Iron deficiency, ischaemic strokes, and right-to-left shunts: From pulmonary arteriovenous malformations to patent foramen ovale?

Has the recent identification of iron deficiency as a risk factor for ischaemic stroke in patients with pulmonary arteriovenous malformations (AVMs) unmasked a new paradigm for stroke/infarct pathogenesis? This commentary reviews evidence that spans associations between iron deficiency and ischaemic strokes, iron deficiency enhancement of platelet aggregation in response to serotonin/5HT, settings in which plasma 5HT is elevated, and clinical trial confirmation that 5HT receptor antagonists prevent ischaemic stroke. The critical leap which directs attention away from atherothrombotic events at the neurovascular wall is that ischaemic strokes due to pulmonary AVMs are attributable to compromised pulmonary capillary bed filtration of venous blood. Right-to-left shunting is continuous through pulmonary AVMs, but also occurs intermittently in approximately 30% of the general population with intracardiac shunts such as patent foramen ovale (PFO). The testable hypothesis presented is that paradoxical embolism of venous platelet-based aggregates may constitute part of the causal chain between iron deficiency and ischaemic stroke, not only in the rare disease state of pulmonary AVMs, but also in major subgroups of the general population.