Efficacy and safety of percutaneous patent foramen ovale closure in patients with a hypercoagulable disorder.

BACKGROUND: Transcatheter closure of patent foramen ovale (PFO) in patients with cryptogenic stroke reduces the rate of recurrent events. Although presence of thrombophilia increases the risk for paradoxical emboli through a PFO, such patients were excluded from large randomized trials. OBJECTIVES: We compared the safety and efficacy of percutaneous PFO closure in patients with and without a hypercoagulable state. METHODS: Data from 800 consecutive patients undergoing percutaneous PFO closure in our medical center were analyzed. All patients were independently evaluated by specialists in neurology, cardiology, hematology, and vascular medicine. A post-procedural treatment of at least 3 months of anticoagulation was utilized in patients with thrombophilia. Follow-up events included death, recurrent neurological events, and the need for reintervention for significant residual shunt. RESULTS: A hypercoagulable state was found in 239 patients (29.9%). At median follow-up of 41.9 months, there were no differences in the frequencies of stroke or transient ischemic attack between patients with or without thrombophilia (2.5% in non-hypercoagulable group vs. 3.4% in hypercoagulable group, log-rank test p = 0.35). There were no significant differences in baseline demographics, echocardiographic characteristics, procedural success, or complications between groups. CONCLUSION: Percutaneous PFO closure is a safe and effective therapeutic approach for patients with cryptogenic stroke and an underlying hypercoagulable state.

Long-term experience and outcomes with transcatheter closure of patent foramen ovale.

OBJECTIVES: This study sought to examine the frequency of indications for and the immediate and long-term clinical outcomes of transcatheter closure of patent foramen ovale (PFO). BACKGROUND: Transcatheter PFO closure is commonly performed for several indications, including cryptogenic stroke, despite conflicting data regarding the efficacy of this intervention. METHODS: We report the outcomes of 800 consecutive patients (52% male, 50 ± 14 years of age) who underwent PFO closure at our institution after multidisciplinary evaluation over a 16-year period. RESULTS: Indications for closure included cryptogenic cerebrovascular event (94%), hypoxemia (2%), peripheral embolism (3%), and migraine headaches (2%). Procedural success was 99% with effective closure obtained in 93% of patients. At a mean follow-up of 42.7 ± 33.4 months, 21 patients suffered a recurrent ischemic neurologic event (12 strokes, and 9 transient ischemic attacks) for an incidence rate of 0.79 events per 100 person-years and freedom from recurrent events of 91.6% at 10 years. There was no device-based difference in the rate of recurrent ischemic neurologic events (p = 0.82). Only Eustachian valve prominence (hazard ratio: 9.04; 95% confidence interval: 2.07 to 39.44; p = 0.0034) was associated with recurrent neurologic events. CONCLUSIONS: Transcatheter PFO closure is safe and feasible in patients with several clinical indications. The long-term efficacy of this intervention in patients with paradoxical embolism appears superb in this observational study. Carefully selected patients with features suggestive of paradoxical embolism are the most likely to benefit from PFO closure and should be the focus of future investigation.

The brain's heart - therapeutic opportunities for patent foramen ovale (PFO) and neurovascular disease.

Patent foramen ovale (PFO), a common congenital cardiac abnormality, is a connection between the right and left atria in the heart. As a "back door to the brain", PFO can serve as a conduit for paradoxical embolism, allowing venous thrombi to enter the arterial circulation, avoiding filtration by the lungs, and causing ischemic stroke. PFO-related strokes affect more than 150,000 people per year in the US, and PFO is present in up to 60% of migraine patients with aura, and in one out of four normal individuals. So, in such a highly prevalent condition, what are the best treatment and prevention strategies? Emerging studies show PFO-related neurovascular disease to be a multi-organ condition with varying individual risk factors that may require individualized therapeutic approaches - opening the field for new pharmacologic and therapeutic targets. The anatomy of PFO suggests that, in addition to thrombi, it can also allow harmful circulatory factors to travel directly from the venous to the arterial circulation, a concept important in finding novel therapeutic targets for PFO-related neurovascular injury. Here, we: 1) review emerging data on PFO-related injuries and clinical trials; 2) discuss potential mechanisms of PFO-related neurovascular disease in the context of multi-organ interaction and heart-brain signaling; and 3) discuss novel therapeutic targets and research frontiers. Clinical studies and molecular mapping of the circulatory landscape of this multi-organ disease will both be necessary in order to better individualize clinical treatment for a condition affecting more than a quarter of the world's population.

