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RLYB212 is a human monoclonal anti‐human platelet antigen (HPA)‐1a immunoglobulin gamma 1 in clinical development as a subcutaneous injection for the prevention of maternal alloimmunization to fetal HPA‐1a leading to fetal and neonatal alloimmune thrombocytopenia (FNAIT). This analysis developed a target‐mediated drug disposition (TMDD) model to simultaneously characterize RLYB212 pharmacokinetics (PK) and HPA‐1a‐positive platelet dynamics in HPA‐1b/b (HPA‐1a‐negative) volunteers. The model was then used to perform simulations to inform a dosing regimen in a phase II clinical study in pregnant women, where simulations accounted for physiological changes throughout pregnancy. Allometric scaling (0.75) for clearance and intercompartment transfer rate and volume (1) was included in the base model to account for variations in body weight. A 0.06 mg RLYB212 dose with a loading dose of 0.12 mg was identified as the optimal dosing regimen of RLYB212, which maintained exposures below the target upper boundary of ~10 ng/mL throughout pregnancy. This work presents an application of the TMDD model that advances the quantitative clinical pharmacology toolkit to understand monoclonal antibody PK in pregnancy.

Objective: Pregnancies at risk of fetal and neonatal alloimmune thrombocytopenia (FNAIT) are commonly treated using weekly intravenous immunoglobulin (IVIG) at 1 g/kg maternal weight. IVIG is an expensive multidonor human blood product with dose-related side effects. Our aim was to evaluate the effectiveness of IVIG at a lower dose, i.e. 0.5 g/kg. Methods: This was a randomized controlled multicenter trial conducted in Sweden, the Netherlands and Australia. Pregnant women with human platelet antigen alloantibodies and an affected previous child without intracranial hemorrhage (ICH) were enrolled. The participants were randomized to IVIG at 0.5 or 1 g/kg per week. The analyses were per intention to treat. The primary outcome was fetal or neonatal ICH. Secondary outcomes were platelet count at birth, maternal and neonatal IgG levels, neonatal treatment and bleeding other than ICH. Results: A total of 23 women were randomized into two groups (low dose: n = 12; standard dose: n = 11). The trial was stopped early due to poor recruitment. No ICH occurred. The median newborn platelet count was 81 × 10 9 /l (range 8-269) in the 0.5 g/kg group versus 110 × 10 9 /l (range 11-279) in the 1 g/kg group (p = 0.644). Conclusion: The risk of adverse outcomes in FNAIT pregnancies treated with IVIG at 0.5 g/kg is very low, similar to that using 1 g/kg, although our uncompleted trial lacked the power to conclusively prove the noninferiority of using the low dose.

Healthy neonates exhibit a well-functioning haemostatic system despite peculiarities regarding composition of clotting factors and inhibitors as well as impaired platelet aggregation. Thrombocytopenia and severe bleeding events are feared in sick infants. Recombinant factor VIIa (rFVIIa) is a haemostatic agent used as a last resort in neonates with refractory bleedings. Aim of this study was to investigate in-vitro (i) changes in thrombin generation with different platelet counts, (ii) effects of rFVIIa under conditions of thrombocytopenia and (iii) potentially differing dose-response of rFVIIa in cord blood as a surrogate for neonatal blood compared to adult blood. Thrombin generation parameters were observed in cord blood plasma and adult plasma with various platelet counts, with or without addition of rFVIIa, respectively. Low platelet counts did not influence thrombin generation in cord blood in contrast to adult blood. RFVIIa primarily affected lag time throughout all platelet concentrations. Interestingly, peak height was reduced exclusively in cord blood plasma after addition of rFVIIa. No significant differences regarding dose-response were observed between cord blood and adult blood. In contrast to adult blood, thrombocytopenia in cord blood does not significantly influence thrombin generation. Even at very low platelet counts there is enough negatively charged surface to support rFVIIa action in plasma from cord blood and adult blood in-vitro .

ObjectivesTo evaluate intestinal blood flow changes after intravenous immunoglobulin (IVIg) infusion among neonates with Rh isoimmunization and alloimmune thrombocytopenia.MethodsThis 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.ResultsThe 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).ConclusionsThere was no significant change in the celiac and SMA blood flows following IVIg therapy in neonates with Rh isoimmunization and alloimmune thrombocytopenia.

