Transcatheter closure of patent foramen ovale (PFO) has increasingly become accepted therapy for patients with a history of multiple cryptogenic strokes.1–3 As more patients undergo transcatheter closure of PFO, and septal defects (atrial and ventricular septal defects), complications associated with these procedures will continue to be reported in the literature.4–6 One of the more worrisome complications that has previously been reported is thrombus formation on the septal occlusion device.7-10 This particular complication though rare, if present on the left atrial disc of the device, can result in significant neurologic sequelae. Currently, there are no guidelines or treatment protocols for thrombus formation that develop on septal occlusion devices. We describe a case of left atrial thrombus formation on a CardioSeal septal occlusion device 14 days after closure of a patent foramen ovale in a 59-year-old patient with a history of multiple cryptogenic strokes and known elevation of factor VIII. Medical therapy with heparin and aspirin was initiated, with resolution of thrombus on the left atrial disc of the device. Case Report. A 59-year-old gentleman with a past history of multiple cryptogenic strokes while on coumadin was diagnosed by transesophageal echocardiography (TEE) with a PFO with atrial septal aneurysm, and paradoxical right to left flow (rapid and heavy shunting of microbubbles with performance of valsalva maneuver). The septum was hypermobile with 2 cm excursion. Duplex sonograms for deep venous thrombosis of the lower extremities, and for cerebrovascular disease of the carotid arteries were negative. Hematology evaluation was negative except for an elevated factor VIII level. Because no other source for the neurologic events could be demonstrated, the etiology of the multiple strokes was presumed to be secondary to possible embolization of small clots through the patent foramen ovale. The patient was presented with the therapeutic options of continuing medical therapy (coumadin), or interventional or surgical closure of PFO. Because of his active lifestyle and desire to eventually stop taking coumadin, the patient gave informed consent for transcatheter/device closure of his PFO. Cardiac catheterization was performed under general anesthesia. After placement of the venous and arterial sheaths, the patient received a 3,000-unit bolus of heparin. The activated clotting time (ACT) was maintained at a level of greater than 200 seconds for the duration of the case. After performance of right heart catheterization, bubble study was performed (demonstrated by TEE) confirming the presence of a heavy amount of microbubbles crossing from the right to the left atrium (Figure 1). Balloon sizing of the PFO was performed with a 20 mm NuMED sizing balloon (NuMED, Hopkinton, New York). The stretched diameter of the PFO measured 13–14 mm by fluoroscopy and TEE. Balloon sizing was performed to better define the morphology of the atrial septum (to determine the presence or absence of a long tunnel). Because of the septal anatomy (aneurysmal, and hypermobile septum) (Figure 1), a 33 mm CardioSeal Septal Occlusion device (CSO) (NMT Medical, Boston, Massachusetts) was selected to close the PFO. It was felt that the 33 mm device would better “sandwich” the septum (compared to the 23 or 28 mm device), and prevent less septal excursion. The CSO was deployed without difficulty. The device arms were in good position, and the device profile was flat against the atrial septum (Figure 2). Repeat bubble study demonstrated complete closure of the PFO. Coumadin was restarted 3 hours after device closure. A recommendation was also made to start aspirin therapy after PFO closure, however the patient opted to continue taking Coumadin alone. Prior to discharge the following morning, transthoracic echo (TTE) and chest x-ray was performed. The device was seen in good position by TTE and CXR. There were no clots or thrombi seen on the device by TTE. The patient remained well for 14 days when he suddenly developed weakness and numbness of both lower extremities upon rising from a squatting position. The patient immediately called the office, and was told to come to the emergency room. One hour later in the emergency room, the lower extremity weakness had completely resolved. Both the prothrombin time (PT) 33.5 seconds (9.0–11.5 seconds) and international normalized ratio (INR) 3.2 (2.0–3.5) were therapeutic. Transthoracic echo failed to demonstrate clot formation on the device. Chest x-ray demonstrated proper position of the device arms. CT scan of the brain was unchanged from baseline without evidence of acute stroke. The patient was admitted, and therapy with heparin initiated (weight-based protocol-the patient initially received a bolus of 6,000 units of heparin followed by a rate of 1,400 units/hour, partial thromboplastin time of 50–80 seconds was maintained while on heparin drip). The decision was made to perform transesophageal echocardiography (TEE) to better image the septal occlusion device. TEE demonstrated the presence of 2 clots measuring 4 mm in circumference on the left atrial disc of the device (Figure 3). After discovery of the clots on the septal occlusion device, both hematology and cardiothoracic surgery consult were obtained. The hematology service recommended continuing heparin therapy with the addition of one aspirin (ASA 325 mg). Cardiothoracic surgery concurred with this treatment plan. Five days after initiating heparin and ASA therapy, repeat TEE demonstrated resolution of the left atrial thrombus (Figure 4). The patient was restarted on coumadin, and kept on heparin