Thrombosis, Translational Medicine, and Biomarker Research: Moving the Needle.

Arterial and venous thromboembolism are leading causes of morbidity and death worldwide. Despite significant advances in the diagnosis, prognostication, and treatment of thrombotic diseases over the past 3 decades, the adoption of findings stemming from translational biomarker research in clinical practice remains limited. Biomarkers provide an opportunity to enhance our understanding of pathophysiological processes and optimize treatment strategies.

How I do it: Endoscope-assisted in situ arterial reconstruction of the lower limb.

Arterial reconstruction with the great saphenous vein is a frequently performed vascular surgery technique for revascularization of chronic limb threatening ischemia. Surgeon variations of the procedure are common and aim to balance patency, limb salvage, complications, hospital resources, and technical feasibility. We describe a minimally invasive revascularization option using endoscope assistance for in situ great saphenous vein-arterial bypass to treat infrainguinal occlusive disease.

The contribution of the sinusoidal endothelial cell receptors CLEC4M, stabilin-2, and SCARA5 to VWF-FVIII clearance in thrombosis and hemostasis.

Quantitative abnormalities in factor VIII (FVIII) and its binding partner, von Willebrand factor (VWF), are associated with an increased risk of bleeding or thrombosis, and pathways that regulate the clearance of VWF-FVIII can strongly influence their plasma levels. In 2010, the Cohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) on genome-wide association study meta-analysis identified variants in the genes for the sinusoidal endothelial receptors C-type lectin domain family 4 member M (CLEC4M), stabilin-2, and scavenger receptor class A member 5 (SCARA5) as being associated with plasma levels of VWF and/or FVIII in normal individuals. The ability of these receptors to bind, internalize, and clear the VWF-FVIII complex from the circulation has now been reported in a series of studies using in vitro and in vivo models.

The mechanistic and structural role of von Willebrand factor in endotoxemia-enhanced deep vein thrombosis in mice.

Background: Although the concept of immunothrombosis has established a link between inflammation and thrombosis, the role of inflammation in the pathogenesis of deep vein thrombosis remains to be fully elucidated. Further, although various constituents of venous thrombi have been identified, their localizations and cellular and molecular interactions are yet to be combined in a single, multiplexed analysis.

Objectives: The objective of this study was to investigate the role of the von Willebrand factor (VWF) in inflammation-associated venous thrombosis.

Role of von Willebrand factor in venous thromboembolic disease.

Objective: Evolving evidence of the shared risk factors and pathogenic mechanisms in arterial and venous thrombosis questions of the strict vascular dichotomy of arterial vs venous. The connection between arterial and venous thrombosis has been highlighted by common underlying inflammatory processes, a concept known as thromboinflammatory disease. Using this relationship, we can apply knowledge from arterial disease to better understand and potentially mitigate venous disease.

Stabilin-2 deficiency increases thrombotic burden and alters the composition of venous thrombi in a mouse model.

Background: Stabilin-2 is an endocytic scavenger receptor that mediates the clearance of glycosaminoglycans, phosphatidylserine-expressing cells, and the von Willebrand factor-factor VIII (FVIII) complex. In a genome-wide screening study, pathogenic loss-of-function variants in the human STAB2 gene associated with an increased incidence of unprovoked venous thromboembolism (VTE). However, the specific mechanism(s) by which stabilin-2 deficiency influences the pathogenesis of VTE is unknown.

von Willebrand Factor Is a Critical Mediator of Deep Vein Thrombosis in a Mouse Model of Diet-Induced Obesity.

Objective: Obesity is characterized by chronic low-grade inflammation and consequentially a hypercoagulable state, associating with an increased incidence of venous thromboembolism. Increased VWF (von Willebrand factor) plasma concentration and procoagulant function are independent risk factors for venous thromboembolism and are elevated in obese patients. Here, we explore the pathobiological role of VWF in obesity-associated venous thrombosis using murine models.

The scavenger receptor SCARA5 is an endocytic receptor for von Willebrand factor expressed by littoral cells in the human spleen.

Background: Scavenger receptors play a significant role in clearing aged proteins from the plasma, including the large glycoprotein coagulation factors von Willebrand factor (VWF) and factor VIII (FVIII). A large genome-wide association study meta-analysis has identified genetic variants in the gene SCARA5, which encodes the class A scavenger receptor SCARA5, as being associated with plasma levels of VWF and FVIII.

Objectives: The ability of SCARA5 to regulate the clearance of VWF-FVIII was characterized.

Investigating von Willebrand Factor Pathophysiology Using a Flow Chamber Model of von Willebrand Factor-platelet String Formation.

Von Willebrand factor (VWF) is a multimeric glycoprotein coagulation factor that mediates platelet adhesion and aggregation at sites of endothelial damage and that carries factor VIII in the circulation. VWF is synthesized by endothelial cells and is either released constitutively into the plasma or is stored in specialized organelles, called Weibel-Palade bodies (WPBs), for on-demand release in response to hemostatic challenge. Procoagulant and proinflammatory stimuli can rapidly induce WPB exocytosis and VWF release.

Reflections as near-peer facilitators of an inquiry project for undergraduate anatomy: Successes and challenges from a term of trial-and-error.

Near-peer facilitators (senior students serving as facilitators to their more junior peers) bring a unique student-based perspective to teaching. With fewer years of teaching experience however, students who become involved in a facilitator role typically develop related skills quickly through a process of trial-and-error within the classroom. The aim of this paper is to report on the authors' own experiences and reflections as student near-peer facilitators for an inquiry-based project in an undergraduate anatomy course.