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Experimental Designs for In Vitro Assessment of Valve Thrombosis Chapter | 28 415
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CONCLUSIONS
In conclusion, in this chapter, we explored the current understanding in evaluating the blood compatibility of biomaterials
and discussed practical testing requirements with a focus on hemocompatibility assessment of prosthetic heart valves.
We also reviewed the most relevant studies regarding in vitro assessment of prosthetic heart valves and summarized the
attempts to minimize the risk of valve thrombosis. As Chaux and associates state [162], the elusive “Holy Grail” for heart
valve replacement continues to be a prosthesis that does not require anticoagulation, has excellent hemodynamic performance, and is durable throughout the projected lifetime of all possible recip ients. Considering the significant progress
that has been made in understanding the mechanisms of valve thrombosis and considering the enhanced capabilities of
modern scientific testing and measurement, vigorous efforts are under way to achieve this long-standing goal.
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7.
Chapter 29
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Ventricular Assist Device Thrombosis:
Past, Present, and Future
Edward J. Sawey
1
Virginia Commonwealth University Health System, Richmond, VA, United States;2Hunter Holmes McGuire VA Medical Center, Richmond, VA,
United States
1,2
, Anit Mankad
1,2
and Neil P. Lewis
1,2
INTRODUCTION AND HISTORY
As new treatments emerge for advanced disease, we often discover new complications or diseases that need to be
addressed. While the left-ventricular assist device (LVAD) has increased life expectancy and quality of life in advanced
heart failure patients, it has come with some adverse consequences. In this chapter, we will cover LVAD thrombosis in
detail, from the history and incidence in the first-generation devices up to the newest generation of devices.
The first generation of electrically driven LVADs, the HeartMate XVE and the Novacor device, were pulsatile flow
devices. They were large, cumbersome, and noisy, but became the first LVADs approved as a bridge to transplantation
(BTT) [1,2]. The Novacor device required anticoagulation to prevent pump thrombosis. The HeartMate XVE did not
require anticoagulation because of its textured inner surface. Neither of these devices had a high incidence of pump
thrombosis. Regrettably, the Novacor device suffered from a high incidence of stroke, with a 10-fold higher stroke
incidence compared with the HeartMate XVE [50]. This led most institutions to use the HeartMate XVE. The major
drawback to these devices was their high rate of mechanical malfunction and failure due to lack of durability. The average
time to mechanical failure requiring device replacement for pulsatile LVADs was 1.5 years [2].
The concept of using an LVAD as a permanent treatment for end-stage heart failure was assessed in the landmark
Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) trial. Two
groups were random ized to either continuous pulsatile LVAD (HeartMate XVE) support or optimal medical management.
The results were highly encouraging, with a 1-year survival in the device arm of 52% versus 25% in the medical management arm. Patients treated with LVAD were signi ficantly less physically limited and had significantly less depression
than those managed with optimal medical therapy. Only 7 of the 68 device-treated patients died because of LVAD failure.
The event rate of device malfunction was 0.75 event per patient year. The take-home message from this trial was that
although pulsatile VADs made patients feel better and were useful as a BTT, they were not durable enough to be truly
considered for destination therapy (DT) [3].
The next generation of devices, HeartMate II and HeartWare, were based on a continuous-flow (CF) design. The US
FDA approved a nonrandomized, prospective clinical trial to determine the safety and effectiveness of the HeartMate II
LVAD as a bridge to cardiac transplantation in 2005. Of the 133 patients that were enrolled, 100 patients (75%) reached the
primary end point of heart transplantation, cardiac recovery, or survival at 180 days with ongoing mechanical support [4].
The results of the initial BTT trial prompted US approval of the HeartMate II for indication of BTT in April 2008.
