- Email: [email protected]
New Treatments for Left Ventricular Assist Device-Associated Bleeding?∗
JACC: HEART FAILURE
VOL.
ª 2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER INC.
-, NO. -, 2015
ISSN 2213-1779/$36.00 http://dx.doi.org/10.1016/j.jchf.2015.07.011
EDITORIAL COMMENT
New Treatments for Left Ventricular Assist Device-Associated Bleeding?* Martin Strueber, MD
I
n 2004, our program in Hannover, Germany, was
gone. I presented this finding during an invited
among the first centers in the world gaining
presentation at the International Society for Heart &
clinical experience with a new ventricular assist
Lung Transplantation annual meeting in 2007 about
device (VAD) called the HeartMate II (HMII) (Thoratec
our initial HMII experience.
Corporation, Pleasanton, California). At that time,
The response at the time was skeptical, and our
hopes were not high because the pilot trial was
subsequent publication was rejected several times
designed to cover a 180-day bridge-to-transplant
because of 2 questions:
approach. There were concerns about pump thrombosis;
therefore,
anticoagulation
protocols
were
maximized at that time. Within 18 months, we learned 2 important facts for the future of VAD therapy. The good news was that
1. Is there any proof that the acvWS is caused by the VAD or is there no causal evidence? 2. If acvWS is present in all HMII patients, why do some bleed and others do not?
many patients felt fabulous on the device, and some
We retested our patients when one-half of the
chose to withdraw from the heart transplant list, even
initial cohort had received heart transplants. We were
though they were part of a bridge-to-transplant trial.
able to show that the problem was gone when the
Some patients of the very early cohorts even
pump was removed after transplant. The acvWS
demonstrated the possibility to live on this device for
remained in the second half of the group that was still
more than 5 years. This opened the door for the use of
on the VAD. The first question was now answered (1).
such devices not only as a bridge but also as a definitive therapy.
In the meantime, other groups were working on the subject and coming to similar results. The Columbia
The second observation was a new pattern of
group reported on acvWS being present in all of the
bleeding events: gingiva bleeds, nose bleeds, and
HMII patients tested at their institution. Importantly,
gastrointestinal (GI) bleeding became a problem that
they pointed out that the incidence of GI bleeding was
could not be solved by modifying the anticoagulation
an age-dependent process (2). Other groups, such as
protocol. Because the clinical picture resembled the
the Texas Heart Institute, pointed out that GI bleeding
description of Heyde syndrome in patients with aortic
was associated with the formation of arteriovenous
stenosis, we checked the von Willebrand factor (vWF)
malformations (AVMs) in the small bowel (3).
in all of our HMII patients. Indeed, all of them pre-
It is a straightforward process to establish the
sented acquired von Willebrand syndrome (acvWS)
diagnosis of acvWS, but it is much more of a challenge
2a. In all patients, the large monomers of vWF were
for a laboratory to quantify the loss of large monomers. Because quantitative analysis is usually completed in batches, we were able to compare HMII and HeartWare HVAD patients in a cross-sectional analysis.
*Editorials published in JACC: Heart Failure reflect the views of the authors and do not necessarily represent the views of JACC: Heart Failure or the American College of Cardiology. From the Spectrum Health Hospitals, Richard DeVos Heart & Lung Transplant Program and Michigan State University, Grand Rapids,
We learned from this analysis that all patients had acvWS, and the median value for both devices was the same; however, among individuals, there was a wide variation of the degree of vWF losses (4). This
Michigan. Dr. Strueber has served as a consultant for HeartWare
could give us part of the answer to the second ques-
Incorporated and Thoratec Corporation.
tion. The degree of vWF degradation varies among
2
Strueber
JACC: HEART FAILURE VOL.
