Toward personalized treatment for patients with low von Willebrand factor and quantitative von Willebrand disease

The biological mechanisms involved in the pathogenesis of type 2 and type 3 von Willebrand disease (VWD) have been studied extensively. In contrast, although accounting for the majority of VWD cases, the pathobiology underlying partial quantitative VWD has remained somewhat elusive. However, important insights have been attained following several recent cohort studies that have investigated mechanisms in patients with type 1 VWD and low von Willebrand factor (VWF), respectively. These studies have demonstrated that reduced plasma VWF levels may result from either (1) decreased VWF biosynthesis and/or secretion in endothelial cells and (2) pathological increased VWF clearance. In addition, it has become clear that some patients with only mild to moderate reductions in plasma VWF levels in the 30 to 50 IU/dL range may have significant bleeding phenotypes. Importantly in these low VWF patients, bleeding risk fails to correlate with plasma VWF levels and inheritance is typically independent of the VWF gene. Although plasma VWF levels may increase to > 50 IU/dL with progressive aging or pregnancy in these subjects, emerging data suggest that this apparent normalization in VWF levels does not necessarily equate to a complete correction in bleeding phenotype in patients with partial quantitative VWD. In this review, these recent advances in our understanding of quantitative VWD pathogenesis are discussed. Furthermore, the translational implications of these emerging findings are considered, particularly with respect to designing personalized treatment plans for VWD patients undergoing elective procedures

Low VWF: Insights into pathogenesis, diagnosis, and clinical management

von Willebrand disease (VWD) constitutes the most common inherited human bleeding disorder. Partial quantitative von Willebrand factor (VWF) deficiency is responsible for the majority of VWD cases. International guidelines recommend that patients with mild to moderate reductions in plasma VWF antigen (VWF:Ag) levels (typically in the range of 30-50 IU/dL) should be diagnosed with low VWF. Over the past decade, a series of large cohort studies have provided significant insights into the biological mechanisms involved in type 1 VWD (plasma VWF:Ag levels ,30 IU/dL). In striking contrast, however, the pathogenesis underpinning low VWF has remained poorly understood. Consequently, low VWF patients continue to present significant clinical challenges with respect to genetic counseling, diagnosis, and management. For example, there is limited information regarding the relationship between plasma VWF:Ag levels and bleeding phenotype in subjects with low VWF. In addition, it is not clear whether patients with low VWF need treatment. For those patients with low VWF in whom treatment is deemed necessary, the optimal choice of therapy remains unknown. However, a number of recent studies have provided important novel insights into these clinical conundrums and the molecular mechanisms responsible for the reduced levels observed in low VWF patients. These emerging clinical and scientific findings are considered in this review, with particular focus on pathogenesis, diagnosis, and clinical management of low VWF

Perioperative management of patients with von Willebrand disease

Surgical procedures represent a serious hemostatic challenge for patients with von Willebrand disease (VWD), and careful perioperative management is required to minimize bleeding risk. Risk stratification includes not only the nature of the surgery to be performed but the baseline plasma vonWillebrand factor (VWF) levels, bleeding history, and responses to previous challenges. Baseline bleeding scores (BSs) may assist in identification of patients with a higher risk of postsurgical bleeding. There remains a lack of consensus between best practice guidelines as to the therapeutic target and assays to be monitored in the postoperative period. Hemostatic levels are maintained until bleeding risk abates: usually 3 to 5 days forminor procedures and 7 to 14 days formajor surgery. Hemostatic supplementation ismore complex in VWD than in other bleeding disorders owing to the combined but variable deficiency of both plasma VWF and factor VIII (FVIII) levels. For emergency surgery, coadministration of VWF and FVIII is required to ensure hemostasis; however, for elective procedures, early infusion of VWF replacement therapy will stabilize endogenous FVIII. Because endogenous FVIII production is unaffected in patients with VWD, repeated VWF supplementation (particularly with plasma-derived FVIII-containing products) may lead to accumulation of FVIII. Frequent monitoring of plasma levels and access to hemostatic testing are, therefore, essential for patients undergoing major surgery, particularly with more severe forms of VWD

Von Willebrand factor promotes wound healing

In this issue of Blood, Ishihara et al report an entirely novel role for von Willebrand factor (VWF) in promoting wound healing. In particular, they demonstrate that the heparin-binding domain (HBD) within the A1 domain of VWF can bind to a variety of different growth factors, including vascular endothelial growth factor-A (VEGF-A) and platelet-derived growth factor-BB (PDGF-BB). Following a dermal skin injury, delayed wound healing, accompanied by reduced local growth factor concentrations and impaired local angiogenesis, was observed in VWF mice compared with controls (see figure). In contrast, treatment of skin wounds with fibrin matrices functionalized with VWF HBD complexed with VEGF-A and PDGF-BB resulted in improved wound healing in both VWF mice and type 2 diabetic mice. Collectively, these exciting findings suggest that VWF plays a critical role in recruiting growth factors to sites of injury and thereby in regulating tissue repair

