Access to this full-text is provided by Frontiers.
Content available from Frontiers in Pediatrics
This content is subject to copyright.
REVIEW
published: 26 February 2021
doi: 10.3389/fped.2021.625632
Frontiers in Pediatrics | www.frontiersin.org 1February 2021 | Volume 9 | Article 625632
Edited by:
Marianne Nellis,
Cornell University, United States
Reviewed by:
Lisa A. Hensch,
Baylor College of Medicine,
United States
Zaccaria Ricci,
Bambino Gesù Children Hospital
(IRCCS), Italy
*Correspondence:
Muhammad Bakr Ghbeis
muhammad.ghbeis@
cardio.chboston.org
Specialty section:
This article was submitted to
Pediatric Critical Care,
a section of the journal
Frontiers in Pediatrics
Received: 03 November 2020
Accepted: 06 January 2021
Published: 26 February 2021
Citation:
Ghbeis MB, Vander Pluym CJ and
Thiagarajan RR (2021) Hemostatic
Challenges in Pediatric Critical Care
Medicine—Hemostatic Balance in
VAD. Front. Pediatr. 9:625632.
doi: 10.3389/fped.2021.625632
Hemostatic Challenges in Pediatric
Critical Care Medicine—Hemostatic
Balance in VAD
Muhammad Bakr Ghbeis 1
*, Christina J. Vander Pluym 2and Ravi Ram Thiagarajan 1
1Division of Cardiac Critical Care, Department of Cardiology, Boston Children’s Hospital, Harvard Medical School, Boston,
MA, United States, 2Division of Advanced Cardiac Therapies, Department of Cardiology, Boston Children’s Hospital, Harvard
Medical School, Boston, MA, United States
Ventricular assist devices (VAD) are used more in children. Safe and effective
anticoagulation is required for successful management of children supported with
ventricular assist devices. Developmental hemostasis, device hemocompatibility, plastic
to body ratio, surgical variable techniques, lack of knowledge on pharmacokinetics of
anticoagulants, and wide variability in anticoagulation protocols have all contributed to
increased incidence of bleeding and thromboembolic complications. New collaborative
learning networks, such as the ACTION network, provide opportunities to define
best practices, optimize, and reduce anticoagulation related adverse events. ACTION
was established Dec 2017. It consists of expert clinicians in heart failure, as well
as researchers, parents, and patients, with goals to improve outcomes, share data,
improve education and standard practice for children with heart failure (1, n.d). Changes
in pediatric VAD anticoagulation strategy from using mainly heparin to DTI such as
bivalirudin have helped reduce bleeding and clotting complications.
Keywords: hemostasis, ventricular assistance device, anticoagulation, thrombosis, bleeding, heparin, bivalirudin,
TEG-PM
INTRODUCTION
Since FDA approval of the Belin Heart EXCOR ventricular assist device (VAD) in North America
over a decade ago (1) pediatric VAD use has increased with favorable reduction (>50%) in
waiting list mortality and improved survival following heart transplantation (2). The 4th Annual
Pediatric Interagency Report for Mechanical Circulatory Support (Pedimacs) published in 2019
reports that 1,031 devices were placed in 856 children at 44 centers during September 2012
through December 2019 (3). Increase in VAD use is largely due to increasing use of intracorporeal
continuous flow devices (4). Despite increasing VAD use, hemocompatibility related adverse
event, including bleeding and thrombosis with current antithrombosis agents remain among the
significant challenges in children supported on VAD (5). Safety and efficacy of antithrombotic
agents in these patients are in ongoing need of evaluation. While the use of antithrombotic
therapies worldwide was consistent, variability in practices among VAD centers was noted (6).
Achieving optimal anticoagulation and antithrombosis in VAD patients requires a balanced control
of thrombin and platelets inhibition against physiologic hemostasis. In infants and young children,
achieving this balance has been challenging due to several unique physiologic factors including
developmental hemostasis as originally described by Monagle et al. (7). This report summarizes
these challenges and describes the current antithrombotics use in children supported with VAD.
1Available online at: www.actionlearningnetwork.org/collaborative.
Ghbeis et al. Hemostatic Balance in Pediatric VADs
Pediatric VAD Device Options
a. Berlin Heart EXCOR, a pulsatile paracorporeal pump, is the
first and only Food and Drug Administration durable VAD for
use in children as a bridge to transplantation. The Berlin Heart
device is used as a single or biventricular assist. Placement
requires median sternotomy and use of cardiopulmonary
bypass. Berlin Heart EXCOR ventricular assist device can be
used to support children weighing >3 kg up to adulthood, in
the form of univentricular and biventricular support. With
previous heparin based anticoagulation regimen (Edmonton
Anticoagulation and Antiplatelet Protocol), the rate of stroke
was consistently ∼30%, but has since decreased over the last
5 years with the adoption of multiple interventions, including
use of steroids to mitigate inflammation, (8) use of consistent
team to manage anticoagulation (9), and adoption of DTI for
primary anticoagulation (10).
b. Paracorporeal continuous flow devices include temporary
circulation support devices such as Pedimag R
/Centrimag R
,
Rotaflow R
, and the Revolution R
pumps (11). These are
placed via median sternotomy and use of cardiopulmonary
bypass is limited to supporting the most challenging patients
whose size and anatomy necessitate use of this paracorporeal
pump. Despite the described continuous flow technology
increased risk of thrombosis in children with body surface area
(BSA) <1.0 m2(12), it’s applications continue to evolve with
tendency toward longer term support in select populations
(13). TandemHeart is also a paracorporeal continuous flow
device which is used more in the adult populations. One
main advantage of this device is that cannulas are placed
percutaneously so no need exists for thoracotomy, however
the size of the cannulas is the limiting factor and thus pediatric
experience remains limited (14).
c. Intracorporeal VADs are currently the most common VAD
type placed in older children, composing around 50% as per
the most recent annual Pediatric Interagency Registry for
Mechanical Circulatory Support (Pedimacs) report. This shift
in the use of VAD for children is attributed to advancements
in device design with associated lower adverse event profile
(3). Per Morales et al., 34% of Intracorporeal patients are
still supported with the device at 6 months and nearly 20%
at 1 year, which is in stark contrast to paracorporeal device
types, which have close to zero patients remaining on device
support at 1 year. They also estimated 50% of the patients are
receiving Intracorporeal VAD as a bridge to candidacy (3). The
HeartWare_ HVAD system (Medtronic, Mounds View, MN)
is one of the earlier intracorporeal continuous flow pump to
be used in larger children and adolescents even before FDA
approval for adults only in 2012. The smallest known patient
with this device is 2.7 years old and 13.1 Kg. It is reported
that close to 50% of children with HeartWare devices are
Abbreviations: ACTION, Advanced Cardiac Therapies Improving
Outcomes Network; AT, Antithrombin 3; BMP, basic metabolic panel;
CRP, C-Reactive Protein; DTI, Direct Thrombin Inhibitor; HIT, heparin-
induced thrombocytopenia; INR, international normalized ratio; LDH, Lactate
dehydrogenase; PT, prothrombin time; PTT, Partial thromboplastin time;
TEG-PM, Thromboelastography with Platelet Mapping; VAD, Ventricular
assist devices.
discharged home (15). The HeartMate VAD represents the
newest in centrifugal continuous-flow VAD technology. Its
optimized hemocompatibility profile, particularly HM3, and
shear stress reduction makes it with the least side effects profile
among all the devices. The smallest reported patient supported
with this device is 8.8 years and 19.1 Kg. Per O’Connor et al.,
adverse events related to the HM3 device were uncommon
so far (median 78 days, 2–646), with no episodes of pump
thrombosis, pump dysfunction requiring operative exchange,
or stroke (16). The Jarvik 2015 VAD is the most recent and
promising intracorporeal continuous flow pump for infants
and smaller children. The preliminary enrolment weight range
is 8–20 kg with BSA range of 0.4–1.0 m2. As described in
its website, www.pumpkintrial.com, the PumpKIN trial is a
prospective, multi-center, single-arm feasibility study that will
evaluate the safety of the Jarvik 2015 as a bridge to transplant
or recovery in children. Of note, patients eligible for the
PumpKIN trial are limited severe heart failure with two-
ventricles (17).