In 2008, a direct comparison of a CF LVAD with a pulsatile LVAD was made in the DT clinical trial sponsored by the
Thoratec Corp. A total of 200 patients, 134 in the CF device arm and 66 in the pulsatile device arm, were followed for at
least 2 years until death, transplantation, or device explantation. Overall, actuarial survival was significantly better in
patients who received the CF device (68% at 1 year and 58% at 2 years) versus the pulsatile group (55% at 1 year and 24%
at 2 years) [5]. The HeartMate II device was also US FDA approved for DT, albeit a few years later.
Cardiovascular Thrombus. https://doi.org/10.1016/B978-0-12-812615-8.00029-6
Copyright © 2018 Elsevier Inc. All rights reserved.
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CF LVADs have had significant issues with pump thrombosis since their inception. Unlike the HeartMate XVE,
patients must maintain continuous therapeutic anticoagulation to prevent thrombus formation in CF pumps. Although there
are significant issues with bleeding related to LVADs and anticoagulation, they are generally not associated with severe
debility or mortality [6] . Pump thrombosis is far more clinically consequential, as it is associated with debilitating stroke,
reoperation for pump replacement, and significant mortality. As will become apparent throughout this chapter, there has
been considerable controversy over the classification and prevention of these thrombotic events. The remainder of this
chapter will explore the etiology, pathophysiology, diagnosis, and treatment of LVAD thrombosis in detail.
INCIDENCE AND EVENT RATE
CF LVADs have thus proven to be the best option at the time of this writing for long-term support in end-stage congestive
heart failure. At least 18,385 patients have received LVADs in the United States since 2007 [7] and that number is likely to
increase in magnitude due to the high incidence of end-stage heart failure. Consequently, pump thrombosis is and will
continue to be a significant cause of morbidity and mortality in this population.
The definition of pump thrombosis for the purposes of research is significantly different from the definition of pump
thrombosis for clinical diagnosis and treatment. When discussing the incidence of pump thrombosis, most studies
encompass a definition that includes actual visualization of a thrombus inside the pump after explantation as a necessary
criterion. Most of these studies do allow for tracking probable pump thrombosis in patients whose device failed, leading to
patient mortality. This definition is not very useful for clinical purposes; clinical diagnostic definitions and criteria will be
discussed later in this chapter.
INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) tracks device malfunction and/or
pump thrombosis and reports the patient count and event count quarterly. The overwhelming majority of patients in the
INTERMACS database are HeartMate II recipients. Events are divided into early and late events, which correspond to
the first 3 months after implant and 3 months or more after implant, respectively. Per the INTERMACS 2016 Q3 report [7],
the early percentage of patients experiencing an event was 8.1% versus 19.1% in the late group. Due to the longer period of
follow-up in the late group, the actual event rate per 100 patient months decreased by almost 50%, with INTERMACS
reporting 3.51 early events versus 1.89 events in the late group. Still, these data imply that greater than 25% of the LVAD
population is experiencing pump thrombosis.
During the premarket approval studies for the HeartMate II device, freedom from device malfunction resulting in
device replacement or death was 95% at 6 months and 93% at 1 year [8]. Approximately 1/3 of these events were for pump
thrombosis. Postmarketing approval trials studies of the HeartMate II device provide a reference occurrence of thrombosis
of 2%e4% per patient year. Pump thrombosis rates were noted to persist at this low rate of incidence until early 2011. At
this time, there was large increase in the inci dence of pump thrombosis reported by the Cleveland Clinic, Barnes Jewish
Hospital, and Duke University Medical Center. At 3 months postimplantation, the confirmed pump thrombosis rate rose
almost fourfold from 2.2% prior to March 2011 to 8.4% by 2013 [9]. Of the 72 pump thrombosis events in 66 patients, 11
of these patients were managed by emergent heart transplantation. A total of 21 pump thromboses were managed by pump
replacement in 19 patients.
Another analysis of the incidence of pump thrombosis in the HeartMate II device was conducted by Kirklin et al. [10].