-, NO. -, 2015 - 2015:-–-
New Treatments for LVAD-Associated Bleeding?
patients, and the formation of GI AVMs, which is an
What may be the future role of ADAMTS-13 inhi-
age-dependent process, increases the risk for lower GI
bition in VAD therapy? Because shear stress is a
bleeding.
constant phenomenon in VAD patients, continuous
The current ideas on the interaction of vWF and
inhibition by high-dose drugs or by antibodies does
continuous-flow VADs are that high shear stress to
not seem reasonable. However, an intervention in
the blood within the VAD leads to a physiological
patients with acute bleeding events may be a
uncoiling of the spherical vWF, exposing binding
reasonable course of action.
sites for attachment to the endothelium or to a
What are the alternatives? In 2014, an interna-
cleaving enzyme called a disintegrin and metal-
tional expert group of hematologists, molecular bi-
loproteinase with a thrombospondin type 1 motif,
ologists, and clinicians met to answer this question.
member 13 (ADAMS-13). The response of vWF is
They found that there is no evidence-based concept
physiological because a role of vWF is to form white
at the present time for treatment of bleeding events.
clots with platelets in sites of endothelial injury and
Withholding antithrombotic therapy is a step used in
high shear environments. An example is a coronary
many cases, the addition of antifibrinolytic therapy
stent thrombosis, caused by endothelial injury and
can be a first-line therapy (7), and the infusion of
high shear. The nonphysiological part of it is the
vWF containing factor VIII concentrates may be an
constant exposure to high shearing in the VADs.
additional therapy. The National Heart, Lung, and
Because these pathophysiological encounters were
Blood Institute guidelines recommend the use of
made with the use of continuous-flow VADs, the
such concentrates prior to surgical interventions in
question is: When do we go from establishing path-
acvWS (8). All of these interventions carry the risk of
ophysiology to therapeutic interventions?
thrombosis and are usually limited to stopping a
For this, the paper of Bartoli et al. (5) in this issue
bleeding event. In these events, ADAMTS-13 inhibi-
of JACC: Heart Failure becomes significant. First of
tion may add an additional option. “Less shear”
all, they established an ex vivo model to simulate
seemed to be the requirement for the development
shear stress–induced degradation of vWF. This alone
of new VADs. The next generation of devices needs
is a milestone to enable the search for therapeutic
to prove if the reduction in shear stress is sufficient
means. A limitation to this concept is the lack of an
to mitigate this problem. Does nonpulsatile blood flow play a role? It was
endothelialized circulatory system. The lack of large monomers may be due to degra-
suspected that nonpulsatile blood flow induces
dation by ADAMTS-13 or by sequestration on the
AVMs. This theory has been contradicted now by
endothelial surface. The interplay of both mecha-
Goda et al. (9) reporting on the clinical experience
nisms in the presence of a VAD is unknown.
with the Synergy (CircuLite, acquired by Heartware
To choose the tetracycline analogue doxycycline
Inc., Framingham, Massachusetts) micro-pump: This
for inhibition of ADAMTS-13 seems very reasonable
VAD has been used clinically for partial ventricular
because many VAD patients have been treated with
support. All patients had preserved pulse but were
this drug and so far no adverse events have been
supported with a micro pump with high shear stress.
reported. However, the dose suggested by Bartoli
A high degree of GI bleeding was found in these pa-
et al. (5) was a much higher dose compared to the
tients as well. Dealing with this complex phenome-
current use of tetracycline as an anti-infective agent,
non seems to be the ultimate challenge for the future
higher and only produced a 10% reduction of
of long-term VAD therapy because bleeding and
ADAMTS-13 activity. Is this enough?
thrombosis are the limiting factors of its use.
As was discussed in the paper, inhibition of ADAMTS-13 and the loss of its physiological function
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
may lead to thrombus formation, pump thrombosis,
Martin Strueber, Heart & Lung Transplant Surgery,
and thromboembolic events. Rauch et al. (6) pre-
Heart Failure Surgery & MCS, Spectrum Health
sented a more aggressive approach by inhibiting
Hospitals, 330 Barclay Street NE, Grand Rapids,
ADAMTS-13 with a monoclonal antibody.
Michigan 49503. E-mail: [email protected].
