title: Ischaemic strokes in patients with pulmonary arteriovenous malformations and hereditary hemorrhagic telangiectasia: associations with iron deficiency and platelets.
abstract: BACKGROUND
  Pulmonary first pass filtration of particles marginally exceeding ∼7 µm (the size of a red blood cell) is used routinely in diagnostics, and allows cellular aggregates forming or entering the circulation in the preceding cardiac cycle to lodge safely in pulmonary capillaries/arterioles. Pulmonary arteriovenous malformations compromise capillary bed filtration, and are commonly associated with ischaemic stroke. Cohorts with CT-scan evident malformations associated with the highest contrast echocardiographic shunt grades are known to be at higher stroke risk. Our goal was to identify within this broad grouping, which patients were at higher risk of stroke.
  
  
  METHODS
  497 consecutive patients with CT-proven pulmonary arteriovenous malformations due to hereditary haemorrhagic telangiectasia were studied. Relationships with radiologically-confirmed clinical ischaemic stroke were examined using logistic regression, receiver operating characteristic analyses, and platelet studies.
  
  
  RESULTS
  Sixty-one individuals (12.3%) had acute, non-iatrogenic ischaemic clinical strokes at a median age of 52 (IQR 41-63) years. In crude and age-adjusted logistic regression, stroke risk was associated not with venous thromboemboli or conventional neurovascular risk factors, but with low serum iron (adjusted odds ratio 0.96 [95% confidence intervals 0.92, 1.00]), and more weakly with low oxygen saturations reflecting a larger right-to-left shunt (adjusted OR 0.96 [0.92, 1.01]). For the same pulmonary arteriovenous malformations, the stroke risk would approximately double with serum iron 6 µmol/L compared to mid-normal range (7-27 µmol/L). Platelet studies confirmed overlooked data that iron deficiency is associated with exuberant platelet aggregation to serotonin (5HT), correcting following iron treatment. By MANOVA, adjusting for participant and 5HT, iron or ferritin explained 14% of the variance in log-transformed aggregation-rate (p = 0.039/p = 0.021).
  
  
  CONCLUSIONS
  These data suggest that patients with compromised pulmonary capillary filtration due to pulmonary arteriovenous malformations are at increased risk of ischaemic stroke if they are iron deficient, and that mechanisms are likely to include enhanced aggregation of circulating platelets.
authors.affiliation: National Heart & Lung Institute (NHLI) Cardiovascular Sciences, Imperial College London, United Kingdom.
authors.forename: Claire L
authors.initials: CL
authors.lastname: Shovlin
authors.affiliation: National Heart & Lung Institute (NHLI) Cardiovascular Sciences, Imperial College London, United Kingdom ; Imperial College School of Medicine, Imperial College London, United Kingdom.
authors.forename: Basel
authors.initials: B
authors.lastname: Chamali
authors.affiliation: National Heart & Lung Institute (NHLI) Cardiovascular Sciences, Imperial College London, United Kingdom ; Respiratory Medicine, Imperial College Healthcare NHS Trust, London, United Kingdom ; Imperial College School of Medicine, Imperial College London, United Kingdom.
authors.forename: Vatshalan
authors.initials: V
authors.lastname: Santhirapala
authors.affiliation: Respiratory Medicine, Imperial College Healthcare NHS Trust, London, United Kingdom ; Imperial College School of Medicine, Imperial College London, United Kingdom.
authors.forename: John A
authors.initials: JA
authors.lastname: Livesey
authors.affiliation: Haematology, Imperial College Healthcare NHS Trust, London, United Kingdom.
authors.forename: Gillian
authors.initials: G
authors.lastname: Angus
authors.affiliation: Haematology, Imperial College Healthcare NHS Trust, London, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: Manning
authors.affiliation: Haematology, Imperial College Healthcare NHS Trust, London, United Kingdom ; Centre for Haematology, Investigative Sciences, Imperial College London, United Kingdom.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Laffan
authors.affiliation: Clinical Chemistry, Imperial College Healthcare NHS Trust, London, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Meek
authors.affiliation: Respiratory Medicine, Imperial College Healthcare NHS Trust, London, United Kingdom.
authors.forename: Hannah C
authors.initials: HC
authors.lastname: Tighe
authors.affiliation: Department of Imaging, Imperial College Healthcare NHS Trust, London, United Kingdom.
authors.forename: James E
authors.initials: JE
authors.lastname: Jackson
mesh_terms: D000328:Adult; D001792:Blood Platelets / Q000502:physiology*; D002545:Brain Ischemia / Q000150:complications*; D005260:Female; D006801:Humans; D000090463:Iron Deficiencies; D008297:Male; D008875:Middle Aged; D010974:Platelet Aggregation; D011651:Pulmonary Artery / Q000002:abnormalities*; D011667:Pulmonary Veins / Q000002:abnormalities*; D012307:Risk Factors; D020521:Stroke / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D013683:Telangiectasia, Hereditary Hemorrhagic / Q000150:complications*