until therapeutic INR was achieved. The patient was discharged home on coumadin and ASA. Discussion. Thrombus formation on a septal occlusion device is a rare but feared complication.7–10 Therapy has involved either surgical explantation of the device9,10 or medical management to lyse or dissolve thrombus on the surface of the septal occlusion device.11,12 We describe a case of thrombus formation on the left atrial disc of a CSO 14 days after device implantation in a 59-year-old gentleman with a past history of multiple cryptogenic strokes. The thrombi were discovered by transesophageal echocardiography after the patient presented with transient weakness of both lower extremities. Hematology evaluation to rule out the presence of a hypercoagulable state prior to undergoing device closure of PFO demonstrated normal levels of anticardiolipin antibodies, protein C, Protein S, antithrombin III, homocysteine, and lupus anticoagulant. The patient was also tested for the presence of Factor V Leiden and factor II (prothrombin 20210A mutation), both of which were negative. The only positive test was an elevated factor VIII level of 251 (normal range = 55–145). Prior to undergoing device closure the patient had been on coumadin. As part of our protocol for patients who undergo transcatheter PFO closure, coumadin is discontinued 2 days prior to the procedure. Patients are then instructed to take 1 adult ASA (325 mg) for 2 days prior to device closure. After the procedure, both coumadin and ASA are restarted (usually within 3–5 hours after catheterization). We routinely keep patients on coumadin for 6 months, and aspirin for 12 months after device implantation. This patient failed to take the recommended ASA in addition to the coumadin that he was already taking. As previously discussed, work-up to rule out a hypercoagulable state in this patient was essentially negative, except for an elevated factor VIII level. Factor VIII is a glycoprotein that is involved in the intrinsic pathway of blood coagulation. It is synthesized in the liver and secreted into plasma where it forms a complex with von Willebrand factor. Factor VIII is a cofactor that accelerates the conversion of Factor X to Xa. Factor VIII has recently been reported as an independent marker for increased thrombotic risk.13–15 Treatment options available for thrombus formation on septal occlusion devices range from medical management,11,12 to surgical explantation of the device.9,10 Because there are no set guidelines, or specific treatment regimen for this complication, the decision was made to consult both the cardiothoracic and hematology services regarding possible treatment options. Both services recommended medical management. The opinion of the cardiothoracic service was based on the fact that the clots were small, and that this clinical entity was not significantly different from small clot/thrombus formation on prosthetic/left sided mechanical valves.16 The hematology service felt that initial medical therapy with heparin and ASA was warranted before attempting use of the newer and more potent thrombolytic agents to try to decrease the risk of bleeding. Heparin was selected as first line therapy in our patient because of its proven efficacy, ease of monitoring and safety (less risk of bleeding problems). Heparin is an acidic mucopolysaccharide composed of D-glucuronic acid and D-glucosamine, present in many tissues, especially the liver and the lungs, having anticoagulant properties. While not as potent as the newer thrombolytic agents (urokinase, streptokinase, tissue plasminogen activator), it is believed to act by inhibiting the conversion of prothrombin to thrombin and thus fibrinogen to fibrin (major component of thrombi).17 Heparin has also been described to enhance the conversion of plasminogen to plasmin.18 Plasmin is the active portion of the fibrinolytic or clot-lysing system, it is a proteolytic enzyme with a high specificity for fibrin, with the ability to dissolve formed fibrin clots. In general, arterial thrombi (the thrombus was found on the left atrial disc of the CSO) are composed mainly of platelet aggregates bound together by fibrin.19 For the above reason the decision was made to add ASA to the treatment regimen. The antithrombotic effect of aspirin is due to its ability to inhibit synthesis of thromboxane A2 which is a potent inducer of platelet aggregation.20 In summary, we describe a case of thrombus formation on the left atrial disc of a CSO in a patient with elevated factor VIII level, with subsequent resolution after therapy with heparin and aspirin. This case illustrates the importance of both transesophageal echo (to demonstrate clot formation on the septal occlusion device) and the need to perform a thorough hematology work-up to rule out the presence of a hypercoagulable state prior to PFO closure. Because of recent studies describing factor VIII as an independent marker for increased thrombotic risk,13–15 it may be worthwhile to consider obtaining a factor VIII level as part of the work-up to rule out a hypercoagulable state in patients prior to undergoing device closure. What remains unclear is the optimal management of patients with history of multiple cryptogenic strokes who have a PFO. Certainly, enrollment of these patients into prospective randomized clinical trials (medical vs. interventional vs. surgical closure) appears warranted. In addition, optimal management post device closure (ASA alone, coumadin alone, ASA and coumadin, or ASA and clopidogrel) to prevent thrombus formation on the septal occluder needs further study.
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