Down syndrome with neonatal alloimmune thrombocytopenia due to anti-HLA A31 and B61 antibodies.

Neonatal alloimmune thrombocytopenia (NAIT) arises from fetomaternal platelet incompatibility that results in transplacental passage of maternal antibodies mostly against fetal human platelet antigens (HPA), whereas NAIT due to anti-human leukocyte antigen (HLA) antibodies is extremely rare. Here, we report a case of Down syndrome (DS) with NAIT that was attributed to HLA antibodies. A boy with DS was delivered at 36 weeks' gestation. His platelet count declined to 13.0 × 109/L, suggestive of NAIT rather than other conditions, including transient abnormal myelopoiesis. Random platelet concentrates and intravenous immunoglobulin administration resolved the thrombocytopenia without clinical complications. Immunoserological investigations detected anti-HLA, but no anti-HPA antibodies in samples from the patient and the mother. HLA typing and cross-matching indicated that anti-HLA antibodies to paternal HLA A31 and B61, which had probably been induced during a prior pregnancy, led to NAIT in this case. Although it is a rare condition, healthcare providers should consider NAIT due to HLA antibodies and be vigilant for subsequent cases in DS.

Practical guidance for the management of adults with immune thrombocytopenia during the COVID-19 pandemic.

This document aims to provide practical guidance for the assessment and management of patients with thrombocytopenia, with a particular focus on immune thrombocytopenia (ITP), during the COVID-19 pandemic. The intention is to support clinicians and, although recommendations have been provided, it is not a formal guideline. Nor is there sufficient evidence base to conclude that alternative approaches to treatment are incorrect. Instead, it is a consensus written by clinicians with an interest in ITP or coagulation disorders and reviewed by members of the UK ITP forum.

Neonatal familial Evans syndrome associated with joint hypermobility and mitral valve regurgitation in three siblings in a Saudi Arab family.

The occurrence of autoimmune hemolytic anemia and immune thrombocytopenia in the absence of a known underlying cause led to the diagnosis of Evans syndrome in a 9-month-old male. Subsequently, a similar diagnosis was made in two siblings (a 3-year-old boy and a 1-day-old girl). The 9-month-old had a chronic course with exacerbations. He was treated with steroids, intravenous immunoglobulin and colchicine with a variable response. He died of congestive heart failure at the age of 8 years. The brotherâs disease course was one of remission and exacerbation. With time, remissions were prolonged and paralleled an improvement in joint hypermobility. The sister died of sepsis after a chronic course with severe exacerbations. Only two families with Evans syndrome have been reported in the English medical literature. In one report (in a Saudi Arab family), the disease was associated with hereditary spastic paraplegia.

Congenital posthemorrhagic hydrocephalus: a case of fetomaternal alloimmune thrombocytopenia.

Fetal/neonatal alloimmune thrombocytopenia (NAIT) results from fetomaternal mismatch for human platelet alloantigens leading to antibody-mediated destruction of fetal platelets. This is one of the most common causes of severe thrombocytopenia in the newborn with an incidence of 1/800-1,000. In the most severe cases, NAIT may result in intracranial hemorrhage and may lead to death or neurologic sequelae. We report a case of fetal hydrocephalus caused by NAIT and discuss the importance of making an accurate prenatal diagnosis to improve the management of the current pregnancy and the outcome of subsequent pregnancies. Screening of female siblings of affected cases is recommended in order to detect at-risk individuals.

An unusual cause of neonatal coagulopathy and liver disease.

Congenital thyrotoxicosis is a rare and potentially fatal illness. We report a case in a preterm infant delivered to a mother known to have autoimmune endocrine disease. Diagnosis was difficult because the infant's presenting symptoms and signs closely resembled congenital viral infection with co-existent hepatic dysfunction and coagulopathy. The associated hepatic dysfunction was so severe that liver biopsy was scheduled before the diagnosis emerged. A high degree of clinical suspicion coupled with prenatal identification of pregnancies at risk of complication by congenital thyrotoxicosis is imperative to facilitate prompt diagnosis and treatment.

Urinary hepcidin in congenital chronic anemias.

