Neonatal Thrombocytopenia and the Role of the Platelet Mass Index in Platelet Transfusion in the Neonatal Intensive Care Unit

Background: Neonatal thrombocytopenia is a common hematological abnormality that occurs in 20­35% of all newborns in the neonatal intensive care unit. Platelet transfusion is the only known treatment; however, it is the critical point to identify neonates who are really at risk of bleeding and benefit from platelet transfusion as it also has various potential harmful effects. Aims: To investigate the prevalence and risk factors of neonatal thrombocytopenia and its relationship to intraventricular hemorrhage in the neonatal intensive care unit and to determine whether the use of platelet mass index-based criteria could reduce the rate of platelet transfusion. Study Design: Retrospective cohort study. Methods: This study was conducted in the neonatal intensive care unit of a tertiary university hospital. The medical records of neonates in the neonatal intensive care unit with platelet counts <150×109/L between January 2013 and July 2016 were analyzed. Results: During the study period, 2,667 patients were admitted to the neonatal intensive care unit, and 395 (14%) had thrombocytopenia during hospitalization. The rate of intraventricular hemorrhage was 7.3%. Multiple logistic regression analysis showed that although lower platelet counts were associated with a higher intraventricular hemorrhage rate, the effects of respiratory distress syndrome, sepsis, and patent ductus arteriosus were more prominent than the degree of thrombocytopenia. Thirty patients (7%) received platelet transfusion, and these patients showed a significantly higher mortality rate than their non-platelet transfusion counterparts (p<0.001). In addition, it was found that the use of platelet mass index-based criteria for platelet transfusion in our patients would reduce the rate of platelet transfusion by 9.5% (2/21). Conclusion: Neonatal thrombocytopenia is usually mild and often resolves without treatment. As platelet transfusion is associated with an increased mortality rate, its risks and benefits should be weighed carefully. The use of platelet mass index-based criteria may reduce platelet transfusion rates in the neonatal intensive care unit, but additional data from prospective studies are required.

Activated NK cells cause placental dysfunction and miscarriages in fetal alloimmune thrombocytopenia.

Miscarriage and intrauterine growth restriction (IUGR) are devastating complications in fetal/neonatal alloimmune thrombocytopenia (FNAIT). We previously reported the mechanisms for bleeding diatheses, but it is unknown whether placental, decidual immune cells or other abnormalities at the maternal-fetal interface contribute to FNAIT. Here we show that maternal immune responses to fetal platelet antigens cause miscarriage and IUGR that are associated with vascular and immune pathologies in murine FNAIT models. Uterine natural killer (uNK) cell recruitment and survival beyond mid-gestation lead to elevated NKp46 and CD107 expression, perforin release and trophoblast apoptosis. Depletion of NK cells restores normal spiral artery remodeling and placental function, prevents miscarriage, and rescues hemorrhage in neonates. Blockade of NK activation receptors (NKp46, FcɣRIIIa) also rescues pregnancy loss. These findings shed light on uNK antibody-dependent cell-mediated cytotoxicity of invasive trophoblasts as a pathological mechanism in FNAIT, and suggest that anti-NK cell therapies may prevent immune-mediated pregnancy loss and ameliorate FNAIT.Fetal/neonatal alloimmune thrombocytopenia (FNAIT) is a gestational disease caused by maternal immune responses against fetal platelets. Using a FNAIT mouse model and human trophoblast cell lines, here the authors show that uterine natural killer cell-mediated trophoblast apoptosis contributes to FNAIT pathogenesis.

Fatal alloimmune thrombocytopenia due to anti-HLA alloimmunization in a twin pregnancy: A very infrequent complication of assisted reproduction.

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.

Fetal/Neonatal Alloimmune Thrombocytopenia: Pathogenesis, Diagnostics and Prevention.

