Acta Biomaterialia 94 (2019) 2–10

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Acta Biomaterialia
journal homepage: www.elsevier.com/locate/actabiomat

Review article

The blood compatibility challenge. Part 1: Blood-contacting medical

devices: The scope of the problem
Iqbal H. Jaffer, Jeffrey I. Weitz ⇑
Thrombosis and Atherosclerosis Research Institute and McMaster University, Hamilton L8L 2X2, ON, Canada

a r t i c l e i n f o a b s t r a c t

Article history: Blood-contacting medical devices are an integral part of modern medicine. Such devices may be used for
Received 3 May 2019 only a few hours or may be implanted for life. Despite advances in biomaterial science, clotting on med-
Received in revised form 12 June 2019 ical devices remains a common problem. Systemic administration of antiplatelet drugs or anticoagulants
Accepted 13 June 2019
is often needed to reduce the risk of clotting. Although effective, such therapy increases the risk of bleed-
Available online 18 June 2019
ing, which can be fatal. This chapter (a) describes some of the commonly used blood-contacting devices
and their potential complications, (b) provides an overview of the mechanisms that drive device-
Keywords:
associated clotting, and (c) reviews the strategies employed to attenuate clotting on blood-contacting
Medical devices
Coagulation
medical devices.
Biomaterials
Anticoagulation Statement of significance
Thrombosis
This paper is part 1 of a series of 4 reviews discussing the problem of biomaterial associated thrombo-
genicity. The objective was to highlight features of broad agreement and provide commentary on those
aspects of the problem that were subject to dispute. We hope that future investigators will update these
reviews as new scholarship resolves the uncertainties of today.
Ó 2019 The Authors. Published by Elsevier Ltd on behalf of Acta Materialia Inc. This is an open access
article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
2. Scope of the problem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
2.1. CVCs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
2.2. Cardiac devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
2.3. Extra-corporeal circuits. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
3. Mechanism of clotting on medical devices. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
3.1. Protein adsorption. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
3.2. Cell adhesion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
3.3. Contact activation triggers thrombin generation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
3.4. Complement activation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

Abbreviations: CVC, central venous catheter; VAD, ventricular assist device (LVAD or RVAD – left or right VAD); CPB, cardiopulmonary bypass; ECMO, extracorporeal
membrane oxygenator; VTE, venous thromboembolism; DVT, deep vein thrombosis; BHV, bioprosthetic heart valve; MHV, mechanical heart valve; PCI, percutaneous
coronary intervention; CDC, centers for disease control and prevention; CABG, coronary artery bypass graft; F, factor (as in coagulation factor); ADP, adenosine diphosphate;
DOAC, direct oral anticoagulant; LMWH, low molecular weight heparin; VKA, vitamin k antagonist.
⇑ Corresponding author at: Thrombosis & Atherosclerosis Research Institute, 237 Barton Street East, Hamilton, Ontario L8L 2X2, Canada.
E-mail address: weitzj@taari.ca (J.I. Weitz).

https://doi.org/10.1016/j.actbio.2019.06.021
1742-7061/Ó 2019 The Authors. Published by Elsevier Ltd on behalf of Acta Materialia Inc.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
 I.H. Jaffer, J.I. Weitz / Acta Biomaterialia 94 (2019) 2–10 3

4. Methods to prevent clotting on medical devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

4.1. Antithrombotic strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
4.2. Surface modification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
5. Conclusions and future directions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