BACKGROUND: Hepcidin, a regulator for iron homeostasis, is induced by inflammation and iron burden and suppressed by anemia and hypoxia. This study was conducted to determine the hepcidin levels in patients with congenital chronic anemias. PROCEDURE: Forty-nine subjects with anemia, varying degrees of erythropoiesis and iron burden were recruited. Eight children with immune thrombocytopenia were included as approximate age-matched controls. Routine hematologic labs and urinary hepcidin (uhepcidin) levels were assessed. For thalassemia major (TM) patients, uhepcidin was obtained pre- and post-transfusion. RESULTS: In TM, uhepcidin levels increased significantly after transfusion, demonstrated wide variance, and the median did not significantly differ from controls or thalassemia intermedia (TI). In both thalassemia syndromes, the hepcidin to ferritin ratio, a marker of the appropriateness of hepcidin expression relative to the degree of iron burden, was low compared to controls. In TI and sickle cell anemia (SCA), median uhepcidin was low compared to controls, P = 0.013 and <0.001, respectively. In thalassemia subjects, uhepcidin levels were positively associated with ferritin. In subjects with SCA, uhepcidin demonstrated a negative correlation with reticulocyte count. CONCLUSIONS: This study examines hepcidin levels in congenital anemias. In SCA, hepcidin was suppressed and inversely associated with erythropoietic drive. In thalassemic syndromes, hepcidin was suppressed relative to the degree of iron burden. Transfusion led to increased uhepcidin. In thalassemia, the relative influence of known hepcidin modifiers was more difficult to assess. In thalassemic syndromes where iron overload and anemia have opposing effects, the increased erythropoietic drive may positively influence hepcidin production.

Long-term effects of fetal and neonatal alloimmune thrombocytopenia and its antenatal treatment on the medical and developmental outcomes of affected children.

Alloimmune thrombocytopenia (AIT) is characterized by severe thrombocytopenia, usually diagnosed after birth, which may result in intracranial hemorrhage (ICH) in as many as 20% of cases. The course of AIT typically worsens in subsequent pregnancies. Administration to mother of intravenous gammaglobulin (IVIG) and/or corticosteroids to increase the fetal platelet counts of a subsequent affected fetus is widely used to avoid ICH. The objective of this study was to evaluate the long-term effects of AIT and its antenatal treatment on the medical and developmental outcomes of affected children. Seventy-one pairs of untreated (older) and antenatally treated (younger) siblings with AIT were compared. A medical questionnaire and the Behavioral Assessment System for Children (BASC) were completed over the telephone by mothers. In this sample, birth platelet counts of treated fetuses were significantly higher than those of the untreated fetuses. Treated children were born at significantly lower gestational ages and with significantly lower birthweights than untreated children. No treated child suffered a perinatal ICH compared with 12 untreated siblings. Treated siblings also had fewer vision problems (three versus 14 in the untreated group). Children treated as fetuses received higher scores on the BASC Adaptive Skills Composite than their untreated siblings. The antenatal regimen of IVIG and/or corticosteroids did not affect the results. Children with AIT treated as fetuses had better long-term developmental-behavioral outcomes than their untreated siblings, perhaps because of higher in utero platelet counts. We speculate that platelets may possibly play a role in neurodevelopmental processes in the fetus.

Congenital macrothrombocytopenias.

Congenital macrothrombocytopenias comprise a heterogeneous group of rare disorders, characterized by abnormal giant platelets, thrombocytopenia and bleeding tendency with variable severity. Many of these disorders share common clinical and laboratory features, making accurate diagnosis difficult and patients are often misdiagnosed with and treated for idiopathic thrombocytopenic purpura. Recent progress in the elucidation of underlying defects and further developments of specific diagnostic techniques for several congenital macrothrombocytopenias have renewed our approach to the classification and the diagnosis of the disease. This review summarizes the current knowledge on the clinical and laboratory features of common congenital macrothrombocytopenias and discusses how that knowledge aids in making a proper diagnosis.

Is there a relationship between anti-HPA-1a concentration and severity of neonatal alloimmune thrombocytopenia?

