Modulation of Haemostatic Balance in Combined von Willebrand Disease and Antithrombin Deficiency: A Comprehensive Family Study.

Introduction: Maintaining the balance between procoagulant and anticoagulant factors is essential for effective haemostasis. Emerging evidence suggests a modulation of bleeding tendency by factors in the anticoagulant and fibrinolytic systems.

Aim: This study investigates the clinical and laboratory characteristics of a family with combined von Willebrand disease (VWD) and antithrombin (AT) deficiency.

Distinct Tissue-Dependent Composition and Gene Expression of Human Fetal Innate Lymphoid Cells.

The human fetal immune system starts to develop in the first trimester and likely plays a crucial role in fetal development and maternal-fetal tolerance. Innate lymphoid cells (ILCs) are the earliest lymphoid cells to arise in the human fetus. ILCs consist of natural killer (NK) cells, ILC1s, ILC2s, and ILC3s that all share a common lymphoid origin.

Emerging mutation in SARS-CoV-2 facilitates escape from NK cell recognition and associates with enhanced viral fitness.

In addition to adaptive immunity, natural killer (NK) cells of the innate immune system contribute to the control of viral infections. The HLA-E-restricted SARS-CoV-2 Nsp13232-240 epitope VMPLSAPTL renders infected cells susceptible to NK cells by preventing binding to the inhibitory receptor NKG2A. Here, we report that a recently emerged methionine to isoleucine substitution at position 2 (pM2I) of Nsp13232-240 impairs binding of the mutated epitope to HLA-E and diminishes HLA-E/peptide complex stability.

Design of an international, phase IV, open-label study of simoctocog alfa in women/girls with hemophilia A undergoing surgery (NuDIMENSION).

Background: Although hemophilia A mainly affects males, carriers (defined as females with hemophilia A, as well as symptomatic or asymptomatic hemophilia A carriers) are at risk of excessive bleeding, particularly during trauma or during surgical procedures. Clinical trials have focused on male patients with severe disease, and data for females are limited. Improved, evidence-based treatment guidelines for management of hemophilia A carriers are required.

Comprehensive evaluation of anti-emicizumab antibodies in acquired hemophilia A: a detailed case study and methodological evaluation.

Background: Acquired hemophilia A (AHA) is a rare and severe bleeding disorder characterized by autoantibodies inhibiting coagulation factor (F)VIII. Current treatment of AHA involves bypassing agents or FVIII replacement therapy, yet their efficacy is limited in cases of high inhibitor titers. Emicizumab, a humanized bispecific monoclonal antibody, has shown promising hemostatic effectiveness in persons with congenital hemophilia A (HA) and AHA, but a minority of patients developed anti-drug antibodies (ADAs), compromising its efficacy.

MAIT cell heterogeneity across paired human tissues reveals specialization of distinct regulatory and enhanced effector profiles.

Mucosal-associated invariant T (MAIT) cells are unconventional T cells that recognize microbial riboflavin pathway metabolites presented by evolutionarily conserved MR1 molecules. We explored the human MAIT cell compartment across organ donor-matched blood, barrier, and lymphoid tissues. MAIT cell population size was donor dependent with distinct tissue compartmentalization patterns and adaptations: Intestinal CD103 resident MAIT cells presented an immunoregulatory CD39CD27 profile, whereas MAIT cells expressing NCAM1/CD56 dominated in the liver and exhibited enhanced effector capacity with elevated response magnitude and polyfunctionality.

Comprehensive laboratory assessment of lonoctocog alfa versus octocog alfa in severe haemophilia A.

Introduction: Lonoctocog alfa is a single-chain factor VIII (FVIII) molecule with high binding affinity to von-Willebrand-factor. While it is well known that its plasma activity is underestimated by one-stage clotting assays (OSCA), there is a lack of knowledge on the post-infusion performance of lonoctocog alfa in global coagulation assays or its potential impact on the haemostatic balance in vivo.

Aim: To characterize lonoctocog alfa versus octocog alfa in pre- and post-infusion samples obtained from patients undergoing repeated investigation of incremental recovery (IR).