1. Introduction 2. Scope of the problem

Blood-contacting medical devices are widely used in clinical
practice. Medical devices include those that are (a) indwelling such
as intravenous cannulas or peripherally inserted central venous
catheters (CVCs), (b) implanted such as coronary stents, prosthetic
heart valves or ventricular assist devices (VADs), which can assist
the left or right ventricle (LVAD and RVAD, respectively), or (c)
extracorporeal such as dialysis circuits, cardiopulmonary bypass
(CPB) circuits or extracorporeal membrane oxygenator (ECMO) cir-
cuits (Fig. 1A–G).
Another feature that differentiates blood-contacting devices is
the duration of their use. For example, dialysis and CPB circuits
are typically used for only a few hours, whereas ECMO and CVCs
are used for weeks to months, and stents and heart valves remain
in place for many years and typically for life. VADs are unique
among devices because they may be implanted for weeks or for
years depending upon whether they are used as a bridge to heart
transplantation or as destination therapy. Regardless of the type
of device or duration of use, however, all result in the exposure
of a foreign surface to the blood, which can trigger either coagula-
tion leading to clot formation or immune reactions. Blood clots can
foul the device, cause local problems by occluding the vessel in
which the device is implanted, or result in systemic complications
if the clot dislodges and travels to the lungs, brain, or other organs.
We provide here an overview of this problem and with this intro-
duce a short series of four review articles, which highlight both
generally accepted and more controversial aspects of the interac-
tion between blood and biomedical devices from the perspective
of leading experts in the field.
Although there are many blood-contacting devices, we will
focus on the prototypes of those that are commonly used for short,
extended and lifelong indications. These include CVCs, cardiac
devices such as stents, pacemakers, valves, and VADs, and extra-
corporeal circuits.
2.1. CVCs
CVCs are widely used for venous access or drug delivery. They
are inserted into a central vein in the neck (jugular vein), the chest
(subclavian vein), or the groin (femoral vein), or they can be fed
into the subclavian vein through the brachial or cephalic veins in
the arm. Once inserted, CVCs can be used for days, weeks, or even
months. In 2003, it was estimated that more than 5 million CVCs
were inserted in the United States [1,2]. The global CVC market is
currently valued at US$650 million and the market is expected to
grow by at least 5% per year through 2026 [3].
CVCs are associated with a high risk of thrombosis [4]. The mag-
nitude of the problem depends on how thrombosis is defined and
how it is diagnosed. Thus, the incidence of symptomatic venous
thromboembolism (VTE), which includes deep-vein thrombosis
(DVT) at the site of CVC insertion and pulmonary embolism (PE),
clots that break off from the device and travel via the superior vena
cava to lodge in the lungs, ranges from less than 1% to 28%. CVC-
associated thrombosis is a major clinical problem in terms of
venous-access loss, the risk of DVT and PE, and additional costs
associated with VTE treatment and CVC replacement. It is reported
that over 70% of upper extremity DVT is attributable to centrally or