There is uncertainty about the relationship between anti-HPA-1a levels and severity of neonatal alloimmune thrombocytopenia (NAIT). To investigate this relationship further,the concentration of anti-HPA-1a in HPA-1b homozygous women was determined, using a newly developed quantitative ELISA that uses purified anti-HPA-1a to obtain a standard curve. Seventy-eight samples collected from 22 HPA-1b homozygous pregnant women at various stages of pregnancy were tested. These included five women who had delivered babies with severe NAIT. A national HPA-1a antibody standard (NIBSC 93/710), designated as 1 arbitrary unit/mL (AU/mL),was used in each ELISA to calibrate the purified anti-HPA- 1a, enabling the presentation of results as AU/mL. Moreover, selected samples were also assayed by PAK 12 and their reactivity compared with quantity of antibody. The use of the purified HPA- 1a antibody yielded consistent sigmoid curves, enabling the measurement of HPA-1a antibody concentration in the test samples. The antibody concentration was significantly correlated with the antibody titer in the 78 samples studied (R = 0.54, p < 0.001). Furthermore, there was a significant correlation between PAK 12 and the quantitative ELISA in a selected number of cases, with or without NAIT (R = 0.71, n = 10; p < 0.02). On the other hand, there was no correlation of antibody concentration with NAIT incidence (R = -0.046). This study indicates that there is no relationship between anti-HPA-1a concentration and severity of NAIT when ELISA is used, although the correlation between ELISA and other methods, such as monoclonal antibody immobilization of platelet antigens (MAIPA) assay, remains to be determined.

What's happening? The expanding role of apheresis platelet support in neonatal alloimmune thrombocytopenia: current status and future trends.

Despite some unresolved problems that may be associated with platelet transfusion, such as alloimmunisation, refractoriness, bacterial contamination, and the potential side effects related to the development of some biological response modifiers during storage, platelet therapy remains the most effective treatment for the management and prevention of severe thrombocytopenia and hemorrhage [Seghatchian J, Snyder EL, Krailadsiri P, editors. Platelet therapy: current status and future trends. Amsterdam, The Netherlands: Elsevier; 2000]. This appears to be particularly the case in neonatal alloimmune thrombocytopenia (NAIT), which arises due to an incompatibility of the platelet specific antigens between the pregnant mother and her baby. Over 80% of severe NAIT cases in the Caucasian population occur when the mother and baby differ in their HPA-1 epitope (HPA-1a negative and positive respectively) leading, in 10% of cases, to the production of anti-HPA-1a which can cross the placenta and cause NAIT in utero or post-partum. Anti-HPA-5b is the second most cause of NAIT, although severe cases occur only after the first pregnancy. Clinical manifestations of NAIT vary from mild (petechia and bruises) to severe (intracranial haemorrhage with possible death or life long morbidity). A recent study in Scotland indicated that the cost per case of severe NAIT detected during screening of pregnant women, where anti-HPA-1a is detected for the first time, would amount to $98,771 [Turner M, Bessos H, et al. Prospective epidemiological study of the outcome and cost effectiveness of antenatal screening to detect neonatal alloimmune thrombocytopenia (NAIT) due to anti-HPA-1a. Transfusion, in press. Yet, unlike the case with Rhesus hemolytic disease of the new born, the cost-effectiveness of HPA-1 screening in NAIT remains unresolved, as does the most optimal mode of treatment. Therefore, in the absence of a consensus on the screening and optimal management of NAIT, the availability and provision of HPA-1a/5b negative apheresis platelets based on current practice (transfusionguidelines.org.uk) appear to be a clinically effective treatment in NAIT. In that vein, an increasing number of blood transfusion centres are screening blood donors in order to secure panels of donors for the prompt provision of HPA-1a/5b negative apheresis platelets. However, evidence is also accumulating that while platelets derived from various apheresis technologies currently in use may be equivalent in terms of cellular contents (thus meeting specifications), they may differ in terms of the platelet storage lesion, microvesiculation and the development of platelet-derived cytokines and some other biological response modifiers [Seghatchian J. Platelet storage lesion: the influence of various leukoreduction procedures on generation/retention of some biological response modifiers, microvesiculation, distribution of membrane-bound/soluble Prion and the rate of HLA-CLASS1 release. Trans Apher Sci, in press. This manuscript summarises strategy and progress both in the improvement of apheresis platelet quality and provision in NAIT.

Neonatal outcome in patients with rheumatic disease.

Rheumatic autoimmune diseases have a higher prevalence in women, particularly during their childbearing age. Due to improved management, an increasing number of patients plan and carry out one or more pregnancies. Therefore, a growing interest is being paid to the possible consequences of maternal disease and associated treatment on the fetus and newborn infant. If maternal disease is characterized by the presence of IgG isotype autoantibodies, these can cross the placenta with possible antibody-mediated damage to the fetus. This is typically the case of the so called neonatal lupus erythematosus (NLE); a similar mechanism has been shown in infants of patients with immune thrombocytopenic purpura (ITP) and, less frequently, in those from mothers with antiphospholipid syndrome (APS). Indeed, this last condition is often responsible for placental, rather than neonatal, pathology. In addition, immunosuppressive and other drugs administered to the mothers during pregnancy and lactation might affect the fetal and neonatal immune system development. Finally, mothers disease and/or treatment could be related to neuropsychological alteration reported in some of their children.

