von Willebrand Factor as a Biological Sensor of Blood Flow to Monitor Percutaneous Aortic Valve Interventions

Abstract

Rationale: Percutaneous aortic valve procedures are a major breakthrough in the management of patients with aortic stenosis. Residual gradient and residual aortic regurgitation are major predictors of midterm and long-term outcome after percutaneous aortic valve procedures. We hypothesized that (1) induction/recovery of high molecular weight (HMW) multimers of von Willebrand factor defect could be instantaneous after acute changes in blood flow, (2) a bedside point-of-care assay (platelet function analyzer-closure time adenine DI-phosphate [PFA-CADP]), reflecting HMW multimers changes, could be used to monitor in real-time percutaneous aortic valve procedures. Objective: To investigate the time course of HMW multimers changes in models and patients with instantaneous induction/reversal of pathological high shear and its related bedside assessment. Methods and Results: We investigated the time course of the induction/recovery of HMW multimers defects under instantaneous changes in shear stress in an aortic stenosis rabbit model and in patients undergoing implantation of a continuous flow left ventricular assist device. We further investigated the recovery of HMW multimers and monitored these changes with PFA-CADP in aortic stenosis patients undergoing transcatheter aortic valve implantation or balloon valvuloplasty. Experiments in the aortic stenosis rabbit model and in left ventricular assist device patients demonstrated that induction/recovery of HMW multimers occurs within 5 minutes. Transcatheter aortic valve implantation patients experienced an acute decrease in shear stress and a recovery of HMW multimers within minutes of implantation which was sustained overtime. In patients with residual high shear or with residual aortic regurgitation, no recovery of HMW multimers was observed. PFA-CADP profiles mimicked HMW multimers recovery both in transcatheter aortic valve implantation patients without aortic regurgitation (correction) and transcatheter aortic valve implantation patients with aortic regurgitation or balloon valvuloplasty patients (no correction). Conclusions: These results demonstrate that variations in von Willebrand factor multimeric pattern are highly dynamic, occurring within minutes after changes in blood flow. It also demonstrates that PFA-CADP can evaluate in real time the results of transcatheter aortic valve procedures.

Von Willebrand factor multimer quantitation for assessment of cardiac lesion severity and bleeding risk

“…Several important implications of the consistent association of VWF abnormalities and high‐shear cardiac disorders have potential clinical utility. First, in situations in which assessment of cardiac lesion severity is difficult such as the use of intraprocedural PFA‐CADP for quantitation of post‐TAVR paravalvular regurgitation, allowing for procedural adjustment of TAVR 9. The PFA‐CADP cutoff of 140 seconds as identified by Van Belle et al.…”

“…However, there is no standardization of how to quantify VWF multimers. We have proposed the NMR schema, but it is not a new concept, having been reported by Weintsein12 and also in two recent analyses of van Belle and colleagues 5, 9. Some laboratories are not able to produce gels that clearly delineate gel bands greater than 10, limiting the usefulness of the proposed technique.…”

“…Additionally, VWF abnormalities have been described after valve replacement and repair and have been attributed to prosthetic valve dysfunction, perivalvular leak, patient prosthesis mismatch,5, 6, 7 and in the setting of mechanical support with left ventricular assist devices 8. More recently, abnormalities of VWF multimers have been identified in the absence of clinical bleeding and studies suggest that VWF multimers may provide utility as a biological assay for cardiac lesions in real‐time and chronic settings 9. Although this emerging data supports the use of VWF multimers for assessment of some cardiac lesions, a pooled cohort of various valvular and non‐valvular high‐shear cardiac states has not been described.…”

Von Willebrand factor revisited

“…The ratio of the highest multimers (usually >15 mers) is divided by bands 2‐15 of the patient's sample, which can be compared to the ratio observed for normal pooled plasma . This approach yields a value near 1.0 for normal plasma . A limitation of multimer analysis is that it is labor intensive and requires a high degree of expertise.…”

Von Willebrand factor multimers during transcatheter aortic valve replacement—an additional clue for detecting post-procedural aortic regurgitation?

“…The reasons for this growing interest lies not only in the potentially deleterious consequences of an AVWD related bleeding event-not every AVWD patient bleeds, and the bleeding is not always proportional to the severity of the defect-but also in the hypothesis, that as the loss and recovery of HMW multimers rapidly follows the changes in blood shear stress, its measurement can serve as a biological sensor of pathological blood flow in various clinical scenarios (19), such as ppAR following TAVR.…”