His group reviewed the INTERMACS registry and performed an analysis of pump thrombosis in the HeartMate II. They
also detected an increase in the incidence of pump thrombosis. During the period between 2011 and 2012, the freedom
from device exchange due to definitive or probable pump thrombosis was 94%. This represented a small but significant
difference from the 99% freedom from device exchange (2010) following the same criteria. This was concerning because
of the number of devices that needed to be exchanged and because patients after device exchange suffered from a higher
rate of stroke and recurrent pump thrombosis compared with patients who did not require pump exchanges.
As awareness of LVAD throm bosis spread throughout the community there has been a multifaceted change in protocols
to attempt to lower the rate of pump thrombosis. Kirklin et al. produced a follow-up study in 2015 that showed pump
thrombosis rates tapering off but not returning to the initial levels reported in 2010 and 2011 [11]. They hypothesized that
although anticoagulation practices have mostly returned to their more aggressive levels, detection and awareness of pump
thrombosis is higher now compared with 2010, thus inflating the reported rates of pump thrombosis (Fig. 29.1).
In the HeartWare device group, Najjar and colleagues [12] compared the original 382-patient HeartWare BTT group
with the continued-access protocol group and analyzed the number of pump thrombosis events. There was a total of 34
pump thrombosis events in 31 patients. The overall rate of pump thrombosis in the entire cohort was 8.1%, or 0.08 event
per patient year. The INTERMACS 1.89 events per 100 patient months can be converted to 0.23 event per patient year.
Ventricular Assist Device Thrombosis: Past, Present, and Future Chapter | 29 423
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FIGURE 29.1 Hazard curves for the risk of HeartMate II pump thrombosis over time, stratified by year of implant. The dashed lines indicate
70% confidence limits. Note that the hazard for pump thrombosis for the first half of 2014 falls below that for 2012 and 2013. HMII, HeartMate II. Kirklin
JK, Naftel DC, Pagani FD, Kormos RL, Myers S, Acker MA, et al. Pump thrombosis in the Thoratec HeartMate II device: an update analysis of the
INTERMACS Registry. J Heart Lung Transplant 2015;34(12):1515e26. https://doi.org/10.1016/j.healun.2015.10.024.
The most recent data at this writing on HeartWare pump thrombosis can be found from the ENDURANCE trial [13].
This was a noninferiority trial placing the HeartWare in comparison with the HeartMate II. Although there was a twofold
decrease in the need for HeartWare device exchange compared with the HeartMate II, there was no significant difference
between the two devices and the rate of pump exchange because of device thrombosis.
CELLULAR AND MOLECULAR MECHANISMS OF PUMP THROMBUS FORMATION
There are two different types of pump thrombus, red thrombus and white thrombus, each representing a different
mechanism of formation. Red thrombus is composed predominantly of red blood cells in a fibrin mesh. It is formed in areas
of low pressure or stagnation, is soft in consistency, and is fast to form. This is the type of thrombus that forms in our
venous system or left-atrial appendage. This type of thrombus is more common in the HeartWare device [14,15].
White thrombus is composed predominantly of platelets and amorphous debris in a fibrin mesh. It is formed by shear
activation of platelets in areas of turbulent flow and is firm or hard in con sistency. In areas of turbulent flow it is difficult for
the platelets to set up a fibrin mesh that would capture red blood cells. This type of thrombus is more commonly associated
with the HeartMate II device [14,15].
Red thrombus is generally associated with acute catastrophic pump thrombosis, whereas white thrombus is associated
with a more insidious onset of pump thrombosis. Although each type of thrombus is generally associated with a different
device, most pump thrombosis is a combination of both white and red thrombi [14,15] (Fig. 29.2).
Thrombus formation inside the ventricular assist device has several proposed mechanisms. The first and most widely
accepted hypothesis relates to the inherent incompatibility between the surface of the device and the blood components.