Fetal/neonatal alloimmune thrombocytopenia (FNAIT) is a relatively rare condition (1/1000-1/2000) that was granted orphan status by the European Medicines Agency in 2011. Clinical consequences of FNAIT, however, may be severe. A thrombocytopenic fetus or new-born is at risk of intracranial hemorrhage that may result in lifelong disability or death. Preventing such bleeding is thus vital and requires a solution. Anti-HPA1a antibodies are the most frequent cause of FNAIT in Caucasians. Its pathogenesis is similar to hemolytic disease of the newborn (HDN) due to anti-RhD antibodies, but is characterized by platelet destruction and is more often observed in the first pregnancy. In 75 % of these women, alloimmunization by HPA-1a antigens, however, occurs at delivery, which enables development of antibody-mediated immune suppression to prevent maternal immunization. As for HDN, the recurrence rate of FNAIT is high. For advancing diagnostic efforts and treatment, it is thereby crucial to understand the pathogenesis of FNAIT, including cellular immunity involvement. This review presents the current knowledge on FNAIT. Also described is a program for HPA-1a screening in identifying HPA-1a negative pregnant women at risk of immunization. This program is now performed at the Institute of Hematology and Transfusion Medicine in cooperation with the Department of Obstetrics and Gynecology of the Medical Centre of Postgraduate Education in Warsaw as well as the UiT The Arctic University of Norway.

Suppression of in vitro megakaryopoiesis by maternal sera containing anti-HPA-1a antibodies.

Incompatibility of the human platelet antigen-1 (HPA-1) system is the most common cause of fetal/neonatal alloimmune thrombocytopenia (F/NAIT) and is thought to be mediated by accelerated clearance of antibody-opsonized fetal platelets. We evaluated the effect of maternal sera containing anti-HPA-1a antibodies (F/NAIT sera) on in vitro megakaryopoiesis. Compared with control maternal sera, 14 out of 17 F/NAIT sera significantly reduced megakaryocyte (MK) number. This finding was associated with increased apoptosis and cell death of early MKs/MK progenitors, but normal maturation and differentiation of surviving MKs. An analysis of platelet counts in infants born to mothers following antenatal intravenous immunoglobulin (IVIG) ± prednisone therapy demonstrated a significant and moderately strong correlation between the MK growth in cultures and the infants' platelet counts at birth. These findings suggest that maternal anti-HPA-1a antibodies can suppress fetal megakaryopoiesis by inducing early cell death and that this influences the neonatal platelet count. Thus, the ability of maternal antibodies to suppress MK growth is a potential predictive factor for the fetal response to maternal IVIG therapy.

A Doppler velocimetry evaluation of intestinal blood flow characteristics in neonates receiving intravenous immunoglobulin therapy: a prospective observational study.

OBJECTIVES: To evaluate intestinal blood flow changes after intravenous immunoglobulin (IVIg) infusion among neonates with Rh isoimmunization and alloimmune thrombocytopenia. METHODS: This prospective observational study was conducted in level III NICU from July 2011 through August 2012. Thirty three consecutive instances (30 neonates) of IVIg treatment (1 g/kg) were studied. Celiac (CA) and superior mesenteric artery (SMA) doppler evaluations were performed immediately prior (baseline), immediately after and 12 to18 h following IVIg infusion. Peak systolic velocity, end diastolic velocity, time-averaged mean velocity, pulsatility index, resistive index and systolic/diastolic ratio were measured. The doppler indices measured immediately after and 12 to 18 h after IVIg infusion were compared with the baseline values. RESULTS: The mean gestation and birth weight of the cohort were 36 ± 2 wk and 2597 ± 563 g respectively. Doppler flow variables measured immediately after and 12 to 18 h after IVIg were comparable to baseline values, in both the arteries. However, systolic/diastolic ratio in SMA immediately post-IVIg was lower than baseline, [median (IQR): 5 (3, 9) vs. 7 (4, 14), respectively; p=0.02]. None of the study infants developed feed intolerance or necrotizing enterocolitis (NEC). CONCLUSIONS: There was no significant change in the celiac and SMA blood flows following IVIg therapy in neonates with Rh isoimmunization and alloimmune thrombocytopenia.

SUBGALEAL HEMATOMA AS A PERINATAL PRESENTATION OF RARE HEMATOLOGIC PROBLEMS IN NEWBORNS. OWN EXPERIENCE.