It is worthy to note that pediatric patients on intracorporeal
devices are generally less ill, older, and are less likely to
have congenital heart disease compared with patients on
paracorporeal pulsatile or paracorporeal centrifugal flow
devices (3).
d. Impella is a percutaneous ventricular assist device that is a
micro-axial pump. Impella has recently been utilized more
in pediatrics for short-term circulatory support. The most
common indication of its implant was cardiogenic shock
with variable underlying pathophysiology including cardiac
allograft rejection, myocarditis, or cardiomyopathy (18,19). It
is inserted and secured percutaneously (or through a chimney
graft) into the axillary or femoral artery, and then positioned
in the LV across the aortic valve. The continuous blood flow
that is pumped can vary based on the Impella generation, but
most recently up to 5.5 l/min.
Hemostasis and Age
Coagulation Cascade
Maturation related differences in the coagulation cascade in
infants and children presents unique physiologic challenges
compared to adults (7,20). Clinicians are faced with the need
to explore age related changes with each component of the
coagulation cascade, both in physiologic or pathophysiologic
states. These normal physiological differences in maturation
of the coagulation cascade are referred to as “developmental
hemostasis.” During fetal life, maternal coagulation factors are
unable to penetrate the placental barrier. Coagulation factors
synthesis in the fetus starts as early as 5.5 weeks (21). After
birth, coagulation factors have different postnatal patterns of
maturation toward adult values for most components by 6
months of age (22,23). Some factors such as fibrinogen, Factors
V, VIII, von Willebrand (vWF), and XIII are similar to mature
adults even at birth, while Kuhle et al. reported levels of vWF
and high-molecular weight multimers as well as vWF collagen
binding activity remain increased during the first 2 months of life
and then gradually decrease to adult levels (21). While at birth,
plasma concentrations of the direct inhibitors AT (antithrombin)
Frontiers in Pediatrics | www.frontiersin.org 2February 2021 | Volume 9 | Article 625632
Ghbeis et al. Hemostatic Balance in Pediatric VADs
and HCII (heparin cofactor II) are ∼50% of adult values. Then at
about 6 months of age, plasma concentrations of AT and HCII
reach adult levels, α2-M levels are nearly twice those of adult
values and remain increased throughout childhood (21). It is
however also worth noting that variations in AT activity are not
fully explained by age and other factors may play a role (24,25).
Platelets
The only available evidence for altered platelet function in
children is in neonates and in in vitro studies. Michelson
and colleagues reported neonatal platelets to be hyporeactive
to the platelet-activating agents such as thrombin, adenosine,
phosphate/ epinephrine, and thromboxane A2. Yet, the bleeding
time in neonates, a reflection of platelet function, is normal
due to increased red blood cell size, hematocrit, and vWF
multimers (26).
Hemostasis and Congenital Heart Defects
Congenital heart disease (CHD) is known risk factor for
intravascular thrombosis due to altered flow dynamics that can
predispose to areas of flow stasis, and/or higher shear stress,
with platelet activation, and placement of thrombogenic artificial
material. Patients who undergo cardiac surgery are at risk of
both thrombosis and bleeding. These risks are higher in the
<1 year age group (27). Additionally, delay in age based
normalization of coagulation factors in children with CHD has
also been documented. In children with CHD, maturation in
coagulation factors occurs after 48 months of age (28). Given the
body and vessels size for young children, there is an increased
chance for chest re-exploration and post-operative bleeding
following heart surgery. Increased bleeding may be secondary to
an acquired dilutional coagulopathy in these patients with the
use of large priming solution compared with the blood volume
during cardiopulmonary bypass, as well as delayed maturation
of coagulation factors (28). Other clinical factors associated with
coagulation system abnormalities in patients with congenital
heart disease may be related to the physiological effects of
heart failure, which may include decreased hepatic coagulation
factor production (25). Finally, other unique coagulation factor
abnormalities in patients with single ventricle congenital heart
disease is the reported increase in factor VIII following Fontan
operation with increased thromboembolic risk (29).
These issues illustrate challenges to providing antithrombotic
therapies to children supported with VAD. Careful consideration
of developmental hemostasis is required in constructing safe
and efficient antithrombosis protocols in children, particularly
children with congenital heart disease.
THROMBOTIC COMPLICATIONS AND VAD
Thrombotic complications are among the most common serious
adverse events in VAD patients, despite different attempts to
protocolize antiplatelet and anticoagulant therapies with different
ways to accurately monitor its effects (5,30). Different reasons
are believed to cause thrombosis in VAD patients that mainly
involve contact mechanism from artificial surfaces of the device
as well as high shear stress, both of which activate vascular
endothelial cells as well as platelets, and white cells. Inflammation
which has been observed in VAD patients is also believed to
contribute to the prothrombotic state in these patients (31).
Other proposed factors include turbulence at anastomosis sites,
and heat generated by the device.
In the recent Pedimac registry report, the incidence of
hemorrhagic stroke was noted to be 11%. This was lower
compared to prior times and did not vary by device type (3). In
the prospective trial of the Berlin Heart pediatric VAD device,
stroke occurred in 29% (1). Similar to paracorporeal pulsatile
flow devices, paracorporeal continuous flow devices, such as
the Rotaflow (Maquet, Wayne, NJ) and the Centrimag/Pedimag
(Abbott, Abbott Park, IL), were found to have a high rate of
neurologic events at 24% (13). In pediatric HeartWare HVAD
patients, neurologic events were reported as 15.8% of all causes
of death. When compared to young adults, children had more
early bleeding and more early and late neurologic dysfunction.
The recent increased use of DTI for paracorporeal VAD
patients has further reduced the incidence of stroke on DTI
therapy for all devices types to as low as 1.7 events per
1,000 days of support. The Stanford Modified Antithrombotic
Guideline that utilized triple antiplatelet agents in addition to
enoxaparin was shown to reduce the incidence of stroke in
children supported with Berlin Heart EXCOR devices to 0.8
events per 1,000 days of support utilizing.
In terms of time to first neurologic event and ischemic stroke,
intracorporeal continuous flow devices performed better than
both types of paracorporeal devices, pulsatile and continuous
flow. The incidence of stroke was not different for paracorporeal
pulsatile or continuous flow devices (3). In the early HeartMate
3 VAD experience of pediatric and patients with congenital heart
disease, stroke or pump thrombosis were not detected for median
of 78 days of follow-up.
In comparison to children supported with VAD, the incidence
of stroke in adults supported with intracorporeal devices is
reported to be around 17% (32). Similar to children, HeartMate 3
(HM3) VAD, had a lower reported stroke than other devices with
an incidence of 0.46 events per patient-year in the 1st month and
down to 0.04 events per patient-year in the 2 year period (33).
PUMP THROMBOSIS
VAD pump thrombosis represents an increased risk for
morbidity and mortality given association with device
malfunction, thromboembolic events, and hemolysis. Factors
related to pump thrombosis can be related to patient, device,
or anticoagulation management. In adult patients, Bartoli
et al. reported LVAD thrombosis in 2–13% patients with a
continuous-flow LVAD, 4–13% with axial-flow devices, and
2% with centrifugal-flow devices (34). The incidence of pump
thrombosis reported in adult patients on LVAD continuous flow
devices ranged from 0.014 to 0.03 events per patient-year (35),
The HeartMate III device had no reported pump thrombosis for
the first 6 months in a large prospective trial (36), and in another
retrospective large study (37) though there are case reports of
pump thrombosis at 1 year (38).
Frontiers in Pediatrics | www.frontiersin.org 3February 2021 | Volume 9 | Article 625632
Ghbeis et al. Hemostatic Balance in Pediatric VADs
In Pediatric VADs, device thrombosis occurs in 18% of
pediatric patients with a paracorporeal pulsatile device (39).
Pump thrombosis event rate on DTI was 3.7 per 1,000
patient-days for the Berlin Heart EXCOR VAD, and 13.7 per
1,000 patient-days of centrifugal-flow VAD support (11). Pump
thrombosis in HeartWare device in children was reported as 11%
in a multicenter study using the Pediatric Interagency Registry
for Mechanical Circulatory Support (Pedimacs) registry (16). In
the early experience of HM3 in the pediatric and young adult
population, there was no reported pump thrombosis (16).