Pan-cancer profiling of tumor-infiltrating natural killer cells through transcriptional reference mapping.

The functional diversity of natural killer (NK) cell repertoires stems from differentiation, homeostatic, receptor-ligand interactions and adaptive-like responses to viral infections. In the present study, we generated a single-cell transcriptional reference map of healthy human blood- and tissue-derived NK cells, with temporal resolution and fate-specific expression of gene-regulatory networks defining NK cell differentiation. Transfer learning facilitated incorporation of tumor-infiltrating NK cell transcriptomes (39 datasets, 7 solid tumors, 427 patients) into the reference map to analyze tumor microenvironment (TME)-induced perturbations.

Self-conducted sonographic monitoring of the knee in patients with haemophilia-A feasibility study.

Introduction/aim: To evaluate whether patients with haemophilia (PwH) can be enabled to perform ultrasonography (US) of their knees without supervision according to the Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) protocol and whether they would be able to recognize pathologies.

Methods: Five PwH (mean age 29.6 years, range 20-48 years) were taught the use of a portable US device and the HEAD-US protocol.

Transition metal and lanthanide modified MOF-808 for barcode design.

This study explores the utilization of metal-organic frameworks (MOFs), particularly those incorporating lanthanide-based elements for their fluorescence capabilities, to create an advanced barcode system. By exploiting the modular nature of MOFs, we have developed a material capable of dynamic information encoding and robust against counterfeiting efforts. We introduce a novel barcode prototype that exhibits visible color shifts and fluorescence modulation when exposed to a specific sequence of chemical and thermal stimuli.

Accumulation of tissue-resident natural killer cells, innate lymphoid cells, and CD8 T cells towards the center of human lung tumors.

Lung cancer is a leading cause of cancer-related death worldwide. Despite recent advances in tissue immunology, little is known about the spatial distribution of tissue-resident lymphocyte subsets in lung tumors. Using high-parameter flow cytometry, we identified an accumulation of tissue-resident lymphocytes including tissue-resident NK (trNK) cells and CD8 tissue-resident memory T (T) cells toward the center of human non-small cell lung carcinomas (NSCLC).

Antidrug antibodies against the polyethylene glycol moiety inhibit the procoagulant activity of therapeutic polyethylene glycolated factor VIII.

Background: The standard therapy for patients with hemophilia A (HA) is the replacement with factor VIII (FVIII) therapeutics. To overcome the limitation of short half-life of wild-type FVIII protein, polyethylene glycol (PEG) can be coupled to therapeutic FVIII to improve pharmacokinetics.

Objectives: We aimed to characterize antibodies developed against a FVIII therapeutic PEGylated with a 40-kDa PEG (40PEG-BDD) in 2 patients with mild HA.

Cu-MOF-808 as a Sensing Material for Gaseous Hydrogen Sulfide.

The selective detection of hydrogen sulfide (H S) is an important task because of its potentially hazardous effects not only on the environment but also on human health. Here, we present the zirconium-based MOF-808, which was modified with copper salts, as a colorimetric sensor material for the visible, reversible and sensitive H S detection at room temperature. The copper cations, which are incorporated in the oxidation state +II, are installed at the inorganic building units (IBUs) of the framework so that they are accessible for interactions with H S.

Applicability of the European Society of Cardiology Guidelines on the management of acute coronary syndromes to older people with haemophilia A - A modified Delphi consensus by the ADVANCE Working Group.

Introduction: As people with haemophilia (PWH) receive better treatment and live longer they are more likely to encounter cardiovascular disease (CVD) and other comorbidities. ESC guidelines for the acute management of patients presenting with acute coronary syndrome (ACS) are based on the non-haemophilia population.

Aim: To review the guidelines and propose relevant adaptations for PWHA without inhibitors who are treated with prophylaxis and present with ACS.

Comparison of Lung-Homing Receptor Expression and Activation Profiles on NK Cell and T Cell Subsets in COVID-19 and Influenza.

