neonates. The diagnosis is established by demonstrating antibodies against human platelet antigens (HPA) and discordance in platelet antigen typing between parents or between the mother and neonate. We report a case of NAIT that was likely due to maternal sensitization to HPA‐9b (Max^a), a recently recognized, rare platelet‐specific antigen. Pediatr Blood Cancer 2009;53:459–461. © 2009 Wiley‐Liss, Inc.     

Neonatal alloimmune thrombocytopenia associated with anti-human platelet antigen-3a antibody

A sister and brother with neonatal alloimmune thrombocytopenic purpura (NAITP) caused by maternal anti-human platelet antigen (HPA)-3a are reported. The children had transient severe thrombocytopenia in the newborn period, and were treated with intravenous γ-globulin and platelet concentrates from random donors. Although the sister had intracranial hemorrhage on day 2 postnatally, the development of the child has been normal and no neurological sequelae have been observed. The brother only had bloody stool when the platelet count was low, and did not have severe hemorrhagic manifestations. The diagnosis of NAITP was made by the sera from the mother, which contained anti-HPA-3a antibody directed against platelets of the children. The rate of recurrence might be high in this family, because the father of the patients was found to be homozygous for the HPA-3a gene.     

Breast feeding in neonatal alloimmune thrombocytopenia

Infants with neonatal alloimmune thrombocytopenia are at risk of severe intracranial haemorrhage. Placental transfer of maternal immunoglobulin G (IgG) directed against fetal platelet antigens is known to be the underlying mechanism. Since breast milk contains IgG it is theoretically possible that breast feeding of these infants could cause thrombocytopenia. The following case report shows that an infant with neonatal alloimmune thrombocytopenia may be safely breast fed, even when the breast milk contains the platelet specific antibody (HPA-1a).     

Comparison of FDG-PET scans to conventional radiography and bone scans in management of Langerhans cell histiocytosis

Neonatal thrombocytopenia or neutropenia may result from passive transfusion of maternally derived antibodies. Antibodies against platelet antigens are commonly associated with neonatal alloimmune thrombocytopenia (NAIT), and anti‐neutrophil antibodies are frequently identified in alloimmune neonatal neutropenia (ANN). Combined alloimmune cytopenias in the newborn are rarely reported; even fewer reports document human leukocyte antigen (HLA) antibodies as a potential cause of neonatal thrombocytopenia or neutropenia. We describe neutropenia and thrombocytopenia in a newborn associated with markedly elevated maternal HLA antibodies in the absence of anti‐neutrophil or anti‐platelet antibodies to highlight consideration of HLA antibodies in the pathogenesis of ANN and NAIT. Pediatr Blood Cancer 2009;53:97–99. © 2009 Wiley‐Liss, Inc.     

A man‐made disease: Fetal neonatal alloimmune thrombocytopenia due to incompatibility between oocyte donor and gestational mother

The incompatibility causing fetal and neonatal alloimmune thrombocytopenia (FNAIT) results from a fetus inheriting a paternal human platelet antigen (HPA), which is different from the maternal HPA. We present a unique case of FNAIT in a pregnancy involving an oocyte recipient mother with Turner syndrome. This is the first report of FNAIT in which the suggested mechanism involves antibodies produced by a gestational mother against the incompatible HPA of the oocyte donor.     

Neonatal thrombocytopenia

Thrombocytopenia (platelets <150 x 10(9)/L) is one of the most common haematological problems in neonates, particularly those who are preterm and sick. In those preterm neonates with early thrombocytopenia who present within 72 h of birth, the most common cause is reduced platelet production secondary to intrauterine growth restriction and/or maternal hypertension. By contrast, the most common causes of thrombocytopenia arising after the first 72 h of life, both in preterm and term infants, are sepsis and necrotizing enterocolitis. The most important cause of severe thrombocytopenia (platelets <50 x 10(9)/L) is neonatal alloimmune thrombocytopenia (NAIT), as diagnosis can be delayed and death or long-term disability due to intracranial haemorrhage may occur. Platelet transfusion is the mainstay of treatment for severe thrombocytopenia. However, the correlation between thrombocytopenia and bleeding is unclear and no studies have yet shown clinical benefit for platelet transfusion in neonates. Studies to identify optimal platelet transfusion practice for neonatal thrombocytopenia are urgently required.     

