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Chapter 30
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Vascular Closure Devices and
Thrombosis
Matthew J. Ryan and Brian Clapp
King’s College, London, United Kingdom; St Thomas’ NHS Foundation Trust, London, United Kingdom
INTRODUCTION
The percutaneous closure of congenital heart defects is innately satisfying. Both patient and operator can easily appreciate
the benefit of repairing the cardiac anatomy with a procedure that allows the patient to go home the following morning.
Correction can now be considered earlier, with a major complication risk frequently reported as <1%, as well as in patients
whose comorbidities or frailty precluded an otherwise efficacious procedure. These procedures are now performed in a
wide number of centers (37 UK centers implanted patent foramen ovale [PFO] and/or atrial septal defect [ASD] closure
devices in 2014). With growing evidence, increasing experience, and developing simplicity of the available devices, the
procedure will probably become more commonly performed. As this occurs, increasing consideration will need to go to
thrombotic risk and the management of associated thromboses. Our aim in writing this chapter is to summarize the relevant
(if rather limited) literature and propose both some potential management strategies and key avenues of future research in
the field. Due to the large preponderance of device procedures being focused upon the intraatrial septum, this chapter
restricts itself to this area, accepting that similar challenges and complications can be extrapolated to other intracardiac
device procedures.
Paradoxical Embolism
Closure of a PFO is a therapeutic strategy utilized to reduce the risk of recurrent cryptogenic stroke and/or systemic
embolism in patients suspected of having suffered a paradoxical embolism. When considering closure, it is therefore
important to understand the natural history of the condition and the thrombotic risk, both with and without intervention.
Paradoxical embolism as a cause of stroke was first described in the 19th century [1]. Subsequent observations of
thrombi in transit across the intraatrial septum and significantly higher rates of patency of the foramen ovale in patients
with unexplained stroke (40%e50% vs. 20%e25% in the general population) led to recognition of PFO as a potential
causal factor in such “cryptogenic” strokes. While the high background prevalence of PFO suggests that not all strokes in
patients with such a defect are directly attributable, risk analyses suggest that the PFO is causally related in 50% of cases
[2]. While demonstrating an enhanced risk for or the presence of venous thrombosis is desirable, no standard diagnostic
criteria exist, and current clinical consensus is that, once identified, the PFO should be considered causative once more
common etiologies (large- or small-vessel occlusive disease, atrial fibrillation, intracardiac thrombus, arterial dissection, or
uncontrolled hypertension or diabetes) are excluded.
The risk of recurrent ischemic stroke in individuals with a PFO and previous cryptogenic stroke is w1% per annum.
Adverse anatomical and physiological characteristics of PFO (associated atrial septal aneurysm, large aperture [>4 mm],
long tunnel, and significant right-to-left shunt) appear to further increase this risk. There has, therefore, been substantial
interest in the role of PFO closure, both surgical and percutaneous, in the secondary prevention of cryptogenic stroke.
Cardiovascular Thrombus. https://doi.org/10.1016/B978-0-12-812615-8.00030-2
Copyright © 2018 Elsevier Inc. All rights reserved.
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Percutaneous Patent Foramen Oval e Closure to Reduce the Risk of Recurrent Stroke
Platelet inhibition, with either aspirin or a P2Y12inhibitor, is the mainstay of secondary prevention for cryptogenic stroke
in the presence of a PFO, receiving a class I indication in both American and European guidelines. A number of small
studies have demonstrated the superiority of anticoagulation over antiplatelet medication in the prevention of recurrent
ischemic events, albeit at the cost of elevated bleeding risk. Interest has subsequently developed in PFO closure, in the
hope that this might mitigate the risk of recurrent stroke without the need for lifelong anticoagulation in a group of often
young and otherwise well patients.
Percutaneous PFO closure devices are broadly similar in construction. They consist of two membranes (often disk
shaped) supported by a metal framework and joined by a central hub that sits within the PFO tunnel. The device is
compressed into a delivery catheter, which is maneuvered into the left atrium via the venous system. The membranes are
sequentially deployed on either side of the intraatrial septum and the device is released. Rates of complete septal occlusion
on subsequent bubble study vary from 85% to 95%, depending on the study and device utilized (Fig. 30.1).
