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ASAIO Journal:
doi: 10.1097/MAT.0000000000000049
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Acquired von Willebrand Disease During CentriMag Support Is Associated with High Prevalence of Bleeding During Support and After Transition to Heart Replacement Therapy

Morrison, Kerry A.*; Jorde, Ulrich P.*; Garan, Arthur R.*; TakayAma, Hiroo; Naka, Yoshifumi; Uriel, Nir*

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From the *Division of Cardiology, Columbia University Medical Center, Columbia University College of Physicians and Surgeons, New York, New York; and Department of Cardiothoracic Surgery, Columbia University Medical Center, Columbia University College of Physicians and Surgeons, New York, New York.

Submitted for consideration October 2013; accepted for publication in revised form December 2013.

Disclosure: Nir Uriel received consulting fees from HeartWare. Ulrich Jorde and Yoshifumi Naka received consulting fees from Thoratec, HeartWare, and Jarvik. The remaining authors have no conflicts of interest to disclose.

Reprint Requests: Nir Uriel, Division of Cardiology, Columbia University Medical Center, Columbia University College of Physicians and Surgeons, New York, NY 10032. Email: nu2126@columbia.edu.

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Abstract

The Levitronix CentriMag is a magnetically levitated centrifugal-flow pump that can be implanted rapidly in the operating room for both right and left ventricular support. Recently, continuous-flow pumps have been associated with excessive bleeding, which can be at least partially explained by acquired von Willebrand disease (vWD). We investigated whether acquired vWD occurs during CentriMag support and determined the frequency of bleeding complications during device support as well as after transition to long-term support. We found that acquired vWD is common early post CentriMag implantation and is associated with frequent bleeding events and high requirement of blood products.

The Levitronix CentriMag (Levitronix LLC, Waltham, MA) is a magnetically levitated centrifugal-flow ventricular assist device that can be implanted rapidly in the operating room for both right and left ventricular support. Designed for temporary extracorporeal support, the CentriMag is different from other devices in that it operates without mechanical bearings. Eliminating bearings, regions of stasis, and sources of thermal damage reduces, in theory, hemolysis and the risk of device thrombosis.1

Recently, continuous-flow ventricular assist devices have been associated with excessive bleeding, which can be at least partially explained by acquired von Willebrand disease (vWD). Acquired vWD is an acquired bleeding disorder, which may suddenly manifest in individuals, usually in the absence of a personal or family history of bleedings and frequently in association with monoclonal gammopathies, lymphoproliferative, myeloproliferative, and autoimmune disorders.2 There is compelling evidence that acquired vWD may be a contributing cause if not the primary cause of gastrointestinal bleeding in patients supported by continuous-flow devices.3–5 In fact, Uriel et al.6 contributed that the development of acquired von Willebrand syndrome accounted for the cause-and-effect relationship between continuous-flow physiology and gastrointestinal bleeding in patients supported by continuous-flow HeartMate II devices.

We investigated whether acquired vWD occurs during CentriMag support and determined the frequency of bleeding complications during device support as well as after transition to long-term support. The development of von Willebrand syndrome was evidenced by near-total depletion of the typical multimeric structure of the von Willebrand factor (vWF), which is a good biomarker of the integrity of the vascular endothelium. The vWF levels were part of a panel of factors that included von Willebrand antigen, ristocetin cofactor, and the von Willebrand multimers.

Evidence suggests that acquired vWD develops in some patients due to the reduction in high-molecular-weight multimers of vWF. We believe that the shear stress of the CentriMag device may cause proteolysis of the high-molecular-weight multimers of vWF, activation of the fibrinolytic system, and loss of platelet function during support similar to patients supported by HeartMate II devices.6

A retrospective chart review of all patients implanted with Levitronix CentriMag from 2010 to 2011 at Columbia University Medical Center-New York Presbyterian Hospital was performed. All patients tested for vWF levels were included in this analysis.

Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) definitions for bleeding and thromboembolic events were used. As per INTERMACS, a major bleeding event was defined as an episode of suspected internal or external bleeding that resulted in one or more of the following: death, reoperation, hospitalization, or transfusion of red blood cells; it must be noted that hemorrhagic stroke was considered a neurological event and not as a separate bleeding event. An arterial non-central nervous system thromboembolism was defined as an acute systemic arterial perfusion deficit in any noncerebrovascular organ system due to thromboembolism confirmed by one or more of the following: standard clinical and laboratory testing, operative findings, or autopsy findings.

Among the 59 patients implanted with CentriMag at Columbia University Medical Center, 13 (22%) patients who had bleeding problems on support were tested for vWD, and there was no indication to test the remaining 46 CentriMag patients. Patients in this vWD-tested cohort (n = 13) were 53.3 ± 10.1 years old, 9 (69%) were male, 8 (61%) had history of dilated cardiomyopathy, 5 (38%) had hypertension, 2 (15%) had diabetes mellitus, and 3 (23%) had prior cerebral vascular accident.

Twelve (92%) patients had biventricular CentriMag and were supported for a mean time of 37 ± 22 days. Twelve (92%) developed acquired vWD type 2a defined as absence of high-molecular-weight von Willebrand multimers 18 ± 14 days after device implantation. Von Willebrand antigen levels were 317% ± 86% and von Willebrand activity was 113% ± 15%. The majority (92%) of the patients, who acquired vWD on support, had bi-ventricular assist devices, and it is very likely that the dual ventricular assist device therapy was an extremely important factor in the development of vWD. CentriMag pump speed had no effect on the rate of acquired vWD.

Twelve (92%) patients had bleeding events, and six (46%) had thromboembolic events during CentriMag support. Blood product requirements during support were 10.2 ± 11.3 units of packed red blood cells, 2.8 ± 3.7 units of fresh-frozen plasma, and 1.5 ± 2.6 units of platelets. During heart transplant or long-term assist device implantation, CentriMag patients required 4.0 ± 4.2 units of PRBCs, 5.5 ± 5.7 units of FFP, and 12.5 ± 10.4 units of PLTs.

Four patients died during CentriMag support; mean time to death was 32 ± 21 days. Two patients died after long-term assist device implantation: one from infection after 28 days, and the other from embolic stroke after 14 days of support. One patient died from tamponade 30 days after heart transplantation.

A limitation of this study is that it is retrospective in nature, and hence, vWF levels were not measured in all patients to assess whether patients with very low levels may not bleed. A follow-up study prospectively evaluating the existence of a threshold level at which the risk of bleeding substantially increases in CentriMag patients is needed, and such a study could potentially guide anticoagulation medication regimens in this patient population.

In conclusion, acquired vWD is common early post CentriMag implantation and is associated with frequent bleeding events and high requirement of blood products. Given the fact that bleeding causes such significant morbidity in this patient population, patients should be screened for vWD before CentriMag implantation. Reversal of von Willebrand deficiency before heart transplantation or long-term support should be evaluated.

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References

1. Mueller JP, Kuenzli A, Reuthebuch O, et al. The CentriMag: A new optimized centrifugal blood pump with levitating impeller. Heart Surg Forum. 2004;7:E477–E480

2. van Genderen PJ, Michiels JJ. Acquired von Willebrand disease. Baillieres Clin Haematol. 1998;11:319–330

3. Warkentin TE, Moore JC, Morgan DG. Aortic stenosis and bleeding gastrointestinal angiodysplasia: Is acquired von Willebrand’s disease the link? Lancet. 1992;340:35–37

4. Sucker C. The Heyde syndrome: Proposal for a unifying concept explaining the association of aortic valve stenosis, gastrointestinal angiodysplasia and bleeding. Int J Cardiol. 2007;115:77–78

5. Williams RC Jr. Aortic stenosis, von Willebrand factor, and bleeding. N Engl J Med. 2003;349:1773–1774–author reply 1773

6. Uriel N, Pak SW, Jorde UP, et al. 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. J Am Coll Cardiol. 2010;56:1207–1213

ventricular assist device; heart replacement therapy; CentriMag; acquired von Willebrand; bleeding

Copyright © 2014 by the American Society for Artificial Internal Organs

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