Author + information
- Carlo Bartoli, MD, PhD∗ ()
- ↵∗Resident, Division of Cardiovascular Surgery, Hospital of the University of Pennsylvania, Stemmler Hall, Room 351, Philadelphia, Pennsylvania 19104
Thank you for the opportunity to respond to Dr. Lenting and colleagues. In our paper that examined doxycycline to reduce ADAMTS-13-mediated von Willebrand factor (vWF) degradation during left ventricular assist device (LVAD)-like shear stress (1), we referenced a recent paper by Rauch et al. (2).
In their study, Rauch et al. (2) used a monoclonal antibody (mAb508) to block ADAMTS-13/vWF interactions in order to preserve high-molecular-weight vWF multimers. We acknowledge that “anti-ADAMTS-13” antibody was incorrect terminology and that their antibody is in fact an anti-vWF antibody that blocks the ADAMTS-13/vWF interaction. We congratulate Dr. Lenting and colleagues for this important mechanistic work with potential therapeutic implications. However, we disagree with statements made in their recent Letter to the Editor. Other than correcting the terminology, our concern that mAb508 therapy may lead to hypercoagulability and thrombosis remains unchanged.
Continuous-flow LVADs accelerate vWF degradation by ADAMTS-13 (the vWF protease) and cause an acquired vWF deficiency that predisposes patients to episodic bleeding (3). Within this pathophysiologic mechanism, supraphysiologic shear stress from the LVAD triggers high-molecular-weight vWF multimers to undergo quaternary shape-change activation that exposes vWF-binding sites for collagen and platelets as an initial step in primary hemostasis. In parallel, ADAMTS-13 binding sites are exposed, and ADAMTS-13 cleaves vWF into small, nonfunctional degradation fragments. In their study, Rauch et al. (2) demonstrated that mAb508 inhibited vWF by 83% and ADAMTS-13 degradation of vWF by 50%. As a result in the setting of mechanical circulatory support, high-molecular-weight vWF multimers were protected from shear stress-induced metabolism. Importantly, mAb508 not only reduced degradation of vWF under flow conditions but also did not affect the hemostatic potential of vWF multimers to which it bound. As a result, high-molecular-weight vWF multimers were activated but not degraded.
We are concerned that a therapeutic approach in which activated vWF is protected against degradation by ADAMTS-13 may lead to an overabundance of hemostatically active (prothrombotic) high-molecular-weight vWF multimers. Indeed, we can infer from the study by Rauch et al. (2) that mAb508 therapy in patients may lead to the accumulation of prothrombotic vWF multimers that cannot be metabolized (inactivated) by ADAMTS-13. Prothrombotic vWF multimers that encounter the thrombogenic, blood-contacting artificial interior surface of an LVAD may promote LVAD thrombosis. As such, we raise caution if this line of investigation is translated into clinical practice.
We hope that our response has clarified our work. Again, we congratulate Dr. Lenting and colleagues for their novel and important contribution. We are hopeful that these types of investigations may lead to targeted therapy to reduce LVAD-associated bleeding without precipitating LVAD thrombosis.
- American College of Cardiology Foundation