Inhibition of ADAMTS-13 by Doxycycline Reduces von Willebrand Factor Degradation During Supraphysiological Shear Stress

Bartoli, Carlo; Kang, Jooeun; Restle, David; Zhang, David M.; Shabahang, Cameron; Acker, Michael A.; Atluri, Pavan

doi:10.1016/j.jchf.2015.06.016

Cited by 67 publications

(41 citation statements)

References 44 publications

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“…76 vWF multimer densitometry and platelet function assays were measured prior to doxycycline initiation, at day 7, on completion of therapy, and 7 days after therapy completion. In contrast to the previous analysis, 74 this study was not able to replicate the findings seen in ex vivo modeling. The results of this analysis further support the need for further investigation using doses reflecting those used in ex vivo modeling.…”

Section: Target: Acquired Von Willebrand Diseasecontrasting

confidence: 99%

Pharmacotherapeutic Management of Gastrointestinal Bleeding in Patients with Continuous‐Flow Left Ventricular Assist Devices

et al. 2017

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Continuous-flow left ventricular assist devices (CF-LVADs) have become an integral component of the management in patients with advanced heart failure, serving as destination therapy or as a bridge to heart transplantation. Despite significant advances in the design and longevity of the device, the ongoing risk for bleeding remains a significant concern. The genesis of gastrointestinal bleeding (GIB) in patients with CF-LVADs is likely multifactorial and may include components of acquired von Willebrand disease, angiodysplasia, and gastrointestinal arteriovenous malformations, as well as additional risk factors such as history of GIB and increased age. Several pharmacotherapy options have been used, but the data surrounding their overall efficacy remain sparse. The necessity for larger prospective studies is essential to further advance the management of this devastating complication. Within this review, we discuss the known pathophysiologic process of CF-LVAD-related GIB and highlight the therapeutic options discussed within the literature. In addition, we discuss potential therapeutic options based on mechanisms of action as they correlate to known pathophysiologic processes of CF-LVAD-related GIB. Finally, we provide recommendations for constructing drug therapy regimens in patients with CF-LVADs who develop GIB.

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Section: Target: Acquired Von Willebrand Diseasecontrasting

confidence: 99%

Pharmacotherapeutic Management of Gastrointestinal Bleeding in Patients with Continuous‐Flow Left Ventricular Assist Devices

et al. 2017

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“…Acquired von Willebrand syndrome (AvWS) has been reported in patients with continuous flow left ventricular assist devices (cf‐LVADs) , prosthetic blood contacting devices , and severe aortic stenosis . It is known that high shear stress and/or long exposure time causes loss of high molecular weight multimers HMWM) of von Willebrand factor vWF) resulting in poor binding to platelets and subendothelial collagen .…”

mentioning

confidence: 99%

Stress and Exposure Time on von Willebrand Factor Degradation

Jhun

Siedlecki

et al. 2018

Artificial Organs

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Despite the prevailing use of the continuous flow left ventricular assist devices (cf-LVADs), acquired von Willebrand syndrome (AvWS) associated with cf-LVADs still remains a major complication. As AvWS is known to be dependent on shear stress ( ) and exposure time (t exp ), this study examined the degradation of high molecular weight multimers (HMWM) of von Willebrand factor (vWF) in terms of τ and t exp . Two custom apparatus, i.e., capillary-tubing-type degrader (CTD) and Taylor-Couettetype degrader (TCD) were developed for short-term (0.033 sec ≤ t exp ≤ 1.05 s) and long-term (10 s ≤ t exp ≤ 10 min) shear exposures of vWF, respectively. Flow conditions indexed by Reynolds number (Re) for CTD were 14 ≤ Re ≤ 288 with corresponding laminar stress level of 52 ≤ CTD ≤ 1042 dyne/ cm 2 . Flow conditions for TCD were 100 ≤ Re ≤ 2500 with corresponding rotor speed of 180 ≤ ω o ≤ 4000 RPM and laminar stress level of 50 ≤ TCD ≤ 1114 dyne/cm 2 . Due to transitional and turbulent flows in TCD at Re > 1117, total stress (i.e., total = laminar + turbulent) was also calculated using a computational fluid dynamics (CFD) solver, Converge CFD. Inhibition of ADAMTS13 with different concentrations of EDTA (5 mM and 10 mM) was also performed to investigate the mechanism of cleavage in terms of mechanical and enzymatic aspects. Degradation of HMWM with CTD was negligible at all given testing conditions. Although no degradation of HMWM was observed with TCD at Re < 1117 ( total = 1012 dyne/cm 2 ), an increase in degradation of HMWM was observed beyond Re of 1117 for all given exposure times. At Re ~ 2500 ( total = 3070 dyne/ cm 2 ) with t exp = 60 s, a severe degradation of HMWM (90.7 ± 3.8%, abnormal) was observed, and almost complete degradation of HMWM (96.1 ± 1.9%, abnormal) was observed with t exp = 600 s. The inhibition studies with 5 mM EDTA at Re ~ 2500 showed that loss of HMWM was negligible (<10%, normal) for all given exposure times except for t exp = 10 min (39.5 ± 22.3%, borderline-abnormal).

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“…Doxycycline, a known inhibitor of ADAMTS13, has been proposed as a potential solution for VWF degradation due to high shear stress seen with LVAD. Bartoli et al noted that supplementation with doxycyline significantly decreased VWF degradation and improved VWF function. Further studies are needed to assess if doxycycline results in clinically improved bleeding in LVAD patients.…”

Section: Vwf and Lvadmentioning

confidence: 99%

Von Willebrand factor revisited

Yasar

Abdullah

Fay

et al. 2017

J Interven Cardiology

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Degenerative aortic valve stenosis is the most common valvular heart disease seen in developed countries. Since the implementation of transcatheter aortic valve replacement, there has been a surge of efforts to improve procedural technique as well as reduce mortality. Until recently, the mainstay method of assessment of valve implantation as well as paravalvular regurgitation has relied heavily on imaging techniques including transesophageal echocardiography and aortic root angiography. There has been a lot of scientific inquiry to identify biomarkers in the management of patients with aortic stenosis. von Willebrand factor activity and high molecular weight multimer level assessment has emerged as an excellent biomarker with intraoperative, point of care potential. These implications can both supplement imaging modalities as well as potentially serve as a more accurate assessment TAVR complications.

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Inhibition of ADAMTS-13 by Doxycycline Reduces von Willebrand Factor Degradation During Supraphysiological Shear Stress

Cited by 67 publications

References 44 publications

Pharmacotherapeutic Management of Gastrointestinal Bleeding in Patients with Continuous‐Flow Left Ventricular Assist Devices

Pharmacotherapeutic Management of Gastrointestinal Bleeding in Patients with Continuous‐Flow Left Ventricular Assist Devices

Stress and Exposure Time on von Willebrand Factor Degradation

Von Willebrand factor revisited

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