Von Willebrand factor in patients on mechanical circulatory support – a double-edged sword between bleeding and thrombosis

Acquired von Willebrand syndrome occurs in the setting of mechanical circulatory support from device-associated sheer stress, which changes the quaternary structure of high-molecular-weight von Willebrand factor multimers, exposing the cleavage site for ADAMTS-13. Once cleaved, lower-molecular-weight multimers lose their affinity for binding platelets, increasing the susceptibility to bleeding complications. Acquired von Willebrand syndrome has been described in all the currently approved continuous-flow mechanical circulatory support devices. Although theoretically the risk of von Willebrand factor multimer degradation is increased at the higher rotational speeds of axial-flow pumps, disease severity does not differ greatly between axial- and centrifugal-flow devices. Disease-specific therapies for acquired von Willebrand syndrome have not been well studied in patients supported by mechanical circulatory devices. Case reports and case series have noted beneficial effects from octreotide, doxycycline, desmopressin, or Humate-P treatment for patients with recurrent severe bleeding.

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Insights into the mechanism(s) of von Willebrand factor degradation during mechanical circulatory support

Journal of Thoracic and Cardiovascular Surgery ◽

10.1016/j.jtcvs.2013.08.043 ◽

2014 ◽

Vol 147 (5) ◽

pp. 1634-1643 ◽

Cited By ~ 19

Author(s):

Carlo R. Bartoli ◽

Sujith Dassanayaka ◽

Kenneth R. Brittian ◽

Andrew Luckett ◽

Srinivas Sithu ◽

...

Keyword(s):

Von Willebrand Factor ◽

Mechanical Circulatory Support ◽

Circulatory Support ◽

Von Willebrand ◽

Willebrand Factor

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Diagnosis and Management of Acquired von Willebrand Disease in Heart Disease: A Review of the Literature

The Thoracic and Cardiovascular Surgeon ◽

10.1055/s-0038-1673670 ◽

2018 ◽

Vol 68 (03) ◽

pp. 200-211

Author(s):

Mate Petricevic ◽

Jadranka Knezevic ◽

Gordan Samoukovic ◽

Bozena Bradaric ◽

Ivica Safradin ◽

...

Keyword(s):

Heart Disease ◽

Von Willebrand Factor ◽

Structural Heart Disease ◽

Von Willebrand Disease ◽

Circulatory Support ◽

Mechanical Destruction ◽

Acquired Von Willebrand Syndrome ◽

Acquired Von Willebrand Disease ◽

Von Willebrand ◽

Willebrand Factor

AbstractThe incidence of acquired von Willebrand syndrome (AvWS) in patients with heart disease is commonly perceived as rare. However, its occurrence is underestimated and underdiagnosed, potentially leading to inadequate treatment resulting in increased morbidity and mortality.In patients with cardiac disease, AvWS frequently occurs in patients with structural heart disease and in those undergoing mechanical circulatory support (MCS).The clinical manifestation of an AvWS is usually characterized by apparent or occult gastrointestinal (GI) or mucocutaneous hemorrhage frequently accompanied by signs of anemia and/or increased bleeding during surgical procedures. The primary change is loss of high-molecular weight von Willebrand factor multimers (HMWM). Whereas the loss of HMWM in patients with structural heart disease is caused by increased HMWM cleavage by von Willebrand factor (vWF)-cleaving protease, ADAMTS13, AvWS in MCS patients is predominantly a result of a high shear stress coupled with mechanical destruction of vWF itself.This manuscript provides a comprehensive review of the evidence regarding both diagnosis and contemporary management of AVWS in patients with heart disease.

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Mechanical Forces Impacting Cleavage of Von Willebrand Factor in Laminar and Turbulent Blood Flow

Fluids ◽

10.3390/fluids6020067 ◽

2021 ◽

Vol 6 (2) ◽

pp. 67

Author(s):

Alireza Sharifi ◽

David Bark

Keyword(s):