Respiratory viral infections with SARS-CoV-2 and influenza viruses commonly induce a strong infiltration of immune cells into the human lung, with potential detrimental effects on the integrity of the lung tissue. Despite comprising the largest fractions of circulating lymphocytes in the lung, rather little is known about how peripheral blood natural killer (NK) cell and T cell subsets are equipped for lung-homing in COVID-19 and influenza. Here, we provide a detailed comparative analysis of NK cells and T cells in patients infected with SARS-CoV-2 or influenza virus, focusing on the protein and gene expression of chemokine receptors known to be involved in recruitment to the lung.

A Homozygous Deep Intronic Variant Causes Von Willebrand Factor Deficiency and Lack of Endothelial-Specific Secretory Organelles, Weibel-Palade Bodies.

A type 3 von Willebrand disease (VWD) index patient (IP) remains mutation-negative after completion of the conventional diagnostic analysis, including multiplex ligation-dependent probe amplification and sequencing of the promoter, exons, and flanking intronic regions of the VWF gene (VWF). In this study, we intended to elucidate causative mutation through next-generation sequencing (NGS) of the whole VWF (including complete intronic region), mRNA analysis, and study of the patient-derived endothelial colony-forming cells (ECFCs). The NGS revealed a variant in the intronic region of VWF (997 + 118 T > G in intron 8), for the first time.

Autologous NK cells as consolidation therapy following stem cell transplantation in multiple myeloma.

Few approaches have been made toward exploring autologous NK cells in settings of cancer immunotherapy. Here, we demonstrate the feasibility of infusing multiple doses of activated and expanded autologous NK cells in patients with multiple myeloma (MM) post-autologous stem cell transplantation. Infused NK cells were detected in circulation up to 4 weeks after the last infusion.

Peak pressure during gait in patients with severe haemophilia: A controlled cross-sectional study.

Background: Patients with severe haemophilia suffer from bleeding-related joint changes in which the ankle joint is most frequently affected. In the resulting gait changes, the forefoot is involved by reducing the foot pressure. However, it is unclear which changes in foot pressure are present in the individual's foot zones.

CD5 Surface Expression Marks Intravascular Human Innate Lymphoid Cells That Have a Distinct Ontogeny and Migrate to the Lung.

Innate lymphoid cells (ILCs) contribute to immune defense, yet it is poorly understood how ILCs develop and are strategically positioned in the lung. This applies especially to human ILCs due to the difficulty of studying them . Here we investigated the ontogeny and migration of human ILCs with a humanized mouse model ("MISTRG") expressing human cytokines.

Multifaceted pathomolecular mechanism of a VWF large deletion involved in the pathogenesis of severe VWD.

An in-frame heterozygous large deletion of exons 4 through 34 of the von Willebrand factor (VWF) gene was identified in a type 3 von Willebrand disease (VWD) index patient (IP), as the only VWF variant. The IP exhibited severe bleeding episodes despite prophylaxis treatment, with a short VWF half-life after infusion of VWF/factor VIII concentrates. Transcript analysis confirmed transcription of normal VWF messenger RNA besides an aberrant deleted transcript.

New Inhibitors in the Ageing Population: A Retrospective, Observational, Cohort Study of New Inhibitors in Older People with Hemophilia.

Introduction: A second peak of inhibitors has been reported in patients with severe hemophilia A (HA) aged >50 years in the United Kingdom. The reason for this suggested breakdown of tolerance in the aging population is unclear, as is the potential impact of regular exposure to the deficient factor by prophylaxis at higher age. No data on hemophilia B (HB) have ever been reported.

Expansions of adaptive-like NK cells with a tissue-resident phenotype in human lung and blood.

Human adaptive-like "memory" CD56CD16 natural killer (NK) cells in peripheral blood from cytomegalovirus-seropositive individuals have been extensively investigated in recent years and are currently explored as a treatment strategy for hematological cancers. However, treatment of solid tumors remains limited due to insufficient NK cell tumor infiltration, and it is unknown whether large expansions of adaptive-like NK cells that are equipped for tissue residency and tumor homing exist in peripheral tissues. Here, we show that human lung and blood contains adaptive-like CD56CD16 NK cells with hallmarks of tissue residency, including expression of CD49a.