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Fetal/Neonatal Alloimmune Thrombocytopenia (FNAIT) is a significant hematologic disorder arising from maternal immune responses to fetal platelet alloantigens, predominantly Human Platelet Antigen (HPA)-1a. This review first describes the pathogenesis of FNAIT, highlighting the roles of HPA-specific antibodies, particularly HPA-1a, in causing severe thrombocytopenia and intracranial hemorrhage in affected neonates. Current management strategies, including intravenous immunoglobulin and investigational therapies like Nipocalimab, are evaluated for their efficacy and limitations. The review also discusses promising antigen-specific therapies, such as effector-silent monoclonal antibodies and innovative approaches targeting alloantibody-producing B cells. Additionally, the potential of Chimeric Autoantibody Receptor (CAAR) T cell therapy for selective elimination of pathogenic B cells is examined. The necessity for a prophylactic strategy similar to RhD immunoprophylaxis in preventing FNAIT is emphasized, along with the importance of identifying at-risk pregnancies. The development of renewable monoclonal antibodies and suitable animal models are critical steps toward effective prevention and treatment of this disorder. [ABSTRACT FROM AUTHOR]

Abstract: Platelet endothelial cell adhesion molecule-1 (PECAM-1, CD31) is a cell adhesion and signaling receptor that is expressed on hematopoietic and endothelial cells. PECAM-1 is vital to the regulation of inflammatory responses, as it has been shown to serve a variety of pro-inflammatory and anti-inflammatory functions. Pro-inflammatory functions of PECAM-1 include the facilitation of leukocyte transendothelial migration and the transduction of mechanical signals in endothelial cells emanating from fluid shear stress. Anti-inflammatory functions include the dampening of leukocyte activation, suppression of pro-inflammatory cytokine production, and the maintenance of vascular barrier integrity. Although PECAM-1 has been well-characterized and studied, the mechanisms through which PECAM-1 regulates these seemingly opposing functions, and how they influence each other, are still not completely understood. The purpose of this review, therefore, is to provide an overview of the pro- and anti-inflammatory functions of PECAM-1 with special attention paid to mechanistic insights that have thus far been revealed in the literature in hopes of gaining a clearer picture of how these opposing functions might be integrated in a temporal and spatial manner on the whole organism level. A better understanding of how inflammatory responses are regulated should enable the development of new therapeutics that can be used in the treatment of acute and chronic inflammatory disorders. [Copyright &y& Elsevier]

Objective To derive and validate an objective definition of postoperative bleeding in neonates and infants undergoing cardiac surgery with cardiopulmonary bypass. Methods Using a retrospective cohort of 124 infants and neonates, we included published bleeding definitions and cumulative chest tube output over different postoperative periods (eg, 2, 12, or 24 hours after intensive care unit admission) in a classification and regression tree model to determine chest tube output volumes that were associated with red blood cell transfusions and surgical re-exploration for bleeding in the first 24 hours after intensive care unit admission. After the definition of excessive bleeding was determined, it was validated via a prospective cohort of 77 infants and neonates. Results Excessive bleeding was defined as ≥7 mL/kg/h for ≥2 consecutive hours in the first 12 postoperative hours and/or ≥84 mL/kg total for the first 24 postoperative hours and/or surgical re-exploration for bleeding or cardiac tamponade physiology in the first 24 postoperative hours. Excessive bleeding was associated with longer length of hospital stay, increased 30-day readmission rate, and increased transfusions in the postoperative period. Conclusions The proposed standard definition of excessive bleeding is based on readily obtained objective data and relates to important early clinical outcomes. Application and validation by other institutions will help determine the extent to which our specialty should consider this definition for both clinical investigation and quality improvement initiatives. [ABSTRACT FROM AUTHOR]

Platelet Endothelial Cell Adhesion Molecule 1 (PECAM-1) is a major component of the endothelial cell intercellular junction. Previous studies have shown that PECAM-1 homophilic interactions, mediated by amino-terminal immunoglobulin homology domain 1, contribute to maintenance of the vascular permeability barrier and to its re-establishment following inflammatory or thrombotic insult. PECAM-1 glycans account for 30% of its molecular mass, and the newly solved crystal structure of human PECAM-1 immunoglobulin homology domain 1 reveals that a glycan emanating from the asparagine residue at position 25 (Asn-25) is located within the trans homophilic- binding interface, suggesting a role for an Asn-25-associated glycan in PECAM-1 homophilic interactions. In support of this possibility, unbiased molecular docking studies revealed that negatively charged α2,3 sialic acid moieties bind tightly to a groove within the PECAM-1 homophilic interface in an orientation that favors the formation of an electrostatic bridge with positively charged Lys-89, mutation of which has been shown previously to disrupt PECAM-1-mediated homophilic binding. To verify the contribution of the Asn-25 glycan to endothelial barrier function, we generated an N25Q mutant form of PECAM-1 that is not glycosylated at this position and examined its ability to contribute to vascular integrity in endothelial celllike REN cells. Confocal microscopy showed that although N25Q PECAM-1 concentrates normally at cell-cell junctions, the ability of this mutant form of PECAM-1 to support re-establishment of a permeability barrier following disruption with thrombin was significantly compromised. Taken together, these data suggest that a sialic acid-containing glycan emanating from Asn-25 reinforces dynamic endothelial cell-cell interactions by stabilizing the PECAM-1 homophilic binding interface. [ABSTRACT FROM AUTHOR]