The benefit of percutaneous PFO closure in addition to antiplatelets has been uncertain, to the extent that the American
Academy of Neurology recommended against routine closure in patients with cryptogenic stroke as recently as 2016 [3].
The provision and commissioning of PFO closure services have subsequently been heterogeneous. This uncertainty arose
from a number of studies that failed to demonstrate significant benefit of closure over medical therapy (variably defined as
antiplatelet or anticoagulant therapy, or both) in their primary analysis. These trials were limited, however, by inadequate
statistical power, heterogeneous design, short follow-up, and the likely inclusion of patients with alternative causes of
stroke. Subsequent meta-analysis of these data, through both pooled and as-treated analyses, did demonstrate a degree of
benefit [4].
Data in the form of three large and robust randomized trials [5e7] have provided much needed clarity. Each of these
trials, recruiting a total of 2307 patients, randomized patients to either best medical therapy or antiplatelet therapy plus
percutaneous PFO closure. All three studies demonstrated dramatic reductions in the risk of recurrent stroke in the closure
arms (Fig. 30.2). The studies were, by necessity, open label; however, events were adjudicated by clinical events committees blinded to treatment assignments.
FIGURE 30.1 Percutaneous patent foramen ovale closure device.
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FIGURE 30.2 KaplaneMeier charts for stroke-free survival in major randomised trials e RESPECT (top left panel), CLOSE (top right panel) and
REDUCE (bottom panel). PFO, patent foramen ovale.
The CLOSE trial was a randomized trial enrolling 663 individuals with a diagnosis of cryptogenic stroke [5]. They
were carefully characterized to exclude alternative causes. Of these 663 patients, 238 were randomized 1:1 to PFO closure
plus antiplatelet therapy and 235 to antiplatelet therapy alone (the remainder were involved in underpowered exploratory
analyses between antiplatelets and anticoagulation). The trial allowed the use of any commercially available device; 11
different devices were used in total, though more than half of the procedures were performed with the Amplatzer PFO
device. In follow-up of over 5 years, no patients in the closure arm had a stroke, whereas 14 patients in the antiplatelet-only
group developed strokes. This difference was statistically significant, with a point estimate for the hazard ratio of 0.03
(95% CI 0e0.26). Of note, all the strokes in the control arm occurred in patients with either a large PFO or an atrial septal
aneurysm.
RESPECT was a trial of similar design, which randomized 980 patients 1:1 to PFO closure with an Amplatzer septal
occluder or medical therapy [6]. Pharmacotherapy in the control arm was less regulated than in CLOSE, with aspirin,
warfarin, clopidogrel or aspirin plus clopidogrel, or dipyridamole all permitted as combinations. Median follow-up was
5.9 years. The results again significantly favored PFO closure at this more extended follow-up, although it should be noted
that the original prespecified primary end point did not achieve significance. Recurrent ischemic stroke occurred in 3.6% of
patients in the closure arm and 5.8% of patients in the medical therapy arm. Due to the relatively low number of events, the
resulting hazard ratio just met statistical significance (HR 0.55, 95% CI 0.31e0.999). Subgroup analysis again demonstrated greater benefit in the presence of an atrial septal aneurysm and in those with larger shunts.
The REDUCE trial was different in that a 2:1 ratio was used to randomize 664 patients to either device closure plus
antiplatelet therapy or antiplatelet therapy alone [7]. Therapeut ic anticoagulation was not permitted. Procedures were
performed sequentially with the Gore Helex or the Gore Cardioform septal occluder (the latter replacing the former as the
manufacturer and funder’s device). Over follow-up of 3.2 years, significantly fewer strokes were observed in the closure
arm (1.4% vs. 5.4%, HR 0.23, 95% CI 0.09e0.62). The effect of atrial septal aneurysm was not examined; however, the
effect was again superior in those with larger shunts.
While the latter two trials were industry funded and mandated the use of a particular device, the consistency of effect
across devices and populations strongly supported the provision of percutaneous closure to patients with a PFO and
previous cryptogenic stroke. The caveats in these data are the very carefully defined cohort with extensive work put into
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excluding alternative risk factors. The focus was also, both in recruitment and in apparent effect, on those with larger
shunts and atrial septal aneurysms. Given this new evidence it is likely that guidelines will strengthen their recommendations for PFO closure to prevent recurrent stroke.
