New targeted therapy for hemophilia

Maintenance of hemostasis is central to the prevention of thrombosis and bleeding. Diminished thrombin generation and clot formation arising from clotting factor deficiencies, such as hemophilia, disrupt this delicate balance and promote bleeding. Factor replacement is the standard of care for people with hemophilia in wealthy countries, but alternative hemostatic products are required if inhibitors to replacement factors develop. Although the factor VIII (FVIII) mimetic bispecific antibody emicizumab has enhanced the treatment of patients with hemophilia A with inhibitors, the need for alternative therapies for individuals with hemophilia B and other rare bleeding disorders has stimulated the generation of a plethora of new prohemostatic agents that target different facets of the coagulation system. Of these, novel therapies that can safely attenuate endogenous anticoagulant pathways may represent a solution to “rebalance” hemostasis in individuals with inherited or acquired bleeding disorders. To this end, antibody-mediated inhibition of tissue factor pathway inhibitor or aptamer-mediated suppression of antithrombin has already demonstrated positive outcomes in clinical trials with patients with hemophilia. </p

A new thrombomodulin-related coagulopathy

Individuals with bleeding disorders of unknown etiology exhibit bleeding diatheses of varying severity. Challenges persist in identifying the molecular basis of the bleeding experienced by many of these individuals; however, the advent and accessibility of advanced sequencing technologies has enabled the identification of deleterious mutations in a number of genes encoding proteins necessary for optimal hemostatic function.1 On occasion, the connection between genotype and bleeding is not immediately apparent, but further investigation can ultimately yield unexpected insights into the biology underlying key hemostasis pathways

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

Molecular basis of protease-activated receptor 1 signaling diversity

Protease-activated receptors (PARs) are a family of highly conserved G protein-coupled receptors (GPCRs) that respond to extracellular proteases via a unique proteolysis-dependent activation mechanism. Protease-activated receptor 1 (PAR1) was the first identified member of the receptor family and plays important roles in hemostasis, inflammation and malignancy. The biology underlying PAR1 signaling by its canonical agonist thrombin is well characterized; however, definition of the mechanistic basis of PAR1 signaling by other proteases, including matrix metalloproteases, activated protein C, plasmin, and activated factors VII and X, remains incompletely understood. In this review, we discuss emerging insights into the molecular bases for “biased” PAR1 signaling, including atypical PAR1 proteolysis, PAR1 heterodimer and coreceptor interactions, PAR1 translocation on the membrane surface, and interactions with different G-proteins and β-arrestins upon receptor activation. Moreover, we consider how these new insights into PAR1 signaling have acted to spur development of novel PAR1-targeted therapeutics that act to inhibit, redirect, or fine-tune PAR1 signaling output to treat cardiovascular and inflammatory disease. Finally, we discuss some of the key unanswered questions relating to PAR1 biology, in particular how differences in PAR1 proteolysis, signaling intermediate coupling, and engagement with coreceptors and GPCRs combine to mediate the diversity of identified PAR1 signaling outputs

Illustrated state-of-the-art capsules of the ISTH 2022 Congress

The ISTH London 2022 Congress is the first held (mostly) face- to- face again since the COVID- 19   pandemic took the world by surprise in 2020. For 2 years we met virtually, but this year’s in- person format will allow the ever- so- important and quintessential cre-ativity and networking to flow again. What a pleasure and joy to be able to see every-one! Importantly, all conference proceedings are also streamed (and available recorded) online for those unable to travel on this occasion. This ensures no one misses out. The 2022 scientific program highlights new developments in hemophilia and its treatment, acquired and other inherited bleeding disorders, thromboinflammation, platelets and co-agulation, clot structure and composition, fibrinolysis, vascular biology, venous thrombo-embolism, women’s health, arterial thrombosis, pediatrics, COVID- related thrombosis,vaccine- induced thrombocytopenia with thrombosis, and omics and diagnostics. These areas are elegantly reviewed in this Illustrated Review article. The Illustrated Review is a highlight of the ISTH Congress. The format lends itself very well to explaining the sci-ence, and the collection of beautiful graphical summaries of recent developments in the field are stunning and self- explanatory. This clever and effective way to communicate research is revolutionary and different from traditional formats. We hope you enjoy this article and will be inspired by its content to generate new research ideas.</p