INTRODUCTION: Bleeding to the subgaleal space is a rare and often serious complication of childbirth. Delivery with the use of vacuum or forceps is considered as the main risk factor of subgaleal hemorrhage. Reports of other possible causes (including fetal ones) appear rarely. OBJECTIVES: The aim of this study is to present and analyze two unusual cases of bleeding to subgaleal space in neonates delivered through caesarean section, in whom two different concomitant hematologic problems were diagnosed. The authors demonstrate also the mechanisms leading to the formation of subgaleal hematoma as well as discuss the impact of the final diagnosis on the course of the perinatal period and the need to modify medical practice in a variety of clinical situations in both newborns and their mothers. MATERIAL AND METHODS: Authors present two consecutive cases of severe subgaleal hemorrhage. RESULTS: In the first newborn hemophilia was finally diagnosed. The second neonate was diagnosed with neonatal alloimmune thrombocytopenia. CONCLUSIONS: Subgaleal hemorrhage is a rare complication of delivery. In severe cases, other possible risks should be considered apart from the traumatic delivery only. An early identification of potential hematological risk factors can influence the effectiveness of the treatment and help to modify the follow-up of both the infant and its mother.

Fetal/neonatal alloimmune thrombocytopenia.

In fetal/neonatal alloimmune thrombocytopenia (FNAIT), antibodies against paternal antigens present on fetal platelets are produced by the mother. These antibodies will cross the placenta and can cause thrombocytopenia of the unborn. One severe consequence of thrombocytopenia is intracranial bleeding which may lead to death or severe sequelae. FNAIT index cases in one family are usually detected at birth only since antenatal screening programmes have not been installed so far. Subsequent pregnancies of immunized mothers may require special diagnostic and prophylactic interventions, and interdisciplinary counselling and treatment involving obstetricians, pediatricians and immunohematologists may prove useful for optimized care. This short review covers pathogenesis, clinical presentation, diagnostic, and therapeutic options in FNAIT.

Review of neonatal alloimmune thrombocytopenia.

Neonatal alloimmune thrombocytopenia (NAIT), with an incidence of one in 1000 live births, is the most common cause of severe thrombocytopenia and intra-cerebral haemorrhage in term neonates. NAIT results from trans-placental passage of maternal antibodies against a paternally derived fetal platelet alloantigen. Clinical presentation varies from unexpected thrombocytopenia on a blood film in a well newborn to intracranial haemorrhage (ICH). In contrast to haemolytic disease of the newborn, NAIT can present in a first pregnancy, and subsequent pregnancies are usually more severely affected. The role of antenatal screening for maternal alloantibodies instead of fetal blood sampling to identify at-risk fetuses remains uncertain, but there is a trend towards less invasive maternally directed treatment for at-risk pregnancies. Neonatal management is aimed at preventing or limiting thrombocytopenic bleeding with transfusion of antigen-matched platelets.

Neonatal alloimmune thrombocytopenia: a case study.

Neonatal alloimmune thrombocytopenia (NAIT) is a life-threatening disorder caused by fetomaternal platelet incompatibility analogous to that seen in rhesus (Rh) disease. In NAIT , maternal immunoglobulin G (IgG) antiplatelet antibodies cross the placenta, resulting in rapid destruction and removal of fetal platelets by the reticuloendothelial system. Studies have shown that NAIT has an incidence of 1 of 1,000 live births, with a mortality rate of 10-15 percent and the risk of long-term morbidities up to 20-60 percent if intracranial hemorrhage (ICH) occurs. This column will discuss the pathophysiology, differential diagnosis, morbidities, and treatment of NAIT and conclude with a relevant case study.

Diagnosis and management of neonatal thrombocytopenia.

Thrombocytopenia is the most common haematological abnormality in newborns admitted to neonatal care units and serves as an important indicator of underlying pathological processes of mother or child. In most cases thrombocytopenia is mild to moderate and resolves within the first weeks of life without any intervention. However, in some neonates thrombocytopenia is severe or may reflect an inborn platelet disorder. As clinical course and outcome of thrombocytopenia depend on the aetiology of thrombocytopenia, an appropriate work-up is essential to guide therapy in neonates with thrombocytopenia and to avoid severe bleeding.

A review of pathophysiology and current treatment for neonatal alloimmune thrombocytopenia (NAIT) and introducing the Australian NAIT registry.