Fig. 1. Examples of medical devices. A) double lumen central venous catheter, B) bileaflet mechanical heart valve with Dacron sewing ring, C) bioprosthetic heart valves by
Edwards, St. Jude Medical, and LivaNova (from left to right), D) transcatheter aortic valves by Edwards and Medtronic, E) coronary stent by Boston Scientific, F) oxygenator
and heat exchanger used in cardiopulmonary bypass circuits, and G) a left ventricular assist device, Heartmate 2, by Thoratec. Copyrights belong to the respective manufacturers.
4 I.H. Jaffer, J.I. Weitz / Acta Biomaterialia 94 (2019) 2–10
peripherally inserted CVCs [4]. This issue is particularly relevant to
patients with cancer who need CVCs for cancer treatment delivery
and who are at increased risk of cancer-associated VTE. Therefore,
methods to reduce the risk of CVC-associated thrombosis are
urgently needed.
Prophylactic anticoagulation does not appear to reduce the risk
of CVC-associated DVT. Instead, maneuvers to mitigate complica-
tions range from modifications in the methods for CVC insertion
and sites of CVC placement [2] to the use of specialized coatings
(see associated article on surface modification (part 4 of this ser-
ies)) to prevent biofilm or thrombus formation on the surface of
the devices [4–6]. Despite some progress, none of these maneuvers
have had a major impact on the complication rate. Therefore, with
the increasing usage of CVCs for venous access and drug delivery,
more work needs to be done to render them less prone to throm-
botic or infectious complications.
2.2. Cardiac devices
Coronary stents are the most commonly used cardiac devices.
Stents are implanted during or after narrowed or occluded coro-
nary arteries have been widened with a balloon catheter to prevent
the artery from narrowing again [7]. It is estimated that from 2001
to 2011, over 8.1 million percutaneous coronary interventions
(PCI) were performed and that at least one stent was deployed in
most of these procedures [8]. Therefore, coronary stenting is
widely performed worldwide.
Stent technology has rapidly evolved with a shift from bare
metal stents to drug-eluting stents, and on to bio-engineered
stents and bioresorbable vascular scaffolds. This evolution reflects
improvements designed to prevent re-narrowing of the stented
artery and to reduce the risk of stent thrombosis. Despite the
advances, however, stent thrombosis remains a potential problem
and most stented patients are treated with dual antiplatelet ther-
apy consisting of aspirin plus clopidogrel, ticagrelor or prasugrel
for at least 6 to 12 months to reduce this risk [9].
Although larger in caliber than coronary stents, stents used in
patients with peripheral artery disease in the legs also are even
more prone to occlusion and to in-stent thrombosis, which can
lead to chronic limb ischemia or acute limb loss [10,11]. Multiple
technologies have been developed to try to deal with this chal-
lenge, including the use of drug-eluting balloons and stents.
Nonetheless, there still is room for improvement in coronary and
peripheral artery stent technology.
Prosthetic heart valves are another cardiac device whose uti-
lization is expanding with the aging of the population. The Centers
for Disease Control and Prevention (CDC) reports that 110,915 sur-
gical prosthetic heart valve procedures were performed in the Uni-
ted States in 2014 [12]. Prosthetic heart valves can be implanted
surgically or using a transcatheter approach. Surgically implanted
valves are either bioprosthetic valves (BHVs), which are also
known as tissue valves because they are constructed from bovine
pericardium or modified porcine heart valves, or mechanical heart
valves (MHVs). The vast majority of surgically implanted valves are
BHVs; MHVs represent only 10% of all surgically implanted valves
[13].
Transcatheter valve replacement is increasing in popularity and
is now used routinely for implantation of aortic valves in
moderate-risk and high-risk patients [14]. Although the procedure
is not yet perfected for mitral valve procedures, the technologies
for transcatheter mitral valve repair and replacement are rapidly
evolving [15,16]. Consequently, it is expected that transcatheter
valve replacement will soon overtake surgical implantation, and
it has already done so in some countries [17].
Despite advances in the technology and the procedures,
patients with prosthetic valves are prone to stroke or systemic
embolism because of clotting on the artificial valve surface [18].
Patients with MHVs are at the highest risk for clotting and require
life-long anticoagulation therapy with a vitamin K antagonist such
as warfarin [14]. Those with BHVs have a lower risk for stroke, but
anticoagulation therapy is often given for the first 3 to 6 months
after valve implantation to prevent clotting on the sewing ring
until it becomes covered with an endothelial layer [19,20]. After
this initial period of anticoagulation, patients are often switched
to aspirin.
Patients undergoing transcatheter aortic valve replacement also
are at risk for stroke, particularly in the first 3 months after valve
implantation [21]. It is common practice to treat these patients
with dual antiplatelet therapy with aspirin and clopidogrel for
the first few months after valve implantation and to continue them
on aspirin alone thereafter [14]. Ongoing studies are evaluating
whether administration of direct oral anticoagulants (DOACs) such
as rivaroxaban, apixaban or edoxaban on top of aspirin is more
effective than dual antiplatelet therapy for stroke prevention after
transcatheter valve replacement [22–24]. The first such study was
stopped early because of excess clotting and bleeding with rivarox-
aban so the utility of this approach remains in doubt [25].
VADs represent the smallest proportion of cardiac devices but
account for a large portion of healthcare expenditures because
the devices are expensive and because patients with LVADs require
intensive management. It is estimated that 2152 LVADs were
implanted between 2004 and 2011 in the Medicare population in
the United States [26]. This number has been increasing year after
year and several thousand more patients will be eligible for this
therapy because the incidence of end-stage heart failure is increas-
ing [26].
Pump thrombosis, clotting within the device, is a common
problem in patients with LVADs [27]. The incidence of pump
thrombosis varies depending on the type of device but can be as
high as 3% at 3 months and 5% at 6 months [28]. Pump thrombosis
can trigger device failure or can lead to thromboembolic complica-
tions including stroke. The optimal strategy to prevent thrombosis
is uncertain. Most centers bridge patients from heparin to warfarin
after LVAD implantation and give concomitant treatment with
aspirin and/or clopidogrel [29]. Despite such treatment, however,
pump thrombosis can still occur, highlighting the thrombogenicity
of LVADs. In addition to thrombosis, other common complications
with LVADs include infection and bleeding. Therefore, advances in
LVAD technology are still needed.
2.3. Extra-corporeal circuits
Extra-corporeal circuits are used to supplement the function of
the heart and lungs during cardiac surgery (CPB) or when the heart
and lungs are failing (ECMO). CPB is used to facilitate cardiac sur-
gery by creating a motionless and bloodless field that facilitates
complex interventions such as coronary artery bypass grafting
(CABG) or heart valve replacement. The CDC reports that in 2014,
160,240 CABG operations and 110,915 heart valve operations were
performed [12]; most of these procedures would have been under-
taken with the use of CPB [30].
ECMO, which utilizes a pump similar to that used for CPB,
enables more extended augmentation of the function of the lungs
(veno-venous) or the heart and lungs (veno-arterial) in critically ill
patients [31]. The use of ECMO has increased by over 400% since
2006 [31]. A report from the over 600 centres that participate in
a registry coordinated by the Extracorporeal Life Support Organiza-
tion reveals that 87,366 ECMO runs have been performed since ini-
tiation of the registry in 1990 [32]. The mean survival of ECMO
patients is about 69% and survival to discharge or transfer is about
55% [32].
 I.H. Jaffer, J.I. Weitz / Acta Biomaterialia 94 (2019) 2–10 5