Pregnancy in women with idiopathic thrombocytopaenic purpura.

INTRODUCTION: Idiopathic thrombocytopaenic purpura (ITP) is a common haematological disorder in young women. The management of ITP in pregnancy is controversial, particularly with regards to the mode of delivery. To date, there is no systematic study of the outcome of these pregnancies in Singapore. AIM: To study the outcomes of pregnancies in Asian women with a proven diagnosis of ITP. MATERIALS AND METHODS: Retrospective study of 27 pregnancies in 18 women managed at the Singapore General Hospital from 1 January 1994 to 30 June 2001. RESULTS: The mean age of the women was 30 years (range, 20 to 41 years) and the mean parity was 1 (range, 0 to 3). Thrombocytopaenia (platelet count < 150 x 10(9)/L) occurred in 18 pregnancies (67%). There were 3 first trimester missed abortions (11%), 1 termination of pregnancy (4%), 1 stillbirth (4%) and 22 livebirths (81%) in this series. The mode of delivery was spontaneous vaginal in 14 women (64%), vacuum extraction in 2 women (9%), elective caesarean section in 5 women (23%) and emergency caesarean section in 1 woman (4%). All liveborn neonates were delivered in good condition at term. Neonatal thrombocytopaenia occurred in 4 neonates (18%). Two neonates had cord platelet counts of less than 50 x 10(9)/L and 1 required therapy with corticosteroids and intravenous immune globulins. No bleeding complications occurred in any of the neonates. CONCLUSION: Our experience supports the increasingly prevalent practice of managing pregnancies in women with ITP with a conservative approach to investigations and treatment. Caesarean sections should be performed for obstetric indications only, given the rarity of bleeding complications in the offspring of these women and the lack of evidence to support its role in the prevention of neonatal intracranial haemorrhage.

Idiopathic thrombocytopenia in pregnancy.

Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disorder in which antiplatelet autoantibodies bind to the antigens on platelet surfaces, resulting in their destruction. It is one of the most common autoimmune disorders that physicians manage today. Although it can present itself at any age, it tends to occur in young women. Hence, it commonly affects women in the childbearing age group. It is a haematological disorder for which diagnostic and treatment strategies are not well defined. In the past decade, there have been attempts for consensus in the management of patients with ITP, resulting in practice guidelines being published. The management of pregnant patients with ITP, however, has its special problems with the added responsibility of caring for 2 lives, the mother and her fetus. The choice of drugs is limited to those without teratogenic risks to the fetus and the overall aim is to prevent haemorrhage in both mother and fetus during the antenatal and peripartum periods. There are more data now to show that invasive procedures do not necessarily reduce fetal bleeding risk and are associated with more maternal morbidities, thus favouring the trend towards more conservative management.

[Neonatal alloimmune thrombocytopenic purpura caused by anti-HPA-1a alloantibodies. Case report]. / Neonatalna aloimuna trombocitopenijska purpura (NATP) uzrokovana anti-HPA-1a aloprotutijelima. Prikaz bolesnika.

We report the case of serologically proven HPA-1a NATP. The child was born after uneventful 4th pregnancy. Immediately after birth generalized petechiae and signs of gastrointestinal bleeding were present. Isolated thrombocytopenia with the platelet number of 29 x 10(9)/L was observed. Serological investigation (PSIFT and MAIPA) showed high titre anti-HPA-1a antibody and low titre anti-HLA antibody in mother's sera. Mother's platelets were HPA-1a negative and she was HLA DR 52 positive. Father's platelets were HPA-1a positive. Cross-match between mother's sera and father's platelets was positive. 24 hours after the introduction of corticosteroid therapy platelet number increased to 73 x 10(9)/L and 48 hours later to 155 x 10(9)/L. The child was treated by corticosteroids because the NATP was severe and antigen negative platelets (mother or donor) or IVGG were not available. According to data from the literature the efficiency of corticosteroid therapy in NATP is questionable, but in this case it provided sufficient increase of platelet number with the stop of newborn bleeding.

Immune-mediated thrombocytopenias: basic and immunological aspects.