Overall, time to first device malfunction/thrombus in children
was significantly better in intracorporeal devices types, than
paracorporeal device types, with the paracorporeal pulsatile
pumps performing significantly better than paracorporeal
continuous flow devices (3).
Pump thrombosis can start as either fibrin-rich (red) or
platelet-rich (white) thrombi. Fibrin thrombi form around
stagnant blood flow whereas platelets thrombi form in areas
of turbulence. Management of pump thrombosis included
surgical or pharmacological. Some pharmacological options
are intravenous thrombotic agents such as fibrinolytics (e.g.,
alteplase) and glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors (e.g.,
eptifibatide) (40). Most reports of tPA use for pump thrombosis
is inconclusive with evidence of increased bleeding complications
(35). Similarly, GPIIb/IIIa inhibitor also increased risk of
bleeding complications (40). A common practice in adult
VAD institutions for pump thrombosis includes intensifying
antiplatelet therapies, increasing the International Normalized
Ratio (INR) goal when warfarin therapy is resumed, and/or DTI
targeting a high activated partial thromboplastin time (aPTT)
(40). With increasing reports of HIT among VAD adult patients,
some institutions now use Bivalirudin as the agent of choice
for pump thrombosis (40). Other studies have shown that
bivalirudin therapy for management of pump thrombosis was
associated with high recurrence rates and suggest need for other
therapies including surgical pump replacement (41). Similarly
others found that surgical intervention resulted in less mortality,
stroke, and resolution of hemolysis than a medical strategy
alone (42).
Pediatric VAD pump thrombosis treatment is based on adults’
experience with case reports of using bivalirudin and low-dose
systemic tissue plasminogen activator (TPA). When there are
concerns of hemolysis impact on kidney function or if the
patient is close to a previous surgery, device exchange should
be considered (43). ACTION is currently working on settings
shared guidelines for pediatric VAD management including
pump thrombosis protocols (44).
Bleeding
Bleeding is similarly among the most common complications
for VAD patients. Some known factors are the historic lack of
a standardized approach to anti-coagulation and anti-platelet
dosing or monitoring in children, surgical techniques due
to size and complexity, as well as developmental hemostasis
in children.
In adults, major bleeding events are the most common
adverse event within the first 3–12 months of continuous
flow LVAD implantation. Gastrointestinal hemorrhage was the
most common site of bleeding (up to 40%, particularly after 3
months) (45,46). Based on the Pediatric Interagency Registry
for Mechanical Circulatory Support (PediMACS) report for
outcomes of children supported with temporary devices, the
most frequent early adverse events were bleeding (28%) (13). In
the Australian retrospective report for children on HeartWare
HVAD and Berlin Heart EXCOR VADs, major bleeding occurred
in 39% of the patients, with the majority of these events
happening while on unfractionated heparin and on more than
one antiplatelet agent (47). In a meta-analysis for children
on durable Ventricular Assist Devices (87% of which were
Berlin Heart), the incidence of bleeding overall was 37%.
Reported bleeding events included gastrointestinal bleeding 15%,
intracranial hemorrhage 16% or chest re-exploration 23% (6). In
children and young adults with HeartWare devices, the event rate
of early bleeding was 2-times higher in children than in young
adults, but the overall bleeding incidence was the same, 23%
(16). In the early HeartMate 3 VAD experience of pediatric and
patients with congenital heart disease, significant post-operative
bleeding was uncommon and was reported in only two patients
(6%) with a median age of 15.7 years (8.8–47.3) (16). These
findings may help understand bleeding risk better given the fact
that these are larger devices in smaller size patients.
The role of improved understanding of anticoagulation and
antithrombosis management for pediatric VAD patients was
more recently noted. In patients on Berlin EXCOR VAD, using
the Sanford protocol, bleeding events incidence rate was 8.6 per
1,000 days of support (48). VanderPluym et al. reported in the
largest multicenter experience of DTI use for anticoagulation
therapy in pediatric paracorporeal VAD support, major bleeding
present in 16% of the cases (2.6 events per 1,000 patient days of
support on DTI) (10).
Additionally, bleeding events are minimized by following
certain management tips. Achieving prompt hemostasis
following the VAD placement is of importance, and was a
fundamental requirement for patients in the DTI therapy
protocol for example with 90% of patients starting DTI
12 h postoperatively or after (10). Cognizant anticoagulation
management and monitoring in the early post-operative
periods, as well as during switching between agents is highly
recommended. Other management tips for bleeding while on
VAD are by decreasing intensity of the antithrombotic regimen
and/or discontinuing the antiplatelet agents.
Anticoagulation Management
Hemostasis in pediatric patients on VAD is a common challenge,
and the optimal antithrombotic therapy for children with VADs
is unknown. Pediatric VAD anticoagulation and antithrombotic
management is widely variable with a shift toward more
aggressive antithrombotic therapy. This shift could be in
part due to previous experience of high rates of thrombotic
complications in children with paracorporeal pulsatile-flow
devices. Furthermore, developmental hemostasis in children, and
coagulation challenges brought on by the presence of CHD,
a population at risk for needing VAD, continues to challenge
clinicians managing VAD in the pediatric populations (27).
Frontiers in Pediatrics | www.frontiersin.org 4February 2021 | Volume 9 | Article 625632
Ghbeis et al. Hemostatic Balance in Pediatric VADs
TABLE 1 | Pediatric VAD anticoagulation protocols.
Post op Long term Anti-platelets Monitoring Other
Edmonton protocol (5) Heparin Enoxaparin ≤12 months
Warfarin >12 months
Dual antiplatelet therapy:
Dipyridamole 4 mg/kg/day
Aspirin 1 mg/kg/day
TEG-PM
Stanford protocol (49) Heparin Enoxaparin ≤12 months
Warfarin >12 months
Triple anti-platelet therapy:
Aspirin 30 mg/ kg/day
Dipyridamole 15 mg/kg/day
Clopidogrel 1 mg/kg/day
None Steroids for signs of
inflammation
DTI (ACTION)
harmonization protocol
(10)
Bivalirudin Bivalirudin transitioned
to Couamdin
Aspirin TEG-PM or VerifyNow Steroids for signs of
inflammation
TEG-PM, Thromboelastography with Platelet Mapping; ACTION, Advanced Cardiac Therapies Improving Outcomes Network; DTI, Direct Thrombin Inhibitor.
The three main known pediatric anticoagulation
pediatric VAD protocols based on the historic timeline are
illustrated below Table 1:
a. Edmonton Protocol: includes initiating unfractionated
heparin when bleeding is minimal at 24–48 h post-
implantation with long-term anticoagulation using
Enoxaparin for patients ≤12 and warfarin for patients
>12 months of age. Dual antiplatelet therapy starts at 48 h
with dipyridamole begun at 4 mg/kg/day, followed by Aspirin
1 mg/kg/day divided twice daily after chest tubes removal.
Thromboelastography with Platelet Mapping (TEG-PM) is
used for both anticoagulation and antiplatelet titration.
b. Stanford Protocol: includes similar anticoagulation strategy
starting with heparin and converting to Enoxaparin or
Warfarin, but adds a 3rd anti-platelet agent and targets a
weight based dose (Aspirin 30 mg/ kg/day, Dipyridamole
15 mg/kg/day, Clopidogrel 1 mg/kg/day), with no titration
to effect based on TEG-PM, and recommends using use
of prednisone for signs of inflammation (fibrinogen >600
mg/dL) (48).
c. ACTION Direct Thrombin Inhibitor (DTI) Harmonization
Protocol: Includes starting bivalirudin once surgical and
coagulopathic bleeding has resolved with evidence of
normalizing coagulation laboratories. Bivalirudin is titrated
to achieve an aPT T goal of 60–90 s in patients with standard
risk bleeding, and 50–60 s for those at high risk bleeding.
Antiplatelet agents are also used, and include Aspirin, with
confirmation of therapeutic range by TEG-PM or VerifyNow.
Steroids (prednisone) is used for signs of inflammation as in
the Stanford protocol.