Fig. 2. Blood-contacting medical device associated thrombosis. Protein adsorption on the surface of medical devices induces platelet adhesion, activation and aggregation.
Factor XII adsorbed to the surface undergoes autoactivation, and the resulting factor XIIa converts prekallikrein to kallikrein and initiates coagulation and thrombin
generation. In addition to inducing fibrin deposition on the surface, thrombin promotes platelet activation. Platelet aggregates deposited on the surface are stabilized by fibrin
strands to form a platelet-fibrin thrombus. Kallikrein, thrombin and other coagulation enzymes activate complement, inducing a local inflammatory response. Leukocytes
also adhere to the surface where they become activated and can contribute to both inflammation and thrombosis.

With both CPB and ECMO, high concentrations of heparin are
required to prevent clotting in the extracorporeal circuit. The con-
centrations of heparin used during these procedures are over 10-
fold higher than those used to treat patients with established
thrombosis, which highlights the thrombogenicity of the circuitry.
With these high concentrations of heparin, patients are at
increased risk for bleeding. Therefore, novel strategies to prevent
clotting in extracorporeal circuits are needed.
3. Mechanism of clotting on medical devices
Whereas the healthy endothelium has mechanisms to resist
thrombosis, foreign surfaces have no such safe-guards. Instead,
medical devices promote coagulation through the activation of a
series of inter-connected processes that include protein adsorp-
tion, platelet and leukocyte adhesion, thrombin generation, and
complement activation (Fig. 2).
Each of these processes will be briefly described here. Details
are provided in part 2 (protein adsorption) and part 3 (cascade sys-
tems) of this series.
3.1. Protein adsorption
Rapid adsorption of plasma proteins onto artificial surfaces is
the initiating event in thrombus formation because the protein
layer modulates subsequent reactions (see Part 2 of this series:
Protein adsorption phenomena governing blood reactivity). The
dynamics of protein adsorption are related to the chemical and
physical properties of the surface and the proteins. Adsorbed pro-
teins can form a surface monolayer with a thickness of 2–10 nm
and the concentrations of proteins on the surface can be 1000-
fold higher than those in plasma [33]. Surface adsorption often is
reversible, and the composition of adsorbed proteins changes over
time. This phenomenon, which was first described for the proteins
of the contact system by Leo Vroman, is known as the Vroman
effect [34,35]. The Vroman effect is particularly evident on nega-
tively charged hydrophilic surfaces [36], and appears to be inde-
pendent of flow [37].
Fibrinogen is one of the first plasma proteins to deposit on arti-
ficial surfaces. Other adhesive proteins, including fibronectin and
von Willebrand factor, also adsorb to the surface, and together
with fibrinogen, mediate platelet adhesion. Adsorbed fibrinogen
is often replaced with components of the contact system, including
factor (F) XII, high molecular weight kininogen, prekallikrein and
FXI [36]. Activation of surface-bound FXII not only triggers throm-
bin generation via the intrinsic pathway of coagulation, but also
induces complement activation. With cross-talk between the com-
plement and coagulation pathways, complement activation ampli-
fies thrombin generation. Therefore, the protein monolayer serves
as a dynamic modulator of thrombosis on artificial surfaces [38].
3.2. Cell adhesion
Adsorbed proteins mediate the attachment of platelets, leuko-
cytes and red blood cells to artificial surfaces; activation of non-
adherent platelets is also a concern. Fibrinogen is the major protein
responsible for platelet adhesion. The platelet-fibrinogen interac-
tion is mediated by aIIbb3, the most abundant integrin on the pla-
telet surface [39]. Whereas aIIbb3 on the surface of circulating
platelets must undergo conformational activation via inside-out
signaling before it is capable of binding fibrinogen, even in its qui-
escent state, aIIbb3 is capable of binding fibrinogen adsorbed to
artificial surfaces [39]. This is a high affinity interaction, and
adsorbed fibrinogen concentrations as low as 7 ng/cm2 are capable
of mediating platelet adhesion [40]. Although adsorbed fibronectin
and von Willebrand factor also bind platelets, they are less impor-
tant mediators of platelet adhesion on artificial surfaces than fib-
rinogen [40,41].
Platelets adherent to artificial surfaces become activated and
release thromboxane A2, adenosine diphosphate (ADP) and other
agonists [42]. By activating nearby platelets, these substances
amplify platelet adhesion, activation and aggregation on the artifi-
cial surface. This leads to platelet thrombus formation, and ongoing
6 I.H. Jaffer, J.I. Weitz / Acta Biomaterialia 94 (2019) 2–10

