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Relative preservation of high molecular weight von Willebrand factor multimers during HM 3 support–plain physics or a matter of clinical consequence?

2016; Elsevier BV; Volume: 35; Issue: 7 Linguagem: Inglês

10.1016/j.healun.2016.06.007

1557-3117

Ulrich P. Jorde,

Heart Failure Treatment and Management

Nothing whets the intelligence more than a passionate suspicion. (“Nichts schaerft Intelligenz mehr als ein leidenschaftlicher Verdacht” -Stefan Zweig 1Zweig S. Brennendes geheimnis (“A burning secret”). In: Erstes Erlebnis. Vier Geschichten aus Kinderland. Insel-Verlag, Leipzig. 1911.Google Scholar) In this issue of the journal , Netuka et al. examine degradation of von Willebrand factor (vWf) large multimers and functional parameters of vWf deficiency in subjects supported by the newly developed HM 3 LVAD as well as in a control group of HM II subjects.2Netuka I.K.T. Kvasnika J. Hrachovinova I. Ivak P. Marecek F. Bilkova J. Malikova I. Jancova M. Maly J. Sood P. Sundareswaran K.S. Connors J.M. Mehra M.R. Evaluation of Von Willebrand Factor with a Fully Magnetically Levitated, Centrifugal Continuous Flow Left Ventricular Assist Device In Advanced Heart Failure.JHLT. 2016; (In press)Google Scholar Their primary objective was to investigate whether the low shear stress conditions attributed to the HM 3 device would translate into less degradation of the large high molecular weight vWf multimers (HMWM). The HMWMs represent the most adhesive and haemostatically active forms of VWF, a classic hematological fact that first caught the attention of cardiovascular physicians when loss of HMWM was associated with an increased risk of bleeding events in patients with aortic stenosis.3EC H Gastrointestinal bleeding in aortic stenosis.N Eng J Med. 1958; 259: 196Google Scholar, 4Warkentin T.E. Moore J.C. Morgan D.G. Aortic stenosis and bleeding gastrointestinal angiodysplasia: is acquired von Willebrand׳s disease the link?.Lancet. 1992; 340: 35-37Abstract PubMed Scopus (238) Google Scholar We now understand that destruction of HMWM is a shear stress dependent phenomenon not only observed in aortic stenosis, but also in a wide range of (if not all) continuous flow mechanical circulatory support devices. VWF is secreted from endothelial cells in the form of ultralarge multimeric structures which can be rapidly cleaved by the plasma enzyme ADAMTS13 (A Disintegrin And Metalloproteinase with Thrombospondin type 1 Motif, 13) into smaller multimers5Zhang X. Halvorsen K. Zhang C.Z. Wong W.P. Springer T.A. Mechanoenzymatic cleavage of the ultralarge vascular protein von Willebrand factor.Science. 2009; 324: 1330-1334Crossref PubMed Scopus (409) Google Scholar; yet this process requires unfolding of the multimers and exposure of the cleavage site. This unfolding of vWF is promoted by shear stress. Increased cleavage by ADAMTS13 is believed to contribute to loss of HMWM and recent investigations have demonstrated that pharmacological inhibition of ADAMTS13 results in preservation of HMWM under high shear stress conditions in a mock loop.6Bartoli C.R. Kang J. Restle D.J. Zhang D.M. Shabahang C. Acker M.A. Atluri P. Inhibition of ADAMTS-13 by Doxycycline Reduces von Willebrand Factor Degradation During Supraphysiological Shear Stress: Therapeutic Implications for Left Ventricular Assist Device-Associated Bleeding.JACC Heart Fail. 2015; 3: 860-869Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar In contrast, speed manipulation within the operational range of the most studied HM II device does not decrease von Willebrand factor degradation.7Kang J. Zhang D.M. Restle D.J. Kallel F. Acker M.A. Atluri P. Bartoli C.R. Reduced continuous-flow left ventricular assist device speed does not decrease von Willebrand factor degradation.J Thorac Cardiovasc Surg. 2016; 151 (1747-1754 e1)Abstract Full Text Full Text PDF Scopus (30) Google Scholar, 8Patel S.P.J. Rand J. Goldstein D. Jorde U. Saeed O. Speed Reduction Does Not Restore High Molecular Weight Von Willebrand Multimers during Heart Mate II Support: An In-Vivo Analysis.JHLT. 2016; 35: S244-S245Abstract Full Text Full Text PDF Google Scholar In aortic stenosis, valve replacement will eliminate the source of pathological shear stress and cure the acquired vWF deficiency. In the setting of mechanical circulatory support, device removal is not an option and, after testing many devices in various settings,9Morrison K.A. Jorde U.P. Garan A.R. Takayama H. Naka Y. Uriel N. Acquired von Willebrand disease during CentriMag support is associated with high prevalence of bleeding during support and after transition to heart replacement therapy.ASAIO journal. 