Heparin
Unfractionated heparin (UFH) is the first-line anticoagulant
therapy in the children with heart disease. It is the most
common anticoagulant agent for the immediate post-operative
VAD placement period. The criteria to start it are typically
absence of bleeding and surgical hemostasis. Heparin dose
is typically titrated thereafter using a target activated partial
thromboplastin time (aPTT), most commonly between 50 and
80 s (6).
However, heparin has many known challenges but mostly
related to the heterogeneous biochemical composition of
different molecular weight glycosaminoglycans as well as its
dependence upon AT. The heterogeneity in composition of
commercial formulations of UFH can result in a wide inter-
patient variability in dose–response. The differences in AT
levels that change from fetal to adult life is a key additional
variant that needs to be considered in infants and children
managed with heparin. Heparin-induced thrombocytopenia
(HIT) and the osteopenia with its long term use are reported
and known risks of heparin exposure (15). There have also
been reports of potentially genetic variances in the AT protein
with point mutations at the glycosylation sites where AT binds
to heparin, which may impair the strength of the covalent
bonding (50).
Measuring the heparin response to titrate heparin dose is a
known area of controversy. Activated clotting time (ACT) is a
point of care assay which measures time to clot initiation of whole
blood. This test has several limitations including variability in
technical methods for clot activation and detection. Additionally,
ACT is not specific to the effects of heparin and reflect other
physiologic factors that impact coagulation (51).
Although aPTT is the most commonly used blood test to
titrate heparin anticoagulation effect in pediatrics VAD patients,
anti-factor Xa activity is increasingly used (6). The anti-factor Xa
activity (anti-Xa) assay chromogenically quantifies the heparin–
AT complex, and is therefore highly dependent upon serum AT
levels; hence anti-Xa activity is frequently low in neonates and
infants (52). AT replacement during the perioperative period to
augment heparin response is reported in a number of studies. The
threshold for replacing AT is variable and ranges <70% in older
children and <60% in neonates (6).
BIVALIRUDIN
Bivalirudin is an intravenous DTI that inhibits both circulating
and fibrin-bound thrombin. It is relatively new and semisynthetic
drug. It does not bind to plasma proteins and inhibits both
free and clot-bound thrombin. It is not dependent on AT and
is less immunogenic than heparin. It may also inhibit platelet
adhesion. Bivalirudin has a short half-life of 25–35 min secondary
Frontiers in Pediatrics | www.frontiersin.org 5February 2021 | Volume 9 | Article 625632
Ghbeis et al. Hemostatic Balance in Pediatric VADs
to its intravascular proteolytic degradation and minimal renal
clearance (∼20%). Clinical studies in pediatric showed safety and
efficacy of bivalirudin in different settings including procedural
anticoagulant, post cardiac surgery ECMO, heart transplant (53,
54). In a single institution experience in 54 children placed on
ECLS for a total of 56 runs, Bivalirudin use showed no differences
in outcomes compared to heparin, however resulted in longer
freedom from first circuit intervention (55). Bivalirudin has also
been used safely in pediatric in cases of contraindications to
heparin (i.e., HIT) (56) or when unreliable heparin monitoring
exists (i.e., severe hemolysis and hyperbilirubinemia) (57). The
DTI experience in children is growing. The collective experience
of 10 pediatric VAD centers across North America using
bivalirudin in children supported with paracorporeal VADs was
recently described by VanderPluym et al. Bivalirudin use in this
settings was associated with a lower or a comparable rate of stroke
to other known anticoagulation and antiplatelet regimens. The
risk of bleeding was also comparable in older children supported
with intracorporeal continuous flow VADs (10).
The starting dose of bivalirudin is 0.3 mg/kg/h, which is
halved in patients with renal dysfunction Table 2. Measuring
aPTT is the standard test to monitor anticoagulation with DTI
with goal ranging between 2 and 3 times baseline aPTT value
for standard bleeding risk patients, and 1.5–2 times baseline
aPTT value for high bleeding risk patients. Patients are initially
monitored every 4 h until a stable Bivalirudin dosing is achieved,
and then daily Table 3. In a small retrospective case-control study
for pediatric patients on ECMO, time to reach goal therapeutic
anticoagulation level was shorter in bivalirudin compared to
heparin (11 vs. 29 h, P=0.01) (58). INR is frequently elevated
in patients on Bivalirudin. This is believed to be a false elevation
due to the interaction between DTI and the thromboplastin
and tissue factor contained in the PT assay, along with the
high molar concentrations of the DTIs needed to achieve
their anticoagulant effect (59). aPTT sample contamination
is infrequently encountered. While hepzyme can be used to
neutralize contaminating heparin, concomitant INR is used to
identify contamination since INR will not increase with heparin
contamination alone. INR monitoring can also be utilized more
when bivalirudin dose is escalated which is observed to happen
over time (10) at which time there would also be a more “plateau”
effect rather than linear aPTT to dose response effect. Some
explanation of this phenomenon was related to the increased
in fibrinogen levels over time in these patients, which in turn
competes with the bivalirudin for the thrombin binding sites (58).
The cost effectiveness of bivalirudin remains an area of
controversy since the drug by itself is far more expensive than
heparin. Ongoing efforts are undergoing to understand this
more, however in ECMO patients and when including the
cost of AT replacement and the various laboratory monitoring,
the overall cost for anticoagulation was decreased in patients
receiving bivalirudin, particularly in children younger than 1
year (58).
Antiplatelet Agents
Antiplatelet therapy has been the main focus for evolving
pediatric VAD anticoagulation protocols which could have been
TABLE 2 | ACTION initial bivalirudin dosing.
Goal: aPTT
Standard risk (of bleeding): aPTT 60–90 (∼2-3x baseline)*
High risk (of bleeding): aPTT 50–60 (∼1.5-2x baseline)**
Renal function (GFR) Initial dosing
Normal (>60
ml/min/1.73 m2)
0.3 mg/kg/h IV infusion
Mild-moderate (30–60
ml/min/1.73 m2)
0.2 mg/kg/h IV infusion
Severe (<30
ml/min/1.73 m2)
0.1 mg/kg/h IV infusion
*Baseline aPTT may be elevated if previously on AC agent, therefore use age/intuitional
normative range.
**Given the risk of early bleeding, most of patients will begin in the “High risk” category for
the 1st several days on support, then transition to “Standard risk”.
TABLE 3 | ACTION maintenance bivalirudin titration.
Goal: aPTT
Standard risk (of bleeding): aPTT 60–90 (∼2-3x baseline)
High risk (of bleeding): aPTT 50–60 (∼1.5-2x baseline)
If aPTT 5–15 s out
of range:
Increase or decrease by 15% (round up to closest
2nd decimal)
Recheck 2–3 h after dose change
If aPTT in target
range, no change
Recheck 2–3 h, then can decrease frequency
when stable
If aPTT ≥15–30 s
out of range
Increase or decrease by 25% (round up to closest
2nd decimal
Recheck 2–3 h after dose change
If aPTT >3x
baseline or ∼120 s
With normal renal function: hold 15 min and
reduce by 30%
With mild to moderate renal dysfunction: hold for
45 min and reduce by 40%
With severe renal dysfunction: hold 2 h and
recheck PTT before restarting
driven based on the early Berlin Heart EXCOR experience.
Dual and triple antiplatelet therapy had dominated most of
the earlier regimens, however with the evolving of improved
and consistent anticoagulation agents, i.e., DTI, the emphasis
on the dosing with multi antiplatelet agents’ nature has been
less popular. We use primarily one agent at our institution
with consideration to switch or add another agent if there
is evidence of sub-therapeutic effect based on the available
laboratory tests (Platelets mapping and VerifyNow). TEG-PM
is a functional assay to test for pathologic bleeding etiology or
to confirm therapeutic anticoagulation and antiplatelet effects.
In this testing technology, the thrombus integrity is measured
mechanically and in real time. It is then represented by a
characteristic curve, which is interpreted based on normal
reference. The clot strength is measured by the maximal
amplitude (MA) on the curve, which is also used to evaluate ADP
(adenosine-diphosphate) or AA (arachiodonic acid) pathways
inhibition, which form the platelets mapping test portion (60).
VerifyNow is a functional assay point-of-care testing which
evaluates platelet aggregation by a turbidimetric-based optical
detection (61).
