Transcatheter patent foramen ovale (PFO) closure is a safe and effective treatment for secondary prevention after a PFO-associated stroke as demonstrated in multiple large randomized clinical trials. However, these trials excluded a significant proportion of patients who could have benefited from percutaneous PFO closure due to coexisting potential confounders such as additional thromboembolic risk factors, namely thrombophilia. Since scarce and conflicting data existed on such patients, current clinical management guidelines on patients with PFO mainly recommended against PFO closure in patients with thrombophilia and failed to provide any recommendation on the type and duration of antithrombotic treatment after transcatheter PFO closure. In the past 2 years, there has been new evidence supporting transcatheter PFO closure as a clinically meaningful alternative (vs. medical treatment) in this high-risk group of patients, along with additional data supporting the important role of systematic screening for thrombophilia in PFO-associated cerebrovascular events. This review article provides an updated overview of the incidence, clinical characteristics and outcomes of PFO closure in patients with thrombophilia, also commenting on the most appropriate medical treatment after PFO closure and future perspectives in the field.
Transcatheter patent foramen ovale (PFO) closure is a safe and effective treatment for secondary prevention after a PFO-associated stroke [
In the past 2 years, there has been new evidence supporting transcatheter PFO closure as a clinically meaningful alternative (vs. medical treatment) in this high-risk group of patients [
Thrombophilia is defined as an abnormality of the coagulation or fibrinolytic system that results in a hypercoagulable state (HCS) increasing the risk of venous or arterial intravascular thrombus and thromboembolic events [
The predisposition for intravascular thrombus may arise from heritable genetic mutations (inherited thrombophilias) or acquired factors (acquired thrombophilias, like trauma, surgery, malignancy, autoimmune diseases, etc.), which would lead to a hypercoagulability state due to an excess or hyperfunction of a procoagulant factor or a deficiency of an anticoagulant moiety [
The prevalence of a specific type of thrombophilia in the general population varies greatly in the literature, ranging from 0.1% to 20% depending on different factors, such as definition, tests used for diagnosis, use of confirmatory tests, etc [
The presence of a PFO has been shown to be a common finding in the general population, with a prevalence between 20% and 34% [
Two mechanisms have been proposed to explain the role PFO in systemic embolism: (1) paradoxical embolism, which implies the passage of a right-sided venous thrombus to the left circulation through the PFO, specially during transient or persistent elevations on right-heart pressures which would allow to the passage of blood (or thrombus) from the right atrium to the left atrium, and (2)
Patients with inherited or acquired thrombophilia represent a unique challenge in the setting of stroke and PFO. The combination of a hypercoagulability state and a PFO is not uncommon in clinical practice, with studies on patients with PFO showing a thrombophilia prevalence ranging from 5% to 31% [
The first report on transcatheter PFO closure in patients with thrombophilia was reported in 2004 by Giardini et al. [
The most recent clinical management guidelines in patients with PFO from the European Society of Cardiology (ESC) [
The ESC position statement recommendations on routine laboratory tests for prothrombotic states (thrombophilia testing) stated that these tests are not generally warranted to guide the need for permanent oral anticoagulation (OAC) [
According to ESC guidelines, in the setting of hypercoagulability, deep vein thrombosis and/or pulmonary embolism, PFO closure may be considered when there is a need for temporary OAC or a high risk of recurrence despite permanent OAC, particularly in pulmonary embolism cases, where PFO was reported to be an independent predictor of new brain lesions at follow-up despite optimal OAC [
Since the publications of the last ESC and AAN guidelines, there has been new evidence of high clinical relevance regarding thrombophilia screening and most importantly, to the indication of transcatheter PFO closure in this high-risk population, including new evidence suggesting a role of PFO closure in primary prevention. This new evidence may help to clarify some controversial results from historical data and would support a new approach for the management of these patients.