2014; 60: 241-242Crossref PubMed Scopus (13) Google Scholar, 10Goda M. Jacobs S. Rega F. Peerlinck K. Jacquemin M. Droogne W. Vanhaecke J. Van Cleemput J. Van den Bossche K. Meyns B. Time course of acquired von Willebrand disease associated with two types of continuous-flow left ventricular assist devices: HeartMate II and CircuLite Synergy Pocket Micro-pump.The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2013; 32: 539-545Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar, 11Kalbhenn J. Schmidt R. Nakamura L. Schelling J. Rosenfelder S. Zieger B. Early diagnosis of acquired von Willebrand Syndrome (AVWS) is elementary for clinical practice in patients treated with ECMO therapy.J Atheroscler Thromb. 2015; 22: 265-271Crossref PubMed Scopus (69) Google Scholar clinicians have accepted that vWF deficiency is a uniform phenomenon and the price we pay when implanting continuous flow pumps. Yet, the association of vWF deficiency and clinical bleeding remains poorly understood. On the one hand, bleeding is one of the most common causes of readmission in CF-LVAD patients 12Uriel N. Pak S.W. Jorde U.P. Jude B. Susen S. Vincentelli A. Ennezat P.V. Cappleman S. Naka Y. Mancini D. Acquired von Willebrand syndrome after continuous-flow mechanical device support contributes to a high prevalence of bleeding during long-term support and at the time of transplantation.Journal of the American College of Cardiology. 2010; 56: 1207-1213Abstract Full Text Full Text PDF PubMed Scopus (445) Google Scholar, 13Hasin T. Marmor Y. Kremers W. Topilsky Y. Severson C.J. Schirger J.A. Boilson B.A. Clavell A.L. Rodeheffer R.J. Frantz R.P. Edwards B.S. Pereira N.L. Stulak J.M. Joyce L. Daly R. Park S.J. Kushwaha S.S. Readmissions after implantation of axial flow left ventricular assist device.Journal of the American College of Cardiology. 2013; 61: 153-163Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar and often persists even after discontinuation of anticoagulation and ASA.14Katz J.N. Adamson R.M. John R. Tatooles A. Sundareswaran K. Kallel F. Farrar D.J. Jorde U.P. study T. Safety of reduced anti-thrombotic strategies in HeartMate II patients: A one-year analysis of the US-TRACE Study.The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation. 2015; 34: 1542-1548Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar On the other hand, most LVAD patients do NOT bleed despite vWF deficiency as well as ongoing anticoagulation and antiplatelet therapy. Attempts to functionally characterize vWf deficiency using ratios of ristocetin cofactor or collagenase binding activity to vW antigen to possibly identify those at bleeding risk and tailor antithrombotic therapy have failed.15Meyer A.L. Malehsa D. Budde U. Bara C. Haverich A. Strueber M. Acquired von Willebrand syndrome in patients with a centrifugal or axial continuous flow left ventricular assist device.JACC Heart Fail. 2014; 2: 141-145Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar To worsen matters, device related hemolysis and thrombosis are frequent occurrences during mechanical circulatory support hindering efforts to lower antithrombotic (i.e. pro-hemorraghic) measures.16Levin A.P. Saeed O. Willey J.Z. Levin C.J. Fried J.A. Patel S.R. Sims D.B. Nguyen J.D. Shin J.J. Topkara V.K. Colombo P.C. Goldstein D.J. Naka Y. Takayama H. Uriel N. Jorde U.P. Watchful Waiting in Continuous-Flow Left Ventricular Assist Device Patients With Ongoing Hemolysis Is Associated With an Increased Risk for Cerebrovascular Accident or Death.Circulation Heart failure. 2016; : 9Google Scholar, 17Starling R.C. Moazami N. Silvestry S.C. Ewald G. Rogers J.G. Milano C.A. Rame J.E. Acker M.A. Blackstone E.H. Ehrlinger J. Thuita L. Mountis M.M. Soltesz E.G. Lytle B.W. Smedira N.G. Unexpected abrupt increase in left ventricular assist device thrombosis.N Engl J Med. 2014; 370: 33-40Crossref PubMed Scopus (616) Google Scholar Consequently, improved hemocompatibility is a principal goal in the development of future durable MCS devices. Most recently, the early Conformite Europeene (CE) mark results for the HM 3 suggested less hemolysis and thrombosis18Netuka I. Sood P. Pya Y. Zimpfer D. Krabatsch T. Garbade J. Rao V. Morshuis M. Marasco S. Beyersdorf F. Damme L. Schmitto J.D. Fully Magnetically Levitated Left Ventricular Assist System for Treating Advanced HF: A Multicenter Study.Journal of the American College of Cardiology. 2015; 66: 2579-2589Crossref PubMed Scopus (174) Google Scholar; a clinical finding that would be consistent with less shear stress. In their current study and to some degree in follow-up to their clinical experience in the CE trial, Netuka et al. demonstrate better preservation of HMWM with the newly developed HM 3 device compared to the HM II. Despite the exploratory nature of the study and its small sample size, this novel finding is compelling given strict concordance of their laboratory findings with the HM II to historical HM II data as well as “triple” verification of all their data in two different laboratories. The authors appropriately address limitations incl. group differences in age, ethnic homogeneity of the study group, as well as a very important difference in antiplatelet therapy (HM II, but not HM 3 patients received ASA). Importantly, results are put in perspective with prior studies examining vWf deficiency induced by CF-LVADS. These studies revealed uniform vWf deficiency when examining patients supported by axial (HM II12Uriel N. Pak S.W. Jorde U.P. Jude B. Susen S. Vincentelli A. Ennezat P.V. Cappleman S. Naka Y. Mancini D. Acquired von Willebrand syndrome after continuous-flow mechanical device support contributes to a high prevalence of bleeding during long-term support and at the time of transplantation.Journal of the American College of Cardiology. 