Acquired von Willebrand syndrome and factor VIII in patients with moderate to severe mitral regurgitation undergoing transcatheter mitral valve repair

The acquired von Willebrand syndrome (AvWS), which predisposes to bleeding events, is often related to valvular heart diseases. We investigated possible implications of AvWS and factor VIII levels in patients with moderate to severe mitral regurgitation (MR) undergoing transcatheter mitral valve repair (TMVR).


| INTRODUCTION
Von Willebrand factor (vWF) is produced in megakaryocytes and endothelial cells and functions as a large human adhesive glycoprotein. 1,2 Inherited von Willebrand Disease (vWD) represents the most common inherited bleeding disorder, which was first described by Erik von Willebrand in 1926. 3 In contrast to the inherited form, acquired von Willebrand syndrome (AvWS) is a rare disorder 4 with an estimated prevalence of 0.04%, although this figure might be underestimated. 5 AvWS is often associated with cardiovascular diseases especially congenital and valvular heart diseases. 6 AvWS is similar to inherited type 2A vWD showing decreased vWF-dependent platelet adhesion due to a loss of high-molecular-weight von Willebrand Factor multimers. 7 Heyde syndrome comprises the combination of AvWS, valvular heart disease and bleeding tendencyin particular gastrointestinal bleeding-8 as a result of an increased clearance of vWF related to shear-induced proteolysis of high-molecular-weight vWF multimers when passing the abnormal valve. 9,10 High-molecular-weight vWF multimer abnormalities have been reported in patients with different valvular diseases e.g. aortic and mitral valve stenosis as well as mitral valve regurgitation. 11 VWF deficiency can be completely reversed after aortic valve replacement therapy 12 thus, vWF has been proposed as a new hemodynamic biomarker for monitoring surgical or percutaneous aortic valve replacement procedures. [13][14][15] It has been reported that defects of high-molecular-weight vWF multimers were resolved within minutes during transcatheter aortic valve replacement (TAVR) but not after ballon valvuloplasty procedures. 16 Similarly, the presence of AvWS has been described in patients with moderate to severe mitral valve dysfunction. 1 Blackshear et al. investigated a population of 53 patients with mild to severe mitral regurgitation and reported that more severe mitral valve regurgitation was associated with progressive worsening of vWF activity and bleeding tendency. 17 Lower levels of high-molecular-weight vWF multimers were associated with poor prognosis concerning surgery-free survival. 17 In contrast to patients with aortic valve stenosis undergoing TAVR only little data exist regarding vWF function in patients with mitral valve regurgitation treated by transcatheter mitral valve repair (TMVR). We therefore investigated AvWS and factor VIII in a large cohort of patients with moderate to severe mitral regurgitation undergoing a transcatheter mitral valve repair.

| Study population
From August 2017 to May 2020 123 patients with symptomatic moderate to severe or severe mitral valve regurgitation were prospectively enrolled in our investigator initiated single-center RETORT-MR trial (Regensburg Trial on TMVR Techniques in Mitral Regurgitation). All patients gave informed consent before enrollment and the RETORT-MR trial was approved by the local ethics committee. No external funding was obtained to support the study. Comprehensive measurements of von Willebrand Factor activity (vWFAct), von Willebrand antigen (vWFAg), vWFAct/vWFAg ratio and factor VIII before and 4 weeks after the percutaneous mitral valve repair were available in 85 patients.
Clinical data were collected from all participants and serial blood and urine sampling was performed. In addition, transthoracic (TTE) and transesophageal (TOE) echocardiography was conducted. Special attention was paid to history of bleeding events and antiplatelet or anticoagulant medication. EuroScore II and logEuroScore were calculated to assess operative risk. 18 After discussion of every case in the interdisciplinary heart team 83 of the included patients underwent transcatheter mitral valve repair using the MitraClip NT, NTR, or XTR system, Abbott Vascular (Menlo Park, CA) and two patients received PASCAL devices, Edwards Lifesciences (Irvine, CA).