Acute idiopathic or autoimmune thrombocytopenic purpura (AITP) is a disorder found mainly in children, usually preceded by a viral infection, with a higher incidence in the autumn and winter. The platelet-specific autoantibodies in acute childhood AITP are more often of the IgM class. Chronic AITP occurs mostly in adults. The platelet immunofluorescence test (PIFT) detects platelet-specific autoantibodies with a sensitivity of 65-75%. The autoantibodies in chronic AITP are classified as IgG in 95%, IgM in 26% and IgA in 4% of cases. The antibodies are usually bound to platelets and are detectable as free circulating antibodies in about 40%. AITP in pregnancy may cause neonatal AITP by autoantibodies of the IgG class which pass the placenta barrier. The rare neonatal alloimmune thrombocytopenic purpura (NAITP) are caused by IgG alloantibodies against HPA-1a in 75-90%, HPA1b in 3-5%, HPA 3a in 4-5%, HPA5b in 6-19% and against private platelet antigens in 3%. To confirm the diagnosis of NAITP requires extensive serological testing of the child, and the parents have to be typed for the important platelet-specific antigens by PIFT, monoclonal antibody immobilisation of platelet antigens (MAIPA) and/or enzyme-linked immunosorbent assay (ELISA) techniques. Three mechanisms of drug-induced thrombocytopenias are described. Platelets of both the donor and the patient are destroyed in post-transfusion thrombocytopenic purpura (PTP) but PTP does not occur again if incompatible platelets are re-administered.

Neonatal thrombocytopenia: incidence, serological and clinical observations.

In this study, platelet counts were determined from the cord blood of consecutive 9142 newborns. Neonates with known autoimmune thrombocytopenia were not included. The platelet count < 100 x 10(9)/L was found in 64 newborns. In five of them, neonatal alloimmune thrombocytopenia (NAIT) was diagnosed. The overall incidence of neonatal thrombocytopenia was 0.7%, the incidence of NAIT was about 10 times less. Serological and clinical observations are summarized from 238 thrombocytopenic newborns (54 from the above group and 184 previously referred to serological investigations). All of the newborns were divided into two groups: NAIT (46 cases) and other thrombocytopenias (192 cases). Among platelet-specific antibodies in NAIT, 91.4% were anti-HPA-1a, the rest were anti-HPA-1b and anti-HPA-5b. In the majority of the cases, antibodies were detectable by the platelet suspension immunofluorescence test (PSIFT) and monoclonal antibody immobilization of platelet antigens (MAIPA) assay. In 19.6% cases, antibodies were detectable by MAIPA only. In 10.9% of these cases, antibodies were undetectable. Thrombocytopenia < 50 x 10(9)/L and hemorrhagic diathesis were more often observed in NAIT than in other thrombocytopenias, whereas associated disorders that could contribute to thrombocytopenia, here observed almost only in the latter group. We also report certain other observations, such as the presence of anti-HLA antibodies, a rise in the anti-HPA-1 a antibody titer after infection without pregnancy, and a higher incidence of petechiae in nonimmune thrombocytopenia as compared with the incidence of low platelet counts.

Maternal thrombocytopenia. Predicting neonatal thrombocytopenia with cordocentesis.

OBJECTIVE: To evaluate the efficacy of cordocentesis for predicting fetal thrombocytopenia in the presence of maternal thrombocytopenia. STUDY DESIGN: We studied platelet counts obtained by cordocentesis from 42 consecutive immune thrombocytopenia purpura patients. Platelet counts were obtained on 36 neonates, and the statistical analysis included only these infants. Presence of maternal antiplatelet antibodies, interval from fetal sampling to delivery, neonatal platelet counts and outcome were evaluated. Thrombocytopenia was defined as a platelet count < or = 150,000/microL, with < or = 50,000 microL considered severe. RESULTS: No procedure-related complications occurred. A moderate correlation existed between fetal and neonatal platelet counts (r = .48, P = .003), unrelated to the interval between sampling and delivery. Eight of 36 fetuses had thrombocytopenia, and 4 were confirmed at delivery. Two neonates had thrombocytopenia at birth but not at cordocentesis. Two neonatal thrombocytopenia cases were severe. Neither was categorized as severe antenatally. The sensitivity, specificity, and positive and negative value for predicting severe neonatal thrombocytopenia were 0%, 100%, 0%, and 94%, respectively. Grade 1 intraventricular hemorrhages occurred in two neonates delivered at 35 weeks' with normal platelet counts. CONCLUSION: Cordocentesis was not reliable in predicting severe neonatal thrombocytopenia; however, the high negative predictive value was reassuring. The clinical utility of the technique and the population in which it should be used remain to be defined.