consumption of circulating platelets may result in a decrease in the cuitry and the membrane oxygenator or dialysis membrane [52].
platelet count [43–45]. Complement activation also occurs with catheters and vascular
grafts [53]. The complement cascade is initiated via three distinct
pathways; the classical, alternative and lectin pathways. Artificial
3.3. Contact activation triggers thrombin generation
surfaces trigger complement activation via the classical and alter-
native pathways. Kallikrein generated on artificial surfaces cleaves
In addition to tissue factor mediated coagulation, components
FXIIa to generate b-FXIIa, which by activating the first component
of the contact system adsorb to artificial surfaces, thereby facilitat-
of complement, initiates the classical pathway. C3 and C5 deposit
ing activation of the intrinsic pathway of coagulation [46].
on artificial surfaces, particularly extracorporeal circuits [54–56].
Adsorbed FXII undergoes autoactivation to become the enzyme
Kallikrein activates C3 and C5, while FIXa, FXa and thrombin acti-
FXIIa, which then activates prekallikrein and FXI [47,48]. Because
vate C5 [57,58]. The resultant C3a and C5a serve as potent
high-molecular-weight kininogen, which serves as a cofactor in
chemoattractants for leukocytes and promote their adhesion to
these reactions, binds to artificial surfaces, further activation of
the surface and their subsequent activation [54]. Therefore, plate-
FXII and the contact pathway occurs [48]. Prekallikrein activation
let and leukocyte activation and the coagulation and complement
results in the generation of kallikrein, which activates more FXII
systems are intimately linked, and both systems are activated on
in a reciprocal fashion. Activation of FXI initiates a series of prote-
artificial surfaces; more details about this complex interaction
olytic reactions that culminate in thrombin generation. Thrombin
are provided in the third part of this series.
not only converts fibrinogen to fibrin monomers, but also serves
as a potent platelet agonist, thereby promoting local platelet aggre-
gation [44]. The fibrin monomers polymerize and are then cross-
4. Methods to prevent clotting on medical devices
linked by FXIIIa [43]. The crosslinked fibrin strands stabilize the
platelet aggregates thus creating a platelet-fibrin thrombus.
Thrombus formation on medical devices is associated with sig-
Thrombus formation can foul the device and can cause it to fail.
nificant morbidity and mortality and increases healthcare costs.
Recent studies suggest that clotting on extracorporeal circuits
Several strategies have been employed to mitigate thrombosis.
and vascular grafts also is mediated via the intrinsic pathway.
These include pharmacological methods such as systemic adminis-
Thus, an antibody against FXIIa attenuated thrombosis in a rabbit
tration of antiplatelet drugs (e.g. aspirin, clopidogrel) or anticoag-
ECMO model [49] and reduced platelet and fibrin deposition on
ulants (e.g. warfarin). However, administration of antithrombotic
vascular grafts in a baboon arterio-venous shunt model [50]. Other
agents is associated with an increased risk of bleeding, which can
studies done by us have demonstrated that CVCs [51] and MHVs
be fatal. Therefore, modifications to the material surfaces that min-
[18] also induce clotting via activation of factor XII.
imize defense reactions or provide localized antithrombotic activ-
ity would be beneficial. An overview on these different strategies is
3.4. Complement activation given in Fig. 3.
Despite improvements in the materials used to construct these
Complement activation occurs during CPB, hemodialysis, and devices, patients with coronary or peripheral artery stents, heart
ECMO when blood comes into contact with the extracorporeal cir- valves, and LVADs still require antithrombotic therapy with antico-

Fig. 3. Methods to prevent clotting on medical devices.

