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

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Abstract
The objective of the study was to determine the prevalence of bleeding during continuous-flow left ventricular assist device support and to identify potential mechanisms for those bleeding events. Bleeding is frequently reported with continuous-flow left ventricular assist devices and may result from anticoagulation coupled with bleeding diathesis such as acquired von Willebrand syndrome. Accordingly, the prevalence of coagulation abnormalities including laboratory assessment for von Willebrand syndrome, bleeding events during device support, and at heart transplantation were evaluated. A retrospective study in all HeartMate II (HM II) (Thoratec Corp., Pleasanton, California) patients who underwent implantation between April 1, 2004, and August 1, 2009, was performed. Bleeding was defined as the need for transfusion >7 days after device insertion of 1 U of packed red blood cells. Transfusion at heart transplantation was compared with that in HeartMate XVE patients. Seventy-nine HM II devices were implanted. Anticoagulation included warfarin in 68.3%, aspirin in 55.7%, and dipyridamole in 58.2% of the patients. Of the patients, 44.3% had bleeding episodes at 112 ± 183 days after left ventricular assist device implantation, with 50% experiencing an event within 2 months. Gastrointestinal bleeding was the most frequent event. At the index event, the international normalized ratio averaged 1.67 ± 0.53, and the platelet count was 237 ± 119 × 10(9)/l. Comparison of the transfusion requirements at heart transplantation of 35 HM II patients with 62 HeartMate XVE patients demonstrated twice the transfusion requirements in HM II patients (packed red blood cells, 6.3 ± 0.8 U vs. 3.8 ± 0.5 U; platelets, 12.5 ± 5.4 U vs. 8.6 ± 6.4 U; fresh frozen plasma, 9.6 ± 4.9 U vs. 4.9 ± 3.6 U; and cryoprecipitate, 4.3 ± 3.6 U vs. 2.2 ± 3.5 U; p < 0.05 for all). High molecular weight von Willebrand factor multimers were measured in 31 HM II patients and were reduced in all patients; 18 of these 31 (58%) patients had bleeding. Patients with the HM II had a high incidence of bleeding events during device support and at heart transplantation. All HM II patients had reduced high molecular weight von Willebrand factor multimers. The role of these abnormalities in the high incidence of bleeding deserves further investigation. Furthermore, alterations in anticoagulation should be considered during device support and before surgery in patients supported with the HM II.

Figures

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
Nir Uriel, MD,* Sang-Woo Pak, MD,† Ulrich P. Jorde, MD,* Brigitte Jude, MD, PHD,‡
Sophie Susen, MD, P
HD,‡ Andre Vincentelli, MD,§ Pierre-Vladimir Ennezat, MD,‡
Sarah Cappleman, BA,† Yoshifumi Naka, MD, P
HD,† Donna Mancini, MD*
New York, New York; and Lille, France
Objectives The objective of the study was to determine the prevalence of bleeding during continuous-flow left ventricular
assist device support and to identify potential mechanisms for those bleeding events.
Background Bleeding is frequently reported with continuous-flow left ventricular assist devices and may result from anticoag-
ulation coupled with bleeding diathesis such as acquired von Willebrand syndrome. Accordingly, the prevalence
of coagulation abnormalities including laboratory assessment for von Willebrand syndrome, bleeding events dur-
ing device support, and at heart transplantation were evaluated.
Methods A retrospective study in all HeartMate II (HM II) (Thoratec Corp., Pleasanton, California) patients who underwent im-
plantation between April 1, 2004, and August 1, 2009, was performed. Bleeding was defined as the need for transfu-
sion 7 days after device insertion of1Uofpacked red blood cells. Transfusion at heart transplantation was com-
pared with that in HeartMate XVE patients.
Results Seventy-nine HM II devices were implanted. Anticoagulation included warfarin in 68.3%, aspirin in 55.7%, and
dipyridamole in 58.2% of the patients. Of the patients, 44.3% had bleeding episodes at 112 183 days after
left ventricular assist device implantation, with 50% experiencing an event within 2 months. Gastrointestinal
bleeding was the most frequent event. At the index event, the international normalized ratio averaged 1.67
0.53, and the platelet count was 237 119 10
9
/l. Comparison of the transfusion requirements at heart
transplantation of 35 HM II patients with 62 HeartMate XVE patients demonstrated twice the transfusion re-
quirements in HM II patients (packed red blood cells, 6.3 0.8 U vs. 3.8 0.5 U; platelets, 12.5 5.4 U vs.