2010; 56: 1207-1213Abstract Full Text Full Text PDF PubMed Scopus (445) Google Scholar, Circulite10Goda M. Jacobs S. Rega F. Peerlinck K. Jacquemin M. Droogne W. Vanhaecke J. Van Cleemput J. Van den Bossche K. Meyns B. Time course of acquired von Willebrand disease associated with two types of continuous-flow left ventricular assist devices: HeartMate II and CircuLite Synergy Pocket Micro-pump.The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2013; 32: 539-545Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar) or centrifugal (Heartware15Meyer A.L. Malehsa D. Budde U. Bara C. Haverich A. Strueber M. Acquired von Willebrand syndrome in patients with a centrifugal or axial continuous flow left ventricular assist device.JACC Heart Fail. 2014; 2: 141-145Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar) flow pumps. On this background, the speculation that the flow path design rather than directional flow characteristics cause shear stress for blood components is not trivial and may have important implications for further attempts to miniaturize pumps. Thus, Netuka et al. are to be congratulated to provide us with the first in-vivo study in patients with advanced heart failure examining quantitative and qualitative characteristics of acquired vWf deficiency in two pumps with different shear stress as well as flow patterns. As we strive to develop pumps with better hemocompatibility, such assessments may provide important phenotypic information when assessing bleeding risks. In this promise lays a major appeal to those caring for LVAD patients; eliciting a passionate suspicion that we may soon solve the bleeding conundrum. LVAD patients bleed and HMWM are low – preserving HMWM may reduce bleeding. Here we have to exercise some caution. In fact, while the conclusion might be intuitive, there is no evidence arising from this paper or elsewhere in the literature suggesting that bleeding would be decreased if HMWM were somewhat preserved. In fact, like others before them, the authors were unable to show a correlation between HMWM preservation and currently applied metrics of vWf functionality. Bleeding in LVAD is a multifactorial phenomenon uniquely characterized not only by the LVAD induced coagulation abnormalities, but also the presence – and possibly induction of - arteriovenous malformations. What if we were to observe less mucosal bleeding in the HM 3 cohort of the ongoing MOMENTUM trial?19Heatley G. Sood P. Goldstein D. Uriel N. Cleveland J. Middlebrook D. Mehra M.R. Investigators M. Clinical trial design and rationale of the Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy With HeartMate 3 (MOMENTUM 3) investigational device exemption clinical study protocol.The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation. 2016; 35: 528-536Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar Should we ascribe it to possibly less blood trauma or to the pulsatile flow generated by the HM 3? Or both? Or neither? It certainly seems biologically plausible that a more pulsatile flow in concert with better HMMW preservation should translate into less clinical bleeding.20Wever-Pinzon O. Selzman C.H. Drakos S.G. Saidi A. Stoddard G.J. Gilbert E.M. Labedi M. Reid B.B. Davis E.S. Kfoury A.G. Li D.Y. Stehlik J. Bader F. Pulsatility and the risk of nonsurgical bleeding in patients supported with the continuous-flow left ventricular assist device HeartMate II.Circulation Heart failure. 2013; 6: 517-526Crossref PubMed Scopus (176) Google Scholar On the other hand, one may argue that the observed difference in HMWM preservation is as meaningless to bleeding as the small pulse amplitude generated by the HM 3 is to vascular loading conditions.21Patel S.R. Jorde U.P. Creating adequate pulsatility with a continuous flow left ventricular assist device: just do it!.Curr Opin Cardiol. 2016; 31: 329-336Crossref PubMed Scopus (21) Google Scholar The puzzle of CF-LVAD induced mucosal bleeding has many pieces. Netuka et al. have not solved the puzzle, but they may have provided an important piece bringing us one step closer to understanding one of the major complications of CF-LVAD support. Dr. Jorde, Professor of Medicine, is a consultant to St. Jude Medical (No honoraria).