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

Fluids ◽  
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.

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

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.

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

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.

Acquired von Willebrand Syndrome with Mechanical Circulatory Support

2019 ◽  
pp. 269-276
Author(s):  
Evan C. Klein ◽  
Lisa Baumann Kreuziger
Keyword(s):  
Molecular Weight ◽  
Von Willebrand Factor ◽  
Mechanical Circulatory Support ◽  
Axial Flow ◽  
Circulatory Support ◽  
Severe Bleeding ◽  
Acquired Von Willebrand Syndrome ◽  
Mechanical Circulatory Support Devices ◽  
Von Willebrand ◽  
Willebrand Factor

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.

Porcine von Willebrand Factor Binding to Human Platelet GPIb Induces Transmembrane Calcium Influx

1996 ◽  
Vol 75 (04) ◽  
pp. 655-660 ◽  
Author(s):  
Mario Mazzucato ◽  
Luigi De Marco ◽  
Paola Pradella ◽  
Adriana Masotti ◽  
Francesco I Pareti
Keyword(s):  
Monoclonal Antibody ◽  
Shear Stress ◽  
Platelet Aggregation ◽  
Von Willebrand Factor ◽  
Human Platelet ◽  
Platelet Glycoprotein ◽  
Dependent Manner ◽  
Transmembrane Flux ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryPorcine von Willebrand factor (P-vWF) binds to human platelet glycoprotein (GP) lb and, upon stirring (1500 rpm/min) at 37° C, induces, in a dose-dependent manner, a transmembrane flux of Ca2+ ions and platelet aggregation with an increase in their intracellular concentration. The inhibition of P-vWF binding to GP lb, obtained with anti GP lb monoclonal antibody (LJ-Ib1), inhibits the increase of intracellular Ca2+ concentration ([Ca2+]i) and platelet aggregation. This effect is not observed with LJ-Ib10, an anti GP lb monoclonal antibody which does not inhibit the vWF binding to GP lb. An anti GP Ilb-IIIa monoclonal antibody (LJ-CP8) shown to inhibit the binding of both vWF and fibrinogen to the GP IIb-IIIa complex, had only a slight effect on the [Ca2+]i rise elicited by the addition of P-vWF. No inhibition was also observed with a different anti GP IIb-IIIa monoclonal antibody (LJ-P5), shown to block the binding of vWF and not that of fibrinogen to the GP IIb-IIIa complex. PGE1, apyrase and indomethacin show a minimal effect on [Ca2+]i rise, while EGTA completely blocks it. The GP lb occupancy by recombinant vWF fragment rvWF445-733 completely inhibits the increase of [Ca2+]i and large aggregates formation. Our results suggest that, in analogy to what is seen with human vWF under high shear stress, the binding of P-vWF to platelet GP lb, at low shear stress and through the formation of aggregates of an appropriate size, induces a transmembrane flux of Ca2+, independently from platelet cyclooxy-genase metabolism, perhaps through a receptor dependent calcium channel. The increase in [Ca2+]i may act as an intracellular message and cause the activation of the GP IIb-IIIa complex.

scholarly journals Platelet Aggregation Induced by a Monoclonal Antibody to the A1 Domain of von Willebrand Factor

Blood ◽  
1998 ◽  
Vol 91 (10) ◽  
pp. 3792-3799 ◽  
Author(s):  
Hilde Depraetere ◽  
Nadine Ajzenberg ◽  
Jean-Pierre Girma ◽  
Catherine Lacombe ◽  
Dominique Meyer ◽  
...  
Keyword(s):  
Shear Stress ◽  
Platelet Aggregation ◽  
Von Willebrand Factor ◽  
Inhibitory Effect ◽  
Platelet Glycoprotein ◽  
Rotational Viscometer ◽  
Induce Platelet Aggregation ◽  
Static Conditions ◽  
Von Willebrand ◽  
Willebrand Factor

