Bleeding disorder of unknown cause: an illustrated review on current practice, knowledge gaps, and future perspectives.

In more than half of the individuals with a clinically relevant bleeding tendency who are referred to hemostasis experts, no biological etiology can be found after extensive laboratory testing. These persons are diagnosed with an unexplained bleeding tendency or "bleeding disorder of unknown cause" (BDUC). The mucocutaneous bleeding phenotype of individuals with BDUC is generally comparable to that of individuals with inherited bleeding disorders such as von Willebrand disease or platelet function disorders.

Symptom burden, coagulopathy and heart disease after acute SARS-CoV-2 infection in primary practice.

SETANTA (Study of HEarT DiseAse and ImmuNiTy After COVID-19 in Ireland) study aimed to investigate symptom burden and incidence of cardiac abnormalities after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)/COVID-19 and to correlate these results with biomarkers of immunological response and coagulation. SETANTA was a prospective, single-arm observational cross-sectional study condcuted in a primary practice setting, and prospectively registered with ClinicalTrials.gov (identifier: NCT04823182).

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.

R1205H (Vicenza) causes conformational changes in the von Willebrand factor D'D3 domains and enhances von Willebrand factor binding to clearance receptors LRP1 and SR-AI.

Background: von Willebrand factor (VWF)-R1205H variant (Vicenza) results in markedly enhanced VWF clearance in humans that has been shown to be largely macrophage-mediated. However, the biological mechanisms underlying this enhanced clearance remain poorly understood.

Objectives: This study aimed to investigate the roles of (i) specific VWF domains and (ii) different macrophage receptors in regulating enhanced VWF-R1205H clearance.

Examining variability in the diagnosis and management of people with bleeding disorders of unknown cause: communication from the ISTH SSC Subcommittee on von Willebrand Factor.

Background: Bleeding disorder of unknown cause (BDUC) is characterized by a bleeding phenotype in the setting of normal hemostatic testing. No standardized diagnostic criteria or treatment algorithms exist for people with BDUC. To address the unmet need, the International Society on Thrombosis and Haemostasis von Willebrand Factor Scientific Subcommittee performed a real-world survey aimed at addressing knowledge gaps, developing consensus pathways, and ultimately improving care.

Novel functions for von Willebrand factor.

For many years, it has been known that von Willebrand factor (VWF) interacts with factor VIII, collagen, and platelets. In addition, the key roles played by VWF in regulating normal hemostasis have been well defined. However, accumulating recent evidence has shown that VWF can interact with a diverse array of other novel ligands.

O-glycan determinants regulate VWF trafficking to Weibel-Palade bodies.

von Willebrand factor (VWF) undergoes complex posttranslational modification within endothelial cells (ECs) before secretion. This includes significant N- and O-linked glycosylation. Previous studies have demonstrated that changes in N-linked glycan structures significantly influence VWF biosynthesis.

Standardization of definition and management for bleeding disorder of unknown cause: communication from the SSC of the ISTH.

In many patients referred with significant bleeding phenotype, laboratory testing fails to define any hemostatic abnormalities. Clinical practice with respect to diagnosis and management of this patient cohort poses significant clinical challenges. We recommend that bleeding history in these patients should be objectively assessed using the International Society on Thrombosis and Haemostasis (ISTH) bleeding assessment tool.

Glycolytic reprogramming fuels myeloid cell-driven hypercoagulability.

Background: Myeloid cell metabolic reprogramming is a hallmark of inflammatory disease; however, its role in inflammation-induced hypercoagulability is poorly understood.

Objectives: We aimed to evaluate the role of inflammation-associated metabolic reprogramming in regulating blood coagulation.

Methods: We used novel myeloid cell-based global hemostasis assays and murine models of immunometabolic disease.

The Nijmegen ultra-sensitive Bethesda Assay detects very low-titer factor VIII inhibitors in patients with congenital and acquired hemophilia A.

Background: An inhibitor can develop in congenital hemophilia A (HA) patients against exogenous infused factor (F)VIII, whereas in acquired HA (AHA) inhibitors initially develop against endogenous FVIII. Inhibitors can be detected with the Nijmegen Bethesda Assay (NBA), which has an international cut-off level of 0.60 Nijmegen Bethesda Units/mL (NBU/mL).

VWF-ADAMTS13 axis dysfunction in children with sickle cell disease treated with hydroxycarbamide vs blood transfusion.

Previous studies have reported elevated von Willebrand factor (VWF) levels in patients with sickle cell disease (SCD) and demonstrated a key role for the VWF-ADAMTS13 axis in the pathobiology of SCD vaso-occlusion. Although blood transfusion is the gold standard for stroke prevention in SCD, the biological mechanisms underpinning its improved efficacy compared with hydroxycarbamide are not fully understood. We hypothesized that the improved efficacy of blood transfusion might relate to differences in VWF-ADAMTS13 axis dysfunction.

Unraveling coagulation factor-mediated cellular signaling.

Blood coagulation is initiated in response to blood vessel injury or proinflammatory stimuli, which activate coagulation factors to coordinate complex biochemical and cellular responses necessary for clot formation. In addition to these critical physiologic functions, plasma protein factors activated during coagulation mediate a spectrum of signaling responses via receptor-binding interactions on different cell types. In this review, we describe examples and mechanisms of coagulation factor signaling.

Dimethyl fumarate and 4-octyl itaconate are anticoagulants that suppress Tissue Factor in macrophages via inhibition of Type I Interferon.

Excessive inflammation-associated coagulation is a feature of infectious diseases, occurring in such conditions as bacterial sepsis and COVID-19. It can lead to disseminated intravascular coagulation, one of the leading causes of mortality worldwide. Recently, type I interferon (IFN) signaling has been shown to be required for tissue factor (TF; gene name F3) release from macrophages, a critical initiator of coagulation, providing an important mechanistic link between innate immunity and coagulation.

A cross-sectional follow-up study of physical activity in adults with moderate and severe haemophilia.

Aim: To conduct a cross-sectional follow-up assessment of physical activity (PA) in people with moderate and severe haemophilia (PwMSH) from the Irish Personalised Approach to the Treatment of Haemophilia (iPATH) study.

Methods: Between June-December 2021, participants' PA was measured over one week using accelerometery, and was compared with their previously measured data from the original iPATH assessment. Self-awareness of PA and the impact of the Covid-19 pandemic on PA, pain, mobility and function were retrospectively examined using a survey.

Endothelial cell activation, Weibel-Palade body secretion, and enhanced angiogenesis in severe COVID-19.

Background: Severe COVID-19 is associated with marked endothelial cell (EC) activation that plays a key role in immunothrombosis and pulmonary microvascular occlusion. However, the biological mechanisms through which SARS-CoV-2 causes EC activation and damage remain poorly defined.

Objectives: We investigated EC activation in patients with acute COVID-19, and specifically focused on how proteins stored within Weibel-Palade bodies may impact key aspects of disease pathogenesis.

Low von Willebrand Disease: A Bleeding Disorder of Unknown Cause?

von Willebrand disease (VWD) represents the most common inherited bleeding disorder. The majority of VWD cases are characterized by partial quantitative reductions in plasma von Willebrand factor (VWF) levels. Management of patients with mild to moderate VWF reductions in the range of 30 to 50 IU/dL poses a common clinical challenge.