Figure 3. Schematic Model of the Implicative Pathophysiology of Pulmonary Arteriovenous Malformation–Related Ischemic Stroke.

Iron deficiency, which in patients with hereditary hemorrhagic telangiectasia (HHT) is most likely to be a result of underreplacement of hemorrhagic losses, has been shown to mediate a complex serotonergic proaggregatory platelet response facilitated by a dysfunctional platelet monoamine oxidase.³ Patients with ischemic stroke with pulmonary arteriovenous malformations (PAVMs) have also been found to have elevated plasma fibrinogen levels, a protein that normally serves to crosslink the glycoprotein (Gp) IIb-IIIa platelet receptors (inset), further accentuating the role of platelet aggregation.³ While iron deficiency has also been associated with elevated serum factor VIII levels and venous thromboembolism (VTE), clinical³ and epidemiologic¹⁹ studies have not found conventional VTE to be commonly associated with PAVM-related ischemic stroke. Recurrent endothelial injury (e.g., from dysplastic vasculature) or other molecular mechanisms of hypercoagulability implicated in different right-to-left shunts (e.g., elevated homocysteine levels in patent foramen ovale)³⁸ may further constitute additional thromboembolic or clot-independent mechanisms of cerebrovascular injury. APPT = activated partial thromboplastin time; FAD = feeding artery diameter; FVII = factor VIII; Hb = hemoglobin; RBC = red blood cell.