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Millions of infants are born prematurely every year worldwide. Prematurity, particularly at lower gestational ages, is associated with high mortality and morbidity and is a significant global health burden. Pregnancy complications and preterm birth syndrome strongly impact neonatal clinical phenotypes and outcomes. The vascular endothelium is a pivotal regulator of fetal growth and development. In recent years, the key role of uteroplacental pathologies impairing endothelial homeostasis is emerging. Conditions leading to very and extremely preterm birth can be classified into two main pathophysiological patterns or endotypes: infection/inflammation and dysfunctional placentation. The first is frequently related to chorioamnionitis, whereas the second is commonly associated with hypertensive disorders of pregnancy and fetal growth restriction. The nature, timing, and extent of prenatal noxa may alter fetal and neonatal endothelial phenotype and functions. Changes in the luminal surface, oxidative stress, growth factors imbalance, and dysregulation of permeability and vascular tone are the leading causes of endothelial dysfunction in preterm infants. However, the available evidence regarding endothelial physiology and damage is limited in neonates compared to adults. Herein, we discuss the current knowledge on endothelial dysfunction in the infectious/inflammatory and dysfunctional placentation endotypes of prematurity, summarizing their molecular features, available biomarkers, and clinical impact. Furthermore, knowledge gaps, shadows, and future research perspectives are highlighted., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 Amelio, Provitera, Raffaeli, Tripodi, Amodeo, Gulden, Cortesi, Manzoni, Cervellini, Tomaselli, Pravatà, Garrido, Villamor, Mosca and Cavallaro.)

Extracorporeal membrane oxygenation (ECMO) is a life-saving support for cardio-respiratory function. Over the last 50 years, the extracorporeal field has faced huge technological progress. However, despite the improvements in technique and materials, coagulation problems are still the main contributor to morbidity and mortality of ECMO patients. Indeed, the incidence and survival rates of the main hemorrhagic and thrombotic complications in neonatal respiratory ECMO are relevant. The main culprit is related to the intrinsic nature of ECMO: the contact phase activation. The exposure of the human blood to the non-endothelial surface triggers a systemic inflammatory response syndrome, which chronically activates the thrombin generation and ultimately leads to coagulative derangements. Pre-existing illness-related hemostatic dysfunction and the peculiarity of the neonatal clotting balance further complicate the picture. Systemic anticoagulation is the management's mainstay, aiming to prevent thrombosis within the circuit and bleeding complications in the patient. Although other agents (i.e., direct thrombin inhibitors) have been recently introduced, unfractionated heparin (UFH) is the standard of care worldwide. Currently, there are multiple tests exploring ECMO-induced coagulopathy. A combination of the parameters mentioned above and the evaluation of the patient's underlying clinical context should be used to provide a goal-directed antithrombotic strategy. However, the ideal algorithm for monitoring anticoagulation is currently unknown, resulting in a large inter-institutional diagnostic variability. In this review, we face the features of the available monitoring tests and approaches, mainly focusing on the role of point-of-care (POC) viscoelastic assays in neonatal ECMO. Current gaps in knowledge and areas that warrant further study will also be addressed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Cortesi, Raffaeli, Amelio, Amodeo, Gulden, Manzoni, Cervellini, Tomaselli, Colombo, Araimo, Artoni, Ghirardello, Mosca and Cavallaro.)

Background: Viscoelastic coagulation tests provide valuable information in neonatal intensive care units (NICUs), but the lack of reference intervals still limits their decision-making power according to gestational age. The aim of the present study is to evaluate the hemostasis of a cohort of full-term (FT) and late-preterm (LP) infants using the viscoelastic coagulation monitor (VCM®) system, a new portable device that uses untreated whole blood., Methods: An observational study was performed to identify non-coagulopathic FT and LP infants admitted to III° level NICU (January 2020 to December 2021) with a VCM test in the first 72 h of life., Results: Forty-five patients were enrolled, 26 FT and 19 LP. No statistical differences in hemostatic parameters were observed between FT and LP nor between stable and unstable neonates. Clotting time (CT) was positive correlated with PT ( p = 0.032), not with aPTT ( p = 0.185). From linear regression, platelet resulted associated with: clot formation time (CTF, p = 0.003), alpha angle (Alpha, p = 0.010), amplitude at 10 (A10, p = 0.001), amplitude at 20 min (A20, p < 0.001), maximum clot firmness (MCF, p < 0.001); and fibrinogen was associated with: A10 ( p = 0.008), A20 ( p = 0.015) and MCF ( p = 0.024). Compared to the adult reference population, neonates showed shorter CT (mean (SD): 5.3 (1.4) vs. 7.0 (0.9) min, p < 0.001), CFT (2.4 (0.7) vs. 2.8 (0.6) minutes, p < 0.001) and higher Alpha (60.8 (6.3) vs. 55 (5)°, p < 0.001). In addition, the neonatal cohort showed an early transient difference in amplitude and fibrinolysis, as follows: A10 (28.0 (5.0) vs. 26 (4) VCM units, p =0.004), A20 (34.8 (5.0) vs. 33 (4) VCM units, p =0.012), and LI30 (99.8 (0.5) vs. 99 (1)%, p <0.001)., Conclusions: The viscoelastic profile of FT and LP infants assessed with VCM showed a hemostatic competence characterized by accelerated coagulation and clot formation time, in line with other viscoelastic techniques. VCM system provides promising applications in the NICU setting., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Amelio, Raffaeli, Amodeo, Gulden, Cortesi, Manzoni, Pesenti, Ghirardello, Mosca and Cavallaro.)

