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Thromb Haemost. 2019 Aug 4. doi: 10.1055/s-0039-1693739. [Epub ahead of print]

Recurrence Risk in Patients with Cryptogenic Stroke, Patent Foramen Ovale, and Thrombophilia: A Systematic Review and Meta-Analysis.

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Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark.
Department of Neurology, Aarhus University Hospital, Aarhus, Denmark.
Thrombosis and Hemostasis Research Unit, Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark.
Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.



 A patent foramen ovale (PFO) is frequently associated with cryptogenic stroke in the young. Endovascular closure is superior to antithrombotic treatment in prevention of recurrence, but in the presence of a concomitant thrombophilia, the best preventive strategy is unknown. This review investigates if thrombophilia increases the risk of recurrence in patients with cryptogenic stroke and PFO and attempts to evaluate the best antithrombotic strategy after PFO closure in these patients.


 Medline, Embase, and Web of Science were searched until April 2018. Study quality was assessed by the National Heart, Lung and Blood Institute Quality assessment tool. Odds ratio (OR) and hazard ratio for recurrence were pooled in a random effect model stratified by secondary preventive strategy.


 Eleven studies were included. Inherited or acquired thrombophilia was associated with an increased risk of recurrence (OR = 2.41, 95% confidence interval [CI]: 1.44-4.06). Looking only at patients treated with PFO closure, the risk of recurrence just lost significance (OR = 2.07, 95% CI: 0.95-4.48). The antithrombotic treatment after PFO closure was heterogeneous and recurrent events occurred in patients with both inherited and acquired thrombophilia treated by antiplatelet as well as anticoagulant therapy.


 Thrombophilia is associated with an increased risk of recurrence in patients with PFO and cryptogenic stroke, which may persist after PFO closure. This suggests a need for antithrombotic therapy after PFO closure. Study heterogeneity precludes strong conclusions on antithrombotic treatment, but life-long antiplatelet therapy to patients without preexisting indication for anticoagulant therapy seems reasonable.


Conflict of interest statement

None of the authors have any conflicts of interest regarding the present paper but have the following general conflicts of interest: C.Z.S. was funded by a grant from Novo Nordisk Foundation and received speaker's fee from Bayer. A.M.H. received speaker's fee from CSL Behring, Bayer, Bristol-Myers Squibb, Leo Pharma, and Astellas Pharma and unrestricted research support from Octapharma, CSL Behring, and Leo Pharma. C.V.B.H. has no conflict of interest.

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