High-dose Intravenous Gammaglobulin for Neonatal Alloimmune Thrombocytopenia in Twins

ABSIRACT. Pietz J., Kiefel V., Sontheimer D., Kobialka B., Linderkamp O and Mueller-Eckhardt C. (Division of Neonatology, Children's Hospital, University of Heidelberg, and Institute of Clinical Immunology and Transfusion Medicine, University of Giessen, FRG). High-dose intravenous gammaglobulin for neonatal alloimmune thrombocytopenia in twins. Acta Paediatr Scand 80: 129, 1991.
We report the successful treatment of neonatal alloimmune thrombocytopenia with repeated infusions of high-dose immunoglobulin G (400 mg/kg/d for 5 days) in twins. Platelet counts increased within 3 days from less than 20×10⁹/1 to more than 70 × 10⁹/1. The first twin survived without neurological or other sequelae. The second twin had probably developed intracranial hemorrhage (ICH) in utero. This infant developed long-term neurological sequelae with blindness, cerebral palsy and infantile spasms. Implications of the therapeutic approach and prevention of severe complications in pregnancies with known risk for neonatal alloimmune thrombocytopenia are discussed.     

Evaluation and treatment of thrombocytopenia in the neonatal intensive care unit

Phlebotomy-induced anaemia excepted, thrombocytopenia is the most common haematological abnormality in neonatal intensive care unit (NICU) patients. Roughly one-quarter of all NICU patients and half of all sick preterm neonates develop thrombocytopenia. Whereas a large number of varied precipitating conditions has been identified, early-onset thrombocytopenia (>72 h) is most commonly associated with fetomaternal conditions complicated by placental insufficiency and/or fetal hypoxia, e.g. maternal pre-eclampsia and fetal intrauterine growth restriction. The resulting neonatal thrombocytopenia is usually mild to moderate, resolves spontaneously and requires no specific therapy. Deviation from this pattern of thrombocytopenia suggests the presence of more significant precipitating conditions. The most important of these are the immune thrombocytopenias, and every NICU should develop investigation and treatment protocols to manage these cases promptly and avoid unnecessary risk of haemorrhage. In contrast, late-onset thrombocytopenia (>72 h) is almost always associated with sepsis or necrotizing enterocolitis and the associated thrombocytopenia is severe, prolonged and often requires treatment by platelet transfusion. Unfortunately, evidence-based guidelines for platelet transfusion therapy in NICU patients are currently unavailable, making it difficult to define widely accepted thresholds for transfusion and leading to a significant variation in transfusion practice between centres.
Conclusion : While improving this situation remains a pressing need, the growing evidence that impaired megakaryocytopoiesis and platelet production are major contributors to many neonatal thrombocytopenias suggests that recombinant haemopoietic growth factors, including thrombopoietin and interleukin-11, may be useful future therapies to ameliorate neonatal thrombocytopenia.     

Intrauterine fetal transfusions in the management of fetal anemia and fetal thrombocytopenia

During the past 40 years, rhesus alloimmunization has gone from being one of the major causes of perinatal mortality to an almost eradicated disease. The unraveling of the pathophysiology, the development of reliable diagnostic tools, a very effective prophylaxis program, and for those (nowadays rare) cases slipping through the prevention system the availability of treatment by intrauterine blood transfusions, together constitute one of the great triumphs in modern medicine. Although Rh-D alloimmunization remains the most common indication for fetal blood transfusion therapy, an increasing percentage of these procedures is used to treat other causes of fetal anemia such as Kell alloimmunization and parvovirus B19 infection. Apart from transfusing blood, the same technique can be used to transfuse platelets to thrombocytopenic fetuses. This chapter describes the technique of fetal transfusion, and reviews the current management of fetal anemia and fetal thrombocytopenia.     

Congenital amegakaryocytic thrombocytopenia

Congenital amegakaryocytic thrombocytopenia (CAMT) is clinically characterized by thrombocytopenia presenting at birth in a child without congenital or skeletal malformations, reduced or absent bone marrow megakaryocytes, and eventual progression to bone marrow failure. Molecular studies in most cases confirm homozygous or compound heterozygous mutations in the thrombopoietin receptor c-Mpl. In addition to the clinical importance of recognizing this disorder, characterization of mutations identified in patients with CAMT has led to insights into thrombopoietin receptor structure and function. This review will summarize the diagnosis, pathophysiology, and management of CAMT.