The incidence of first stroke in individuals with an incidentally detected PFO and no prior symptoms is low (w0.1%
per annum). The indication for closure is therefore limited to secondary prevention. Despite ex tensive investigation there
remains no high-quality evidence for closure to improve symptoms of migraine, and this indication has all but been
abandoned.
Atrial Septal Defect
Percutaneous closure is the first-line treatment of patients with hemodynamically significant secundum ASD. The devices
are similar to those used in PFO, although a larger variety of sizes are available to allow closer fit with the septal anatomy,
and most of the devices have a self-centering waist to allow closure of larger defects. The procedure presents a greater
degree of challenge to the operator than PFO closure, although it is associated wi th equally positive results. Whil e the
primary intent is normally the prevention of right-heart failure in the context of significant left-to-right shunt, when
performed for this indication there is evidence that early intervention significantly reduces the incidence of late atrial
arrhythmias [8]. This is probably due to the prevention of adverse stretch and remodelling of both atria. An associated
reduction in incident ischemic stroke was observed in surgical studies (0% vs. 13%) [9]. Confirmatory data for percutaneous closure are lacking; however, given the documented effects on atrial remodeling, a similar effect seems probable.
Percutaneous ASD closure may also be performed following stroke and presumed paradoxical embolism. These indications account for 3% e 14% of percutaneous ASD closure procedures, depending on the study. As in many aspects of
adult congenital heart disease, there is a lack of quality randomized evidence to support ASD closure for recurrent
cryptogenic stroke prevention, compared with PFO. From a pragmatic standpoint, the clinical decision remains straightforward: a patient who has sustained a paradoxical embolus through a nonehemodynamically significant ASD has no
reason to expect a different outcome compared with those with a PFO. Hemodynamically significant defects need closure
irrespective of the thrombotic risks.
THROMBOSIS IN PERCUTANEOUS ATRIAL SEPTAL OCCLUSION DEVICES
As with many of the interventions covered in this book, implanting foreign materials within the circulation brings an innate
risk of thrombosis. The implantation of these devices into the intraatrial septum creates perhaps the “perfect storm” for a
device thrombosis: the deployment of a complex structure in the shared wall of two chambers, both of which are points of
slower and less laminar flow, in individuals with a demonstrated predisposition to thrombosis. The most conspicuous
aspect of thrombosis in these devices is perhaps, therefore, how infrequently they are observed.
Preprocedure Assessment
The critical step in planning atrial septal closure is the identification of the right patient to undergo the procedure. A
systematic assessment of other potentially ca usative risk factors for stroke is essential to ensure appropriate treatment.
Typical investigations and the treatment of the associated conditions are outlined in Table 30.1. This is particularly
important where an indication for anticoagulation can be identified: the available data suggest that even where the PFO is
causative, anticoagulation may well be noninferior to PFO closure in preventing recurrent cryptogenic stroke, while the
device provides no protection from strokes related to atrial arrhythmias or thrombophilia. The RESPECT investigators
noted significantly reduced use of anticoagulation in the PFO closure arm. This coincided with a threefold higher risk of
pulmonary embolism in those treated with PFO closure devices where their intended medical therapy was anticoagulation
and the patient had a documented history of venous thromboembolism. It is clear that where such risk factors are identified,
the patient will be better served having these addressed than risking closing the PFO and undertreating the primary pathology. In circumstances in which the cause of stroke is not clear, each case merits detailed discussion in a multidisciplinary forum. An excellent summary of the workup for patients with cryptogenic stroke was published in 2016 [10].
While a number of factors contribute to device selection, from the thrombosis perspective there is evidence that the
Amplatzer and Cardioform devices are associated with significantly fewer thrombotic events. These devices share common
features: both involve nitinol frames with membranes to facilitate closure, polyester in the case of the Amplatzer and
polytetrafluoroethylene in the Cardioform device. Older devices, such as the CardioSEAL and STARFlex devices, have
resulted in higher rates of device thrombosis, in excess of 5% in some studies [11,12]. It has been suggested previously that
this is related to the use of uncoated met al struts in their construction.