Blood Flow ◽

Shear Stress ◽

Von Willebrand Factor ◽

Circulatory Support ◽

Acquired Von Willebrand Syndrome ◽

Tensile Forces ◽

Constant Shear Stress ◽

Valve Diseases ◽

Von Willebrand ◽

Willebrand Factor

Von Willebrand factor (VWF) is a large multimeric hemostatic protein. VWF is critical in arresting platelets in regions of high shear stress found in blood circulation. Excessive cleavage of VWF that leads to reduced VWF multimer size in plasma can cause acquired von Willebrand syndrome, which is a bleeding disorder found in some heart valve diseases and in patients receiving mechanical circulatory support. It has been proposed that hemodynamics (blood flow) found in these environments ultimately leads to VWF cleavage. In the context of experiments reported in the literature, scission theory, developed for polymers, is applied here to provide insight into flow that can produce strong extensional forces on VWF that leads to domain unfolding and exposure of a cryptic site for cleavage through a metalloproteinase. Based on theoretical tensile forces, laminar flow only enables VWF cleavage when shear rate is large enough (>2800 s−1) or when VWF is exposed to constant shear stress for nonphysiological exposure times (>20 min). Predicted forces increase in turbulence, increasing the chance for VWF cleavage. These findings can be used when designing blood-contacting medical devices by providing hemodynamic limits to these devices that can otherwise lead to acquired von Willebrand syndrome.

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Hemolysis and von Willebrand factor degradation in mechanical shuttle shear flow tester

Journal of Artificial Organs ◽

10.1007/s10047-020-01219-3 ◽

2021 ◽

Author(s):

Yasuyuki Shiraishi ◽

Yuma Tachizaki ◽

Yusuke Inoue ◽

Masaki Hayakawa ◽

Akihiro Yamada ◽

...

Keyword(s):

Shear Stress ◽

Shear Flow ◽

Von Willebrand Factor ◽

Exposure Time ◽

Ventricular Assist Devices ◽

Circulatory Support ◽

Shear Stresses ◽

Ventricular Assist ◽

Von Willebrand ◽

Willebrand Factor

AbstractChronic blood trauma caused by the shear stresses generated by mechanical circulatory support (MCS) systems is one of the major concerns to be considered during the development of ventricular assist devices. Large multimers with high-molecular-weight von Willebrand factor (VWF) are extended by the fluid forces in a shear flow and are cleaved by ADAMTS13. Since the mechanical revolving motions in artificial MCSs induce cleavage in large VWF multimers, nonsurgical bleeding associated with the MCS is likely to occur after mechanical hemodynamic support. In this study, the shear stress (~ 600 Pa) and exposure time related to hemolysis and VWF degradation were investigated using a newly designed mechanical shuttle shear flow tester. The device consisted of a pair of cylinders facing the test section of a small-sized pipe; both the cylinders were connected to composite mechanical heads with a sliding-sleeve structure for axial separation during the withdrawing motion. The influence of exposure time, in terms of the number of stress cycles, on hemolysis and VWF degradation was confirmed using fresh goat blood, and the differences in the rates of dissipation of the multimers were established. The plasma-free hemoglobin levels showed a logarithmic increase corresponding to the number of cycles, and the dissipation of large VWF multimers occurred within a few seconds under high shear stress flow conditions.

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The influence of surface roughness on the damage of von Willebrand Factor under shear flow condition

The International Journal of Artificial Organs ◽

10.1177/03913988211056961 ◽

2021 ◽

pp. 039139882110569

Author(s):

Xu Mei ◽

Bin Lu ◽

Min Zhong ◽

Yuxin Zhu ◽

Liudi Zhang ◽

...

Keyword(s):

Molecular Weight ◽

Surface Roughness ◽

Flow Condition ◽

Mechanical Circulatory Support ◽

Circulatory Support ◽

Blood Damage ◽

Mechanical Circulatory Support Devices ◽

Von Willebrand ◽

Willebrand Factor ◽

Support Devices

Despite technological advances in mechanical circulatory support devices to treat end-stage heart failure, blood damage induced by non-physiological shear stress in operation often triggered clinical hemocompatibility complications. The loss of high molecular weight von Willebrand Factor (HMW-VWF) has been considered as an essential cause of gastrointestinal bleeding. In addition to the mechanics factors, interface factors may also affect blood damage, especially the surface characteristics. In this study, the effect of surface roughness on VWF damage under flow condition was investigated. A roller pump circulation experimental platform with a roughness embedded sample chamber was constructed to provide blood shearing flow condition. VWF molecular weight analysis, VWF antigen (VWF-Ag) concentration assay, and VWF ristocetin cofactor activity (VWF-Rico) assay were performed on the sheared blood samples. These variables are the main functional indicators of VWF. It was found that the surface roughness induced VWF damage is mainly caused by the loss of HMW-VWF rather than reducing the total amount of VWF. The threshold value of surface roughness for a rapid increase in the degradation of HMW-VWF under low flow rate was obtained between Ra 0.4 and 0.6 μm, which was smaller than the threshold for hemolysis. Our findings indicated that VWF is more sensitive to the interface factor of surface roughness than red blood cells, thus has a higher requirement for blood pump design. It could provide reference for the material design and processing in developing mechanical circulatory support devices.

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