Heart-brain signaling in patent foramen ovale-related stroke: differential plasma proteomic expression patterns revealed with a 2-pass liquid chromatography-tandem mass spectrometry discovery workflow.

Patent foramen ovale (PFO) is highly prevalent and associated with more than 150,000 strokes per year. Traditionally, it is thought that PFOs facilitate strokes by allowing venous clots to travel directly to the brain. However, only a small portion of PFO stroke patients have a known tendency to form blood clots, and the optimal treatment for this multiorgan disease is unclear. Therefore, mapping the changes in systemic circulation of PFO-related stroke is crucial in understanding the pathophysiology to individualize the best clinical treatment for each patient. We initiated a study using a novel quantitative, 2-pass discovery workflow using high-resolution liquid chromatography-mass spectrometry/mass spectrometry coupled with label-free analysis to track protein expression in PFO patients before and after endovascular closure of the PFO. Using this approach, we were able to demonstrate quantitative differences in protein expression between both PFO-related and non-PFO-related ischemic stroke groups as well as before and after PFO closure. As an initial step in understanding the molecular landscape of PFO-related physiology, our methods have yielded biologically relevant information on the synergistic and functional redundancy of various cell-signaling molecules with respect to PFO circulatory physiology. The resulting protein expression patterns were related to canonical pathways including prothrombin activation, atherosclerosis signaling, acute-phase response, LXR/RXR activation, and coagulation system. In particular, after PFO closure, numerous proteins demonstrated reduced expression in stroke-related canonical pathways such as acute inflammatory response and coagulation signaling. These findings demonstrate the feasibility and robustness of using a proteomic approach for biomarker discovery to help gauge therapeutic efficacy in stroke.

May-Thurner syndrome in patients with cryptogenic stroke and patent foramen ovale: an important clinical association.

BACKGROUND AND PURPOSE: We aimed to investigate the incidence of May-Thurner syndrome in patients with cryptogenic stroke with patent foramen ovale. METHODS: This was a retrospective study. All consecutive patients with cryptogenic stroke having undergone patent foramen ovale closure from January 1, 2002, to December 31, 2007, at our institute were included in this study. Pelvic magnetic resonance venography studies of all patients were reviewed to determine if features of May-Thurner syndrome were present. Medical records and invasive venography studies of all patients were reviewed when available. All patients with May-Thurner syndrome features on magnetic resonance venography were reviewed by a vascular medicine specialist to define any previous incidence of deep vein thrombosis or any signs of chronic venous insufficiency. All patients also had lower limb venous duplex performed to rule out lower limb venous thrombosis. RESULTS: A total of 470 patients from January 1, 2002, until December 31, 2007, with cryptogenic stroke underwent patent foramen ovale closure at our institute. Thirty patients (6.3%) had features consistent with May-Thurner syndrome on magnetic resonance venography. These patients were predominantly female (80%) with a mean age of 43.6+/-11.9 years. Twelve patients (40%) had abnormalities in their laboratory thrombophilia evaluation and 13 females (54.1%) were taking hormone-related birth control pills. Only 2 patients had a history and signs of chronic venous insufficiency. All patent foramen ovales demonstrated right-to-left shunting on transesophageal echocardiography. Atrial septal aneurysms/hypermobile atrial septa were present in 70% of patients with May-Thurner syndrome. CONCLUSIONS: May-Thurner syndrome has an important clinical association with cryptogenic stroke and patent foramen ovale.

Use of the chromogenic factor X assay to predict the international normalized ratio in patients transitioning from argatroban to warfarin.