8.6 6.4 U; fresh frozen plasma, 9.6 4.9 U vs. 4.9 3.6 U; and cryoprecipitate, 4.3 3.6 U vs. 2.2 3.5 U;
p 0.05 for all). High molecular weight von Willebrand factor multimers were measured in 31 HM II patients
and were reduced in all patients; 18 of these 31 (58%) patients had bleeding.
Conclusions Patients with the HM II had a high incidence of bleeding events during device support and at heart transplanta-
tion. All HM II patients had reduced high molecular weight von Willebrand factor multimers. The role of these
abnormalities in the high incidence of bleeding deserves further investigation. Furthermore, alterations in anti-
coagulation should be considered during device support and before surgery in patients supported with the
HM II. (J Am Coll Cardiol 2010;56:1207–13) © 2010 by the American College of Cardiology Foundation
Left ventricular assist device (LVAD) therapy is being
increasingly used in patients with advanced heart failure as
either a bridge to transplantation or an alternative to
transplantation (i.e., destination therapy [DT]). The limited
durability and thrombotic complications of the first-
See page 1214
generation mechanical support devices precluded wide-
spread application. Newer generation mechanical devices
using axial continuous-flow pumps have been increasingly
used as a bridge to transplantation. Axial flow pump design
includes a single moving part, the rotor, suspended by
From the *Department of Medicine, College of Physicians and Surgeons, Columbia
University, New York, New York; Department of Surgery, College of Physicians and
Surgeons, Columbia University, New York, New York; ‡Department of Medicine,
University of Lille, Lille, France; and the §Department of Surgery, University of Lille,
Lille, France. Dr. Jorde has received consulting fees from Trantec. Dr. Naka is a
consultant for Terumo Heart Inc., Thoratec Co., and Cardiomems. Dr. Mancini is a
consultant for Celladon Corp. and ACORN Inc. All other authors have reported that
they have no relationships to disclose.
Manuscript received February 19, 2010; revised manuscript received May 20, 2010;
accepted May 25, 2010.
Journal of the American College of Cardiology Vol. 56, No. 15, 2010
© 2010 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00
Published by Elsevier Inc. doi:10.1016/j.jacc.2010.05.016
bearings that quietly spin at
8,800 to 10,000 rpm. The re-
duced size, increased durability,
ease of implantation, and re-
duced infections associated with
these pumps are some of the
advantages of these new devices.
Clinical trials using these newer
pump designs have demonstrated
efficacy in providing hemody-
namic support and a favorable
risk-to-benefit ratio in both bridge
to transplantation (1) and DT (2)
populations. However, thrombo-
embolic events are still frequent
adverse events with these devices,
which require the use of long-term
anticoagulation therapy with both
warfarin and antiplatelet drugs.
Bleeding complications associated
with these devices range from as
low as 17.5% (3) to as high as 63 events/100 patient-years
(4). Owing to the need for anticoagulation, a greater
prevalence of bleeding is anticipated with continuous-flow
devices such as the HeartMate II (HM II) (Thoratec Corp.,
Pleasanton, California) than with the pulsatile devices such
as the HeartMate XVE (HM XVE) (Thoratec Corp.).
Whether this bleeding tendency is simply a consequence of
anticoagulation therapy has recently been challenged by
reports that suggest that the device design affects hemostatic
factors and results in acquired von Willebrand (VW) syn-
drome (5–7).
Accordingly, we reviewed our experience with a commonly
used axial flow pump, the HM II, to better define the
prevalence of bleeding in these patients and the need for
transfusion during subsequent surgeries, notably heart trans-
plantation (HT). In those patients with bleeding complica-
tions, hemostasis studies were performed to determine whether
acquired WV syndrome developed in these patients.
Methods
A retrospective chart review was performed from April 1,
2004, to August 1, 2009, of all continuous-flow device
patients who underwent implantation at a single large
medical center. Minor bleeding was defined as observable
blood loss without the need for transfusion. Major bleeding
was defined as need for blood transfusion 7 days after
device insertion. Hemorrhagic events analyzed included
hemorrhagic stroke and bleeding requiring at least1Uof
packed red blood cells. Blood transfusion for hemolysis (n 1)
was excluded from the bleeding analysis. Thrombotic events
analyzed included ischemic stroke, pump thrombosis, and
systemic embolic events. Stroke was defined as any neuro-
logic event lasting 24 h and categorized as having a
hemorrhagic or thromboembolic etiology according to the
results of intracranial imaging. Pump thrombosis was de-
fined as any thrombus within the device or its conduits
associated with clinical signs of impaired pump perfor-
mance.