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TABLE 30.1 Table of Risk Factors for Noncryptogenic Stroke
Risk Factor Choice of Investigation Therapeutic Strategy
Atrial fibrillation Cardiac monitoring (minimum 7 days, consider
Aortic arch atheroma/extracranial arterial disease
Intracardiac thrombus (LAA, LV,
T-in-T) or alternative shunt
Hypercoagulable state Coagulation screen, factor V Leiden, protein C/S,
Vascular risk factors Ambulatory BP monitor, HbA1
BP, blood pressure; CT, computed tomography; HbA1c, hemoglobin A1c; LAA, left-atrial appendage; LV, left-ventricular; MRI, magnetic resonance im-
aging; T-in-T, thrombus-in-transit.
Adapted from Windecker S, Kolh P, Alfonso F, Collet J-P, Cremer J, Falk V, Filippatos G, Hamm C, Head SJ, Ju¨ni P, Kappetein AP, Kastrati A, Knuuti J,
Landmesser U, Laufer G, Neumann F-J, Richter DJ, Schauerte P, Sousa Uva M, Stefanini GG, Taggart DP, Torracca L, Valgimigli M, Wijns W, Witkowski
A. 2014 ESC/EACTS guidelines on myocardial revascularization: the task force on myocardial revascularization of the European Society of Cardiology
(ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J 2014;35:2541e619.
implantable loop recorder)
Vascular imaging (ultrasound, CT, or MRI
angiography)
Transthoracic echocardiogram, transesophageal
echocardiogram, cardiac MRI
lupus anticoagulant
, lipid profiles,
smoking
c
Anticoagulation
Dual antiplatelets; carotid
endarterectomy
Anticoagulation or surgery
Anticoagulation
Risk factor modification, pharmacotherapy, smoking cessation
Consideration should also be given to the patient’s age. Although there is not a specific cutoff for the procedure,
paradoxical embolism accounts for a lower proportion of strokes in older patients. The evidence base for septal closure to
prevent recurrent cryptogenic stroke has been built in patients <60 years of age. Above this age, as alternative risk factors
become more prevalent, closure should be considered only in exceptional circumstances.
Detailed preprocedural transesophageal echocardiography is particularly important. The demonstration of specific
anatomical features (an atrial septal aneurysm, large shunt, long or wide PFO tunnel, or prominent Chiari network or
Eustachian valve) increases the probability of cryptogenic stroke. Sites disposed to intracardiac thrombus (the atrial appendages, the left-ventricular apex, and the septal defect itself) should be carefully assessed. The presence of adverse
characteristics likely to lead to incomplete occlusion or suboptimal device positioning may also affect the treatment
strategy.
Periprocedural Thrombosis
Although it is rare, a high degree of vigilance for thrombus formation is appropriate throughout the procedure. Patients
should be pretreated with dual antiplatelets to ensure adequate platelet inhibition, and unfractionated heparin should be
administered in appropriate doses (100 units/kg) to maintain an activated clotting time >250 s. Periprocedural imaging is
invaluable; this allows immediate recognition of intracardiac thrombus both pre- and postdeployment, as well as assessing
for malposition, which may predispose the patient to later thrombus formation. In general, this will be performed with
transesophageal echocardiography (TEE); however, intracardiac echocardiography is a useful alternative where local
expertise is available, particularly where general anesthesia is not appropriate or there is no independent operator for TEE
[13,14].
In the literature, periprocedural thrombosis is isolated to individual reports and small case series. Of six reported cases
identified in the literature, three were apparent on intraprocedural TEE and three when TEE was performed 30e60 min
postprocedure [15e17]. Four thrombi were located on the occlusion device (three on the left- and one on the right-atrial
aspects), while two developed on the delivery sheath. All thrombi were successfully treated, one by device removal, two by
systemic anticoagulation, and three by systemic thrombolysis with tenecteplase. No clinical sequelae developed and no
recurrence was identified on follow-up imaging in all cases.
Where periprocedural device throm bosis does occur, removal of the device with aspiration of the thrombus from the
delivery sheath where possible should be the first line. Where the device is already released, the limited available data
suggest that both anticoagulation and thrombolysis are effective; the decision between strategies will be informed by the
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size, location, and mobility of the thrombus as well as the presence of any elevated bleeding risk. There is a single case
report of successful treatment with abciximab in a pediatric patient [18]. After initial management, it is advisable that the
patient be formally anticoagulated until endothelialization is complete.