Fetomaternal or neonatal alloimmune thrombocytopenia (NAIT) is a rare but serious condition associated with significant fetal and neonatal morbidity and mortality. The most useful predictor of severe disease is a history of a sibling with an antenatal intracranial haemorrhage. However, NAIT can occur during the first pregnancy and may not be diagnosed until the neonatal period. Antenatal treatment options include maternal intravenous immunoglobulin (IVIG) and corticosteroid treatment, fetal blood sampling (FBS) and intrauterine platelet transfusion (IUT) and early delivery. FBS (with or without IUT) can be used to direct and monitor response to therapy, and to inform mode and timing of delivery. However, this procedure is associated with significant risks, including fetal death, and is generally now reserved for high-risk pregnancies. This review highlights the current understanding of the epidemiology and pathophysiology of NAIT and summarises current approaches to investigation and management. It also introduces the newly established Australian NAIT registry. Owing to the relative rarity of NAIT, accruing sufficient patient numbers for studies and clinical trials at an institutional level is difficult. This national registry will provide an opportunity to collect valuable information and inform future research on this condition.

Platelet antibody screening by flow cytometry is more sensitive than solid phase red cell adherence assay and lymphocytotoxicity technique: a comparative study in Thai patients.

The objective of this study was to compare the sensitivity and specificity of lymphocytotoxicity test (LCT), solid phase red cell adherence assay (SPRCA) and flow cytometry in detecting platelet reactive antibodies against human leukocyte antigens (HLA) class I and human platelet antigens (HPA). Sera from 38 thrombocytopenic patients and 5 mothers of thrombocytopenic newborns were screened for platelet reactive antibodies by these three methods using screening platelets and/or lymphocytes panels derived from six subjects. The sensitivity and specificity of each method and levels of agreement were analysed. HLA antibodies were found in 18, 17 and 19 out of 43 patients' sera tested by LCT, SPRCA and flow cytometry, respectively. Four out of 43 patients' sera were reactive against HPA by flow cytometry, but were reactive to only 2 sera by SPRCA. Using flow cytometry as the reference method, the sensitivities/specificities of SPRCA and LCT in HLA antibody detection were 84.21/95.83% and 94.73/100%, respectively, with a good strength of agreement. SPRCA had 50% sensitivity and 100% specificity in HPA antibody detection compare to flow cytometry. Flow cytometry appeared to be the most sensitive technique compared with SPRCA and LCT for both HPA and HLA antibody screening. SPRCA sensitivity was too low for HPA antibody detection, but this might be because of the small number of samples. There was one serum from the mother of a baby suffering neonatal alloimmune thrombocytopenia (NAIT), in whom SPRCA could not detect HPA antibodies, while flow cytometry came out positive. Therefore, SPRCA should not be used in NAIT investigation and flow cytometry should be employed instead.

Reconsidering fetal and neonatal alloimmune thrombocytopenia with a focus on screening and prevention.

Uncertainty regarding the pathophysiology of fetal and neonatal alloimmune thrombocytopenia (FNAIT) has hampered the decision regarding how to identify, follow-up and treat the women and children with this potentially serious condition. Since knowledge of the condition is derived mainly from retrospective studies, understanding of the natural history of this condition remains incomplete. General screening programs for FNAIT have still not been introduced, mainly because of a lack of reliable risk factors and effective treatment. Now, several prospective screening studies involving up to 100,000 pregnant women have been published and the results have changed the understanding of the pathophysiology of FNAIT and, thereby, the approach toward diagnostics, prevention and treatment in a more appropriate way.

Hemorragia intracraneal intraútero por trombopenia neonatal aloinmune: a propósito de dos casos y revisión de la literatura / In utero intracranial hemorrhage caused by neonatal alloimmune thrombocytopenia (NAIT). Report of two cases and literature update

