ADAMTS‐13 and von Willebrand factor: a dynamic duo

South, Kieron; Lane, David A.

doi:10.1111/jth.13898

Cited by 70 publications

(59 citation statements)

References 114 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Based on these data, further work was performed to explore the mechanistic roles of inflammation and endothelial dysfunction in mediating chorioretinal changes. Plasma von Willebrand factor (vWF; an endothelial activation marker) [ 15 ] and endothelin-1 (ET-1; an endogenous vasoconstrictor strongly linked with endothelial dysfunction) [ 16 ] were measured. Both vWF and ET-1 were markedly elevated before OLT, correlating significantly with severity of liver disease (MELD and variceal staging) and decreased substantially when rechecked 6 weeks after transplantation ( Table 2 ).…”

Section: Resultsmentioning

confidence: 99%

The Eye as a Non-Invasive Window to the Microcirculation in Liver Cirrhosis: A Prospective Pilot Study

Gifford

Moroni

Farrah

et al. 2020

JCM

View full text Add to dashboard Cite

Microcirculatory dysfunction is associated with organ failure, poor response to vasoactive drugs and increased mortality in cirrhosis, but monitoring techniques are not established. We hypothesized that the chorioretinal structures of the eye could be visualized as a non-invasive proxy of the systemic microvasculature in cirrhosis and would correlate with renal dysfunction. Optical Coherence Tomography (OCT) was performed to image the retina in n = 55 cirrhosis patients being assessed for liver transplantation. OCT parameters were compared with established cohorts of age- and sex-matched healthy volunteers (HV) and patients with chronic kidney disease (CKD). Retinal thickness, macular volume and choroidal thickness were significantly reduced relative to HV and comparable to CKD patients (macular volume: HV vs. cirrhosis mean difference 0.44 mm3 (95% CI 0.26–0.61), p ≤ 0.0001). Reduced retinal thickness and macular volume correlated with renal dysfunction in cirrhosis (macular volume vs. MDRD-6 eGFR r = 0.40, p = 0.006). Retinal changes had resolved substantially 6 weeks following transplantation. There was an inverse association between choroidal thickness and circulating markers of endothelial dysfunction (endothelin-1 r = −0.49, p ≤ 0.001; von Willebrand factor r = −0.32, p ≤ 0.05). Retinal OCT may represent a non-invasive window to the microcirculation in cirrhosis and a dynamic measure of renal and endothelial dysfunction. Validation in different cirrhosis populations is now required.

show abstract

Section: Resultsmentioning

confidence: 99%

The Eye as a Non-Invasive Window to the Microcirculation in Liver Cirrhosis: A Prospective Pilot Study

Gifford

Moroni

Farrah

et al. 2020

JCM

View full text Add to dashboard Cite

show abstract

“…ADAMTS13 cleaves the cryptic peptide bond Tyr1605-Met1606 in VWF-A2 domain converting the prothrombotic ULVWF to smaller and less adhesive multimers, preventing aberrant platelet aggregation and thrombus[28, 29]. Deficiency of ADAMTS13 activity resulting from hereditary or acquired etiologies results in TTP[5, 29]. It has been shown that ADAMTS13 adopts a “closed” conformation through the interaction between the spacer and CUB domains[13, 14].…”

Section: Discussionmentioning

confidence: 99%

AFM Imaging Reveals Multiple Conformational States of ADAMTS13

et al. 2019

View full text Add to dashboard Cite

BackgroundADAMTS13 (A disintegrin and metalloprotease with a thrombospondin type 1 motif 13) cleaves Von Willebrand factor (VWF) to regulate its size, thereby preventing aberrant platelet aggregation and thrombus. Deficiency of ADAMTS13 caused by either genetic mutations or by inhibitory autoantibodies against ADAMTS13 leads to thrombotic thrombocytopenic purpura (TTP). Recently, ADAMTS13 was reported to adopt a “closed” conformation with lower activity and an “open” one resulting from the engagements of VWF D4-CK domains or antibodies to the distal domains of ADAMTS13, or mutations in its spacer domain. These engagements or mutations increase ADAMTS13 activity by ~ 2.5-fold. However, it is less known whether the conformation of ADAMTS13 is dynamic or stable.ResultsWild type ADAMTS13 (WT-ADAMTS13) and the gain-of-function variant (GOF-ADAMTS13) with five mutations (R568K / F592Y / R660K / Y661F / Y665F) in spacer domain were imaged by atomic force microscopy (AFM) at pH 6 and pH 7.5. The data revealed that at both pH 6 and pH 7.5, WT-ADAMTS13 adopted two distinct conformational states (state I and state II), while an additional state (state III) was observed in GOF-ADAMTS13. In the present study, we propose that state I is the “closed” conformation, state III is the “open” one, and state II is an intermediate one. Comparing to pH 7.5, the percentages of state II of WT-ADAMTS13 and state III of GOF-ADAMTS13 increased at pH 6, with the decrease in the state I for WT-ADAMTS13 and state I and state II for GOF-ADAMTS13, suggesting lower pH extended the conformation of ADAMTS13.ConclusionBoth WT- and GOF-ADAMTS13 exist multiple conformational states and lower pH might alter the tertiary structure and/or disrupt the intra-domain interactions, increasing the flexibility of ADAMTS13 molecules.Electronic supplementary materialThe online version of this article (10.1186/s13036-018-0102-y) contains supplementary material, which is available to authorized users.