REFERENCES 1. Meyer AL, Malehsa D, Bara C, et al. Acquired von
2. Uriel N, Pak SW, Jorde UP, et al. Acquired von
and at the time of transplantation. J Am Coll
Willebrand syndrome in patients with an axial flow left ventricular assist device. Circ Heart Fail 2010; 3:675–81.
Willebrand syndrome after continuous-flow mechanical device support contributes to a high prevalence of bleeding during long-term support
Cardiol 2010;56:1207–13. 3. Demirozu ZT, Radovancevic R, Hochman LF, et al. Arteriovenous malformation and gastrointestinal
JACC: HEART FAILURE VOL.
-, NO. -, 2015
Strueber
- 2015:-–-
New Treatments for LVAD-Associated Bleeding?
bleeding in patients with the HeartMate II left ventricular assist device. J Heart Lung Transplant 2011;30:849–53. 4. Meyer AL, 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. J Am Coll Cardiol HF 2014;2: 141–5. 5. Bartoli
CR,
Kang
J,
Restle
DJ,
et
al.
Inhibition of ADAMTS-13 by doxycycline reduces von Willebrand factor degradation during
supraphysiological shear stress. J Am Coll Cardiol HF 2015;3:XXX–XXX. 6. Rauch A, Legendre P, Christophe OD, et al. Antibody-based prevention of von Willebrand factor degradation mediated by circulatory assist devices. Thromb Haemost 2014;112:1014–23. 7. Ide M, Bolliger D, Taketomi T, Tanaka KA. Lessons from the aprotinin saga: current perspective on antifibrinolytic therapy in cardiac surgery. J Anesth 2010;24:96–106. 8. Nichols WL, Hultin MB, James AH, et al. von Willebrand disease (VWD): evidence-based diag-
nosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA). Haemophilia 2008;14:171–232. 9. Goda M, Jacobs S, Rega F, et al. 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. J Heart Lung Transplant 2013;32:539–45.
KEY WORDS acquired vWS, bleeding, HeartMate II, LVAD, pump thrombosis
3
VOL.
ª 2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER INC.
-, NO. -, 2015
ISSN 2213-1779/$36.00 http://dx.doi.org/10.1016/j.jchf.2015.07.011
EDITORIAL COMMENT
New Treatments for Left Ventricular Assist Device-Associated Bleeding?* Martin Strueber, MD
I
n 2004, our program in Hannover, Germany, was
gone. I presented this finding during an invited
among the first centers in the world gaining
presentation at the International Society for Heart &
clinical experience with a new ventricular assist
Lung Transplantation annual meeting in 2007 about
device (VAD) called the HeartMate II (HMII) (Thoratec
our initial HMII experience.
Corporation, Pleasanton, California). At that time,
The response at the time was skeptical, and our
hopes were not high because the pilot trial was
subsequent publication was rejected several times
designed to cover a 180-day bridge-to-transplant
because of 2 questions:
approach. There were concerns about pump thrombosis;
therefore,
anticoagulation
protocols
were
maximized at that time. Within 18 months, we learned 2 important facts for the future of VAD therapy. The good news was that
1. Is there any proof that the acvWS is caused by the VAD or is there no causal evidence? 2. If acvWS is present in all HMII patients, why do some bleed and others do not?
many patients felt fabulous on the device, and some
We retested our patients when one-half of the
chose to withdraw from the heart transplant list, even
initial cohort had received heart transplants. We were
though they were part of a bridge-to-transplant trial.
able to show that the problem was gone when the
Some patients of the very early cohorts even
pump was removed after transplant. The acvWS
demonstrated the possibility to live on this device for
remained in the second half of the group that was still
more than 5 years. This opened the door for the use of
on the VAD. The first question was now answered (1).
such devices not only as a bridge but also as a definitive therapy.