Maintenance Antiplatelet Therapy Following Implantation
Following implantation all patients should be commenced on maintenance dual antiplatelet therapy (DAPT) with aspirin
and clopidogrel (or an alternative P2Y
allow proper endothelialization of the device. In general, this is 1e6 months, de pending on the device and operator;
however, it may be increased if there are concerns that this process may be delayed. The decision on duration of antiplatelet
monotherapy is highly operator dependent (from 6 months to lifelong). The antiplatelet strategy in the intervention arms of
the recent randomized trials varied from 3 days of mandated DAPT (in REDUCE, though most patients received a longer
duration) to 3 months (in CLOSE).
inhibitor). These should be continued in combination for a duration sufficient to
12
Postprocedure Device Thrombosis
Postprocedure device thrombosis is rare. The reported rate is 0.5%e1%, which is relatively consistent across randomized
and observational studies [4e7,11,19] of contemporary devices (Amplatzer and Cardioform). There appears to be no
consistently significant difference in the rate of thrombosis betwe en closures performed for PFOs and ASDs, or between
indications for implantation (paradoxical embol ism vs. hemodynamic).
We have limited explanations as to why some patients develop thromboses. From a mechanical perspective, there is a
clear association with both device fracture and suboptimal positioning such that cavities are created between the atrial wall
and the device. Primary device failure also appears to be an important component. A histopathological study of nine
surgically extracted ASD and PFO devices identified five with echocardiographic evidence of thrombosis [20]. Three of
these devices (one Amplatzer ASD, one CardioSEAL, and one STARFlex) demonstrated either malpositioning or inadequate disk deployment. Strut dehiscence was seen in the other two Cardia PFO devices.
There is good evidence that postprocedure atrial fibrillation or flutter (AFF), persistent atrial septal aneurysm, and
prominence of the Eustachian valve also contribute to increased risk. Postprocedure AFF occurs in up to 6.6% of patients
following percutaneous closure. Given the increased risk of device thrombosis and other complications in patients who
have AFF, periodic ECG monitoring, either with Holter monitors or with 12-lead ECGs, should be considered. Where AFF
develops in patients following device implantation, traditional scoring systems for thromboembolic risk are invalid, and the
majority of operators would recommend therapeutic anticoagulation to reduce the risk of thrombosis and systemic
embolism.
Delayed endothelialization is poorly understood; however, it is also likely to contribute, as the prothrombotic risk of the
device appears to persist until this process has completed. Two investigations of coagulation activation following
percutaneous closure have demonstrated a significant increase in prothrombin fragment 1 and 2 levels on the first postoperative day [21,22]. These levels gradual ly returned to baseline over the following 3 months. Platelet activation was not
affected in one study and decreased in the other, though all patients were treated with aspirin. Thrombosis has also been
noted to occur more frequently following early discontinuation of the second antiplatelet medication, reinforcing the
importance of potent platelet inhibition during the initial period of endothelialization. Several authors have reported
conducting thrombophilia screening after device thrombosis, with a low rate of return. This should have been performed
preimplantation in all of those undergoing closure for paradoxical embolism, although it may be considered if not previously performed in those undergoing ASD closure.
Nickel allergy has also been proposed as a contributor to device thrombosis, as well as a number of loosely defined
postimplantation syndromes. While isolated case reports identify aggregations of eosinophils and other inflammatory
infiltrates within thrombi, there is little evidence at present to substantiate this hypothesis.
Given the low overall incidence of this complication and the variable time to the development of thrombosis, routine
TEE follow-up is not indicated where the procedure has been straightforward and the patient is asymptomatic and in sinus
rhythm. Where factors leading to increased risk of thrombosis are identified, or the clinical situation necessitates
discontinuation of one or both antiplatelet drugs, consideration should be given to follow-up TEE imaging. This can assess
the degree of endothelialization, which in turn may inform subsequent management.