Frontiers in Pediatrics | www.frontiersin.org 6February 2021 | Volume 9 | Article 625632
Ghbeis et al. Hemostatic Balance in Pediatric VADs
While antiplatelet therapy is historically the main focus for
pediatric VAD anticoagulation, and it remains an essential part
of it, there is some evidence that TEG-PM in pediatric VAD
patients have high intraindividual variability (62). There are also
some preliminary reports of a significant role for timing of drug
administration and interval frequency which might help improve
our understanding of cases of suboptimal response. Adult VAD
literature reports a common practice for addition of antiplatelet
agents to the anticoagulation regimen, with acknowledgment for
treatment resistance and consideration for routine assessment
for such.
VITAMIN K ANTAGONIST (VKA)
Most adult VAD patients supported on intracorporeal devices
are maintained on vitamin K antagonist (VKA) such as warfarin
with goal INR that varies mostly between 2 and 3 (63).
Similarly, pediatric VAD patients with intracorporeal devices
are primarily maintained on VKA with goal INR ranging
from 2 to 3.5, which may vary based on patients and device
factors. VKA are typically started when the patient is extubated,
with advancing diet. VKA effect is heavily influenced by diet,
status of illness, and polypharmacy. Studies to estimate time in
therapeutic range for pediatric patients are lacking, but reports
from adult studies show the time in therapeutic range as only
30–50% (64).
DOAC
Direct oral anticoagulants (DOAC) are increasingly used in
place of VKA. DOAC medications include factor Xa inhibitors
(apixaban and rivaroxaban) and DTI (dabigatran). Few positive
features are ease of administration with oral formulations,
lack of dependency on AT, lack of dietary interaction, and
the requiring less monitoring. Indications for use in the adult
populations include venous thromboembolism prophylaxis and
atrial fibrillation. A prospective, randomized, open label phase
II multi-national clinical trial of a direct oral anticoagulant
(DOAC), Apixaban, in children and infants with congenital and
acquired heart disease is currently underway (48).
DOAC use in adult VAD patients is not well-established.
Two examples of such experience are a small study of seven
patients using dabigatran with no excess rate of bleeding
or thrombosis (65) and a single center, randomized trial of
dabigatran vs. warfarin which was terminated early due to
increased thromboembolic events associated with dabigatran
(66). Additionally, given the negative experience with dabigatran
use in mechanical heart valves, routine use could not be
recommended without more reassuring clinical trials (67).
PRE-OP MANAGEMENT
Prior to VAD device placement, laboratory assessment is
recommended to identify potential risk factors for adverse events
related to immediate and long-term anticoagulation use. These
can include platelet count, prothrombin time and International
Normalized Ratio (INR), partial thromboplastin time, fibrinogen,
basic metabolic panel (BMP). Other optional labs include
Thromboelastography with platelet mapping (TEG with PM), C-
reactive protein CRP, Lactate dehydrogenase (LDH), cystatin C,
screening for heparin induced thrombocytopenia (HIT screen).
In addition to these labs, past medical history is obtained to
identify prior thrombotic and bleeding events along with any
family history that predisposes the patient to complications.
Thrombophilia evaluation can be completed if there is past or
family history of thrombotic events suggesting either an acquired
or inherited thrombophilia. These labs include: anticardiolipin,
beta-2 glycoprotein, lupus anticoagulant, factor V Leiden,
prothrombin gene 20210A mutation, AT3, and proteins C and S.
POST OP MANAGEMENT
Postoperative management details are critical in establishing a
stable and sustained VAD circulation. Cognizant anticoagulation
management and monitoring in the early post-operative
periods, as well as during switching between agents is
highly recommended. The majority of bleeding events and
thromboembolic events in pediatric VAD patients occurred while
patients were on unfractionated heparin or transitioning between
heparin and warfarin (47).
At our institution, postoperative inpatient management
include antiplatelet and anticoagulation strategies in the early
postoperative period Table 4. This is initiated and managed by
the VAD team in consultation with the CICU. Standard heparin
anticoagulation for cardiopulmonary bypass is utilized with full
protamine reversal in the operating room. Following admission
to CICU, once hemostasis is achieved (chest tube output <2
cc/kg/h for 4 consecutive hours) and following correction
of acquired coagulopathy (coagulation labs normalizing with
platelet count >100,000, INR <1.4, aPTT <40 s and fibrinogen
>100), we start bivalirudin with initial aPTT goal of 50–
60, and escalate the goal to 70–90 over the next few days,
based on the appearance of the pump. Antiplatelet agents are
usually introduced based on appearance of the pump (started
sooner if formation of fibrin or clot). We utilize TEG with
platelet mapping, and delay initiation of antiplatelet agents
until clot strength is >70 mm. As such, antiplatelet agents
are generally started 1–2 weeks after VAD implantation for
patients on bivalirudin and 5–7 days for patients on warfarin
therapy supported on intracorporeal devices. Patient supported
on paracorporeal devices remain on bivalirudin for the duration
of VAD support, based on data supporting the low rate of
hemocompatibility related adverse events using DTI. Patients
supported on intracorporeal devices are bridged with bivalirudin
or unfractionated heparin to VKA, with target INR goal of 2–
3.5. A dedicated Multidisciplinary Anticoagulation Management
Team is crucial to optimal anticoagulation management in VAD
patients and should include a pharmacist, Cardiac Critical Care,
and VAD physicians.
Procedure Anticoagulation Management
Given that the majority of bleeding and thromboembolic
events in pediatric VAD patients occur while patients were
Frontiers in Pediatrics | www.frontiersin.org 7February 2021 | Volume 9 | Article 625632
Ghbeis et al. Hemostatic Balance in Pediatric VADs
TABLE 4 | Inpatient anticoagulation management of pediatric VAD patients.
Prior to VAD placement
Baseline labs
Minimum Platelet count, PT, INR, PTT, fibrinogen, basic
metabolic panel (BMP)
Additional TEG with PM, CRP, LDH, cystatin C, HIT screen
Medical and family
history
Thrombotic and bleeding events
If +medical or family
history
Anticardiolipin, beta-2 glycoprotein, lupus
anticoagulant, factor V Leiden, prothrombin
gene 20210A mutation, antithrombin 3, and
proteins C and S
Post VAD placement
Post-operative day 0 Following hemostasisa, Bivalirudin is started at
0.1–0.3 mg/kg/h with initial aPTT goal of
50–60, and escalating the goal to 70–90 over
the next few days
Post-Operative day 1 and after
Paracorporeal Bivalirudin remains for the duration of VAD
support
Antiplatelet agents are started within 1–2
weeks, and are delayed until clot strength is
>70 mm based on TEG-PM. They may start
sooner if formation of fibrin or clot on the pump
Intracorporeal Bivalirudin or unfractionated heparin is bridged
to VKA, with target INR goal of 2–3.5
Antiplatelet agents are started within 5–7 days
aHemostasis: chest tube output <2 cc/kg/h for 4 consecutive hours, correction of
acquired coagulopathy with platelet count >100,000, INR <1.4, aPTT <40 and fibrinogen
>100.
on unfractionated heparin or transitioning off heparin, it
is imperative that the anticoagulation and antithrombosis
around any procedure is carefully managed. Antithrombosis
considerations surrounding procedures are specific to the clinical
state of the patient and the pump, and the bleeding risk of
the procedure. As such, decisions to be made in conjunction
with all team members, as risk of thrombotic and bleeding
events is naturally highest during procedures, even those deemed
relatively minor. These decisions need to be individualized
taking into consideration the thrombotic risk of the patient
and pump, weighed against the bleeding risk of the procedures.
Nonessential procedures should be deferred till after VAD
support, and essential procedures require discussion with all
team members to understand bridging plan so that cessation of
antithrombotic agents is minimized, while procedural hemostasis
is maximized.
As a general principle we recommend the following:
- For procedures deemed low risk of bleeding
Continue all antiplatelet agents, and dose reduce anticoagulation
agent for lower therapeutic target around the procedures
- For procedures deemed high risk of bleeding
∗Hold antiplatelet agents around 3 days prior to procedure
∗Hold bivalirudin ∼1–4 h prior to skin incision (depending on
renal function)
∗Hold unfractionated heparin 4 h prior to skin incision
∗VKA, start holding 3 days prior to procedure with daily INR
measurement. Once INR <2, then start LMWH or continuous
infusion of DTI or UFH
∗LMWH, hold night before and morning of procedure.
