Personalized approaches to the treatment of hemostatic disorders

The last 20 years has seen dramatic improvements in the clinical management of hemostatic and thrombotic disorders. We have witnessed the introduction of novel therapeutic agents into the clinic, including direct oral anticoagulants (DOACs), and the rapid evolution of personalized therapy for patients with the development of high-throughput genetic analysis and gene therapy. Moreover, growing awareness of nonlinear genotype-phenotype correlations in disease presentation, including bleeding or thrombosis risk, has catalyzed the concept of tailored individualized therapies. Many of these clinical milestones have been made possible by improved understanding of the fundamental biology and thus pathophysiology underpinning hemostatic disorders, as well as development of novel technologies and diagnostic tools. This review series aims to provide an overview of some of these advancements, with a particular focus on novel and personalized approaches to the management of disorders of hemostasis and thrombosis

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

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

Von Willebrand factor and cancer; metastasis and coagulopathies

Von Willebrand factor (VWF) is a multimeric procoagulant plasma glycoprotein that mediates platelet adhesion along the endothelium. In addition to its role maintaining normal hemostasis, more recently novel biological functions for VWF have been described, including inflammation, angiogenesis, and metastasis. Significantly increased plasma VWF levels have been reported across a variety of cancer patient cohorts. Given that VWF is established as a risk factor for venous thrombosis, this is of direct clinical importance. Moreover, elevated VWF has also been observed localized within the tumor microenvironment, correlating with advanced disease stage and poorer clinical outcome. Critically, evidence suggests that elevated VWF levels in cancer patients may not only contribute to cancer associated coagulopathies but may also mediate cancer progression and metastasis. Studies have shown that VWF can promote pro-inflammatory signaling, regulate angiogenesis and vascular permeability, which may facilitate tumor cell growth and extravasation across the vessel wall. Endothelial secreted VWF multimers contribute to the adhesion and transendothelial migration of tumor cells key for tumor dissemination. In support of this, VWF inhibition attenuated metastasis in vivo. Perhaps most intriguingly, specific tumor cells have been reported to acquire de novo VWF expression which increases tumor-platelet heteroaggregates and confers enhanced metastatic activity. Current knowledge on the roles of VWF in cancer and in particular its contribution to metastasis and cancer associated coagulopathies is summarized in this review

von Willebrand factor sialylation - a critical regulator of biological function

Essentials Von Willebrand Factor (VWF) is extensively glycosylated with serial studies demonstrating that these carbohydrate determinants play critical roles in regulating multiple aspects of VWF biology. Terminal sialic acid residues, expressed on both the N- and O-linked glycans of VWF, regulate VWF functional activity, susceptibility to proteolysis and plasma clearance in vivo. Quantitative and qualitative variations in VWF sialylation have been reported in patients with von Willebrand Disease, as well as in a number of other physiological and pathological states. Further studies are warranted to define the molecular mechanisms through which N- and O-linked sialylation impacts upon the multiple biological activities of VWF. von Willebrand factor (VWF) undergoes complex post-translational modification prior to its secretion into the plasma. Consequently, VWF monomers contain complex N-glycan and O-glycan structures that, together, account for approximately 20% of the final monomeric mass. An increasing body of evidence has confirmed that these carbohydrate determinants play critical roles in regulating multiple aspects of VWF biology. In particular, studies have demonstrated that terminal ABO blood group has an important effect on plasma VWF levels. This effect is interesting, given that only 15% of the N-glycans and 1% of the O-glycans of VWF actually express terminal ABO(H) determinants. In contrast, the vast majority of the N-glycans and O-glycans on human VWF are capped by terminal negatively charged sialic acid residues. Recent data suggest that sialylation significantly regulates VWF functional activity, susceptibility to proteolysis, and clearance, through a number of independent pathways. These findings are of direct clinical relevence, in that quantitative and qualitative variations in VWF sialylation have been described in patients with VWD, as well as in patients with a number of other physiologic and pathologic conditions. Moreover, platelet-derived VWF is significantly hyposialylated as compared with plasma-derived VWF, whereas the recently licensed recombinant VWF therapeutic is hypersialylated. In this review, we examine the evidence supporting the hypothesis that VWF sialylation plays multiple biological roles. In addition, we consider data suggesting that quantitative and qualitative variations in VWF sialylation may play specific roles in the pathogenesis of VWD, and that sialic acid expression on VWF may also differ across a number of other physiologic and pathologic conditions