The screening for thrombophilia in the overall cryptogenic stroke population, including a small proportion of patients with PFO, has been recently evaluated by Omran et al. [
Lim et al. [
The first contemporary effort to clarify the role of transcatheter PFO closure among patients with thrombophilia was performed by Hviid et al. [
Prospective comparisons of transcatheter PFO closure in patients with or without thrombophilia were lacking until the recent results from Liu et al. [
Finally, the most recent evidence in the field came from a retrospective registry from Ben-Assa et al. [
Recent evidence suggested that in some high thromboembolic risk scenarios, PFO closure may be superior to medical therapy for primary prevention of neurological events. In a single-center retrospective study [
At a mean follow-up of 46 months, 23 (17%) patients experienced an outcome event (16 patients, 31% of the non-PFO closure group vs. seven patients, 8% of the PFO closure group) (
The recommended antithrombotic treatment following transcatheter PFO closure in the general population is based on the most recent ESC clinical guidelines [
In conclusion, new evidence strongly suggests that stroke patients with PFO should be systematically screened for thrombophilia in order to identify those who are at higher risk and may benefit from transcatheter PFO closure, alongside optimal antithrombotic management, which remains to be determined in such a complex population. Transcatheter PFO closure in patients with thrombophilia is as safe and effective as in patients without thrombophilia, with very low complication rates and comparable long-term clinical outcomes, and a low rate of recurrent neurological events. If PFO closure should be proposed as the primary prevention of PFO-associated stroke remains to be determined, and this should be properly addressed in prospective randomized trials.
Josep Rodés-Cabau has received institutional research grants from Abbott Vascular Canada, and holds the Research Chair Fondation "Famille Jacques Larivière" for the Development of Structural Heart Disease Interventions. The rest of authors do not disclose any potential conflict of interest with respect to the content of this study.
Recurrent cerebral ischemic events before transcatheter patent foramen ovale (PFO) closure in patients with or without thrombophilia. Event-free rate and 95% confidence intervals (dashed lines) of recurrent cerebral ischemia before percutaneous PFO closure in patients who did (squares) and those who did not have an associated thrombophilia (triangles). Reproduced from Giardini et al. [
Rate of primary endpoints in patients with or without thrombophilia according to their treatment allocation after a patent foramen ovale (PFO)-related cerebrovascular event. Kaplan-Meier cumulative estimates demonstrate that PFO closure significantly reduced recurrent events of stroke or transient ischemic attack compared with medical therapy in patients with thrombophilia to a greater extent than medical therapy alone. Reproduced with permission from Liu et al [
Long-term outcomes of patients with or without hypercoagulable state after patent foramen ovale (PFO) closure as primary prevention strategy before a left systemic cerebrovascular event. Kaplan-Meier estimates of survival free of neurological events in patients with significant hypercoagulable state according to closure of PFO. Dash line represents patients who underwent PFO closure whereas the continuous line represents patients who received only medical treatment. Reproduced from Buber et al. [
Thrombophilia screening in patients with a PFO-related thromboembolic event
Prevalence in general population (%) | Risk for thromboembolic event in general population | Confirmatory test required |
Supporting evidence in PFO patients | ||
---|---|---|---|---|---|
Venous hypercoagulability | |||||
Factor V Leiden |
4–104 | 5–10-fold (heterozygous)4 | No | [ |
|
50–100-fold (homozygous)4 | |||||
Prothrombin G2010A mutation | 1–54 | 3–5-fold (heterozygous)4 | No | [ |
|
Protein C deficiency |
0.2–0.54 | 6.5–8-fold4 | Yes | [ |
|
Protein S deficiency |
0.74 | 1.6–11.5-fold4 | Yes | [ |
|
Antithrombin III deficiency |
0.174 | 5–8.1-fold4 | Yes | [ |
|
Increased factor VIII activity |
4.44 | 0.3–1.8-fold2 | Yes | [ |
|
Elevated lipoprotein (a) | 204 | 1.6–2.2-fold26 | Yes | [ |
|
Mixed hypercoagulability | |||||
Methylenetetrahydrofolate reductase (MTHFR) mutation |
113 | 3-fold4 | No | [ |
|
Antiphospholipid syndrome |
1–5425 | 0.6–10-fold27 | Yes | [ |
The timing for screening depends on the type of test and the timing of the clinical event. For genetic mutations, the test can be performed at any time, but for functional or antibody tests, these should be ideally performed 1 to 2 months after the thrombotic clinical event to avoid false results in the initial test.