Shear-induced platelet aggregation (SIPA) involves von Willebrand Factor (vWF) binding to platelet glycoprotein (GP)Ib at high shear stress, followed by the activation of αIIbβ3. The purpose of this study was to determine the vWF sequences involved in SIPA by using monoclonal antibodies (MoAbs) to vWF known to interfere with its binding to GPIb and to αIIbβ3. Washed platelets were exposed to shear rates between 100 and 4,000 seconds−1 in a rotational viscometer. SIPA was quantitated by flow cytometry as the disappearance of single platelets (DSP) in the sheared sample in the presence of vWF, relative to a control in the absence of shear and vWF. At a shear rate of 4,000 seconds−1, DSP was increased from 5.9% ± 3.5% in the absence of vWF to 32.7% ± 6.3% in the presence of vWF. This increase in SIPA was not associated with an elevation of P-selectin expression. vWF-dependent SIPA was completely abolished by MoAb 6D1 to GPIb and partially inhibited by MoAb 10E5 to αIIbβ3. Three MoAbs to vWF were compared for their effect on SIPA at 4,000 seconds−1 in the presence of vWF: MoAb 328, known to block vWF binding to GPIb in the presence of ristocetin, MoAb 724 blocking vWF binding to GPIb in the presence of botrocetin, and MoAb 9, an inhibitor of vWF binding to αIIbβ3. Similar to the effect of MoAb 6D1, MoAb 328 completely inhibited the effect of vWF, whereas MoAb 9 had a partial inhibitory effect, as MoAb 10E5 did. In contrast, MoAb 724, as well as its F(ab′)2 fragments, promoted shear-dependent platelet aggregation (165% of the DSP value obtained in the absence of MoAb 724), indicating that MoAb 724 was responsible for an enhanced aggregation, which was independent of binding to the platelet Fcγ receptor. In addition, the enhancement of aggregation induced by MoAb 724 was abrogated by MoAb 6D1 or 10E5 to the level of SIPA obtained in the presence of vWF incubated with a control MoAb to vWF. Finally, the activating effect of MoAb 724 was also found under static conditions at ristocetin concentrations too low to induce platelet aggregation. Our results suggested that on binding to a botrocetin-binding site on vWF, MoAb 724 mimics the effect of botrocetin by inducing an active conformation of vWF that is more sensitive to shear stress or to low ristocetin concentration.

scholarly journals Clinical Significance of Inhibitors in Acquired von Willebrand Syndrome

Blood ◽  
1998 ◽  
Vol 91 (10) ◽  
pp. 3623-3629 ◽  
Author(s):  
Hiroshi Mohri ◽  
Shigeki Motomura ◽  
Heiwa Kanamori ◽  
Michio Matsuzaki ◽  
Shin-ichiro Watanabe ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Immunoglobulin Therapy ◽  
High Dose ◽  
Severe Bleeding ◽  
Bleeding Tendency ◽  
Intravenous Immunoglobulin Therapy ◽  
Acquired Von Willebrand Syndrome ◽  
Underlying Diseases ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Of 260 patients enrolled, 25 patients (9.6%) were associated with acquired von Willebrand syndrome (AvWS). We studied 25 patients with AvWS, retrospectively. AvWS was diagnosed by reduced levels of von Willebrand factor (vWF) (decrease of von Willebrand factor antigen [vWF:Ag] and von Willebrand ristocetin cofactor [vWF:RCoF]), a decrease of ristocetin-induced platelet agglutination (RIPA), sometimes decreased high-molecular-weight multimers, and prolonged bleeding time with neither prior nor family histories of bleeding problems and the evidence of normal vWF:RCoF in their families. The inhibitor of vWF was determined by mixing patient plasma with pooled normal plasma. Eight patients in this study had the inhibitors to vWF that were of the IgG class; the subclasses were IgG1 (7 cases) and IgG2 (1 case). Multimeric analysis of vWF showed selective loss of large multimers in most patients with AvWS similar to that of congenital type-2 von Willebrand disease (vWD). All inhibitors blocked ristocetin-mediated vWF binding to platelets. Five out of 6 IgGs evaluated here recognized the 39/34-kD fragment (residues 480/481-718) and Fragment III (residues 1-1365) that implied binding domain of glycoprotein Ib (GPIb), whereas 1 recognized Fragment I (residues 911-1365). A close relationship was found between the presence of the inhibitor and bleeding tendency. Of the 7 patients with inhibitors, 6 patients (86%) had a bleeding tendency, as well as 1 of the 15 patients without inhibitors (6%). The efficacy of treatment of underlying diseases and/or therapy with deamino D-arginine vasopressin (DDAVP) for the treatment of AvWS also depends on the presence of an inhibitor. Four of 8 patients with inhibitors (50%) had poor response to treatment of the underlying disease and/or therapy with DDAVP, as well as 1 of the 16 patients without inhibitors (6%). These results indicate that patients with AvWS developing inhibitors to vWF are likely to have bleeding problems and might be resistant to treatment of underlying diseases and/or therapy with DDAVP for bleeding to AvWS. We also showed evidence that intravenous immunoglobulin therapy (0.3 g/kg, 3 days) was effective to correct a hemostatic defect and manage severe bleeding in a patient with AvWS developing inhibitors. We might consider an additional treatment including expensive high-dose immunoglobulin therapy when uncontrollable bleeding is continued after the treatment of the underlying diseases and/or therapy with DDAVP.

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