Consider bridging with UFH or DTI depending on thrombotic
risk of pump and patient.
Prompt re-initiation of anticoagulation is required once
hemostasis achieved and in discussion with all team members
to ensure risk of re-bleeding is minimized, with hourly
pump examinations for paracorporeal pumps for 24 h
post procedure.
HEMOLYSIS
Hemolysis is a common phenomenon seen after VAD
implantation, particularly in children. Patient size and anatomy,
Device hemocompatibility profile, and shear stress, as well
as anticoagulant management all contribute to increased
hemolysis. Hemolysis can also be an important marker of device
thrombosis, and thus early recognition is important. Routine
laboratory monitoring with plasma free hemoglobin (product
of erythrocyte destruction), lactate dehydrogenase (LDH),
or haptoglobin should be considered. Increasing plasma free
hemoglobin is associated with renal dysfunction. Supplemental
iron, folic acid, and erythropoietin, along with a lower threshold
for transfusions were recommended by (11).
VAD Acquired Hemostatic
Pathophysiologies
High shear stress effects result in loss of high molecular weight
von Willebrand (vWF) multimers which significantly reduces
its size which in turn provides less hemostasis. Acquired von
Willebrand syndrome (AVWS) is reported in patients following
VAD placement. In a prospective cohort for 37 adult patients,
significant loss of HMW vWF multimers was reported within
30 days of CF-VAD implantation, yet only 10 of the 37 patients
experienced bleeding complications. This suggested that loss of
HMW vWF multimers alone could not predict bleeding risk
(68). Device hemocompatiblity is likely to be a factor in this
syndrome, as AVWS in patients with HM III was less severe than
in patients with HMII, which also correlated with less bleeding
symptoms (69).
Platelets aggregation function is also believed to be impaired
in VAD patients. In adult VAD patients, and unlike AVWS,
platelet function defects were found equally present with both
VAD types, HM II, and HM III (69).
FUTURE DIRECTIONS
Ventricular assist devices are increasingly used in children,
not only as a bridge to transplantation, but also as bridge to
decision and many patients are starting to discharge to home.
Safe and effective anticoagulation is required for successful
management of children supported with ventricular assist
devices. Developmental hemostasis, device hemocompatibility,
plastic to body ratio, surgical variable techniques, lack of
Frontiers in Pediatrics | www.frontiersin.org 8February 2021 | Volume 9 | Article 625632
Ghbeis et al. Hemostatic Balance in Pediatric VADs
knowledge on pharmacokinetics of anticoagulants, and wide
variability in anticoagulation protocols have all contributed
to increased incidence of bleeding and thromboembolic
complications. New collaborative learning networks, such
as the ACTION network, provide opportunities to define
best practices, optimize and reduce anticoagulation related
adverse events. Changes in anticoagulation strategy from
the use of heparin to a DTI such as bivalirudin have helped
reduce bleeding and clotting complications. The future of
this field lies in the development of VAD with improved
biocompatibility profiles that can help reduce the need for
anticoagulants therapies and reduce the risk of bleeding and
thrombosis complications.
AUTHOR CONTRIBUTIONS
The main content of the article was provided by MG. CV and RT
reviewed, minimally edited, and confirmed the article materials
provided. All authors contributed to the article and approved the
submitted version.
REFERENCES
1. Fraser CD Jr, Jaquiss RD, Rosenthal DN, Humpl T, Canter CE, Blackstone EH,
et al. Prospective trial of a pediatric ventricular assist device. N Engl J Med.
(2012) 367:532–41. doi: 10.1056/NEJMoa1014164
2. Zafar F, Castleberry C, Khan MS, Mehta V, Bryant R III, Lorts A, et al. Pediatric
heart transplant waiting list mortality in the era of ventricular assist devices. J
Heart Lung Transplant. (2015) 34:82–88. doi: 10.1016/j.healun.2014.09.018
3. Morales DLS, Rossano JW, VanderPluym C, Lorts A, Cantor R, St Louis JD,
et al. Third annual pediatric interagency registry for mechanical circulatory
support (pedimacs) report: preimplant characteristics and outcomes. Ann
Thorac Surg. (2019) 107:993–1004. doi: 10.1016/j.athoracsur.2019.01.038
4. Thangappan K, Zafar F, Morales D. Milestone: more than 1,200 children
bridged to transplantation with MCS. In: AATS Confernce Presentation.
American Association for Thoracic Surgery (2020).
5. Steiner ME, Bomgaars LR, Massicotte MP. Berlin heart EXCOR pediatric
VAD IDE study investigators antithrombotic therapy in a prospective
trial of a pediatric ventricular assist device. ASAIO J. (2016) 62:719–
27. doi: 10.1097/MAT.0000000000000434
6. Huang JY, Monagle P, Massicotte MP, VanderPluym CJ. Antithrombotic
therapies in children on durable ventricular assist devices: a literature review.
Thromb Res. (2018) 172:194–203. doi: 10.1016/j.thromres.2018.02.145
7. Attard C, van der Straaten T, Karlaftis V, Monagle P, Ignjatovic V.
Developmental hemostasis: age-specific differences in the levels of hemostatic
proteins. J Thromb Haemost. (2013) 11:1850–4. doi: 10.1111/jth.12372
8. Byrnes JW, Bhutta AT, Rettiganti MR, Gomez A, Garcia X, Dyamenahalli U,
et al. Steroid therapy attenuates acute phase reactant response among children
on ventricular assist device support. Ann Thorac Surg. (2015) 99:1392–
8. doi: 10.1016/j.athoracsur.2014.11.046
9. Byrnes JW, Prodhan P, Williams BA, Schmitz ML, Moss MM, Dyamenahalli
U, et al. Incremental reduction in the incidence of stroke in children supported
with the Berlin EXCOR ventricular assist device. Ann Thorac Surg. (2013)
96:1727–33. doi: 10.1016/j.athoracsur.2013.06.012
10. VanderPluym CJ, Cantor RS, Machado D, Boyle G, May L, Griffiths E, et al.
Utilization and outcomes of children treated with direct thrombin inhibitors
on paracorporeal ventricular assist device support. ASAIO. (2020) 66:939–
45. doi: 10.1097/MAT.0000000000001093
11. Tume SC, Conway J, Ryan KR, Philip J, Fortkiewicz JM, Murray J.
Developments in pediatric ventricular assist device support. World J Pediatr
Congenit Heart Surg. (2019) 10:759–68. doi: 10.1177/2150135119880890
12. Miera O, Kirk R, Buchholz H, Schmitt KR, VanderPluym C, Rebeyka
IM, et al. A multicenter study of the HeartWare ventricular assist
device in small children. J Heart Lung Transplant. (2016) 35:679–
81. doi: 10.1016/j.healun.2016.01.019
13. Lorts A, Eghtesady P, Mehegan M, Adachi I, Villa C, Davies R, et al.
Outcomes of children supported with devices labeled as “temporary”
or short term: a report from the pediatric interagency registry for
mechanical circulatory support. J Heart Lung Transplant. (2018) 37:54–
60. doi: 10.1016/j.healun.2017.10.023
14. Kulat B, Russell HM, Sarwark AE, Zingle R, Moss ST, Mongé
MC, et al. Modified tandem heart ventricular assist device for
infant and pediatric circulatory support. Ann Thorac Surg. (2014)
93:1437–41. doi: 10.1016/j.athoracsur.2014.05.093
15. VanderPluym CJ, Adachi I, Niebler R, Griffiths E, Fynn-Thompson F, Chen
S, et al. Outcomes of children supported with an intracorporeal continuous-
flow left ventricular assist system. J Heart Lung Transplant. (2019) 38:385–
93. doi: 10.1016/j.healun.2018.09.015
16. O’Connor MJ, Lorts A, Davies RR, Fynn-Thompson F, Joong A, Maeda K,
et al. Early experience with the HeartMate 3 continuous-flow ventricular
assist device in pediatric patients and patients with congenital heart disease:
a multicenter registry analysis. J Heart Lung Transplant. (2020) 39:573–
9. doi: 10.1016/j.healun.2020.02.007
17. Baldwin JT, Adachi I, Teal J, Almond CA, Jaquiss RD, Massicotte MP,
et al. Closing in on the PumpKIN trial of the Jarvik 2015 ventricular assist
device. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu. (2017) 20:9–
15. doi: 10.1053/j.pcsu.2016.09.003
18. Parekh D, Jeewa A, Tume SC, Dreyer WJ, Pignatelli R, Horne D, et al.
Percutaneous mechanical circulatory support using impella devices for
decompensated cardiogenic shock: a pediatric heart center experience. ASAIO
J. (2018) 64:98–104. doi: 10.1097/MAT.0000000000000581
19. Batsides G, Massaro J, Cheung A, Soltesz E, Ramzy D, Anderson MB.
Outcomes of impella 5.0 in cardiogenic shock: a systematic review and meta-
analysis. Innovations. (2018) 13:254–60. doi: 10.1097/IMI.0000000000000535
20. Monagle P, Barnes C, Ignjatovic V, Furmedge J, Newall F, Chan A, et al.
Developmental haemostasis. Impact for clinical haemostasis laboratories.