Abstract: Aims: To investigate the mechanism by which platelet endothelial cell adhesion molecule 1 (PECAM-1/CD31), an immunoglobulin (Ig)-superfamily cell adhesion and signaling receptor, regulates pro-inflammatory cytokine levels. The purpose of the present investigation was to test the hypothesis that PECAM-1 influences circulating cytokine levels by regulating the trafficking of activated, cytokine-producing leukocytes to sites of inflammation. Main methods: PECAM-1+/+ and PECAM-1−/− mice were subjected to lipopolysaccharide (LPS)-induced endotoxemia, and systemic cytokine levels were measured by Bioplex multiplex cytokine assays. Flow cytometry was employed to enumerate leukocytes at inflammatory sites and to measure cytokine synthesis in leukocyte sub-populations. Enzyme-linked immunosorbent assay (ELISA) was used to measure cytokine levels in tissue samples and in supernatants of in vitro-stimulated leukocytes. Key findings: We confirmed earlier reports that mice deficient in PECAM-1 had greater systemic levels of pro-inflammatory cytokines following intraperitoneal (IP) LPS administration. Interestingly, expression of PECAM-1, in mice, had negligible effects on the level of cytokine synthesis by leukocytes stimulated in vitro with LPS and in peritoneal macrophages isolated from LPS-injected mice. There was, however, excessive accumulation of macrophages and neutrophils in the lungs of PECAM-1-deficient, compared with wild-type, mice — an event that correlated with a prolonged increase in lung pro-inflammatory cytokine levels. Significance: Our results demonstrate that PECAM-1 normally functions to dampen systemic cytokine levels during LPS-induced endotoxemia by diminishing the accumulation of cytokine-producing leukocytes at sites of inflammation, rather than by modulating cytokine synthesis by leukocytes. [Copyright &y& Elsevier]

Aims PECAM-1 is an abundant endothelial cell surface receptor that becomes highly enriched at endothelial cell-cell junctions, where it functions to mediate leukocyte transendothelial migration, sense changes in shear and flow, and maintain the vascular permeability barrier. Homophilic interactions mediated by the PECAM-1 extracellular domain are known to be required for PECAM-1 to perform these functions; however, much less is understood about the role of its cytoplasmic domain in these processes. Main methods CRISPR/Cas9 gene editing technology was employed to generate human endothelial cell lines that either lack PECAM-1 entirely, or express mutated PECAM-1 missing the majority of its cytoplasmic domain (∆ CD-PECAM-1). The endothelial barrier function was evaluated by Electric Cell-substrate Impedance Sensing, and molecular mobility was assessed by fluorescence recovery after photobleaching. Key findings We found that ∆ CD-PECAM-1 concentrates normally at endothelial cell junctions, but has the unexpected property of conferring increased baseline barrier resistance, as well as a more rapid rate of recovery of vascular integrity following thrombin-induced disruption of the endothelial barrier. Fluorescence recovery after photobleaching analysis revealed that ∆ CD-PECAM-1 exhibits increased mobility within the plane of the plasma membrane, thus allowing it to redistribute more rapidly back to endothelial cell-cell borders to reform the vascular permeability barrier. Significance The PECAM-1 cytoplasmic domain plays a novel role in regulating the rate and extent of vascular permeability following thrombotic or inflammatory challenge. [ABSTRACT FROM AUTHOR]

Abstract: Previous studies have reported the existence of eleven different single nucleotide polymorphisms (SNPs) within human PECAM-1 mRNA, several of which have recently been associated with disease. Though SNPs in the PECAM-1 gene have been known for some time, the genetic background on which they exist, and their association into distinct allelic isoforms has not yet been established. To identify the major allelic isoforms of PECAM-1, we determined the nucleotide sequence of individual full-length cloned cDNAs derived from anonymous, unrelated volunteer individuals. Initial sequence analysis of 34 alleles from 17 individuals confirmed the presence of two distinct human PECAM-1 alleles (L98S536R643 and V98N536G643) within the human population. Each of these were found, upon more detailed analysis, to be superimposed on a previously unreported a2479g nucleotide polymorphism within the 3′ untranslated region (3′UTR) that occurred on both allelic isoforms — yielding a total of four major alleles. Multiplex Luminex bead analysis of an additional 259 individuals allowed identification of 117 individuals homozygous for either the L98S536 or V98N536 allele, and sequence analysis around the R643G and a2479g polymorphic sites permitted accurate determination of significant differences in the gene frequencies of LSRa, LSRg, VNGa, and VNGg among Caucasian individuals. Identification of these PECAM-1 allelic isoforms should facilitate future detailed examination of PECAM-1-related disease associations, and may help resolve previously disparate results. [Copyright &y& Elsevier]