STUDY OBJECTIVE: To determine the clinical utility of the chromogenic factor X level for conversion from argatroban to warfarin in hospitalized patients. DESIGN: Prospective observational study. PATIENTS: Sixty-two hospitalized patients with indications for anticoagulation in whom the chromogenic factor X assay was used for conversion from argatroban to warfarin. SETTING: University-affiliated hospital. INTERVENTION: From December 2003-May 2004, data for all patients in whom the chromogenic factor X assay was used for conversion from argatroban to warfarin were screened for inclusion. When the chromogenic factor X level was satisfactory, the clinician discontinued the argatroban and a confirmatory international normalized ratio (INR) was obtained. MEASUREMENTS AND MAIN RESULTS: To determine the ability of the chromogenic factor X level to predict the INR free of argatroban influence, we calculated the sensitivity and specificity by using a cutoff chromogenic factor X level of 45% or less, or greater than 45%, which corresponded to an INR of 2 or greater, or less than 2, respectively. We constructed a receiver operating characteristic curve to illustrate various cutoff levels of chromogenic factor X. Of 146 patients screened, 62 had data that met criteria for analysis. An average of 6 +/- 3 doses of warfarin were administered before the confirmatory coagulation studies were obtained. The average time from the chromogenic factor X measurement to obtainment of confirmatory coagulation studies was 9 +/- 4 hours. Use of a chromogenic factor X level of 45% or less to predict an INR of 2 or greater absent of argatroban influence had a sensitivity of 93%, a specificity of 78%, and an accuracy of 89%. The area under the receiver operating characteristic curve was 0.91 (95% confidence interval 0.81-0.99, p<0.0001). CONCLUSION: The chromogenic factor X level is an accurate alternative when converting hospitalized patients from argatroban to warfarin. A chromogenic factor X level of 45% or less is a reliable predictor that the INR will be therapeutic when argatroban therapy is discontinued.

Heparin-induced antiheparin-platelet antibody associated with retinal venous thrombosis.

OBJECTIVE: To report a case of a 33-year-old white woman in whom retinal venous thromboses developed secondary to heparin-induced antiheparin-platelet antibodies. DESIGN: Interventional case report. METHODS: The patient underwent complete ophthalmic and medical examinations. Laser Doppler measurement of retinal blood circulation also was performed. INTERVENTION: Prolonged anticoagulation with thrombin inhibitors and warfarin. MAIN OUTCOME MEASURES: Visual symptoms, retinal appearance on clinical examination, and measurement of retinal blood flow by laser Doppler technique. RESULTS: The patient experienced a scotoma in the visual field of the left eye, left retinal venous thrombosis, decreased venous blood flow in the left eye, and heparin-induced antiheparin-platelet antibodies in serum. After intervention, the visual symptoms and retinal appearance improved, and retinal blood flow normalized. CONCLUSIONS: Heparin-induced antiheparin-platelet antibody can lead to thrombosis of the ocular circulation. This index case, which is the first one ever reported in association with antiheparin-platelet antibodies, further illustrates the potential side effects of heparin and widens the spectrum of complications of heparin-induced thrombocytopenia (HIT) and HIT thrombosis syndrome (HITTS).

Percutaneous transcatheter closure of patent foramen ovale in patients with paradoxical embolism.

BACKGROUND: Percutaneous transcatheter closure of patent foramen ovale (PFO) is used as an alternative to surgery or long-term anticoagulation for the treatment of patients with paradoxical embolism and PFO. METHODS AND RESULTS: We report the immediate and long-term clinical and echocardiographic outcome of 110 consecutive patients (58 males, mean age 47+/-14 years) who underwent transcatheter closure of PFO because of paradoxical embolism between 1995 and 2001. Procedural success, defined as successful deployment of the device and effective occlusion (no, or trivial, shunt after device placement), was achieved in all (100%) patients. There was no in-hospital mortality, 1 device migration requiring surgical intervention (0.9%), and 1 episode of cardiac tamponade (0.9%) requiring pericardiocentesis. A progressive increment in full occlusion was observed (44%, 51%, 66%, and 71% at 1 day, 6 months, and 1 and 2 years, respectively, after device placement). At a mean follow-up of 2.3 years, 2 patients experienced recurrent neurological events (1 fatal stroke and 1 transient ischemic attack), representing an annual risk of recurrence of 0.9%. In addition, 4 (3.6%) of the patients required reintervention for device malalignment or significant shunt. Kaplan-Meier analysis showed a freedom from recurrent embolic events and reintervention of 96% and 90% at 1 and 5 years, respectively. CONCLUSIONS: Transcatheter closure of PFO is a safe and effective therapy for patients with paradoxical embolism and PFO. It is associated with a high success rate, low incidence of hospital complications, and low frequency of recurrent systemic embolic events.