PFO, patent foramen ovale.
Recommended timing for a confirmatory test is 3 months;
In the context of a positive protein C resistance test;
Can be inherited or acquired. Acquired common causes can be malignancy, liver disease, warfarin or vitamin K deficiency, among others;
Can be inherited or acquired. Acquired common causes can be liver disease, nephrotic syndrome, among others;
In the context of a decreased protein S function;
Can be inherited or acquired. Acquired causes are pregnancy, malignancies, infection and inflammation;
In the context of hyperhomocysteinemia;
Can be acquired, hyperhomocysteinemia (without MTHFR mutation), which is also prothrombotic; common causes can be vitamin B6, B12, and folate deficiencies as well as renal failure, among others;
Acquired. Must have at least 1 test positive (anticardiolipin antibodies, anti-beta2 GP I antibodies and/or lupus anticoagulant).
Transcatheter PFO closure after a PFO-related cerebrovascular event in patients with thrombophilia: safety, efficacy, and long-term clinical outcomes
Study | Study design |
Study population | PFO closure indication | Implanted devices & PFOc success rate | Clinical follow-up | Remarks | |
---|---|---|---|---|---|---|---|
Giardini et al. (2004) [ |
Prospective, comparative, non-randomized | 72 PFO patients screened: | ≥1 documented stroke (51%) or TIA (49%) of unknown origin | Cardioseal STARFLEX® | Median FU: 19 months | No thrombus on the device at 6-months FU TOE. Before closure, patients with thrombophilia had a higher rate of recurrent events that patients without it. | |
PFOc in patients with vs. without thrombophilia | 20 patients (28%) with thrombophilia | Amplatzer PFO occluder® | Primary endpoint: recurrence of TIA or stroke, 4% of overall population without differences among groups | ||||
No cancer patients were included | 99% | ||||||
Kar et al. (2017) [ |
Retrospective analysis | 861 PFO patients screened: | Stroke or TIA (70.7%) | Amplatzer PFO occluder® | Median FU: 43 months | None of the GORE® Helex (33 implants) developed thrombus formation. | |
PFOc in patients with reversible or irreversible thrombophilias | 142 (16.5%) with any kind of thrombophilia | Migraine (20.4%) | Amplatzer Cribriform occluder® | One patient (1.4%) in the irreversible thrombophilia group had a recurrent stroke after PFOc. | |||
Peripheral embolism (3.4%) | |||||||
46.9% underwent PFOc | Right ventricular enlargement (1.4%) | GORE® Helex | |||||
2.7% had cancer as thrombotic state | Desaturation (0.7%) | 100% | |||||
Combination (3.4%) | |||||||
Liu et al. (2020) [ |
Prospective, comparative, non-randomized | 591 Patients screened: | Stroke (81%) or TIA (19%) | Not specified | Median FU: 54 months | ||
PFOc vs. MT in patients with PFO and thrombophilia | 134 patients (22.7%) with thrombophilia: | 100% | Primary endpoint: recurrence of TIA or stroke, PFOc 6 patients (6.7%) vs. MT 15 patients (33.3%) (HR, 0.23; 95% CI, 0.09–0.61; P=0.003) | ||||
- 88 to PFOc | |||||||
- 46 to MT | |||||||
No cancer patients were included | |||||||
Ben-Assa et al. (2021) [ |
Retrospective, comparative | 800 PFO patients screened: | Stroke (69.9%) TIA (14.6%) | Amplatzer PFO occluder® | Median FU: 41 months | 1.3% Recurrent stroke rate in the thrombophilic group. Included high levels of lipoprotein (a) as hypercoagulable state (32.6% of this cohort). | |
PFOc in patients with vs. without thrombophilia | 239 patients (29.9%) with thrombophilia. Cancer was not considered a thrombotic stat nor an exclusion criterion | Multiple cerebrovascular events (10%) | Cardioseal STARFLEX® | Primary endpoint: recurrence of TIA or stroke, thrombophilia group 3.4% vs. 2.5% in the group without it (P=0.35) | |||
Hypoxemia (0.8%) | GORE® | ||||||
Peripheral embolism (2.9%) | 99.20% | ||||||
Migraine (1.7%) |
PFO, patent foramen ovale; PFOc, patent foramen ovale closure; TIA, transient ischemic stroke; FU, follow-up; TOE, transesophageal echocardiogram; MT, medical therapy; HR, hazard ratio; CI, confidence interval.