Blood product requirements during HT were collected
and compared in patients bridged with HM II with patients
bridged with HM XVE.
Platelet counts, prothrombin time, partial thromboplastin
time, international normalized ratio (INR) were obtained in
all patients. von Willebrand factor (vWF) antigen (VWF:
Ag), vWF ristocetin cofactor activity (VWF:Rco), and vWF
multimeric structure were measured in patients with major
bleeding events or before HT and in a random group of
patients with heart failure before HM II support or during
support with other devices. vWF:Ag was measured using an
immunoturbidiumetric assay, and vWF:Rco was measured
using platelet aggregometer PAP4. The multimeric struc-
ture analysis was performed as described by Daniels et al.
(8), and represents a qualitative measurement of the pres-
ence or absence of the largest vWF multimers (high
molecular weight [HMW]). Acquired vW syndrome was
defined as the decrease in or absence of the largest vW
multimers (HMW). Serial testing was obtained in those
patients who underwent HT.
Statistical analysis. Data were collected using Excel Soft-
ware (2007 Microsoft Corp., Redmond, Washington). All
data were analyzed using the Stata version 11.0 (StataCorp.,
College Station, Texas). Categorical variables were summa-
rized by frequencies and percentages, and were analyzed
using chi-square test. Student t test for independent samples
was used to determine differences in normally distributed
data. The Wilcoxon rank sum test was used to determine
differences in non-normal distributions.
Results
Prevalence of bleeding in continuous-flow mechanical
assist devices. Seventy-nine patients (mean age 56 14
years) had an HM II implanted with 64 patients receiving
the device as bridge to transplantation and 15 patients
receiving it as DT. The patient population is described in
Table 1. During a follow-up period of 370 486 days
(range 3 to 1,978 days), 40 patients underwent HT; 15
patients died.
During LVAD support, 44 patients had no significant
bleeding episodes (Normal) and 35 patients (44.3%) had
major bleeding episodes (Bleed). The mean time to bleeding
from LVAD implantation was 112 183 days with 50% of
episodes occurring within 2 months (median 56 days).
The most common bleeding event was gastrointestinal;
24 patients had gastrointestinal bleeding, 21 patients un-
derwent at least 1 endoscopy, whereas 5 patients had
multiple endoscopies. Chest bleeding requiring a surgical
procedure was reported in 7 patients (pericardial effusion/
tamponade in 6 patients and pleural effusion in 1 patient).
Other bleeding sources included oral (after dental extrac-
Abbreviations
and Acronyms
DT destination therapy
HM II HeartMate II
HMW high molecular
weight
HM XVE HeartMate XVE
HT heart transplantation
INR international
normalized ratio
LVAD left ventricular
assist device
vW von Willebrand
vWF von Willebrand
factor
vWF:Ag von Willebrand
factor antigen
vWF:Rco von Willebrand
ristocetin cofactor
1208 Uriel
et al.
JACC Vol. 56, No. 15, 2010
High Rate of Bleeding With Continuous-Flow Devices
October 5, 2010:1207–13
tion, n 1), muscle (n 1), epistaxis (n 1), and
post-menopausal bleeding (4 episodes). Epistaxis was re-
ported in 7 patients, but only 1 patient required blood
transfusion. Transfusion requirements averaged 5.7 U of
packed red blood cells per bleeding patient (range 2 to
140 U) (Table 2).
Major bleeding events were observed more frequently in
older patients (Fig. 1) (60.1 13.5 years vs. 53.4 13.2
years, p 0.03) and those with ischemic cardiomyopathy as
their underlying heart failure etiology (58.8% vs. 33.3%, p
0.03) Hypertension was also more common (61.8% vs.
46.4%, p 0.026).
Anticoagulant use at the time of a bleeding event was not
statistically different between the groups (Table 3). The
INR averaged 1.67 0.53 with an INR 2.5 noted only in
2 patients. The platelet count was 237 119 10
9
/l, with
a low platelet count in 1 patient (48 10
9
/l). Five patients
experienced thromboembolic events: 2 had cerebrovascular
accidents in the middle cerebral artery territory, 1 had a
popliteal artery embolism, and 2 embolic events were noted
after treatment with intravenous immunoglobulin (1 sys-
temic event with a fatal outcome and 1 aortic valve throm-
bus event). The mean time to thromboembolic events after
LVAD implantation was 126 134 days, whereas 50%
experienced the event within 2 months (median 30 days).