| Transcatheter mitral valve repair
Technical aspects of the MitraClip 19 and PASCAL 20 procedure have been described previously.
All patients were under general anesthesia during the procedure and both fluoroscopic and transesophageal echocardiographic guidance were used for percutaneous mitral valve repair. During the procedures, one to three MitraClips and one or two PASCAL devices were implanted in order to achieve a significant reduction of mitral regurgitation. Heparin was administered for periprocedural anticoagulation. After percutaneous mitral valve repair patients received dual antiplatelet therapy consisting of aspirin and clopidogrel for 4 weeks, followed by aspirin administration for 6 months. In case patients had already been treated with oral anticoagulants, aspirin or clopidogrel was added for 1 month.

| Clinical follow-up
Clinical assessment including bleeding history, standardized echocardiographic parameters and serial blood and urine sampling was performed 24 hours before and 4 weeks after percutaneous mitral valve repair. In addition, six-minute walk tests and the EQ-5D-5L questionnaire were performed to investigate patients' physical and mental status.
Two-dimensional transthoracic echocardiography was conducted using the iE-33 ultrasound system with a S5-1 transducer (Philips Medical Systems, Amsterdam, The Netherlands) or the EPIQ CVx ultrasound system with a X5-1 transducer (Philips Medical Systems, Amsterdam, The Netherlands). The quantification of mitral regurgitation was in accordance with the Endovascular Valve Edge-to-Edge Repair Study (EVEREST) criteria. 21

| Statistical analysis
Statistical analysis was performed with SPSS Version 25 (International Business Machines Corporation, IBM, Armonk, NY USA). Data are presented as absolute and relative frequencies or as means ± standard deviations. Differences between continuous variables in paired data were tested with a paired t-test, continuous variables in unpaired data were compared with an unpaired t-test. Analysis of variance was used to compare continuous variables between more than two independent groups. For evaluating differences in unpaired data adjusted for covariates, analysis of covariance was performed. A p-value of <0.05 was considered statistically significant.
The frequency of gastrointestinal bleeding at baseline was 8.2% (n = 7). Two in-hospital bleedings ( Table 2) occurred (2.4%) and at 4 weeks follow-up another bleeding (1.2%) was reported (Table 3). It is noteworthy that the patient suffering from the in-hospital bleeding already had had a history of gastrointestinal bleeding at baseline. Concerning medication this patient was treated with aspirin but with no oral anticoagulant. The documented bleeding case 4 weeks after the MitraClip procedure occurred under dual antiplatelet therapy with aspirin and clopidogrel. Antiplatelet and oral anticoagulation medication is depicted in detail in Table S1 in the supporting information.  By stratifying the cohort into low and high post mitral valve gradients (≥4 mmHg versus <4 mmHg), no significant results were found between the groups at baseline and 4 weeks follow-up (Table S3).
Further, we analyzed the values of vWFAct/vWFAg, vWFAg, vWFAct and Factor VIII at baseline and 4 weeks follow-up with mild residual MR and low post MV gradient (Table S4). Again, no significant results were detected in those groups. This means that the lacking decrease of the analyzed parameters cannot sufficiently be explained by a sustained high transvalvular shear stress, which could be caused either by a TMVR-induced increase of the MV gradient, or a residual mitral regurgitation.  In patients with severe aortic valve stenosis undergoing transcatheter aortic valve replacement (TAVR) an acute recovery of HMWM-vWF levels was observed within a few minutes after successful TAVR. 16

| Limitations
Some limitations of the present study warrant consideration: Our trial was performed at an experienced academic institution, which means that our results might not completely be transferable to less trained centers. Finally, due to the limited number of bleeding events in our study, we were not able to estimate the effect of percutaneous mitral valve repair on an overall bleeding diathesis. We demonstrated significant differences in the values of vWFAct/Ag ratio in respect of degenerative and functional MR as well of elevated postprocedural gradients. In order to investigate the underlying pathophysiological mechanisms like shear stress further experimental studies would be needed.

| CONCLUSION
In this largest investigation of AvWS in patients with mitral regurgitation so far, performing TMVR did not alter vWF levels or vWF activity 4 weeks after the procedure. MR of primary etiology was associated with lower vWFAct/vWFAg ratio, hinting toward HMWM loss due to shear stress caused by eccentric regurgitation jets. In addition, postprocedural transmitral gradient ≥4 mmHg was related to lower vWFAct/vWFAg ratio 4 weeks after the procedure. Bleeding events in the short-term after TMVR were rare despite high perioperative risk, confirming the superior safety profile of percutaneous mitral valve repair.