The Keio Journal of Medicine
Online ISSN : 1880-1293
Print ISSN : 0022-9717
ISSN-L : 0022-9717
CASE REPORT
Warfarin Therapy and Percutaneous Left Atrial Appendage Closure for a Patient with Atrial Fibrillation and Antithrombin-III Deficiency
Sho Shimohama, Masahiro Katsumata, Shumpei Azami, Satoshi Kitagawa, Hikaru Tsuruta, Taku Inohara, Jin Nakahara, Yoshikane Izawa
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Keywords: left atrial appendage thrombus, atrial fibrillation, antithrombin-III deficiency, anticoagulants, ischemic stroke
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2024 Volume 73 Issue 3 Pages 27-30

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Abstract

Some patients develop ischemic stroke despite taking direct oral anticoagulants because of the presence of other risk factors such as coagulopathies. A 65-year-old male patient with non-valvular atrial fibrillation (NVAF) taking rivaroxaban was diagnosed as having embolic stroke and antithrombin-III (AT-III) deficiency. Echocardiography revealed a thrombus in the left atrial appendage (LAA). He was prescribed warfarin, and after resolution of the thrombus, we successfully performed percutaneous LAA closure (LAAC), with no subsequent recurrence or device-related thrombosis. Warfarin and LAAC may be feasible for NVAF patients with AT-III deficiency.

Introduction

Atrial fibrillation (AF) is a frequent arrhythmia that increases the risk of heart failure and cardiogenic cerebral embolism because of decreased cardiac function, increasing the risk of hospitalization and death. Moreover, a previous report suggested that about 1%–2% of patients with non-valvular atrial fibrillation (NVAF) develop ischemic stroke despite receiving sufficient anticoagulation.1 We must consider the presence of other risk factors including coagulopathy as causes of ischemic stroke in NVAF patients taking anticoagulants.2 Antithrombin-III (AT-III) deficiency is a risk factor for the development of ischemic stroke because of the hypercoagulable state,3,4 and patients with AT-III deficiency generally receive heparin or warfarin therapy for prevention of ischemic events.5 However, the appropriate treatment for patients with concomitant NVAF and AT-III deficiency has not been determined.6 Herein, we present the case of a patient with NVAF and AT-III deficiency who presented with ischemic stroke. After treatment with warfarin and left atrial appendage closure (LAAC), the patient has progressed without recurrence.

Case Presentation

A 65-year-old man presented to us complaining of mild dysarthria, and magnetic resonance imaging (MRI) revealed embolic stroke (Fig. 1A). Although the patient was admitted to the hospital within 1 h of the symptom onset, recombinant tissue-plasminogen activator therapy and thrombus mechanical thrombectomy were not performed because of symptom mildness. The patient had been taking rivaroxaban for known NVAF and had no family history of thrombosis. The CHADS2-VASc score was 3 points. Transesophageal echocardiography (TEE) revealed left atrial appendage thrombus (LAAT) (Fig. 1B). TEE also showed spontaneous echo contrast (SEC), lower left atrial appendage (LAA) flow velocity (23.4 cm/s), and left atrial enlargement. Right to left shunt and aortic plaque on TEE were unremarkable. Pulmonary embolism (PE) and DVT were not remarkable on contrast-enhanced computed tomography (CT) and lower limb ultrasonography. Carotid ultrasonography and three-dimensional CT angiography revealed only mild right internal carotid artery stenosis. His blood test revealed low AT-III (56%) under the presence of direct oral anticoagulant (DOAC) (apixaban). The following blood tests were unremarkable: activated partial thromboplastin time, prothrombin time, D-dimer, antinuclear antibodies, antineutrophil cytoplasmic antibodies (proteinase 3 and myeloperoxidase), antiphospholipid antibody, lupus anticoagulant, protein C, protein S, SS-A/Ro antibodies, and SS-B/La antibodies. After starting the patient on intravenous unfragmented heparin, we subsequently switched to oral warfarin considering the possibility of AT-III deficiency. TEE performed 4 weeks later revealed resolution of the LAAT (Fig. 1C). Low AT-III (70%) persisted even after anticoagulant therapy. Because of our concern over the risk of recurrent LAAT, we considered that complete interventional closure of the appendage may be preferable. Five months after stroke onset, we successfully performed percutaneous LAAC (Fig. 1D). The patient is continuing to receive warfarin therapy, and no recurrence or device thrombosis has been observed 6 months since the surgery. We plan to continue the administration of warfarin for AT-III deficiency. The patient provided written consent for the publication of this report.