In the meantime, other groups were working on the subject and coming to similar results. The Columbia
The second observation was a new pattern of
group reported on acvWS being present in all of the
bleeding events: gingiva bleeds, nose bleeds, and
HMII patients tested at their institution. Importantly,
gastrointestinal (GI) bleeding became a problem that
they pointed out that the incidence of GI bleeding was
could not be solved by modifying the anticoagulation
an age-dependent process (2). Other groups, such as
protocol. Because the clinical picture resembled the
the Texas Heart Institute, pointed out that GI bleeding
description of Heyde syndrome in patients with aortic
was associated with the formation of arteriovenous
stenosis, we checked the von Willebrand factor (vWF)
malformations (AVMs) in the small bowel (3).
in all of our HMII patients. Indeed, all of them pre-
It is a straightforward process to establish the
sented acquired von Willebrand syndrome (acvWS)
diagnosis of acvWS, but it is much more of a challenge
2a. In all patients, the large monomers of vWF were
for a laboratory to quantify the loss of large monomers. Because quantitative analysis is usually completed in batches, we were able to compare HMII and HeartWare HVAD patients in a cross-sectional analysis.
*Editorials published in JACC: Heart Failure reflect the views of the authors and do not necessarily represent the views of JACC: Heart Failure or the American College of Cardiology. From the Spectrum Health Hospitals, Richard DeVos Heart & Lung Transplant Program and Michigan State University, Grand Rapids,
We learned from this analysis that all patients had acvWS, and the median value for both devices was the same; however, among individuals, there was a wide variation of the degree of vWF losses (4). This
Michigan. Dr. Strueber has served as a consultant for HeartWare
could give us part of the answer to the second ques-
Incorporated and Thoratec Corporation.
tion. The degree of vWF degradation varies among
2
Strueber
JACC: HEART FAILURE VOL.
-, NO. -, 2015 - 2015:-–-
New Treatments for LVAD-Associated Bleeding?
patients, and the formation of GI AVMs, which is an
What may be the future role of ADAMTS-13 inhi-
age-dependent process, increases the risk for lower GI
bition in VAD therapy? Because shear stress is a
bleeding.
constant phenomenon in VAD patients, continuous
The current ideas on the interaction of vWF and
inhibition by high-dose drugs or by antibodies does
continuous-flow VADs are that high shear stress to
not seem reasonable. However, an intervention in
the blood within the VAD leads to a physiological
patients with acute bleeding events may be a
uncoiling of the spherical vWF, exposing binding
reasonable course of action.
sites for attachment to the endothelium or to a
What are the alternatives? In 2014, an interna-
cleaving enzyme called a disintegrin and metal-
tional expert group of hematologists, molecular bi-
loproteinase with a thrombospondin type 1 motif,
ologists, and clinicians met to answer this question.
member 13 (ADAMS-13). The response of vWF is
They found that there is no evidence-based concept
physiological because a role of vWF is to form white
at the present time for treatment of bleeding events.
clots with platelets in sites of endothelial injury and
Withholding antithrombotic therapy is a step used in
high shear environments. An example is a coronary
many cases, the addition of antifibrinolytic therapy
stent thrombosis, caused by endothelial injury and
can be a first-line therapy (7), and the infusion of
high shear. The nonphysiological part of it is the
vWF containing factor VIII concentrates may be an
constant exposure to high shearing in the VADs.
additional therapy. The National Heart, Lung, and
Because these pathophysiological encounters were
Blood Institute guidelines recommend the use of
made with the use of continuous-flow VADs, the
such concentrates prior to surgical interventions in
question is: When do we go from establishing path-
acvWS (8). All of these interventions carry the risk of
ophysiology to therapeutic interventions?