Comparison of blood transfusion requirements during
HT in patients bridged with continuous-flow devices
versus pulsatile flow devices. Thirty-five patients (age
53 2 years, 84.2% men) with an HM II underwent HT.
Their blood product requirements during surgery were
compared with those of 62 patients (age 53 2 years,
80.6% men) with an HM XVE who underwent HT during
the same time period. More HM II patients were treated
with warfarin (89.5% vs. 31.2%, p 0.001), aspirin (76.3%
vs. 59.0%, p 0.078), and dipyridamole (63.2% vs. 0%, p
0.001). Patients supported with an HM II required twice
the amount of blood products during HT compared with
patients supported with an HM XVE (Table 4). Comparing
HM II patients with a subgroup of HM XVE patients who
also received warfarin treatment revealed the same differ-
ences in transfusion requirements after HT.
Figure 1 Bleeding Frequency per Quartile Age Group
Major bleeding events occurred more frequently in older patients, with patients
older than age 66 years having twice the risk of bleeding during device support
compared with patients younger than 44 years of age. Age groups: 18 to 44
years, n 20; 45 to 59 years, n 19; 60 to 66 years, n 19; 66 years
(n 20); p 0.027.
HM II Patient Characteristics (n 79)
Table 1 HM II Patient Characteristics (n 79)
Age (yrs) 56.3 13.7
Male sex, n (%) 63 (79.8)
Body mass index (kg/m
2
) 25.9 5.0
BTT/DT 63/14
Heart failure etiology, n (%)
ICM 33 (45.2)
DCM 40 (54.8)
Previous thoracic surgery, n (%) 22 (29.0)
Diabetes, n (%) 26 (33.3)
Hypertension, n (%) 37 (47.4)
Left ventricular ejection fraction 16.1 7.2
Obstructive lung disease, n (%) 6 (7.7)
Lietz score (n 63) 9.1
BTT bridge to transplantation; DCM dilated cardiomyopathy; DT destination therapy;
HM II HeartMate II; ICM ischemic cardiomyopathy.
Bleeding Events Requiring Transfusion
Table 2 Bleeding Events Requiring Transfusion
Event Site n Event
GI 24
Chest 7 6 pericardial effusion, 1 hemothorax
Other 3 Dental, LE wound, postmenopausal
Epistaxis 1
Total 35
GI gastrointestinal; LE lower extremity.
Comparison of Clinical Characteristics ofPatients Who Did and Did Not Bleed
Table 3
Comparison of Clinical Characteristics of
Patients Who Did and Did Not Bleed
Characteristic Bleed Normal p Value
Age (yrs) 60.1 13.5 53.4 13.2 0.031
Male sex, n (%) 30 (85.7) 33 (75) 0.239
Basic metabolic index 26.3 5.4 25.3 4.5 0.398
Ejection fraction (%) 16.1 6.0 16.1 8.3 0.998
BTT, n (%) 26/8 (76.5) 37/6 (86.1) 0.279
HF etiology, n (%)
ICM 20 (58.8) 13 (33.3) 0.029
DCM 14 (41.2) 26 (66.7)
Diabetes 12 (35.3) 14 (31.8) 0.747
Hypertension 21 (61.8) 16 (46.4) 0.026
COPD 3 (8.8) 3 (6.8) 1
Lietz score 9.28 4.8 8.97 5.8 0.822
Anticoagulation, n (%)
Warfarin 24 (75.0) 30 (79.0) 0.695
Aspirin 19 (59.4) 25 (65.8) 0.58
Dipyridamole 20 (62.5) 26 (68.4) 0.603
BTT bridge to transplantation; COPD chronic obstructive pulmonary disease; HF heart
failure; other abbreviations as in Table 1.
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Uriel
et al.
October 5, 2010:1207–13
High Rate of Bleeding With Continuous-Flow Devices
Possible mechanism: acquired VW syndrome and
continuous-flow assist devices. Thirty-one patients (27
men) with HM II support were evaluated for vW
syndrome; 18 patients were tested after major bleeding
events and 13 were tested before anticipated surgeries.
All patients had decreased or absent HMW forms of
vWF needed for platelet adhesion, which is sufficient for
the diagnosis of acquired vW syndrome. vWF:Ag was
204 107%, and vWF:Rco was 102 27%, both within
normal range. When the levels of vWF:Ag and vWF:Rco
were divided by the median level and the incidence of
bleeding in those groups were compared, no significant
differences in bleeding events were noted (p 0.45 and
p 0.275, respectively).
All patients tested with bleeding events had vW syn-
drome with decreased to absent HMW vW multimers.
