Ischaemic strokes in patients with pulmonary arteriovenous malformations and hereditary hemorrhagic telangiectasia: associations with iron deficiency and platelets.

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. METHODOLOGY: 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. PRINCIPAL FINDINGS: 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). SIGNIFICANCE: 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.

Low serum iron levels are associated with elevated plasma levels of coagulation factor VIII and pulmonary emboli/deep venous thromboses in replicate cohorts of patients with hereditary haemorrhagic telangiectasia.

BACKGROUND: Elevated plasma levels of coagulation factor VIII are a strong risk factor for pulmonary emboli and deep venous thromboses. OBJECTIVES: To identify reversible biomarkers associated with high factor VIII and assess potential significance in a specific at-risk population. PATIENTS/METHODS: 609 patients with hereditary haemorrhagic telangiectasia were recruited prospectively in two separate series at a single centre. Associations between log-transformed factor VIII measured 6 months from any known thrombosis/illness, and patient-specific variables including markers of inflammation and iron deficiency, were assessed in stepwise multiple regression analyses. Age-specific incidence rates of radiologically proven pulmonary emboli/deep venous thromboses were calculated, and logistic regression analyses performed. RESULTS: In each series, there was an inverse association between factor VIII and serum iron that persisted after adjustment for age, inflammation and/or von Willebrand factor. Iron response elements within untranslated regions of factor VIII transcripts provide potential mechanisms for the association. Low serum iron levels were also associated with venous thromboemboli (VTE): the age-adjusted OR of 0.91 (95% CI 0.86 to 0.97) per 1 µmol/litre increase in serum iron implied a 2.5-fold increase in VTE risk for a serum iron of 6 µmol/litre compared with the mid-normal range (17 µmol/litre). The association appeared to depend on factor VIII, as once adjusted for factor VIII, the association between VTE and iron was no longer evident. CONCLUSIONS: In this population, low serum iron levels attributed to inadequate replacement of haemorrhagic iron losses are associated with elevated plasma levels of coagulation factor VIII and venous thromboembolic risk. Potential implications for other clinical populations are discussed.

Fit optimisation of a distal medial tibia plate.

An iterative method for the fit optimisation of a pre-contoured fracture fixation plate for a given bone data set is presented. Both plate shape optimisation and plate fit quantification are conducted in a virtual environment utilising computer graphical methods and 3D bone and plate models. Two optimised shapes of the undersurface of an existing distal medial tibia plate were generated based on a dataset of 45 3D bone models reconstructed from computed tomography image data of Japanese tibiae. The existing plate shape achieved an anatomical fit on 13% of tibiae from the dataset. Modified plate 1 achieved an anatomical fit for 42% and modified plate 2 a fit for 67% of the bones. If either modified plate 1 or plate 2 is used, then the anatomical fit can be increased to 82% for the same dataset. Issues pertaining to any further improvement in plate fit/shape are discussed.

Plasma salicylate level and aspirin resistance in survivors of myocardial infarction.

To investigate the effect of aspirin on the platelets of survivors of myocardial infarction we correlated plasma salicylate level with platelet reactivity in ten patients and ten normal controls. The patients and controls were tested at the end of 2 week periods on 75, 150 and 300 mg aspirin daily by mouth. Platelet reactivity was measured, under high shear stress conditions, using cartridges containing adrenaline and adenosine diphosphate in a PFA-100 platelet function analyser. The time taken by the developing platelet aggregate to close an aperture in the collagen membrane of the cartridge, the closure time, was taken as an index of platelet reactivity. There was no difference in baseline haematocrit, platelet count or plasma vWF antigen level between the groups. There was a dose-dependent increase in closure time of the adrenaline containing cartridge in the controls (P < 0.001), but not in the patients (P = 0.08), compatible with a reduced anti-platelet effect of aspirin in the patients. Furthermore, plasma salicylate level was higher in the patient group (P < 0.05).