This process is mediated by primary hemostasis and the intrinsic pathway of secondary hemostasis. Primary hemostasis is
initiated by the adsorption of coagulation proteins such as fibrinogen (mostly), fibronectin, vitronectin, and von Willebrand
factor (VWF). Platelets later bind to adsorbed proteins via platelet surface receptors such as glycoprotein (GP) Ib (CD42)
and GP IIb/IIIa (aIIbb3 integrin). Upon adhesion, platelets become activated, releasing dense granules, which cause further
platelet aggregation [16].
All blood pumps, of which LVADs are but one type, create heat that must be dissipated. As LVADs are completely
internalized pumps, all the heat created must be dissipated by blood flowing through the device. In an ex vivo study , it was
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FIGURE 29.2 Types of thrombi and their characteristics. RBC, red blood cell. Permission needed from Blitz A. Pump thrombosisda riddle wrapped
in a mystery inside an enigma. Ann Cardiothorac Surg 2014;3(5):450e71.
shown that temperatures above 37C could increase the amount of plasma adhesive proteins deposited on the surface of a
titanium device. As mentioned earlier, these proteins could activate platelets, initiating a thrombosis event [17].
With regard to platelet activation in response to thermal injury, it has been noted that thrombosis occurs more
frequently in pumps with lower speeds [18]. It has been proposed this is due to the decreased ability of thermal washout
due to the lower pump output [14]. This heat activates the platelets, maki ng degranulation more likely to occur during
contact with the LVAD rotor, thus initiating thrombosis events.
Shear stress on the multiple blood components may also contribute to pump thrombosis. The shear stress induced by
LVAD cleaves VWF into small multimers. The smaller VWF multimers tend to adhere to the surface of the pump and
increase the likelihood of activating platelets passing through the device. Furthermore, platelets themselves are activated by
shear stress, and may manifest elevated activation, having accumulated shear stress over time [19,20].
Areas of blood stasis within the device and within the inflow and outflow cannulas may also provide a nidus for clot
formation. As in Virchow’s triad of stasis, endothelial injury, and hypercoagulability, these conditions many times exist
within or in very closely proximity to the pump, causing thrombosis [21]. These causes of pump thrombosis will be
explored further in the risk factors section of this chapter.
RISK FACTORS FOR PUMP THROMBOSIS
Although the HeartMate II and HeartWare LVADs pump blood through different physical mechanisms, there seems to be a
good degree of overlap in the risk factors for pump thrombosis in patients with either device. The best data we have on risk
factors come from the INTERMACS database, which includes data on both models. First, we will present the risk factors
that overlap in both device models. At the end of this section we will highlight some of the differences in risk factors
between the two devices.
Risk factors for pump thrombosis can generally be broken down into three different categories: pump-related, patientrelated, and management-related (Fig. 29.3).
Of the pump-related risk factors, intrinsic heat generated by rotational movement of the pump, blood-to-surface
interactions, shear stress, and regions of blood flow stasis have been addressed in the previous section.
Inflow and outflow cannula migration and malpositioning are common causes of pump thrombosis. At the time of
LVAD insertion, the recipient heart is nearly always pathologically dilated. The position of the inflow and outflow
cannulas on initial insertion of the device end up changing as the internal dimensions of the heart decrease with the
persistent offloading offered by the CF LVAD. The HeartMate II may also migrate from its pump pocket, thus affecting the
positioning of the cannulas. Early experiences with the HeartMate II device revealed that the inflow and outflow cannula
were prone to bending as the dimensions of the heart became smaller, causing areas of impingement [22,23]. These areas of
impingement have been identi fied as leading to cannula thrombosis.
Patient-related factors are many and frequently problematic to manage. Atrial fibrillation (AF) provides a unique
challenge in that it is a prothrombotic condition that is independent of other factors. Theoretically, clots can form in the
left-atrial appendage and then migrate through to the pump, thus causing thrombosis. There are few data on AF and pump
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