Sixteen patients had gastrointestinal bleeding, and 2 pa-
tients had pericardial bleeding.
In all 6 patients who had vWF levels measured during HM
II support and repeated after HT, there was normalization of
the HMW vWF multimer levels with a statistically significant
elevation in vWF:Ag and vWF:Rco (Table 5). In 1 patient,
normal HMW vWF multimer levels pre-implantation de-
creased with HM II support.
Additionally, vWF levels were measured in a variety of
advanced heart failure conditions in random fashion. Three
patients with advanced heart failure on inotropic support
had normal HMW vWF multimer levels. Two patients
with an HM XVE and 1 patient with a Duraheart (Terumo
Heart Inc., Ann Arbor, Michigan) had normal HMW vWF
multimer levels. One patient with CentriMag BiVad (Tho-
ratec Corp.) support as a bridge to transplantation had
decreased HMW vWF multimers. None of the patients
with normal vWF multimer levels had a bleeding event (18
of31vs.0of6,p 0.001).
Discussion
We examined the prevalence of major bleeding episodes in
advanced heart failure patients supported with a continuous-
flow LVAD (HM II). vWF levels were studied during the
support time, and blood product requirements were collected
in those patients who underwent HT. Thirty-five patients
(44.3%) had major bleeding episodes at a median time of 56
days after device implantation; gastrointestinal bleeding was
the most common source. At HT, HM II patients required
significantly higher amounts of blood products compared with
HM XVE patients, even a subgroup receiving warfarin. Ac-
quired vW syndrome developed in all patients on device
support diagnosed by the decrease in or absence of HMW
vWF multimers. This hemostatic abnormality may explain the
excessive bleeding in the continuous-flow device patients.
In recent years, LVADs using rotary pump technology to
provide continuous flow with reduced pulsatility have
shown great promise (1,2). These continuous-flow LVADs
improve hemodynamics, end-organ function, quality of life,
and functional capacity of patients awaiting HT (1,9).
Recently, Slaughter et al. (2) reported that implantation of
a continuous-flow LVAD, compared with a pulsatile-flow
device, significantly improved survival at 2 years in patients
with advanced heart failure who were ineligible for HT.
Based on these and other clinical data, many centers have
transitioned from pulsatile-flow devices to continuous-flow
devices. With the recent approval of the HM II by the U.S.
Food and Drug Administration as DT, an increase in
LVAD implantation among patients who are ineligible for
HT is anticipated.
Patients with continuous-flow devices require anticoagu-
lation and antiplatelet agents to attenuate the risk of
thromboembolic events. Results from the HM II Pivotal
Trial supported the use of aspirin at a dose of 81 mg/day and
warfarin achieving and maintaining an INR of 2.0 to 3.0 as
soon as post-operative bleeding was controlled. Case series
have suggested that gastrointestinal bleeding may be a more
frequent complication with continuous-flow devices (10).
Crow et al. (4) reported in a series of 101 patients that the
rate of gastrointestinal bleeding was significantly higher in
patients receiving continuous-flow LVADs compared with
pulsatile devices. There were 63 gastrointestinal bleeding
events per 100 patient-years in nonpulsatile device recipi-
ents compared with 6.8 in the pulsatile group (p 0.0004).
Possible pathophysiological explanations for these phenom-
ena included the increased use of anticoagulation and/or the
development of a bleeding diathesis.
Transfusion RequirementsDuring Heart Transplantation
Table 4
Transfusion Requirements
During Heart Transplantation
HM XVE (n 62) HM II (n 35) p Value
Packed red blood cells (U) 3.8 0.5 6.3 0.8 0.0055
Platelets (U) 8.6 6.4 12.5 5.4 0.0027
Fresh frozen plasma (U) 4.9 3.6 9.6 4.9 0.0000
Cryoprecipitate (U) 2.2 3.5 4.3 3.6 0.0035
CellSaver (U) 3.9 2.3 5.0 4.0 0.50
HM HeartMate.
von Willebrand Factor Levels (n 31)
Table 5 von Willebrand Factor Levels (n 31)
During VAD Use After HT p Value
Decreased or absent VW multimers 100% 0% 0.001
VW antigen 203.5 107.1, median 187 309.5 83.0, median 327 0.03
Ristocetin 102.4 26.6, median 117 144.0 53.7, median 120 0.009
VAD ventricular-assist device; VW von Willebrand.