Introducción: La trombopenia neonatal aloinmune (TNAI) es la causa más frecuente de trombopenia grave, aislada y precoz en el recién nacido sano. Es el resultado de la aloinmunización materna frente a antígenos plaquetarios humanos (HPA) del feto. El mecanismo fisiopatológico todavía es poco conocido. El paso de anticuerpos se produce en etapas tempranas de la gestación con consecuencias graves, como la hemorragia intracraneal. Casos clínicos: Se presentan dos casos de hemorragia intracraneal intraútero secundarios a TNAI. El primero de ellos seinicia con una gran hemorragia intraparenquimatosa, y requiere una única transfusión de donante aleatorio para remontar la cifra de plaquetas. El segundo se presenta con una hemorragia intraventricular y se trata con transfusiones seriadas de plaquetasHPA-1a negativas e inmunoglobulina intravenosa. Discusión y conclusiones: La TNAI se presenta generalmente como una trombopenia aislada y grave en el recién nacido. Eldiagnóstico es de exclusión y se confirma mediante la detección de anticuerpos antiplaquetarios en la madre. Dada la gravedad de las consecuencias, ante la sospecha de TNAI, deben realizarse de inmediato transfusiones de plaquetas, preferentemente de las compatibles, para evitar hemorragias. El riesgo de recurrencia en futuras gestaciones es muy elevado, por lo que se debe establecer un protocolo de manejo de éstas. El reto de futuro es el establecimiento de un cribado antenatal, como ya se hace con la isoinmunización Rh (AU)

Introduction: The neonatal alloimmune thrombocytopenia (NAIT) is the commonest cause of early isolated severe thrombocytopenia in the healthy newborn. It’s the result of maternal alloimmunization against fetal platelet antigens. However, the pathophysiologic mechanism is not well known yet. Alloantibodies cross the placenta in early stages of pregnancy provoking serious complications in the newborn such as intracranial hemorrhage. Case report: We present two cases of in utero intracranial hemorrhage caused by TNAI. In one of them a large intraparenchymal hemorrhage (IPH) was the first clinical symptom, how everhe recovered platelet count with just one transfusion of an aleatory donor, not needing further treatment. The second one exhibited at first an intraventricular hemorrhage (IVH) and was treated with serial transfusions of HPA-1a negative platelets and intravenous immunoglobulin (IVIG).Discussion and conclusions: The NAIT appears commonly as an isolated and severe thrombocytopenia in the newborn period. The diagnosis is made after excluding other causes of neonatal thrombocytopenia, and is confirmed proving the presence of maternal antiplatelet alloantibodies. Due to the severity of its consequences, when confronted with the suspicion of TNAI, a platelet transfusion should to be performed immediately preferably with negative antigen platelets to avoid bleeding. Since there is a high risk of recurrence in following gestations the availability of an established protocol is recommended. The future challenge is the establishment of antenatal screening programs similar to that performed in Rh isoimmunization (AU)

Thrombocytopenia in preterm infants with intrauterine growth restriction.

Sick preterm infants often have thrombocytopenia at birth, and this is often associated with intrauterine growth restriction (IUGR), or birth weights less than the 10th percentile. The pathogenesis of the thrombocytopenia and its importance in IUGR are still unclear. We studied the characteristics of preterm IUGR infants with thrombocytopenia. Twenty-seven singleton Japanese preterm IUGR infants were born between January 2002 and June 2007 at Okayama University Hospital. Infants with malformation, chromosomal abnormalities, alloimmune thrombocytopenia, sepsis, and maternal aspirin ingestion were excluded. The infants were divided into group A (n=8), which had thrombocytopenia within 72 h after birth, and group B (n=19), which did not. There were significant differences in birth weight, head circumference, umbilical artery (UA)-pulsatility index (PI), middle cerebral artery-PI, UA-pH, UA-pO2, and UA-pCO2. The infants in group A were smaller, had abnormal blood flow patterns, and were hypoxic at birth. We speculate that the infants with thrombocytopenia were more severely growth-restricted by chronic hypoxia. Thrombocytopenia is an important parameter for chronic hypoxia in the uterine.

Fetal and neonatal alloimmune thrombocytopenia: progress and ongoing debates.

Fetal and neonatal alloimmune thrombocytopenia (AIT) is a result of a parental incompatibility of platelet-specific antigens and the transplacental passage of maternal alloantibodies against the platelet antigen shared by the father and the fetus. It occurs in approximately 1 in 1000 live births and is the most common cause of severe thrombocytopenia in fetuses and term neonates. As screening programs are not routinely performed, most affected fetuses are identified after birth when neonatal thrombocytopenia is recognized. In severe cases, the affected fetus is identified as a result of suffering from an in utero intracranial hemorrhage. Once diagnosed, AIT must be treated antenatally as the disease can be more severe in subsequent pregnancies. While there have been many advances regarding the diagnosis and treatment of AIT, it is still difficult to predict the severity of disease and which therapy will be effective.