Role of von Willebrand factor in venous thromboembolic disease

Abstract

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. A protein that has been extensively studied in atherothrombotic disease and inflammation is von Willebrand factor (VWF). Because many predisposing and provoking factors of venous thromboembolism (VTE) have been shown to directly modulate VWF levels, it is, perhaps, not surprising that VWF has been highlighted by several recent association studies of patients with VTE.

Methods: In the present narrative review, we investigated more deeply the effects of VWF in venous disease by synthesizing the data from clinical studies of deep vein thrombosis of the limbs, pulmonary embolism, portal and cerebral vein thrombosis, and the complications of thrombosis, including post-thrombotic syndrome, venous insufficiency, and chronic thromboembolic pulmonary hypertension. We have also discussed the findings from preclinical studies to highlight novel VWF biochemistry in thrombosis and therapeutics.

Results: Across the spectrum of venous thromboembolic disease, we consistently observed that elevated VWF levels conferred an increased risk of VTE and long-term venous complications. We have highlighted important findings from VWF molecular research and have proposed mechanisms by which VWF participates in venous disease. Emerging evidence from preclinical studies might reveal novel targets for thromboinflammatory disease, including specific VWF pathophysiology. Furthermore, we have highlighted the utility of measuring VWF to prognosticate and risk stratify for VTE and its complications.

Conclusions: As the prevalence of inflammatory processes, such as aging, obesity, and diabetes increases in our population, it is critical to understand the evolving role of VWF in venous disease to guide clinical decisions and therapeutics.

Keywords: Thromboinflammatory; Venous disease; Venous thromboembolism; von Willebrand factor.

Fig 1

The lifecycle of von Willebrand factor (VWF). 1, VWF is synthesized by endothelial cells and megakaryocytes. 2, It is stored in platelet α-granules and Weibel-Palade bodies (WPBs) to undergo stimulated or basal secretion, contributing to both subendothelial and circulating VWF levels. 3, VWF circulates with or without factor VIII (FVIII) and has an estimated half-life of 16 hours, with a high degree of interindividual variability. 4, VWF clearance is mediated by sinusoidal endothelial cells, macrophages, and hepatocytes, with contributions from an array of receptors. ABO glycans present on VWF modify its clearance. ASGP-R, Asialoglycoprotein receptor; CLEC4M, C-type lectin domain family 4 member M; LRP-1, low-density lipoprotein receptor-related protein; MGL, macrophage galactose-type lectin; SCARA5, scavenger receptor class A member 5; Siglec-5, sialic-acid binding immunoglobulin-like lectin 5; SR-A1, scavenger receptor A1.

Fig 2

The extracellular functions of von Willebrand factor (VWF). 1, VWF carries factor VIII (FVIII) in circulation and protects FVIII from proteolytic degradation. 2, VWF binds to subendothelial collagen during hemostatic insult to capture platelets and enable platelet plug formation. Ultra-large (UL) VWF is cleaved by A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) under conditions of shear stress to regulate its thrombotic potential. 3, Stimulated VWF release via many potential noxious stimuli allows for VWF to capture platelets and, possibly, leukocytes and erythrocytes on an intact endothelial surface. ADAMTS13 might also regulate VWF when anchored to the endothelium.

Fig 3

Association of von Willebrand factor (VWF) with thrombus constituents in murine venous thrombi. Using a murine model of deep vein thrombosis (DVT; the inferior vena cava [IVC] stenosis model), the thrombus with IVC wall was dissected and cross-sectioned. A.i, A laminar pattern of red and white thrombus was demonstrated with hematoxylin and eosin (H&E) staining. A.ii, Immunofluorescent staining showing VWF (green) colocalized (yellow) with the endothelium (CD31; red) and in close proximity to recruited leukocytes (DAPI; blue). A.iii, Magnified view of inset in A.ii. Longitudinal thrombus sections (IVC wall removed; B.i) showing an abundance of VWF (green) and its association with platelets (CD41; red) and leukocytes (CD45 and DAPI; purple; B.ii,B.iii). C.i, An isolated red thrombus image was DAB-stained with a VWF antibody to show VWF (brown) localization with erythrocytes (red). C.ii, VWF lamination in lines of Zahn are decorated with leukocytes (purple).

Fig 4

Potential for von Willebrand factor (VWF)-directed therapeutics in venous thromboembolism (VTE). A reduction in VWF-related prothrombotic activity might be achieved through 1, disruption of ultra-large (UL)-VWF multimers via A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13)-mediated cleavage or N-acetylcysteine (NAC) reduction; 2, impairment of VWF–platelet interactions by targeting binding sites on VWF or platelets with antibodies and/or aptamers; and 3, identify sites important for VWF–leukocyte and VWF–erythrocyte interactions as novel mechanisms to target thrombosis but preserve hemostasis.