Thromb Haemost. (2006) 95:362–72. doi: 10.1160/TH05-01-0047
21. Kuhle S, Male C, Mitchell L. Developmental hemostasis: pro- and
anticoagulant systems during childhood. Semin Thromb Hemost. (2003)
29:329–38. doi: 10.1055/s-2003-42584
22. Andrew M, Paes B, Milner R, Johnston M, Mitchell L, Tollefsen DM, et al.
Development of the human coagulation system in the full-term infant. Blood.
(1987) 70:165–172. doi: 10.1182/blood.V70.1.165.165
23. Andrew M, Vegh P, Johnston M, Bowker J, Ofosu F, Mitchell L. Maturation
of the hemostatic system during childhood. Blood. (1992) 80:81998.
doi: 10.1182/blood.V80.8.1998.bloodjournal8081998
24. Ignjatovic V, Summerhayes R, Than J, Gan A, Monagle P.
Therapeutic range for unfractionated heparin therapy: age-related
differences in response in children. J Thromb Haemost. (2006)
4:2280–2. doi: 10.1111/j.1538-7836.2006.02136.x
25. Payne RM, Burns KM, Glatz AC, Li D, Li X, Monagle P, et al. Pediatric heart
network investigators. A multi-national trial of a direct oral anticoagulant in
children with cardiac disease: design and rationale of the Safety of ApiXaban
On Pediatric Heart disease On the preventioN of Embolism (SAXOPHONE)
study. Am Heart J. (2019) 217:52–63. doi: 10.1016/j.ahj.2019.08.002
26. Michelson AD. Platelet function in the newborn. Semin Thromb Hemost.
(1998) 24:507–12. doi: 10.1055/s-2007-996049
27. Manlhiot C, Menjak IB, Brandão LR, Gruenwald CE, Schwartz SM,
Sivarajan VB, et al. Risk, clinical features, and outcomes of thrombosis
associated with pediatric cardiac surgery. Circulation. (2011) 124:1511–
9. doi: 10.1161/CIRCULATIONAHA.110.006304
28. Odegard KC, Zurakowski D, Hornykewycz S, DiNardo JA, Castro RA,
Neufeld EJ, et al. Evaluation of the coagulation system in children with
two-ventricle congenital heart disease. Ann Thorac Surg. (2007) 83:1797–
803. doi: 10.1016/j.athoracsur.2006.12.030
29. Odegard KC, McGowan FX Jr, Zurakowski D, Dinardo JA, Castro
RA, del Nido PJ, et al. Procoagulant and anticoagulant factor
Frontiers in Pediatrics | www.frontiersin.org 9February 2021 | Volume 9 | Article 625632
Ghbeis et al. Hemostatic Balance in Pediatric VADs
abnormalities following the Fontan procedure: increased factor VIII
may predispose to thrombosis. J Thorac Cardiovasc Surg. (2003)
125:1260–7. doi: 10.1016/S0022-5223(02)73605-2
30. Jaquiss RDB, Humpl T, Canter CE, Morales DLS, Rosenthal DN, Fraser CD.
Postapproval outcomes: the berlin heart EXCOR pediatric in North America.
ASAIO. (2017) 63:193–197. doi: 10.1097/MAT.0000000000000454
31. Connors JM. Anticoagulation management of left ventricular assist devices.
Am J Hematol. (2015) 90:175–8. doi: 10.1002/ajh.23836
32. Kirklin JK, Naftel DC, Pagani FD, Kormos RL, Stevenson LW, Blume ED, et al.
Seventh INTERMACS annual report: 15,000 patients and counting. J Heart
Lung Transplant. (2015) 34:1495–504. doi: 10.1016/j.healun.2015.10.003
33. Colombo PC, Mehra MR, Goldstein DJ, Estep JD, Salerno C,
Jorde UP, et al. Comprehensive analysis of stroke in the long-
term cohort of the MOMENTUM 3 study. Circulation. (2019)
139:155–68. doi: 10.1161/CIRCULATIONAHA.118.037231
34. Bartoli CR, Ailawadi G, Kern JA. Diagnosis, nonsurgical management,
and prevention of LVAD thrombosis. J Card Surg. (2014)
29:83–94. doi: 10.1111/jocs.12238
35. Dang G, Epperla N, Muppidi V, Sahr N, Pan A, Simpson P, et al. Medical
management of pump-related thrombosis in patients with continuous-flow
left ventricular assist devices: a systematic review and meta-analysis. ASAIO J.
(2017) 63:373–85. doi: 10.1097/MAT.0000000000000497
36. Mehra MR, Naka Y, Uriel N, Goldstein DJ, Cleveland JC Jr, Colombo PC, et al.
A fully magnetically levitated circulatory pump for advanced heart failure. N
Engl J Med. (2017) 376:440–50. doi: 10.1056/NEJMoa1610426
37. Barac YD, Wojnarski CM, Junpaparp P, Patel CB, Schroder JN, Milano
CA. Early outcomes with durable left ventricular assist device replacement
using the HeartMate 3. J Thorac Cardiovasc Surg. (2020) 160:132–
9. doi: 10.1016/j.jtcvs.2019.09.151
38. Barac YD, Schroder JN, Daneshmand MA, Patel CB, Milano CA. Heartmate
III Replacement for Recurring Left Ventricular Assist Device Pump
Thrombosis. ASAIO, J., (2018) 424–6. doi: 10.1097/MAT.0000000000000713
39. Hetzer R, Loebe M, Potapov EV, Weng Y, Stiller B, Hennig E,
et al. Circulatory support with pneumatic paracorporeal ventricular
assist device in infants and children. Ann Thorac Surg. (1998)
66:1498–506. doi: 10.1016/S0003-4975(98)00914-X
40. Rimsans J, Sylvester KW, Connors JM. Direct Thrombin Inhibitor for
LVAD Thrombosis: A Closer Look. Clin Appl Thromb Hemost., (2017) 405–
9. doi: 10.1177/1076029616672583
41. Weeks P, Sieg A, Rajapreyar I, Nathan S, Jumean M, Patel M, et al. Bivalirudin
for left ventricular assist device thrombosis. J Thromb Thrombolysis. (2018)
46:496–50. doi: 10.1007/s11239-018-1725-z
42. Kiernan MS, Katz JN. Operating in the dark. When is surgery
necessary for left ventricular assist device hemolysis. Circ Heart
Fail. (2016) 9:3141. doi: 10.1161/CIRCHEARTFAILURE.116.0
03141
43. Chetan D, Buchholz H, Bauman M, Anand V, Holinski P, Conway J. Successful
treatment of pediatric ventricular assist device thrombosis. ASAIO J. (2018)
64:28–32. doi: 10.1097/MAT.0000000000000606
44. Lorts A, Smyth L, Gajarski RJ, VanderPluym CJ, Mehegan M, Villa
CR, et al. The creation of a pediatric heart care learning network: the
ACTION Quality Improvement Collaborative. ASAOP J. (2020) 66:441–
6. doi: 10.1097/MAT.0000000000001133
45. Levesque AA, Lewin AR, Rimsans J, Sylvester KW, Coakley
L, Melanson F, et al. Development of multidisciplinary
anticoagulation management guidelines for patients receiving durable
mechanical circulatory support. Clin Appl Thromb Hemost. (2019)
25:1076029619837362. doi: 10.1177/1076029619837362
46. Kirklin JK, Pagani FD, Kormos RL, Stevenson LW, Blume ED, Myers
SL, et al. Eighth annual INTERMACS report: special focus on framing
the impact of adverse events. J Heart Lung Transplant. (2017) 36:1080–
6. doi: 10.1016/j.healun.2017.07.005
47. Huang JY, Ignjatovic V, Sheridan BJ, Mathew J, D’Udekem Y,
Brink J, et al. Bleeding and thrombotic events occur early in
children on durable ventricular assist devices. Thromb Res. (2019)
173:65–70. doi: 10.1016/j.thromres.2018.11.019
48. Rosenthal DN, Lancaster CA, McElhinney DB, Chen S, Stein M, Lin
A, et al. Impact of a modified anti-thrombotic guideline on stroke
in children supported with a pediatric ventricular assist device. J
Heart Lung Transplant. (2017) 1250–7. doi: 10.1016/j.healun.2017.