The protein C pathways

Purpose of review: To provide an overview of the state-of-the-art in protein C (PC) pathway research. Recent findings: The PC pathway is crucial for maintaining hemostasis to prevent venous thromboembolism. This is evident from genetic mutations that result in impaired PC pathway activity and contribute to increased venous thromboembolism risk in affected individuals. In addition to its anticoagulant role, activated PC (APC) also mediates a complex, pleiotropic role in the maintenance of vascular cell health, which it achieves via anti-inflammatory and antiapoptotic cell signaling on endothelial cells. Emerging data have demonstrated that cell signaling by APC, mediated by multiple receptor interactions on different cell types, also confers cytoprotective and anti-inflammatory benefits. Defects in both arms of the PC pathway are associated with increased susceptibility to thrombo-inflammatory disease in various preclinical thrombotic, proinflammatory and neurological disease models. Moreover, recent studies have identified attenuation of anticoagulant PC pathway activity as an exciting therapeutic opportunity to promote hemostasis in patients with inherited or acquired bleeding disorders. Summary: In this review, we provide an overview of some recent developments in our understanding of the PC pathways.</div

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. We detail the molecular basis for cell signaling mediated by coagulation factor proteases via the protease-activated receptor family, considering new insights into the role of protease-specific cleavage sites, cofactor and coreceptor interactions, and distinct signaling intermediate interactions in shaping protease-activated receptor signaling diversity. Moreover, we discuss examples of how injury-dependent conformational activation of other coagulation proteins, such as fibrin(ogen) and von Willebrand factor, decrypts their signaling potential, unlocking their capacity to contribute to aberrant proinflammatory signaling. Finally, we consider the role of coagulation factor signaling in disease development and the status of pharmacologic approaches to either attenuate or enhance coagulation factor signaling for therapeutic benefit, emphasizing new approaches to inhibit deleterious coagulation factor signaling without impacting hemostatic activity.</p

Dysregulated haemostasis in thrombo-inflammatory disease

Inflammatory disease is often associated with an increased incidence of venous thromboembolism in affected patients, although in most instances, the mechanistic basis for this increased thrombogenicity remains poorly understood. Acute infection, as exemplified by sepsis, malaria and most recently, COVID-19, drives 'immunothrombosis', where the immune defence response to capture and neutralise invading pathogens causes concurrent activation of deleterious prothrombotic cellular and biological responses. Moreover, dysregulated innate and adaptive immune responses in patients with chronic inflammatory conditions, such as inflammatory bowel disease, allergies, and neurodegenerative disorders, are now recognised to occur in parallel with activation of coagulation. In this review, we describe the detailed cellular and biochemical mechanisms that cause inflammation-driven haemostatic dysregulation, including aberrant contact pathway activation, increased tissue factor activity and release, innate immune cell activation and programmed cell death, and T cell-mediated changes in thrombus resolution. In addition, we consider how lifestyle changes increasingly associated with modern life, such as circadian rhythm disruption, chronic stress and old age, are increasingly implicated in unbalancing haemostasis. Finally, we describe the emergence of potential therapies with broad-ranging immunothrombotic functions, and how drug development in this area is challenged by our nascent understanding of the key molecular and cellular parameters that control the shared nodes of proinflammatory and procoagulant pathways. Despite the increasing recognition and understanding of the prothrombotic nature of inflammatory disease, significant challenges remain in effectively managing affected patients, and new therapeutic approaches to curtail the key pathogenic steps in immune response-driven thrombosis are urgently required. </p

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

Heterogeneity in bleeding tendency and arthropathy development in individuals with hemophilia

People with hemophilia (PWH) have an increased tendency to bleed, often into their joints, causing debilitating joint disease if left untreated. To reduce the incidence of bleeding events, PWH receive prophylactic replacement therapy with recombinant factor VIII (FVIII) or FIX. Bleeding events in PWH are typically proportional to their plasma FVIII or IX levels; however, in many PWH, bleeding tendency and the likelihood of developing arthropathy often varies independently of endogenous factor levels. Consequently, many PWH suffer repeated bleeding events before correct dosing of replacement factor can be established. Diagnostic approaches to define an individual's bleeding tendency remain limited. Multiple modulators of bleeding phenotype in PWH have been proposed, including the type of disease-causing variant, age of onset of bleeding episodes, plasma modifiers of blood coagulation or clot fibrinolysis pathway activity, interindividual differences in platelet reactivity, and endothelial anticoagulant activity. In this review, we summarize current knowledge of established factors modulating bleeding tendency and discuss emerging concepts of additional biological elements that may contribute to variable bleeding tendency in PWH. Finally, we consider how variance in responses to new gene therapies may also necessitate consideration of patient-specific tailoring of treatment. Cumulatively, these studies highlight the need to reconsider the current one size fits all approach to treatment regimens for PWH and consider therapies guided by the bleeding phenotype of each individual PWH at the onset of therapy. Further characterization of the biological bases of bleeding heterogeneity in PWH, combined with the development of novel diagnostic assays to identify those factors that modulate bleeding risk in PWH, will be required to meet these aspirations