Centering autonomy and choice to support oral PrEP utilization among people who inject drugs: qualitative lessons from HPTN 094 INTEGRA.

Background: Oral Pre-exposure prophylaxis (PrEP) is effective in preventing HIV transmission. However, despite high rates of HIV risk behaviors among people who inject drugs (PWID), this population remains underserved by current HIV prevention efforts in the United States. To address this challenge, we conducted an in-depth exploration of perspectives on using oral PrEP among PWID engaged in the HIV Prevention Trials Network (HPTN) 094 INTEGRA Study.

A fully humanized von Willebrand disease type 1 mouse model as unique platform to investigate novel therapeutic options.

Patients suffering from von Willebrand disease (VWD) have reduced quality-of-life despite current treatment options. Moreover, innovation in VWD therapeutic strategies has essentially stalled and available treatments have remained unchanged for decades. Therefore, there is an unmet need to develop new therapeutic strategies for VWD-patients, especially for the large portion of those with VWD-type 1.

von Willebrand disease.

von Willebrand disease (VWD) is the most common inherited bleeding disorder. The disorder is characterized by excessive mucocutaneous bleeding. The most common bleeding manifestations of this condition include nosebleeds, bruising, bleeding from minor wounds, menorrhagia or postpartum bleeding in women as well as bleeding after surgery.

An Inhibitory Single-Domain Antibody against Protein Z-Dependent Protease Inhibitor Promotes Thrombin Generation in Severe Hemophilia A and FXI Deficiency.

Background:  Protein Z-dependent protease inhibitor (ZPI) is an anticoagulant serpin that targets factor Xa (FXa) in the presence of protein Z (PZ), and factor XIa (FXIa). In factor-VIII-deficient mice, PZ or ZPI gene knock-out mitigates the bleeding phenotype, and pharmacological inhibition of PZ enhances thrombin generation in plasma from patients with hemophilia.

Aims:  To develop a single-domain antibody (sdAb) directed against ZPI to inhibit its anticoagulant activity.

How unique structural adaptations support and coordinate the complex function of von Willebrand factor.

von Willebrand factor (VWF) is a multimeric protein consisting of covalently linked monomers, which share an identical domain architecture. Although involved in processes such as inflammation, angiogenesis, and cancer metastasis, VWF is mostly known for its role in hemostasis, by acting as a chaperone protein for coagulation factor VIII (FVIII) and by contributing to the recruitment of platelets during thrombus formation. To serve its role in hemostasis, VWF needs to bind a variety of ligands, including FVIII, platelet-receptor glycoprotein Ib-α, VWF-cleaving protease ADAMTS13, subendothelial collagen, and integrin α-IIb/β-3.

Implications of von Willebrand Factor in Inflammatory Bowel Diseases: Beyond Bleeding and Thrombosis.

Inflammatory bowel disease (IBD) displays an increased venous and arterial thrombotic risk despite the common occurrence of intestinal bleeding. While some of the mechanisms leading to these thrombotic complications have been studied, other specific changes in the hemostasis profile of IBD patients have been less explored. One such example relates to von Willebrand factor (VWF) whose plasma levels have been reported to be modulated in IBD.

A small-molecule hemostatic agent for the reversal of direct oral anticoagulant-induced bleeding.

Background: The bleeding risk associated with direct oral anticoagulants (DOACs) remains a major concern, and rapid reversal of anticoagulant activity may be required. Although specific and nonspecific hemostatic biotherapies are available, there is a need for small-molecule DOAC reversal agents that are simple and cost-effective to produce, store, and administer.

Objectives: To identify and characterize a small molecule with procoagulant activity as a DOAC reversal agent.

A data-driven approach to implementing the HPTN 094 complex intervention INTEGRA in local communities.

Background: HIV burden in the US among people who inject drugs (PWID) is driven by overlapping syndemic factors such as co-occurring health needs and environmental factors that synergize to produce worse health outcomes among PWID. This includes stigma, poverty, and limited healthcare access (e.g.

The Role of Platelets and von Willebrand Factor in the Procoagulant Phenotype of Inflammatory Bowel Disease.

Aims: Although the risk of thrombosis is well documented for inflammatory bowel disease [IBD] patients, the underlying pathological mechanism seems to be different from other thrombotic conditions. Determining the factors responsible for the increased risk of thrombosis in IBD would help to improve the management of this frequent complication.

Methods: We studied the interplay between platelets, coagulation, and von Willebrand factor [VWF] in 193 IBD patients and in experimental models [acute and chronic] of colitis in wild-type and VWF-deficient mice.

Shear Forces Induced Platelet Clearance Is a New Mechanism of Thrombocytopenia.

Background: Thrombocytopenia has been consistently described in patients with extracorporeal membrane oxygenation (ECMO) and associated with poor outcome. However, the prevalence and underlying mechanisms remain largely unknown, and a device-related role of ECMO in thrombocytopenia has been hypothesized. This study aims to investigate the mechanisms underlying thrombocytopenia in ECMO patients.

Angiopoietin-2 binds to multiple interactive sites within von Willebrand factor.

Background: Biosynthesis of von Willebrand factor (VWF) in endothelial cells drives the formation of storage-organelles known as Weibel-Palade bodies (WPBs). WPBs also contain several other proteins, including angiopoietin-2 (Ang-2).