05.020
49. Sylvia LM, Ordway L, Pham DT, DeNofrio D, Kiernan M. Bivalirudin for
treatment of LVAD thrombosis: a case series. ASAIO J. (2014) 60:744–
7. doi: 10.1097/MAT.0000000000000122
50. Fischer R, Sachs UJ, Heidinger KS, Eisenburger D, Kemkes-Matthes B.
Prevalence of hereditary antithrombin mutations is higher than estimated in
patients with thrombotic events. Blood Coagul Fibrinolysis. (2013) 24:444–
8. doi: 10.1097/MBC.0b013e32835cc143
51. Baumann Kreuziger L, Karkouti K, Tweddell J, Massicotte MP.
Antithrombotic therapy management of adult and pediatric cardiac surgery
patients. J Thromb Haemost. (2018) 16:2133–46. doi: 10.1111/jth.14276
52. Nair AG, Oladunjoye OO, Trenor CC III, LaRonde M, van den
Bosch SJ, Sleeper LA, et al. An anticoagulation protocol for use after
congenital cardiac surgery. J Thorac Cardiovasc Surg. (2018) 156:343–
52.e4. doi: 10.1016/j.jtcvs.2018.02.106
53. Hasija S, Talwar S, Makhija N, Chauhan S, Malhotra P, Chowdhury UK, et al.
Randomized controlled trial of heparin versus bivalirudin anticoagulation in
acyanotic children undergoing open heart surgery. J Cardiothorac Vasc Anesth.
(2018) 32:2633–40. doi: 10.1053/j.jvca.2018.04.028
54. Zaleski KL, DiNardo JA, Nasr VG. Bivalirudin for pediatric
procedural anticoagulation: a narrative review. Anesth Analg. (2019)
128:43–55. doi: 10.1213/ANE.0000000000002835
55. Schill MR, Douds MT, Burns EL, Lahart MA, Said AS, Abarbanell AM.
Is anticoagulation with bivalirudin comparable to heparin for pediatric
extracorporeal life support? results from a high-volume center. Artif Organs.
45:15–21. doi: 10.1111/aor.13758
56. Yuan SM. Heparin-induced thrombocytopenia in pediatrics following
cardiopulmonary bypass. J Coll Physicians Surg Pak. (2019) 10:986–
92. doi: 10.29271/jcpsp.2019.10.986
57. Ezetendu C, Jarden A, Hamzah M, Stewart R. Bivalirudin anticoagulation for
an infant with hyperbilirubinemia and elevated plasma-free hemoglobin on
ECMO. J Extra Corpor Technol. (2019) 51:26–8.
58. Hamzah M, Jarden AM, Ezetendu C, Stewart R. Evaluation of bivalirudin
as an alternative to heparin for systemic anticoagulation in pediatric
extracorporeal membrane oxygenation. Pediatr Crit Care Med. (2020) 21:827–
34. doi: 10.1097/PCC.0000000000002384
59. Hohlfelder B, DeiCicchi D, Sylvester KW, Connors JM. Development of
a predictive nomogram for the change in PT/INR upon discontinuation
of bivalirudin as a bridge to warfarin. Clin Appl Thromb Hemost. (2017)
23:487–93. doi: 10.1177/1076029616638505
60. Corliss BM, Freedman R, Brennan MM, Smith J, Nerva JD, Harris NS, et
al. Laboratory assessments of therapeutic platelet inhibition in endovascular
neurosurgery: complication prediction using the Verify Now P2Y12 assay
and thromboelastography with platelet mapping. J Neurosurg. (2020) 1–9.
doi: 10.3171/2019.12.JNS192396
61. Smith JW, Steinhubl SR, Lincoff AM, Coleman JC, Lee TT, Hillman RS, et al.
Rapid platelet-function assay: an automated and quantitative cartridge-based
method. Circulation. (1999) 99:620–5. doi: 10.1161/01.CIR.99.5.620
62. Ferguson LP, Duong P, Pearce KF, Murphy P, Biss TT. Monitoring
of antiplatelet therapy in children on ventricular assist device support:
comparison of multiplate and thromboelastography platelet mapping. ASAIO
J. (2019) 65:84–93. doi: 10.1097/MAT.0000000000000768
63. Baumann Kreuziger LM, Kim B, Wieselthaler GM. Antithrombotic therapy
for left ventricular assist devices in adults: a systematic review. J Thromb
Haemost. (2015) 13:946–55. doi: 10.1111/jth.12948
64. Baumann Kreuziger LM. Management of anticoagulation and antiplatelet
therapy in patients with left ventricular assist devices. J Thromb Thrombolysis.
(2015) 2015:337–44. doi: 10.1007/s11239-014-1162-6
65. Terrovitis JV, Ntalianis A, Kapelios CJ, Vakrou S, Diakos N, Katsaros L, et al.
Dabigatran etexilate as second-line therapy in patients with a left ventricular
assist device. Hellenic J Cardiol. (2015) 56:20–5.
66. Andreas M, Moayedifar R, Wieselthaler G, Wolzt M, Riebandt J,
Haberl T, et al. Increased thromboembolic events with dabigatran
compared with vitamin K antagonism in left ventricular assist device
patients: a randomized controlled pilot trial. Circ Heart Fail. (2017)
10:3709. doi: 10.1161/CIRCHEARTFAILURE.116.003709
Frontiers in Pediatrics | www.frontiersin.org 10 February 2021 | Volume 9 | Article 625632
Ghbeis et al. Hemostatic Balance in Pediatric VADs
67. Hilal T, Mudd J, DeLoughery TG. Hemostatic complications associated
with ventricular assist devices. Res Pract Thromb Haemost. (2019) 3:589–
98. doi: 10.1002/rth2.12226
68. Crow S, Chen D, Milano C, Thomas W, Joyce L, Piacentino V 3rd,
Sharma R, et al. Acquired von Willebrand syndrome in continuous-flow
ventricular assist device recipients. Ann Thorac Surg. (2010) 90:1263–
9. doi: 10.1016/j.athoracsur.2010.04.099
69. Geisen U, Brehm K, Trummer G, Berchtold-Herz M, Heilmann C, Beyersdorf
F, et al. Platelet secretion defects and acquired von Willebrand syndrome
in patients with ventricular assist devices. J Am Heart Assoc. (2018)
7:6519. doi: 10.1161/JAHA.117.006519
Conflict of Interest: The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could be construed as a
potential conflict of interest.
Copyright © 2021 Ghbeis, Vander Pluym and Thiagarajan. This is an open-access
article distributed under the terms of the Creative Commons Attribution License (CC
BY). The use, distribution or reproduction in other forums is permitted, provided
the original author(s) and the copyright owner(s) are credited and that the original
publication in this journal is cited, in accordance with accepted academic practice.
No use, distribution or reproduction is permitted which does not comply with these
terms.
Frontiers in Pediatrics | www.frontiersin.org 11 February 2021 | Volume 9 | Article 625632
Available via license: CC BY
Content may be subject to copyright.