1210 Uriel
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High Rate of Bleeding With Continuous-Flow Devices
October 5, 2010:1207–13
Multiple studies have been done using warfarin in chronic
heart failure patients. In the HELAS (Heart Failure Long
Term Antithrombotic Study), 197 chronic heart failure
patients were randomized to treatment with aspirin or
warfarin. Major hemorrhage occurred in the warfarin group
at a rate of 0.046 per patient-year and was to the result of
overanticoagulation. Similar results were reported in the
WASH (Warfarin/Aspirin Study in Heart Failure) (11,12).
The WATCH (Warfarin and Antiplatelet Therapy in
Heart Failure Trial) (13) examined the role of anticoagula-
tion in 1,587 chronic heart failure patients and compared
warfarin, aspirin, and clopidogrel. Although increased
bleeding was reported in the warfarin group (5.2% vs. 3.6%
vs. 2.1%, respectively), this bleeding rate is significantly
lower than the event rate observed in our series. In the
context of these studies, our findings suggest that the high
bleeding rate seen in our cohort cannot be totally attributed
to anticoagulation therapy.
In 1958, Heyde et al. (14) reported a high incidence of
gastrointestinal bleeding in aortic stenosis patients (Heyde
syndrome). In the 1990s, Warkentin et al. (15) raised the
question of whether stenotic aortic valves predisposed pa-
tients to the development of acquired vW syndrome, which
could contribute to high bleeding events from gastrointes-
tinal angiodysplasia, which is common in these patients.
Further studies by several investigators have shown that
aortic stenosis and gastrointestinal bleeding are associated
with acquired type 2A vW syndrome, which is characterized
by the loss of HMW vWF multimers (15,16). High shear
forces induce structural changes in the shape of the vWF
molecule, leading to exposure of the bond between amino
acids 842 and 843. This results in proteolysis of the highest
molecular weight multimers of vWF, which are the most
effective in platelet-mediated hemostasis under conditions
of high shear stress (17,18). Aortic valve replacement
reverses this hematological syndrome (19,20). Continuous-
flow LVADs may cause a similar syndrome. Geisen et al. (7)
reported an impaired function of vWF with respect to
binding to collagen and to platelet receptor GPIb (reflected
by ristocetin cofactor activity) and loss of HMW biologi-
cally active vWF multimers in 7 HM II patients. In our
study, all HM II patients who underwent vWF testing had
low to absent levels of HMW vWF multimers. HT reversed
this phenomenon, suggesting that the LVAD support was
causative of acquired VW syndrome. The vWF level
changes in our cohort are especially noteworthy, given the
study by Lip et al. (21) that demonstrated a positive
correlation between heart failure and increased plasma vWF
concentrations, with highest plasma vWF levels in patients
with acute or recent decompensated chronic heart failure.
In a recent study of HM II patients by Boyle et al. (3), the
rate of thromboembolic events (3%) was not dissimilar from
our findings (6.3%). Anticoagulation is indicated but given
the development of acquired vW syndrome in continuous-
flow LVAD patients, the current guidelines recommending
the use of warfarin in conjunction with antiplatelet agents
needs to be reconsidered. The role of routine follow-up of
vWF levels and the adjustment of antiplatelets and/or the
INR levels to the degree of acquired vW syndrome severity
should be studied. Although this study focused on the HM
II, this phenomenon may be occurring with other
continuous-flow devices. vWF abnormalities were also de-
scribed in BiVad devices (7) and centrifugal pumps (6), and
the clinical implication of those findings may be similar:
increased major bleeding events and need for more blood
products during HT.
The effects of this bleeding diathesis may change the
course of the HT in patients bridged with HM II. During
HT surgery, patients with HM II received double the
amount of blood products than did patients bridged with
the HM XVE. Kuduvalli et al. (22) reported that periop-
erative red blood cell transfusion after cardiac procedures
was associated with an increased risk of death during a
1-year follow-up. In general, transfusions of blood products
are associated with increased risk of short- and long-term
complications. Minor transfusion reactions, such as fever
and hypotension, occur frequently. Major transfusion reac-
tion such as transfusion-related acute lung injury and a
pulmonary leukoagglutinin reaction are less common (23).
In our population, transfusion-related acute lung injury
might have been masked because clinical signs can be
confounded by post-operative complications such as atelec-
tasia, congestive heart failure, and pleural fluid or as a
consequence of ischemia and reperfusion injury induced by
cardiopulmonary bypass (24). Other complications may
result from substantial changes in the immune system after
transfusion. Banbury et al. (25) reported that the risk
of infection increased incrementally with each unit of
blood transfused in 15,592 post-cardiac surgery patients.
