Acquired von Willebrand syndrome associated with left ventricular assist device

Abstract

Left ventricular assist devices (LVAD) provide cardiac support for patients with end-stage heart disease as either bridge or destination therapy, and have significantly improved the survival of these patients. Whereas earlier models were designed to mimic the human heart by producing a pulsatile flow in parallel with the patient's heart, newer devices, which are smaller and more durable, provide continuous blood flow along an axial path using an internal rotor in the blood. However, device-related hemostatic complications remain common and have negatively affected patients' recovery and quality of life. In most patients, the von Willebrand factor (VWF) rapidly loses large multimers and binds poorly to platelets and subendothelial collagen upon LVAD implantation, leading to the term acquired von Willebrand syndrome (AVWS). These changes in VWF structure and adhesive activity recover quickly upon LVAD explantation and are not observed in patients with heart transplant. The VWF defects are believed to be caused by excessive cleavage of large VWF multimers by the metalloprotease ADAMTS-13 in an LVAD-driven circulation. However, evidence that this mechanism could be the primary cause for the loss of large VWF multimers and LVAD-associated bleeding remains circumstantial. This review discusses changes in VWF reactivity found in patients on LVAD support. It specifically focuses on impacts of LVAD-related mechanical stress on VWF structural stability and adhesive reactivity in exploring multiple causes of AVWS and LVAD-associated hemostatic complications.

Figure 1

Schematic illustration of an implanted continuous-flow HeartMate2 LVAD (with permission from Thoratec Corporation).

Figure 2

VWF domain structure and potential lateral association. (A) VWF domain structure. ProVWF forms disulfide-linked dimers (B) that further multimerize covalently to multimers in the Golgi (C). These multimers are packaged in the storage granule Weibel-Palade body of endothelial cells (D), where the multimerization process is likely to continue, but factors that regulate its rate and termination remain largely unknown. The stored VWF multimers are released from endothelial cells that are activated by inflammatory stimuli. These newly released VWF multimers form fibrillary meshes that capture platelets (E) and are proteolytically released from the surface of endothelial cells by ADAMTS-13 (F).

Figure 3

Shear-induced platelet activation. Platelets in diluted PRP or whole blood subjected to fluid shear in a cone-plate viscometer abruptly undergo activation above a critical wall shear stress of 8-10 Pa (arrow). Inset shows that this activation is a strong function of the mechanical force applied on the platelet GP Ibα by the VWF that is bound to it. Here, doubling media viscosity more than doubles the extent of cell activation (adapted from Shankaran et al).

Figure 4

VWF multimer found in patients on LVAD. Examples of VWF multimer patterns found in normal plasma pooled from 32 healthy subjects and in patients on LVAD support who developed myocardial infarction (Patient A), no complication (Patient B), and severe GI bleeding (Patient C). Samples were collected before LVAD implant (BL), 3 months after implant (3), and at the time of readmission for the clinical complications (E).