Background and Aim: Intestinal failure-associated liver disease (IFALD) affects one-fifth of neonates receiving parenteral nutrition (PN) for more than 2 weeks. We aimed to define the effect of IFALD on hemostasis of preterm infants. Methods: This is an ancillary analysis of a prospective study aimed at defining coagulation in preterm infants. We included neonates exposed to PN (at least 14 days), in full-enteral feeding. We compared thrombin generation in the presence of thrombomodulin, defined as endogenous thrombin potential-ETP, PT, aPTT between infants with IFALD vs. those without (controls), at birth, and after 30 days. IFALD was defined as conjugated bilirubin ≥1 mg/dl. Results: We enrolled 92 preterm infants (32 IFALD; 60 controls). Cholestatic patients had a lower birthweight, longer exposure to PN, and longer hospitalization. Infants with IFALD showed longer median PT (12.8-vs.-12 sec; p = 0.02) and aPTT (39.2-vs.-36.5 sec; p = 0.04) than controls, with no difference in ETP. Conclusions: Despite prolonged PTs and aPTTs infants with IFALD had similar ETP than those without., (Copyright © 2020 Ghirardello, Raffaeli, Scalambrino, Cortesi, Roggero, Peyvandi, Mosca and Tripodi.)

Objective: To compare the effect of Delayed Cord Clamping (DCC) to Immediate Cord Clamping (ICC) on phototherapy treatment in a cohort of cesarean-delivered newborns with AB0-alloimmunization. Study Design: In a retrospective cohort study neonates with Gestational Age (GA) ≥ 35 weeks and diagnosed with AB0-alloimmunization before implementation of DCC (ICC group) were compared with neonates born after implementation (DCC group). The primary outcome was the need for phototherapy. Secondary outcomes included hospital stay, readmission rate, need for extra intravenous fluids, maximum bilirubin concentration, and hours of life at bilirubin peak. We used regression models to adjust for weight loss, type of feeding, birth weight, and gestational age. Results: In total 336 neonates were included, of which 192 neonates in the ICC group and 144 in the DCC group. There were no differences in basic characteristics between the two groups except for birth weight (ICC 3193 ± 468 g vs. DCC 3053 ± 446 g, p = 0.01) and GA (ICC 38.2 ± 1 weeks of GA, vs. DCC 37.9 ± 1 weeks of GA; p = 0.01). When adjusted for confounding factors, after implementation of DCC, significantly more infants with AB0 alloimmunization needed phototherapy (22.4% vs. 36.8%, RR 1.61 CI: 1.15-2.28; p = 0.006; Number Needed to Harm 7), needed to stay longer in hospital (20.3% vs. 30.5%, RR 1.53 CI: 1.05-2.23; p = 0.03). The maximum bilirubin was higher (11.4 ± 4.0 mg/dl vs. 12.9 ± 3.5 mg/dl, p < 0.001) and occurred later [74 (67-92) hours vs. 84 (70-103) hours; p = 0.04]. There was no difference in the need for intravenous fluids (1.6% vs. 4.9%; not significant) and readmissions (1.6% vs. 3.5%; not significant). Conclusion: Infants with AB0 alloimmunization needed more often phototherapy and were admitted longer after implementation of DCC policy. Further studies are needed to see whether the benefit of DCC outweighs the increased morbidity, admission days, and related hospital costs.