Those infections can include bacteria/viral (e.g., human
immunodeficiency virus, hepatitis B virus, hepatitis C vi-
rus) and transmissible spongiform encephalopathies (e.g.,
Creutzfeldt-Jacob disease) (26). Whether the increase in
blood product transfusions observed in our series carries an
increased risk of the complications mentioned needs to be
investigated.
The effect of LVAD on post-transplantation mortality
was a subject for many studies and yielded conflicting
results. Recently, Patlolla et al. (27) conducted a retrospec-
tive analysis in 11,336 patients entered into the United
Network for Organ Sharing Thoracic Registry to examine
the relationship between intracorporeal and extracorporeal
VAD implantation and post-transplantation mortality.
They reported that intracorporeal ventricular assist devices
are associated with a small increase in mortality in the first
6 months and a clinically significant increase in mortality
beyond 5 years. The increased use of blood products that we
are reporting here may be an explanation for this report, by
increasing allosensitization during LVAD support. In con-
trast, Pal et al. (28) compared the transplantation outcomes
of patients bridged with an LVAD and intravenous ino-
tropes. They reported no increase in post-transplantation
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October 5, 2010:1207–13
High Rate of Bleeding With Continuous-Flow Devices
morbidity or mortality and did not observe an increased
incidence of rejection episodes in the first year after HT.
Furthermore, measured levels of anti– human leukocyte
antigen antibodies were similar in the LVAD group com-
pared with the intravenous inotrope group. Our group’s
analysis of the United Network for Organ Sharing data
for adult heart transplant recipients from January 1, 2001,
to December 31, 2006, found that the use of intracorpo-
real and paracorporeal devices was not associated with
decreased survival after HT (29) and concurs with the
report of Pal et al. (28).
Study limitations. This is a single-center study of a small
number of patients who were screened for vW syndrome if
bleeding was present or if surgery was anticipated. There-
fore, all device-supported patients were not screened. The
incidence and the timing of the development of this
syndrome cannot be derived from this study.
Conclusions
Patients supported by an HM II have a high risk of major
bleeding during the support time and at the time of HT.
The increased prevalence of bleeding with continuous-flow
devices is not explained by excessive anticoagulation ther-
apy. Acquired vW syndrome occurs almost uniformly in
patients on continuous-flow assist devices and appears to be
a significant contributor to the observed bleeding. Bleeding
during HM II support is particularly frequent in older
patients and, unless prevented, may constitute a major
limitation of DT. Routine monitoring of vWF multimers or
of their activity and alteration of anticoagulation treatment
in these patients should be addressed.
Given our current observations, our program has de-
veloped the following approach to bleeding complications
in patients with continuous-flow devices. All anticoagu-
lation medications are discontinued during the bleeding
episode and until hemodynamic stability is achieved. The
bleeding site is identified and corrected, if possible. After
stabilization of hemoglobin levels, anticoagulation treat-
ment is resumed on an individual patient basis consider-
ing the extent of bleeding, the patient’s age, and the risk
of thrombosis. The majority of patients are restarted on
warfarin or aspirin alone. Although we can hypothesize
that platelet inhibitors should be discontinued once a
decrease in HMW vWF multimers is observed, we do not
have enough data to recommend anticoagulation changes
according to vWF studies. A randomized, multicenter,
prospective trial is needed to define the optimal antico-
agulation regimen for patients supported with
continuous-flow devices.
Reprint requests and correspondence: Dr. Donna Mancini,
Division of Cardiology, Columbia University College of Physi-
cians and Surgeons, 622 West 168th Street, PH1273, New York,
New York 10032. E-mail: dmm31@columbia.edu.
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October 5, 2010:1207–13
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Key Words: bleeding y heart transplant y left ventricular assist devices
y von Willebrand syndrome.
1213
JACC Vol. 56, No. 15, 2010
Uriel
et al.
October 5, 2010:1207–13
High Rate of Bleeding With Continuous-Flow Devices
    • "Nearly 30% of those patients also experienced bleeding complications. Other studies and case reports have found similar issues in both continuous flow devices [106][107][108]and pulsatile "
    [Show abstract] [Hide abstract] ABSTRACT: After many decades of improvements in mechanical circulatory assist devices (CADs), blood damage remains a serious problem during support contributing to variety of adverse events, and consequently affecting patient survival and quality of life. The mechanisms of cumulative cell damage in continuous-flow blood pumps are still not fully understood despite numerous in vitro, in vivo, and in silico studies of blood trauma. Previous investigations have almost exclusively focused on lethal blood damage, namely hemolysis, which is typically negligible during normal operation of current generation CADs. The measurement of plasma free hemoglobin (plfHb) concentration to characterize hemolysis is straightforward, however sublethal trauma is more difficult to detect and quantify since no simple direct test exists. Similarly, while multiple studies have focused on thrombosis within blood pumps and accessories, sublethal blood trauma and its sequelae have yet to be adequately documented or characterized. This review summarizes the current understanding of sublethal trauma to red blood cells (RBCs) produced by exposure of blood to flow parameters and conditions similar to those within CADs. It also suggests potential strategies to reduce and/or prevent RBC sublethal damage in a clinically-relevant context, and encourages new research into this relatively uncharted territory.