show abstract

“…Physiological balance of VWF levels is highly regulated through its expression, storage and release in one hand, and clearance on the other hand . If this balance is disturbed in favor of sustained increased levels of VWF, as in TTP, it leads to significant undesired thrombogenicity . The potential for VWF association with increased thrombogenicity is clearly consistent with its role as a mediator of platelet aggregate formation, which is the first and central step in thrombus formation .…”

Section: Introductionmentioning

confidence: 92%

Von Willebrand factor contribution to pathophysiology outside of von Willebrand disease

2018

View full text Add to dashboard Cite

VWF is a large multimeric glycoprotein that was identified through its association with an inherited bleeding disorder first described by physician, Erik von Willebrand in 1926. 1 Bleeding disorder associated with VWF is known as von Willebrand disease (VWD) and has been the leading influence in identification, characterization, and determination of function for VWF molecule. VWD, which has been the subject of many excellent reviews periodically, can be broadly classified into categories that represent qualitative (type II) or quantitative (type I and III) deficiencies of VWF. [2][3][4][5] In either case, VWF deficiency is the culprit leading to prolonged bleeding phenotype, some forms of which are reminiscent of hemophilia that arise as a result of coagulation factor VIII deficiency. 6,7 The phenotypic consequences of VWF deficiency were instrumental in early studies that established the major role of VWF in hemostasis. 8 The two major functions of VWF have been long established as: (a) mediator of platelet adhesion and aggregate formation at the site of vascular injury, leading to formation of platelet plugs to seal the damaged vessel wall and (b) functioning as carrier for factor VIII, thus prolonging its half-life in circulation. 8-10 Although severe deficiencies of VWF clearly correlated to significant bleeding disorders, milder deficiencies were also identified that manifested only as a result of hemostatic challenges, such as surgeries, or menorrhagia. 3,11,12 Wide variation in VWF levels among healthy population hinders diagnosis of mild VWD, but also made it difficult to appreciate potential pathological consequences of high levels of VWF. [13][14][15][16] Nevertheless, based on structural and functional characteristics of the VWF, a potential role for VWF in diseases associated with increased thrombogenicity was not unexpected. Several clinical studies had reported a correlation between elevated levels of VWF and prothrombotic diseases specifically in high-risk populations, including heart disease and stroke; however, direct evidence beyond associations was lacking. [17][18][19][20][21] Discovery of VWF cleaving enzyme, ADAMTS13, and demonstration of its dysfunction in TTP provided clear evidence that excessive VWF levels contribute to undesired thrombogenicity. [22][23][24] Physiological balance of VWF levels is highly regulated through its expression, storage and release in one hand, and clearance on the other hand. 25,26 If this balance is disturbed in favor of sustained increased levels of VWF, as in TTP, it leads to significant undesired thrombogenicity. 27 The potential for VWF association with increased thrombogenicity is clearly consistent with its role as a mediator of platelet aggregate formation, which is the first and central step in thrombus formation. 28 However, based on highly adhesive properties of VWF, its participation in other pathophysiological conditions, specifically those that involve cell adhesion to the vascular wall, has been considered.These include processes that participate...

show abstract

ADAMTS‐13 and von Willebrand factor: a dynamic duo

Cited by 70 publications

References 114 publications

The Eye as a Non-Invasive Window to the Microcirculation in Liver Cirrhosis: A Prospective Pilot Study

The Eye as a Non-Invasive Window to the Microcirculation in Liver Cirrhosis: A Prospective Pilot Study

AFM Imaging Reveals Multiple Conformational States of ADAMTS13

Von Willebrand factor contribution to pathophysiology outside of von Willebrand disease

Contact Info

Product

Resources

About