Gone With the Vane.

Abstract

HomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 39, No. 9Gone With the Vane Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBGone With the Vane Emily R. Legan and Renhao Li Emily R. LeganEmily R. Legan From the Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Emory University School of Medicine, GA. Search for more papers by this author and Renhao LiRenhao Li Correspondence to: Renhao Li, PhD, Department of Pediatrics, Emory University School of Medicine, 2015 Uppergate Dr NE, Room 440, Atlanta, GA 30322. Email E-mail Address: [email protected] From the Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Emory University School of Medicine, GA. Search for more papers by this author Originally published21 Aug 2019https://doi.org/10.1161/ATVBAHA.119.313110Arteriosclerosis, Thrombosis, and Vascular Biology. 2019;39:1702–1704This article is a commentary on the followingTurbulent Flow Promotes Cleavage of VWF (von Willebrand Factor) by ADAMTS13 (A Disintegrin and Metalloproteinase With a Thrombospondin Type-1 Motif, Member 13)Recent advances in mechanical circulatory support (MCS) devices and technology have provided life-saving treatment options for patients with advanced stage heart failure and other severe cardiac and respiratory complications. Some forms of MCS such as left ventricular assist devices (LVADs) provide long-term circulatory support to patients as a destination therapy option or as a temporary solution before heart transplantation. The Interagency Registry for Mechanically Assisted Circulatory Support estimates that 2500 patients receive MCS devices each year.1 The benefits of LVADs have been demonstrated, as marked by over 50% patient survival after 1 year with first-generation LVADs to >80% survival with more recent generations.1,2See accompanying article on page 1831Despite remarkable strides in mechanical assisted technologies, the use of LVADs and other MCS devices still poses serious associated complications including pump thrombosis, neurological dysfunctions, microbial infections, and bleeding. Secondary to cardiac complications, the most common cause for hospital readmission among patients within 30 days post-surgery is gastrointestinal bleeding and epistaxis.3 This is similar to the bleeding symptoms in patients with von Willebrand disease. Indeed, patients with LVADs and similar devices often exhibit a loss of ultralarge multimers of plasma GP (glycoprotein) VWF (von Willebrand factor) and, relatedly, a significant reduction of VWF activity. This bleeding complication has been termed acquired von Willebrand syndrome.4,5 Understanding the mechanism by which LVADs and other MCS devices cause the breakdown of VWF multimers and subsequent dysfunction will help improve the design of future MCS devices and will guide the use of appropriate drugs to inhibit the pathological process.VWF is a large, multimeric protein, the size and structure of which enables the protein to fulfill its key role in facilitating primary hemostasis by recruiting platelets to sites of vascular injury to stop bleeding.6,7 Among plasma proteins, VWF is unique in being highly responsive to shear flow. Under the current paradigm, VWF multimers circulate in a loosely coiled and mostly globular form and then elongate when exposed to shear force.8,9 Elongation of VWF exposes individual domains of the protein, including the A1 domain that binds platelet receptor GP Ibα and the A2 domain that contains the cryptic target site for enzymatic cleavage by the metalloprotease ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13). Tension-induced ligation of VWF with GP Ibα transmits a signal into the platelet that leads to platelet aggregation and clearance.10–12 Cleavage of VWF by ADAMTS13 not only releases adherent platelets from the site of tension but also shortens the VWF multimer and thus reduces its sensitivity to shear flow and reactivity.13,14Many studies have evaluated how VWF and its domains respond to force and vastly improved our understanding of this protein. In addition to single-molecule force spectroscopy,14 current methods to directly analyze the force responsiveness properties of VWF in flow are typically performed while VWF is immobilized.9,14,15 Laminar flow is the only flow regime modeled and investigated under these circumstances. However, clinical needs require that MCS devices use high-speed and high-volume delivery system that often includes other types of flow than laminar flow. Thus, there is a knowledge gap regarding the effects of turbulent and nonphysiological flow on VWF structure.In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Bortot et al16 took a critical first step to fill this important knowledge gap. The authors adapted a vane rheometer to generate tunable laminar, transitional, and turbulent flow. They applied it to whole blood and purified VWF and recombinant ADAMTS13 in solution and evaluated the distribution of VWF multimers. They determined that turbulent flow, not high shear stress alone, can induce ADAMTS13 cleavage of VWF, resulting in a loss of high-molecular-weight multimers. Consequently, the smaller multimers present after exposure to turbulence are less effective at adhering to platelets. The reduction in multimer size combined with reduced platelet binding is comparable to the presentation of type 2A von Willebrand disease (Figure). By presenting the evidence for the turbulent flow being a driving force to induce VWF cleavage in solution, this study provides a molecular basis for acquired von Willebrand syndrome and bleeding in patients after implantation of MCS devices. The authors showed that the vane rheometer can be a tunable system to evaluate VWF response to turbulence, and therapeutic intervention thereof in the future, thus expanding the availability to study additional flow regimes in a controlled manner.Download figureDownload PowerPointFigure. Turbulent flow results in rapid cleavage and size reduction of VWF (von Willebrand factor) multimers. Schematic of laminar and turbulent flow regimes exert differential forces on VWF multimers. The force exerted by the 2 regimes yield differences in the exposure of the cryptic ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) cleavage site in the A2 domain (open circles), resulting in 2 distinct multimer distribution profiles. Turbulent flow regime results in excessive loss in ultralarge VWF multimers, reminiscent of multimer distribution in type 2A von Willebrand disease. Derived from Bortot et al.16Interestingly, a loss of high-molecular-weight VWF multimers is readily observed after just a 10-minute treatment with turbulence in the vane rheometer, and the authors note that a similar loss in patients has been reported as quickly as 180 minutes post-implantation of LVADs. This observation suggests that ADAMTS13 cleavage of VWF in turbulent flow is quite efficient. Its kinetics is dependent on both the treatment time and a certain threshold of turbulence. It is noteworthy that after turbulence treatment in the vane rheometer, the size of VWF multimer is drastically reduced as if nearly all or 50% of the A2 domains in the multimer become unfolded and cleaved as a consequence. Does that mean that turbulent flow somehow exerts tensile force on a majority of the A2 domain in a multimer in solution, even a medium-sized multimer? This would be different from the regime of laminar flow, in which the tensile force is the strongest toward the middle of a multimer.14 Additionally, Bortot et al expertly note that transitional flow can alter dynamics of the A1 domain, which is consistent with recent studies that report enhanced force beyond elongation is required for A1-GP Ibα interaction15 and mechanisms of A1 inhibition by nearby modules.17–19 Overall, the vane rheometer system appears to be an exciting new system to interrogate VWF structure and “disappearance” under turbulent conditions. It may potentially be applied to other mechanosensitive preins in the context of cardiovascular disorders and pathologies.AcknowledgmentsE.R. Legan and R. Li wrote the paper.Sources of FundingThis work was supported, in part, by National Institutes of Health (NIH) grant HL143794. E.R. Legan is partly supported by an NIH training grant GM008367.DisclosuresNone.FootnotesFor Sources of Funding and Disclosures, see page 1703.Correspondence to: Renhao Li, PhD, Department of Pediatrics, Emory University School of Medicine, 2015 Uppergate Dr NE, Room 440, Atlanta, GA 30322. Email renhao.[email protected]edu