Thankfully, when thrombi do develop, clinical sequelae are relatively uncommon and the majority are detected
“incidentally” during planned follow-up imaging. Specific estimates of the incidence of stroke related to device thrombosis
are limited; however, some estimate 5%e15% result in symptomatic embolism. The consequences can be devastating,
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FIGURE 30.3 Transesophageal echocardiography of a patent foramen ovale device with color-coded areas of thrombosis risk (panel A: two-dimensional
bi-caval view; panel B: 3D view). Blue highlight indicates an area of poor apposition, red the device’s central hub and green the transitional epithelium at
the lateral border of the disks.
including major stroke and death. The rate of thrombus detection depends on the imaging modality used for follow-up;
most thrombi will be missed by transthoracic echocardiography alone. In studies examining patients with serial TEE,
around three-quarters of thrombi had developed in the first 4 weeks. The majority of subsequent events will occur in the
first year, although incidents of late thrombosis as long as 8 years postprocedure have been reported [23].
Where the patient presents with new thromboembolic events following septal closure, a detailed study with TEE is
clearly mandated. It is important to recognize, however, that the majority of such events occur in the absence of device
thrombosis. The etiology of these events in patients with complete occlusion of the defect is unclear; however, it reinforces
the notion that the PFO is not attributable in all cryptogenic strokes. In these circumstances, prospective follow-up with
TEE at 6e8 weeks may be prudent. A succinct and useful summary of the echocardiographic assessment for complications
of PFO and ASD closures is available in the literature [24]. Contrast-enhanced cardiac computed tomography and MRI
may be complementary, particularly where the etiology of an atrial mass is uncertain.
The thrombi that have been reported are highly heterogeneous, with the best available data coming from the largest
reported series of 20 device thromboses detected with systematic TEE follow-up in a registry of 1000 ASD and PFO
closures from Krumsdorf and colleagues [11]. Seventeen of these were asymptomatic, with four presenting with thromboembolic neurological events. Thrombi varied in size from 2 to 30 mm (though sizes up to 60 mm have been reported)
and in mobility from highly mobile pedunculated lesions to laminar thrombi not in direct contact with the device. A trend
was observed toward more thrombi being seen on the left-atrial aspect, which is consistent with other reports. Involvement
of both atria is not uncommon.
The location of thrombi relative to the structure of the occlusion device is also variable and dependent on the device
used. Further available data suggest that with the Amplatzer occluder they often adhere to the central hub or the transitional
epithelium at the lateral border of the disks (Fig. 30.3).
No specific descriptions are available for localization of where thrombi have occurred on the Cardioform device. In
older and often now discontinued devices, thrombus tends to form on the exposed metal arms. Sites of fracture and cavities
created between the device and the septum in suboptimally positioned devices also create an expected nidus for problems
to develop.
Management of Device Thrombosis
The management options for thrombosis are anticoagulation (with heparin bridging to a vitamin K antagonist), thrombolysis, and surgical thrombectomy with or without explantation of the device. Given the rarity of events, no specific
management guideline exists. The large randomized trials and registries have reported on the incidence of thrombosis
although not on management or clinical sequelae. The evidence base is limited to case reports and small case series, with
their innate risk of publication bias.
In the same series describing 20 thromboses listed earlier, anticoagulation was used as first-line strategy in 18 cases
[11]. This led to resolution with no sequelae in all but one individual, with no detectable thrombus by 1 month in 11 cases
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FIGURE 30.4 Proposed algorithm for the management of patent foramen ovale/atrial septal defect closure device thrombosis. Note that this algorithm is
based on the authors’ opinion and not on clinical guidelines or high-quality evidence. TIA, transient ischemic attack.
and by 6 months in the remaining 6 cases. Three patients underwent surgery: one for thrombus persisting after long-term
warfarin treatment, on e as primary manag ement after a stroke and failed thrombolysis, and the third for an asymptomatic
thrombus, which was not identifiable at the time of operation. Four of these 20 patients had recurrent neurological episodes
during follow up, none of whom had undergone device extraction. None of these occurred with the current Amplatzer or
CardioSEAL devices. The authors did not report on recurrent device thrombosis or whether anticoagulation had been
discontinued. Further individual case reports have reported successful management with an anticoagulation strategy [25].
While avoiding invasive management, this strategy does not appear to fully mitigate the embolic risk. More than one
report has described patients who developed strokes following the initiation of anticoagulation [26,27]. These thrombi were
generally large and strokes occurred after >1 month of attempted anticoagulation without successful resolution. This
strategy is likely to be reasonable, however, where thrombi have presented asymptomatically and high-risk features are
absent.
Surgical thrombectomy and extraction of the device, along with primary closure of the septal defect, are rarely required.