Objectives: At present, the molecular basis of the VWF-Ang-2 interaction is poorly understood.

Thrombin generation on vascular cells in the presence of factor VIII and/or emicizumab.

Background: The effect of factor VIII (FVIII) or emicizumab on thrombin generation is usually assessed in assays using synthetic phospholipids. Here, we assessed thrombin generation at the surface of human arterial cells (aortic endothelial cells [hAECs] and aortic vascular smooth muscle cells [hVSMCs]).

Objectives: To explore the capacity of hAECs (resting or stimulated) and hVSMCs to support thrombin generation by FVIII or emicizumab.

Does food use disorder exist? Item response theory analyses of a food use disorder adapted from the DSM-5 substance use disorder criteria in a treatment seeking clinical sample.

Background: Increased consumption of food that are high in energy and sugar have been pointed as a major factor in the obesity epidemic. Impaired control of food intake and the concept of food addiction has been developed as a potential contributor. Our objective was to evaluate the dimensionality and psychometric validity of diagnostic criteria for food addiction adapted from the 11 DSM-5 substance use disorder (SUD) criteria (i.

Imlifidase, a new option to optimize the management of patients with hemophilia A on emicizumab.

Background: Emicizumab is a bispecific, chimeric, humanized immunoglobulin G (IgG)4 that mimics the procoagulant activity of factor (F) VIII (FVIII). Its long half-life and subcutaneous route of administration have been life-changing in treating patients with hemophilia A (HA) with or without FVIII inhibitors. However, emicizumab only partially mimics FVIII activity; it prevents but does not treat acute bleeds.

Transplacental delivery of therapeutic proteins by engineered immunoglobulin G: a step toward perinatal replacement therapy.

Background: Transplacental delivery of maternal immunoglobulin G (IgG) provides humoral protection during the first months of life until the newborn's immune system reaches maturity. The maternofetal interface has been exploited therapeutically to replace missing enzymes in the fetus, as shown in experimental mucopolysaccharidoses, or to shape adaptive immune repertoires during fetal development and induce tolerance to self-antigens or immunogenic therapeutic molecules.

Objectives: To investigate whether proteins that are administered to pregnant mice or endogenously present in their circulation may be delivered through the placenta.

MAGT1 deficiency in XMEN disease is associated with severe platelet dysfunction and impaired platelet glycoprotein N-glycosylation.

Background: X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection, and neoplasia (XMEN) disease is a primary immunodeficiency due to loss-of-function mutations in the gene encoding for magnesium transporter 1 (MAGT1). Furthermore, as MAGT1 is involved in the N-glycosylation process, XMEN disease is classified as a congenital disorder of glycosylation. Although XMEN-associated immunodeficiency is well described, the mechanisms underlying platelet dysfunction and those responsible for life-threatening bleeding events have never been investigated.

ADP receptor P2Y12 is the capstone of the cross-talk between Ca mobilization pathways dependent on Ca ATPases sarcoplasmic/endoplasmic reticulum type 3 and type 2b in platelets.

Background: Blood platelet Ca stores are regulated by 2 Ca-ATPases (SERCA2b and SERCA3). On thrombin stimulation, nicotinic acid adenosine dinucleotide phosphate mobilizes SERCA3-dependent stores, inducing early adenosine 5'-diphosphate (ADP) secretion, potentiating later SERCA2b-dependent secretion.

Objectives: The aim of this study was to identify which ADP P2 purinergic receptor (P2Y1 and/or P2Y12) is(are) involved in the amplification of platelet secretion dependent on the SERCA3-dependent Ca mobilization pathway (SERCA3 stores mobilization) as triggered by low concentration of thrombin.

Efficacy of platelet-inspired hemostatic nanoparticles on bleeding in von Willebrand disease murine models.

The lack of innovation in von Willebrand disease (VWD) originates from many factors including the complexity and heterogeneity of the disease but also from a lack of recognition of the impact of the bleeding symptoms experienced by patients with VWD. Recently, a few research initiatives aiming to move past replacement therapies using plasma-derived or recombinant von Willebrand factor (VWF) concentrates have started to emerge. Here, we report an original approach using synthetic platelet (SP) nanoparticles for the treatment of VWD type 2B (VWD-2B) and severe VWD (type 3 VWD).

A nanobody against the VWF A3 domain detects ADAMTS13-induced proteolysis in congenital and acquired VWD.

von Willebrand factor (VWF) is a multimeric protein, the size of which is regulated via ADAMTS13-mediated proteolysis within the A2 domain. We aimed to isolate nanobodies distinguishing between proteolyzed and non-proteolyzed VWF, leading to the identification of a nanobody (designated KB-VWF-D3.1) targeting the A3 domain, the epitope of which overlaps the collagen-binding site.

A gain-of-function filamin A mutation in mouse platelets induces thrombus instability.

Background: Filaminopathies A are rare disorders affecting the brain, intestine, or skeleton, characterized by dominant X-linked filamin A (FLNA) gene mutations. Macrothrombocytopenia with functionally defective platelets is frequent. We have described a filaminopathy A male patient, exhibiting a C-terminal frame-shift FLNa mutation (Berrou et al.