Every study performed a systematic screening for thrombophilia.
Summary of recommendations of current clinical management guidelines on PFO-related stroke focused on patients with thrombophilia
European Society of Cardiology (ESC) | American Academy of Neurology (AAN) |
---|---|
Screening for thrombophilia in patients being considered for PFO closure | |
The role of thrombophilia cannot be generalized. Routine laboratory tests for prothrombotic states (thrombophilia testing) are not warranted to indicate permanent OAC. | In patients being considered for PFO closure, clinicians should perform hypercoagulable studies that would be considered a plausible high-risk stroke mechanism that would lead to a change in management such as requiring lifelong anticoagulation (e.g., persistent moderate- or high-titer antiphospholipid antibodies in a younger patient with cryptogenic stroke). |
Transcatheter PFO closure in patients with thrombophilia | |
In the setting of hypercoagulability, deep vein thrombosis and/or pulmonary embolism, PFO closure may be considered when there is the need for only temporary OAC or a high risk of recurrence despite permanent OAC. | In patients who would otherwise be considered good candidates for PFO closure but require long-term anticoagulation because of suspected or proven hypercoagulability (defined thrombophilia, unprovoked deep venous thrombosis, or unprovoked pulmonary embolism), clinicians should counsel the patient that the efficacy of PFO closure in addition to anticoagulation cannot be confirmed or refuted. |
Adapted from Pristipino et al., [
Medical treatment after transcatheter PFO closure for patients with thrombophilia in recent trials
Study | Treatment in groups without thrombophilia | Treatment in groups with thrombophilia | Remarks |
---|---|---|---|
Giardini et al. (2004) [ |
Aspirin 100 mg/day for the first 6 months and ticlopidine 250 mg b.i.d. for the first 3 months | Warfarin first 6 months | Routine monitoring with complete blood cell count at 30 days, 3 months, 6 months |
Target INR between 2 and 3 | |||
Liu et al. (2020) [ |
Aspirin 81 or 325 mg/day and/or clopidogrel 75 mg/day | Single embolic event: Warfarin for 3 months | Target INR between 2 and 3 |
Duration not specified. | Two or more embolic events: Lifelong warfarin | Choice of medical therapy in group without thrombophilia was left at the discretion of the operator. | |
Ben-Assa et al. (2021) [ |
Aspirin 325 mg/day or aspirin 100 mg/day+clopidogrel 75/day for 3 months, then switched to aspirin 100/day thereafter | Patients with non-arterial HCS+1 episode of provoked thrombotic event |
Non-arterial HCS: antithrombin III, protein C, or protein S deficiency, or who were carriers of the factor V Leiden or prothrombin G20210A mutation |
Same patients but with ≥2 episodes of thrombotic events OR any patient with an arterial HCS: life-long warfarin anticoagulation | Arterial HCS: anticardiolipin antibody, lupus anticoagulant, or hyper-homocysteinemia |
PFO, patent foramen ovale; b.i.d., twice a day; INR, international normalized ratio; HCS, hypercoagulable state.
Provoked thrombotic events: surgery, trauma, immobilization, hormonal therapy, active cancer, or other secondary causes of hypercoagulability.