Fig. 1.

Radiographic findings.(A) Diffusion-weighted MRI showing evidence of new embolic stroke. (B) TEE image showing a left atrial appendage thrombus. (C) TEE image showing resolution of the thrombus 4 weeks after initiation of warfarin treatment. (D) Contrast-enhanced CT after LAAC showing placement of Watchman device (Boston Scientific).

Discussion

We report a case of ischemic stroke with LAAT under DOAC therapy with AT-III deficiency. We continued to administer warfarin to the patient until the thrombus was no longer detected by TEE. We then performed percutaneous LAAC without complications, and the patient has had no recurrent ischemic stroke.

The patient suffered ischemic stroke despite adequate anticoagulant therapy. LAA is the most common site of thrombus in patients with AF with a history of ischemic stroke.7 In patients with AF, LAA remodeling causes decreased doppler flow velocities and promotes thrombus formation.7 A past CT imaging study reported a strong correlation between LAA shape and risk of stroke.8 Patients with a “chicken wing-shaped” LAA were reported to be less likely to suffer stroke or transient ischemic attack.8 In the present case, the LAA morphology was not “chicken wing” type.

AT-III is a physiological inhibitor of serine protease-type coagulation factors such as thrombin and active factor X.5 It is synthesized in the liver and inhibits thrombin, Xa, XIa, and XIIa.5 AT-III deficiency causes hypercoagulability and thrombosis through failure to inhibit thrombin activity.6 Several studies have revealed the existence of AT-III deficiency in patients with ischemic stroke.3 Moreover, a previous study reported a case of NVAF in a patient with AT-III deficiency.9 There are various causes of acquired AT-III deficiency, including disseminated intravascular coagulation, liver disease, nephrotic syndromes, surgery and trauma, and use of heparins. Although a previous study has reported of falsely high AT-III levels caused by DOAC therapy,10 no study has reported an association between DOAC therapy and AT-III deficiency. In our case, there was neither an etiological factor for acquired AT-III deficiency nor a family history of AT-III deficiency. However, some patients with congenital AT-III deficiency have no family history11 or are asymptomatic.12 Therefore, we hypothesized that this patient may have had congenital AT-III deficiency with no past or family history of ischemic events. AT-III deficiency may exist in patients with NVAF, and the risk of ischemic stroke in these patients may remain despite the adequate use of anticoagulants. Therefore, it is important to check for AT-III deficiency in this setting.

Recently, LAAC has emerged as an effective and safe strategy for prevention of stroke in patients with NVAF.13,14,15 LAAC is generally considered in patients at high risk of bleeding because of long-standing use of DOAC,16 although the evidence for patients with coagulopathy is poor. A previous report has suggested a relationship between poor functional outcome and LAAT.17 Another study has suggested the feasibility of LAAC for patients with LAAT, although device-related thrombus is seen in 12.8% of these patients.18 This rate is relatively high in comparison with the usual procedure,19 and the risk of device-related thrombosis for patients with coagulopathies remains uncertain. Anticoagulation therapy appears to be effective for device-related thrombus.20 In our case, no device thrombosis has been observed under warfarin therapy to date, and careful long-term observation is still necessary.

Conclusion

We report a case of ischemic stroke concomitant with NVAF and AT-III deficiency treated by warfarin therapy and LAAC. AT-III deficiency may exist in patients with NVAF, and the risk of stroke may remain despite the proper use of anticoagulants. Use of warfarin therapy and LAAC may be a feasible approach in this setting.

Conflicts of Interest

The authors declare no conflict of interest.

References
 
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