Advances in the management of cancer-associated thrombosis

The association between cancer and venous thromboembolism (VTE) has been established for more than 150 years. Nevertheless, cancer-associated thrombosis still remains a major clinical challenge and is associated with significant morbidity and mortality for patients with cancer. The clinical presentation of cancer-associated thrombosis can be distinct from that of a patient without an underlying malignancy. Moreover, specific cancer types, including pancreatic cancer and hematological malignancies, as well as advanced stage disease can confer a significant thrombotic risk. This risk is further augmented by specific anticancer treatment modalities. The pathophysiology of cancer-associated thrombosis is complex and multifactorial. However, understanding the biological mechanisms underpinning VTE risk may provide insight into novel targeted prophylaxis in cancer patients. Over the last decade, low-molecular-weight heparin has been the preferred anticoagulant agent for patients with cancer-associated thrombosis due to improved efficacy compared with Vitamin K antagonists. However, the advent of direct oral anticoagulants (DOACs) has added to the repertoire of ammunition now at the disposal of clinicians to aid in the management of cancer-associated thrombosis. Several randomized controlled trials have now been published, demonstrating DOAC as a noninferior alternative for both the treatment and prevention of cancer-associated thrombosis. Notwithstanding this, limitations for their widespread use remain, with the potential for increased bleeding risk, drug interactions, and poor DOAC metabolism. This review discusses the evidence base for the incidence and risk factors associated with VTE in cancer, development, and refinement of risk prediction models and novel advances in the therapeutic management of cancer-associated thrombosis

The role of VWF/FVIII in thrombosis and cancer progression in multiple myeloma and other hematological malignancies

Cancer associated thrombosis (CAT) is associated with significant morbidity and mortality, highlighting an unmet clinical need to improve understanding of the pathophysiology of CAT. Multiple myeloma (MM) is associated with one of the highest rates of thrombosis despite widespread use of thromboprophylactic agents. The pathophysiology of thrombosis in MM is multifactorial and patients with MM appear to display a hypercoagulable phenotype with potential contributory factors including raised von Willebrand factor (VWF) levels, activated protein C resistance, impaired fibrinolysis, and abnormal thrombin generation. In addition, the toxic effect of anti-myeloma therapies on the endothelium and contribution to thrombosis has been widely described. Elevated VWF/factor VIII (FVIII) plasma levels have been reported in heterogeneous cohorts of patients with MM and other hematological malignancies. In specific studies, high plasma VWF levels have been shown to associate with VTE risk and reduced overall survival. While the mechanisms underpinning this remain unclear, dysregulation of the VWF and A Disintegrin And Metalloprotease Thrombospondin type 1, motif 13 (ADAMTS-13) axis is evident in certain solid organ malignancies and correlates with advanced disease and thrombosis. Furthermore, thrombotic microangiopathic conditions arising from deficiencies in ADAMTS-13 and thus an accumulation of prothrombotic VWF multimers have been reported in patients with MM, particularly in association with specific myeloma therapies. This review will discuss current evidence on the pathophysiological mechanisms underpinning thrombosis in MM and in particular summarize the role of VWF/FVIII in hematological malignancies with a focus on thrombotic risk and emerging evidence for contribution to disease progression

More on ‘Association between ABO blood groups and risk of SARS-CoV-2 pneumonia’

We read with interest the recent report from Li et al.1 describing an association between ABO blood groups and risk of SARS‐CoV‐2 pneumonia. In an initial study of 265 patients with COVID, the authors observed that blood group O individuals were significantly underrepresented amongst patients who required hospitalization for severe COVID‐19 infection (P < 0·01). Conversely, blood group A was significantly more common in patients with severe COVID‐19 compared to the local population (P = 0·017). Subsequently, in a larger validation cohort that included 2 153 patients with COVID‐19, this ABO effect was reproduced with blood group O again being associated with a significant protective effect (P < 0·001). In keeping with these data, another independent study (n = 2 173) also reported that blood group O was associated with reduced susceptibility to severe COVID‐19.2 Since the pathogenesis underlying COVID‐19 remains poorly understood, we believe that these novel findings provide interesting insights into biological mechanisms that may contribute to interindividual differences in COVID‐19 susceptibility

Endothelial cells orchestrate COVID-19 coagulopathy

Recent data have shown that coagulation activation is common in patients with severe COVID-19. Moreover, autopsy studies have reported widespread microthrombi disseminated throughout the pulmonary vasculature, suggesting that vasculopathy is important in COVID-19 pathogenesis. These post-mortem studies have also highlighted substantial endothelial cell damage, with evidence of apoptosis and loss of tight junctions. Collectively, these data suggest that endothelial cells play a key role in orchestrating the unusual pulmonary intravascular coagulopathy associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.</p