 I.H. Jaffer, J.I. Weitz / Acta Biomaterialia 94 (2019) 2–10
agulants, antiplatelet agents or both to reduce the risk of thrombo-
sis. The following sections (a) explain why some anticoagulants are
better than others for prevention of biomaterial-induced clotting,
and (b) describe approaches to the design of less thrombogenic
biomaterials.
4.1. Antithrombotic strategies
Failure of medical devices is often due to corruption by thrombi.
Thrombosis occurs as a result of flow disturbance and surface bio-
compatibility [38]. Advances in device hemodynamics and
improvements in biomaterials have the potential to reduce activa-
tion of platelets and the coagulation system [59]. Nonetheless,
with current devices, many patients still require treatment with
antiplatelet drugs, anticoagulants or both to prevent thrombosis.
Antiplatelet agents, such as aspirin and clopidogrel, are a main-
stay for the prevention of stent thrombosis and recurrent ischemia
in patients undergoing PCI for acute coronary syndrome, thereby
highlighting the role of platelets in these processes [9]. Although
newer antiplatelet agents such as prasugrel and ticagrelor have
an incremental advantage over clopidogrel for prevention of stent
thrombosis because of their more potent inhibition of P2Y12, they
are associated with an increased risk of bleeding complications
[60,61].
Aspirin inhibits platelet activation by irreversibly acetylating
cyclooxygenase 1 and attenuating the synthesis and release of
thromboxane A2, which is a platelet agonist [62]. Activated plate-
lets also release ADP, which activates adjacent platelets and pro-
motes their aggregation. Clopidogrel, prasugrel and ticagrelor
inhibit P2Y12, the major ADP receptor on the platelet surface
[62]. Clopidogrel and prasugrel produce irreversible inhibition of
the receptor, whereas ticagrelor is a reversible inhibitor [62].
Therefore, antiplatelet agents inhibit biomaterial-induced platelet
activation through different mechanisms.
Anticoagulants inhibit coagulation enzymes in either a direct or
indirect manner. The classic anticoagulants are heparin which
potentiates the inhibition of thrombin and FXa by antithrombin
and vitamin K antagonists (VKAs) such as warfarin, which inhibit
the synthesis of the vitamin K-dependent clotting factors, namely
factors II, VII, IX, and X [63]. Heparin has to be given parenterally
whereas VKAs are taken orally [64–66]. Although heparin and war-
farin are effective for preventing thrombosis and have been avail-
able for decades, they require frequent coagulation monitoring to
ensure that a therapeutic level of anticoagulation is achieved and
maintained [63–66].
Newer anticoagulants within the heparin family include low-
molecular weight heparin (LMWH) and fondaparinux, which can
be given subcutaneously in fixed weight-adjusted doses and do
not require routine coagulation monitoring [66]. However, these
shorter chain heparin fragments are not as effective as heparin at
preventing clotting induced by medical devices [51]. For example,
compared with heparin, fondaparinux was associated with a
higher rate of catheter thrombosis in patients undergoing PCI
[67]. This occurred because shorter heparin chains are less effec-
tive than longer ones at promoting the inhibition of FXIIa, FXIa
and FIXa by antithrombin [51,66]. Consequently, heparin remains
the anticoagulant of choice for CPB and ECMO. Another reason
for the use of heparin for anticoagulation with extracorporeal cir-
cuits is its capacity to be reversed with protamine sulfate [68–
70]. A positively-charged protein derived from salmon sperm, pro-
tamine binds the anionic heparin chains and reverses their antico-
agulant activity. In contrast, fondaparinux cannot be reversed with
protamine, and protamine only partially reverses the anticoagulant
effect of LMWH [70].
The DOACs include rivaroxaban, apixaban, edoxaban, and
betrixaban, which inhibit FXa, and dabigatran, which inhibits
7
thrombin. The DOACs were developed to overcome the limitations
of VKAs. Unlike VKAs, the DOACs can be given in fixed doses with-
out routine coagulation monitoring and they have few drug inter-
actions and their activity is unaffected by dietary vitamin K intake
[71–73]. Currently, the DOACs are licensed for stroke prevention in
atrial fibrillation (AF) and prevention and treatment of venous
thromboembolism (VTE) and they have largely supplanted VKAs
for these indications [74,75]. However, the DOACs are contraindi-
cated in patients with severe renal impairment and in those with
MHVs [76,77].
Compared with warfarin in patients with MHVs, dabigatran was
associated with an increase in both ischemic stroke and bleeding