thrombosis and are usually limited to stopping a
For this, the paper of Bartoli et al. (5) in this issue
bleeding event. In these events, ADAMTS-13 inhibi-
of JACC: Heart Failure becomes significant. First of
tion may add an additional option. “Less shear”
all, they established an ex vivo model to simulate
seemed to be the requirement for the development
shear stress–induced degradation of vWF. This alone
of new VADs. The next generation of devices needs
is a milestone to enable the search for therapeutic
to prove if the reduction in shear stress is sufficient
means. A limitation to this concept is the lack of an
to mitigate this problem. Does nonpulsatile blood flow play a role? It was
endothelialized circulatory system. The lack of large monomers may be due to degra-
suspected that nonpulsatile blood flow induces
dation by ADAMTS-13 or by sequestration on the
AVMs. This theory has been contradicted now by
endothelial surface. The interplay of both mecha-
Goda et al. (9) reporting on the clinical experience
nisms in the presence of a VAD is unknown.
with the Synergy (CircuLite, acquired by Heartware
To choose the tetracycline analogue doxycycline
Inc., Framingham, Massachusetts) micro-pump: This
for inhibition of ADAMTS-13 seems very reasonable
VAD has been used clinically for partial ventricular
because many VAD patients have been treated with
support. All patients had preserved pulse but were
this drug and so far no adverse events have been
supported with a micro pump with high shear stress.
reported. However, the dose suggested by Bartoli
A high degree of GI bleeding was found in these pa-
et al. (5) was a much higher dose compared to the
tients as well. Dealing with this complex phenome-
current use of tetracycline as an anti-infective agent,
non seems to be the ultimate challenge for the future
higher and only produced a 10% reduction of
of long-term VAD therapy because bleeding and
ADAMTS-13 activity. Is this enough?
thrombosis are the limiting factors of its use.
As was discussed in the paper, inhibition of ADAMTS-13 and the loss of its physiological function
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
may lead to thrombus formation, pump thrombosis,
Martin Strueber, Heart & Lung Transplant Surgery,
and thromboembolic events. Rauch et al. (6) pre-
Heart Failure Surgery & MCS, Spectrum Health
sented a more aggressive approach by inhibiting
Hospitals, 330 Barclay Street NE, Grand Rapids,
ADAMTS-13 with a monoclonal antibody.
Michigan 49503. E-mail: [email protected].
REFERENCES 1. Meyer AL, Malehsa D, Bara C, et al. Acquired von
2. Uriel N, Pak SW, Jorde UP, et al. Acquired von
and at the time of transplantation. J Am Coll
Willebrand syndrome in patients with an axial flow left ventricular assist device. Circ Heart Fail 2010; 3:675–81.
Willebrand syndrome after continuous-flow mechanical device support contributes to a high prevalence of bleeding during long-term support
Cardiol 2010;56:1207–13. 3. Demirozu ZT, Radovancevic R, Hochman LF, et al. Arteriovenous malformation and gastrointestinal
JACC: HEART FAILURE VOL.
-, NO. -, 2015
Strueber
- 2015:-–-
New Treatments for LVAD-Associated Bleeding?
bleeding in patients with the HeartMate II left ventricular assist device. J Heart Lung Transplant 2011;30:849–53. 4. Meyer AL, 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. J Am Coll Cardiol HF 2014;2: 141–5. 5. Bartoli
CR,
Kang
J,
Restle
DJ,
et
al.
Inhibition of ADAMTS-13 by doxycycline reduces von Willebrand factor degradation during
supraphysiological shear stress. J Am Coll Cardiol HF 2015;3:XXX–XXX. 6. Rauch A, Legendre P, Christophe OD, et al. Antibody-based prevention of von Willebrand factor degradation mediated by circulatory assist devices. Thromb Haemost 2014;112:1014–23. 7. Ide M, Bolliger D, Taketomi T, Tanaka KA. Lessons from the aprotinin saga: current perspective on antifibrinolytic therapy in cardiac surgery. J Anesth 2010;24:96–106. 8. Nichols WL, Hultin MB, James AH, et al. von Willebrand disease (VWD): evidence-based diag-
nosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA). Haemophilia 2008;14:171–232. 9. Goda M, Jacobs S, Rega F, et al. 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. J Heart Lung Transplant 2013;32:539–45.
KEY WORDS acquired vWS, bleeding, HeartMate II, LVAD, pump thrombosis
3