    Full-text · Article · Mar 2016
    • "However, we could not associate the HCV false positive serological reaction with a higher rate of anti-HLA antibodies (data not shown). It is also well established that continuous flow devices, like LVAD, may cause acquired Von Willebrand disease, probably due to high shear stress that may enhance proteolysis of large Von Willebrand factor (VWF) multimers [11]. An interaction of smaller VWF multimers with the immunoassay may also be a hypothesis to explain this nonspecific reaction of the routinely used HCV serology tests. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Left ventricular assist devices (LVAD) are a therapeutic choice for patients with advanced heart failure prior cardiac transplantation. Patients with a LVAD implant are frequently monitored for hepatitis C virus (HCV) as a positive result may be an exclusion criterion for transplantation. Objectives: To determine the rate of false positive results with immunoassays for HCV antibodies in a LVAD population. Study design: Between June 2011 and January 2015, HCV antibody testing using a chemiluminescent immunoassay (CLIA) (Liaison, Diasorin) was performed for 32 patients prior and post LVAD implantation. A HCV reactive result by CLIA was repeated and further tested by an enzyme linked fluorescent assay (ELFA) (VIDAS, bioMérieux). For patients with a positive HCV CLIA and ELFA test, immunoblot and HCV RNA detection were performed. Results: Prior to LVAD implantation, all patients showed a negative HCV serology. After LVAD implantation, 19 patients (59%) had positive results for HCV antibody using CLIA and ELFA technologies. The HCV immunoblot was negative for 17 patients and indeterminate for two patients. For 15 patients, HCV RNA detection was performed and was undetectable. Actually, no HCV infections were observed among those who were tested for HCV RNA. Conclusions: HCV serological tests routinely used in our laboratories are not reliable in patients with cardiac devices. A positive CLIA and/or ELFA reaction in patients with a LVAD should be confirmed by HCV immunoblot and by HCV RNA PCR detection in order to rule out a HCV infection.
    Full-text · Article · Mar 2016
    • "disease, vWF – von Willebrand factor, vWF:Ag – vWF antigen, vWF:RCo – vWFristocetin cofactor, FVIII:C – FVIII coagulant activity, vWF:CB – vWF collagen binding, N – normal, A – absent, ↓ – low, ↓↓↓ – very low, HMWM – high-molecular-weight multimersBoth, retrospective and prospective studies, report that LVAD implantation leads to substantial reductions in HMWM of vWF[14,15]. The triad: angiodysplasia, aVS2A, and GI bleeding (Fig. 1) share a striking resemblance with Heyde's syndrome. "
    [Show abstract] [Hide abstract] ABSTRACT: Mechanical circulatory support (MCS) is an umbrella term describing the various technologies used in both short-and longterm management of patients with either end-stage chronic heart failure (HF) or acute HF. Most often, MCS has emerged as a bridge to transplantation, but more recently it is also used as a destination therapy. Mechanical circulatory support includes left ventricular assist device (LVAD) or bi-ventricular assist device (Bi-VAD). Currently, 2-to 3-year survival in carefully selected patients is much better than with medical therapy. However, MCS therapy is hampered by sometimes life-Threatening complications including bleeding and device thrombosis. Von Willebrand factor (vWF) has two major functions in haemostasis. First, it plays a crucial role in platelet-subendothelium adhesion and platelet-platelet interactions (aggregation). Second, it is the carrier of factor VIII (FVIII) in plasma. Von Willebrand factor prolongs FVIII half-Time by protecting it from proteolytic degradation. It delivers FVIII to the site of vascular injury thus enhancing haemostatic process. On one hand, high plasma levels of vWF have been associated with an increased risk of thrombosis. On the other, defects or deficiencies of vWF underlie the inherited von Willebrand disease or acquired von Willebrand syndrome. Here we review the pathophysiology of thrombosis and bleeding associated with vWF.
    Article · Dec 2015
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