Antithrombin inhibition using nanobodies to correct bleeding in hemophilia

In this issue of EMBO Molecular Medicine, Barbon et al describe a new approach to rebalancing coagulation in patients with hemophilia (PWH) through targeted inhibition of anticoagulant antithrombin (AT) (Barbon et al, 2020). In contrast to previous studies that used RNA interference (RNAi) therapy to reduce AT levels (Sehgal et al, 2015; Pasi et al, 2017), the authors utilized llama-derived single-domain antibodies (sdAbs or nanobodies) to inhibit AT activity (Fig 1). These engineered sdAbs successfully restored thrombin generation in hemophilic plasma and corrected bleeding phenotype in a murine hemophilia model. Furthermore, long-term AAV8-mediated hepatic expression of the sdAb was well tolerated and associated with a sustained correction in bleeding in hemophilia A and B mice. Collectively, these exciting data uncover a novel AT-targeting approach that may be useful as an alternative therapy for restoring normal hemostasis in PWH

Correcting dominant-negative von Willebrand disease

In this issue of the Journal of Thrombosis and Haemostasis, Campioni et al report correction of dominant-negative von Willebrand disease (VWD) in vivo for the first time. In particular, they demonstrate that targeted inhibition of a mutant VWF allele can significantly improve bleeding phenotype in a Type 2A VWD murine model. Collectively, these data move us another step closer to developing personalized approaches for the treatment of VWD patients that extend beyond traditional von Willebrand factor (VWF) infusion therapy

Novel therapies for hemophilia A – the role of the von Willebrand factor chaperone

The factor VIII–von Willebrand factor (VWF) complexFVIII is a plasma sialoglycoprotein that plays a critical role in maintaining normal hemostasis. Patients with severe hemophilia A have markedly reduced plasma FVIII levels, and thus typically show a significant bleeding phenotype. Accumulating data suggest that plasma FVIII is predominantly derived from biosynthesis within sinusoidal cells and endothelial cells (ECs), particularly in the liver and lung 1. FVIII is initially synthesized as an inactive 2332 amino acid polypeptide composed of three distinct domain types: A, B, and C (domain structure A1–a1–A2–a2–B–a3–A3–C1–C2). Prior to secretion, this single‐chain FVIII undergoes complex post‐translational modification that includes significant glycosylation, sulfation, and limited intracellular proteolytic processing. Consequently, plasma FVIII circulates as a heterodimeric protein consisting of a heavy chain (A1–a1–A2–a2–B) and a light chain (a3–A3–C1–C2), held together through a metal ion‐dependent interaction.</div

New developments in von Willebrand disease

Von Willebrand disease (VWD) constitutes the most common inherited human bleeding disorder. It is associated with a mucocutaneous bleeding phenotype that can significantly impact upon quality of life. Despite its prevalence and associated morbidity, the diagnosis and subclassification of VWD continue to pose significant clinical challenges. This is in part attributable to the fact that plasma von Willebrand factor (VWF) levels vary over a wide range in the normal population, together with the multiple different physiological functions played by VWF in vivo. Over recent years, substantial progress has been achieved in elucidating the biological roles of VWF. Significant advances have also been made into defining the pathophysiological mechanisms underpinning both quantitative and qualitative VWD. In particular, several new laboratory assays have been developed that enable more precise assessment of specific aspects of VWF activity. In the present review, we discuss these recent developments in the field of VWD diagnosis, and consider how these advances can impact upon clinical diagnostic algorithms for use in routine clinical practice. In addition, we review some important recent advances pertaining to the various treatment options available for managing patients with VWD

The biological significance of von Willebrand factor o-linked glycosylation

Glycosylation is a key posttranslational modification, known to occur on more than half of all secreted proteins in man. As such, the role of N- and O-linked glycan structures in modulating various aspects of protein biology is an area of much research. Given their prevalence, it is perhaps unsurprising that variations in glycan structures have been demonstrated to play critical roles in modulating protein function and have been implicated in the pathophysiology of human diseases. von Willebrand factor (VWF), a plasma glycoprotein that is essential for normal hemostasis, is heavily glycosylated, containing 13 N-linked and 10 O-linked glycans. Together, these carbohydrate chains account for 20% of VWF monomeric mass, and have been shown to modulate VWF structure, function, and half-life. In this review, we focus on the specific role played by O-linked glycans in modulating VWF biology. Specifically, VWF O-linked glycans have been shown to modulate tertiary protein structure, susceptibility to ADAMTS13 proteolysis, platelet tethering, and VWF circulatory half-life

Pulmonary immuno-thrombosis in COVID-19 ARDS pathogenesis

Severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) is responsible for coronavirus disease 2019 (COVID-19). Recent data highlight a pivotal role for pulmonary immuno-thrombosis in COVID-19 in the pathogenesis of severe COVID-19