[78,79]. These findings prompted early termination of the study
and a black box warning against the use of dabigatran or other
DOACs in patients with MHVs [76]. Dabigatran failed in this setting
because MHVs activate FXII and trigger the local generation of
thrombin in concentrations that overwhelm those of the drug
[18]. Coagulation activation by MHVs occurs via the contact path-
way [18,20]. Warfarin is better at suppressing this process than
dabigatran because by lowering the levels of factors IX, X and II,
warfarin attenuates thrombin generation through the intrinsic
and common pathways [18]. Because of these findings, VKAs con-
tinue to be the anticoagulant of choice for patients with MHVs and
other devices, including VADs.
Focusing on the contact pathway as the driver of clotting on
medical devices, FXII and FXI are emerging as targets for new anti-
coagulants. In support of this concept, a monoclonal antibody
against FXIIa was as effective as heparin at preventing clotting in
a rabbit ECMO model [49], and knockdown of FXII or FXI with anti-
sense oligonucleotides attenuated CVC thrombosis in rabbits,
whereas FVII knock down did not [80]. FXII and FXI are appealing
targets because of their potential safety. Thus, patients with con-
genital FXII deficiency do not bleed and those with FXI deficiency
have only a mild bleeding diathesis [81,82]. The clinical potential
for ASOs was demonstrated in a phase 2 study in patients undergo-
ing elective knee replacement surgery [83]. Knockdown of FXI was
associated with a significantly lower rate of postoperative VTE than
occurred with LMWH and there was no increase in the risk of
bleeding [83]. However, additional studies are needed to assess
the utility of this and other strategies to inhibit FXI or FXII in
patients with medical devices.
4.2. Surface modification
The goal of surface modification is to attenuate clotting as well
as innate immune system activation by altering the blood-material
interface (see part 4 of this series). This can be accomplished using
physicochemical methods or surface biofunctionalisation [84].
Physicochemical methods influence protein-cell-material interac-
tions by modulating surface topography, charge, and hydropho-
bic/hydrophilic interactions. In contrast, biofunctionalisation is
aimed at endowing the surface with the capacity to actively inter-
fere with enzymatic activation or cell surface receptors, such as the
integrins [84].
Physicochemical methods seek to modify the surface at the
nanometre scale because surface topography, hydrophilicity,
charge and porosity have been shown to affect the interactions of
proteins, platelets [85], leukocytes [85], and endothelial cells
[86]. Many of these principles are considered in the manufacturing
of more thrombosis resistant vascular grafts [87]. Most exciting are
maneuvers that promote the formation of a functionally active
endothelium that resists thrombosis [88]. Typically, such maneu-
vers target natural biological processes that induce systemic
endothelial cell mobilisation from bone marrow progenitor cells
and localized endothelial cell adhesion, proliferation, differentia-
tion, and maturation on the surface of the device [88].
8 I.H. Jaffer, J.I. Weitz / Acta Biomaterialia 94 (2019) 2–10
Biofunctional methods of surface modification include the
application of coatings that can be applied passively or can be
covalently linked to surface directly or via spacers. Heparin-
coated devices are commercially available and widely used. For
such devices, which include catheters and extracorporeal tubing,
heparin is applied as a passive coating to prevent clotting and to
eliminate or reduce the need for systemic anticoagulation. Other
examples of coatings include covalent heparin-antithrombin com-
plex [89], corn trypsin inhibitor [5], a specific inhibitor of FXIIa, and
omniphobic lubricant-infused coating [90]. In addition, progress
has been made in the development of surfaces that locally release
anticoagulants; so-called feedback regulated release materials
[91,92].
5. Conclusions and future directions
Blood-contacting medical devices are widely used. Indeed, as
people live longer and technology advances, the utilization of these
devices will increase exponentially. The risk of device-associated
thrombosis remains a major source of morbidity and mortality.
Preventing this problem requires a multi-pronged approach that
involves more effective and safer antithrombotic agents but above
all the development of less thrombogenic biomaterials. Until such
advances occur, clinicians will continue to walk the tightrope
between preventing thrombosis without causing serious bleeding.
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