The Food and Drug Administration recently approved two novel thrombopoiesis-stimulating agents, Romiplostim (AMG-531, Nplate) and Eltrombopag (Promacta), for the treatment of adults with immune thrombocytopenic purpura. For physicians taking care of critically ill neonates, this offers the opportunity of decreasing platelet transfusions and potentially improving the outcomes of neonates with severe and prolonged thrombocytopenia. However, several developmental factors need to be taken into consideration. First, the population of thrombocytopenic neonates likely to benefit from these agents needs to be carefully selected. Second, the mechanisms underlying neonatal and adult thrombocytopenia differ from each other and are incompletely understood, and pre-clinical evidence suggests that the response of neonates to thrombopoietic factors might be different from that of adults. Finally, the potential non-hematopoietic effects of thrombopoietin have not been well established. Here, we will discuss these issues in detail, and will highlight the critical developmental differences between neonates and adults that need to be considered as we think about introducing these agents into neonatal care.

Chikungunya is an arthropod-borne acute viral disease caused by Chikungunya virus (CHIKV).In this report the vertical transmission of CHIKV is reported in a neonate. Molecular diagnostic technique plays an important role in patient management and disease control. Thrombocytopenia was found to be a major hematological parameter which should be treated at early stage to prevent hemorrhagic manifestations.

The prevailing concept is that gestational alloimmune liver disease (GALD) is caused by maternal antibodies targeting a currently unknown antigen on the liver of the fetus. This leads to deposition of complement on the fetal hepatocytes and death of the fetal hepatocytes and extensive liver injury. In many cases, the newborn dies. In subsequent pregnancies early treatment of the woman with intravenous immunoglobulin can be instituted, and the prognosis for the fetus will be excellent. Without treatment the prognosis can be severe. Crucial improvements of diagnosis require identification of the target antigen. For this identification, this work was based on two hypotheses: 1. The GALD antigen is exclusively expressed in the fetal liver during normal fetal life in all pregnancies; 2. The GALD antigen is an alloantigen expressed in the fetal liver with the woman being homozygous for the minor allele and the father being, most frequently, homozygous for the major allele. We used three different experimental approaches to identify the liver target antigen of maternal antibodies from women who had given birth to a baby with the clinical GALD diagnosis: 1. Immunoprecipitation of antigens from either a human liver cell line or human fetal livers by immunoprecipitation with maternal antibodies followed by mass spectrometry analysis of captured antigens; 2. Construction of a cDNA expression library from human fetal liver mRNA and screening about 1.3 million recombinants in Escherichia coli using antibodies from mothers of babies diagnosed with GALD; 3. Exome/genome sequencing of DNA from 26 presumably unrelated women who had previously given birth to a child with GALD with husband controls and supplementary HLA typing. In conclusion, using the three experimental approaches we did not identify the GALD target antigen and the exome/genome sequencing results did not support the hypothesis that the GALD antigen is an alloantigen, but the results do not yield basis for excluding that the antigen is exclusively expressed during fetal life., which is the hypothesis we favor.

Evans syndrome is a rare and chronic autoimmune disease seen in both paediatric and adult age groups. We present a case of severe thrombocytopenia in a neonate born to a mother with Evans syndrome who showed no response to intravenous immunoglobulin therapy initially and improved after treatment with methylprednisolone.

Objective: The aim of this study was to determine the factors associated with the prognosis of newborns born to mothers with idiopathic thrombocytopenic purpura (ITP), and to compare the infants with/without thrombocytopenia in terms of maternal and neonatal characteristics. Study Design: We reviewed the charts of 29 parturients with ITP and their newborns who were born between January 1998 and December 2008. Result: A total of 16 (55%) gravidas had been diagnosed with ITP before pregnancy and 13 (45%) were diagnosed during pregnancy. Thrombocytopenia was observed in 21 gravidas. In total, 17 (58%) gravidas received treatment to increase the platelet count. The majority of deliveries (72.5%) were vaginal. The infant platelet counts at birth ranged from 20 to 336 × 10 9 per liter. None of the neonates had complications attributable to the mode of delivery. Normal platelet counts were determined in 15 newborns, whereas 14 infants had thrombocytopenia at birth. Three (10.3%) neonates had mild, four neonates (13.7%) had moderate and seven neonates (24.1%) had severe thrombocytopenia. The age of the mothers having infants with thrombocytopenia was significantly higher (30±5.3 vs 25.3±3.8 years), most of the infants (10/14 (71%)) were males ( P <0.05). Conclusion: Pregnancy complicated with ITP generally has a good outcome. Although ITP in pregnancy carries a low risk, careful observation is required for the newborn of gravidas with ITP even when the infant has no bleeding complications at delivery, and infants may require treatment for thrombocytopenia.