Most arterial thrombotic events have a clear atherosclerotic or cardioembolic etiology, but hematologists are frequently asked to assist in the diagnosis and management of a patient with a non-atherosclerotic and non-cardioembolic arterial event, referred to herein as an unexplained arterial thrombosis. Because there is an assorted list of factors that can precipitate an arterial event, we present a systematic diagnostic approach to ensure consideration of not only primary hypercoagulable disorders, but also pro-thrombotic medications or substances, vascular and anatomic abnormalities, and undiagnosed systemic disorders, such as malignancy and autoimmune diseases. We also review existing literature of the role of hypercoagulable disorders in arterial thrombosis and discuss our approach to thrombophilia workup in patients after an unexplained arterial event. We conclude with three representative cases to both illustrate the application of the outlined diagnostic schema and discuss common management considerations, specifically the selection of anticoagulation versus anti-platelet therapy for secondary prevention.

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