Von Willebrand Factor As a Biological Sensor of Blood Flow in Percutaneous Cardiac Procedures

Background:

Acquired deficiency of von Willebrand Factor (VWF) characterized by a quantitative loss of high molecular weight (HMW) multimers of VWF is associated with cardiovascular disorders such as aortic stenosis. It has been shown that HMW-multimers defect is usually corrected after surgical aortic valve replacement. However, the initial time course of loss/recovery of VWF HMW-multimers following acute changes in blood flow in-vivo has not yet been studied. We hypothesized that recovery of HMW-multimers could occur within minutes following correction of the underlying "high shear" condition and as such could be used to monitor acute changes in flow induced by cardiac interventions. We further investigated the potential underlying mechanisms.

Methods:

We investigated the time course of HMW-multimers loss/recovery in an animal model of instantaneous and reversible aortic stenosis (AS) specifically developed for that purpose. This model allowed the evaluation, in the same rabbit, of the dynamic time course of loss and recovery of HMW-multimers. We further investigated the time course of HMW-multimers loss/recovery and its related bedside whole blood assessment (PFA-100 analyzer) in 28 patients included in the WITAVI (Willebrand-TAVI) registry and undergoing 1) implantation of an axial-continuous-flow-LVAD (HeartMate-IIÒ, n=8) and 2) transcatheter aortic valve procedures, either BAV (n=10) or TAVI (n=10). VWF antigen (VWF:Ag) and VWF propeptide (VWFpp) levels were measured by ELISA. VWF multimeric analysis was performed as previously described in patients and newly developed for rabbits. PFA-CADP was assessed by platelet-function analyzer PFA-100® using ADP cartridges.

Results:

In the rabbit model, induction of aortic stenosis was associated with a HMW-multimers defect (normalized ratio = 0.74±0.07; p<0.01 versus no stenosis). Partial recovery of HMW-multimers (0.89±0.12 versus AS baseline; p<0.01) occurred within 5 minutes of stenosis reversion. Thirty minutes after reversion, a complete recovery of HMW-multimers was observed (0.98±0.10). In patients with AS (n=18) a VWF HMW-multimers defect was observed at baseline (0.50±0.18). Among patients with AS, those treated with TAVI experienced an acute decrease in shear stress (4.47±0.41 m.s-1 to 1.81±0.43 m.s^-1, p<0.0001, n=10) after treatment while those undergoing BAV alone experienced a modest improvement in shear stress conditions (4.47±0.25m.s-1 to 3.88±0.65m.s-1; p=0.03, n=8). In patients undergoing TAVI (n=10), similar to what was observed in the rabbit model, recovery of HMW-multimers defect was observed within minutes of valve implantation (p<0.001, Table1). By contrast, in patients undergoing BAV (n=8) no recovery of HMW-multimers defect was observed (p=0.21,Table1). A potential role of the vascular endothelium in the HMW-multimers recovery was also evaluated by measuring the VWFpp levels during TAVI and BAV procedures. In TAVI procedures, VWFppsignificantly increased 5 minutes after valve implantation, and further after 30 and 180 minutes when compared to baseline. In BAV procedures, VWFpp did not increase significantly overtime.

The time course of PFA-CADP time mimicked the recovery of HMW-multimers defect both in TAVI in patients, in whom a rapid correction of PFA-CADP was observed (p<0.001, Table1), and BAV patients, in whom no correction was observed (p=0.69;Table1). Results are expressed as mean±SD, p values are for overall time course comparison (repeated Anova).

Conclusion:

These results demonstrate that variations in the multimeric pattern of VWF are highly dynamic, occurring within minutes of changes in shear stress status. They further demonstrate that VWF multimeric pattern changes could be used in clinical practice as a tool to monitor the quality of the result of percutaneous aortic valve procedures procedures using a bedside analyzer.