A multinational study reporting on surgical complications of percutaneous PFO closure devices identified four explantations for thrombosis among 13,736 implantations (a rate of 0.03%) [28]. A European registry study specific to ASD
closures reported 12 explan tations for thrombosis, among a total of 56 explants. One death was reported in a patient who
had already sustained a large stroke prior to surgery [29]. A number of individual case reports also detail successful
surgical management, either following strokes or with asymptomatic although high-risk thrombi [23,30e34]. Positive
outcomes are reported in the majority of these cases.
Data on the use of thrombolysis in this context are even more limited, with most descriptions coming from patients
presenting with stroke. There are descriptions of resolution with this strategy [35,36]; however, these thrombi are often
highly organized and cases of failed thrombolysis resulting in the need for surgery are also reported [11].
In the absence of clear guidelines or a strong evidence base, a general algorithm based on our review of the literature is
proposed in Fig. 30.4; however, each case should be considered individually and managed using a multidisciplinary
approach, with the combined input of interventional and imaging cardiologists, hematologists, surgeons, and the patients
themselves.
Surgical Considerations
Not all septal defects can be closed percutaneously. This is particularly true for ASD, where nonsecundum defects and very
large or complex defects require surgical closure. Surgical closure of ASDs appears, in observational studies, to improve
stroke risk in a manner similar to percutaneous closure. This is similarly attributable to a reduction in atrial fibrillation due
to improved atrial hemodynamics.
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Surgery for PFO closure is rarely now performed in isolation, although it has been considered in conjunction with other
procedures in which PFO was discovered either intraoperatively or during a preoperativ e assessment. The two studies (both
retrospective) of surgical closure of PFOs to prevent recurrent cryptogenic stroke had conflicting results: one study of 28
patients undergoing surgical closure reported four recurrent events in medium-term follow-up [37], while the other
reporting on 32 patients reported no strokes or transient ischemic attacks (TIAs) over the first 18 postoperative months
[38]. In regard to incidentally discovered PFOs in patients undergoing cardiac surgery for other indi cations, there is
substantial variability in pract ice [39]. Concern exists, however, that closure of these incidental lesions may lead to an
increase in postoperative stroke [40]. Given the overall efficacy and low complication rate of percutaneous closure, open
PFO repair should now be considered only in exceptional circumstances.
Postoperative thrombosis is not a complication unique to the percutaneous approach. Rates of stroke and TIA are
similar between surgical and device-based ASD closure over the first 12 months [41]. A number of cases in the literature
describe thrombus formation within the atria following surgical closure of the intraatrial septum [42e44]. While specific
estimates of the risk of this complication are lacking, it is reasonable to assume that similar risk factors (AFF, suboptimal
reconstruction, early cessation of platelet inhibition) would be at play. Optimal management strategies are likely to be
similar to those for patients who develop thrombosis after percutaneous closure, albeit that very little supportive evidence
exists.
KEY GAPS IN THE EVIDENCE AND AVENUES FOR FURTHER RESEARCH
Despite the number of adequately powered randomized trials, specific questions still need to be answered with regard to
patient selection: particular clarity is needed with regard to small PFOs without an associated atrial septal aneurysm and in
older patients in whom the stroke appears cryptogenic. Evidence regarding the optimal duration of dual and then single
antiplatelet therapy would also be of benefit. Finally, given the incidence of undetected albeit asymptomatic device
thrombosis, a randomized investigation of prospective TEE screening for device complications versus a watch-and-wait
approach, stratified on the basis of risk factors for thrombosis, would be of benefit. Given the rarity of events it is unlikely
that high-quality evidence on the management of these complications will emerge. The development of an expert
consensus, however, would be valuable in supporting operators as the procedures could roll out more widely.
CONCLUSIONS
Percutaneous closure of both PFO and ASD are effective procedures. Device thrombosis, although rare, is a dangerous and
understudied complication that may occur either acutely at the time of implantation or over subsequent years. Postoperative
atrial fibrillation, mechanical failure of the device, early cessation of DAPT, and persistence of an atrial septal aneurysm all
increase the risk of thrombosis. Limited evidence exists to guide treatment strategy once thrombosis has developed;
however, anticoagulation and surgical extraction should both be considered. The management of both the initial implant
and any subsequent complication requires detailed multidisciplinary input with close involvement of the patients
themselves.
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