Low Serum Iron Levels Are Associated with Elevated Plasma Levels Of
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Downloaded from thorax.bmj.com on December 21, 2011 - Published by group.bmj.com Thorax Online First, published on December 14, 2011 as 10.1136/thoraxjnl-2011-201076 Orphan lung disease ORIGINAL ARTICLE 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 John A Livesey,1,2 Richard A Manning,3 John H Meek,4 James E Jackson,5 Elena Kulinskaya,6 Michael A Laffan,3,7 Claire L Shovlin8,9 < Additional materials are ABSTRACT published online only. To view Background Elevated plasma levels of coagulation factor Key messages these files please visit the VIII are a strong risk factor for pulmonary emboli and journal online (http://thorax.bmj. com/content/early/recent). deep venous thromboses. What is the key question? Objectives To identify reversible biomarkers associated < 1Imperial College School of Can we find new risk factors for venous Medicine, Imperial College, with high factor VIII and assess potential significance in thromboemboli (VTE) that might allow the London, UK a specific at-risk population. 2 development of a strategy to prevent pulmonary NHLI Respiratory Sciences, Patients/Methods 609 patients with hereditary emboli and deep venous thromboses? Imperial College, London, UK 3 haemorrhagic telangiectasia were recruited prospectively Department of Haematology, in two separate series at a single centre. Associations What is the bottom line? Hammersmith Hospital, Imperial < College Healthcare NHS Trust, between log-transformed factor VIII measured 6 months By focusing on the known VTE risk factor, London, UK from any known thrombosis/illness, and patient-specific coagulation factor VIII, low serum iron levels are 4Department of Clinical variables including markers of inflammation and iron identified as a biomarker for high factor VIII Biochemistry, Hammersmith deficiency, were assessed in stepwise multiple levels, and clinical VTE. Hospital, Imperial College regression analyses. Age-specific incidence rates of Healthcare NHS Trust, London, Why read on? UK radiologically proven pulmonary emboli/deep venous < 5Department of Imaging, thromboses were calculated, and logistic regression Low serum iron levels are treatable by Hammersmith Hospital, Imperial analyses performed. increasing iron intake, and thus represent College Healthcare NHS Trust, Results In each series, there was an inverse association a potentially reversible risk factor for pulmonary London, UK emboli and deep venous thromboses. 6School of Computing Sciences, between factor VIII and serum iron that persisted after University of East Anglia, UK adjustment for age, inflammation and/or von Willebrand 7Investigative Sciences, Imperial factor. Iron response elements within untranslated College, London, UK regions of factor VIII transcripts provide potential 8NHLI Cardiovascular Sciences, Patients with hereditary haemorrhagic telangi- 3 Imperial College, London, UK mechanisms for the association. Low serum iron levels ectasia (HHT) represent a specific patient group 9Department of Respiratory were also associated with venous thromboemboli (VTE): with unexplained high rates of VTE.4 Pulmonary Medicine, Hammersmith the age-adjusted OR of 0.91 (95% CI 0.86 to 0.97) per emboli and anticoagulation carry particular hazards Hospital, Imperial College 1 mmol/litre increase in serum iron implied a 2.5-fold for these patients who exhibit sustained and Healthcare NHS Trust, London, increase in VTE risk for a serum iron of 6 mmol/litre UK chronic blood losses from nasal and gastrointestinal compared with the mid-normal range (17 mmol/litre). telangiectasia, and usually have arteriovenous Correspondence to The association appeared to depend on factor VIII, as malformations (AVMs) in pulmonary, hepatic and/ Claire L Shovlin, Respiratory once adjusted for factor VIII, the association between or cerebral vascular beds.3 Elevated levels of coag- Medicine, Hammersmith VTE and iron was no longer evident. Hospital, Du Cane Rd, London ulation factor VIII (FVIII) at least 6 months from W12 0NN, UK; Conclusions In this population, low serum iron levels any acute illness, infection or thrombosis are [email protected] attributed to inadequate replacement of haemorrhagic a strong predictor of long-term VTE risk in HHT.4 iron losses are associated with elevated plasma levels of Similarly, elevated FVIII levels are a strong risk Received 7 September 2011 coagulation factor VIII and venous thromboembolic risk. factor for VTE in the general population.56 Accepted 17 November 2011 Potential implications for other clinical populations are In contrast to haemophilia A caused by muta- discussed. tions in the FVIII gene leading to severely reduced FVIII levels, to date, no unique genetic basis for elevated FVIII levels has been identified.7 In the INTRODUCTION CHARGE (Cohorts for Heart and Aging Research in Pulmonary emboli and deep venous thromboses Genomic Epidemiology) genome-wide association cause major morbidity and mortality.1 2 The study of 23 608 people of European descent, all five importance of venous thromboemboli (VTE) is FVIII-associated loci were also associated with emphasised by the Department of Health’s higher levels of von Willebrand factor (vWF),7 the mandatory VTE risk assessment data collection glycoprotein with which FVIII circulates in a non- programme for NHS-funded acute care hospitals. covalent complex. General population studies have CopyrightLivesey JA, ManningArticle RA, author Meek JH, (oret al .theirThorax employer)(2011). doi:10.1136/thoraxjnl-2011-201076 2011. Produced by BMJ Publishing Group Ltd (& BTS) under licence. 1 of 6 Downloaded from thorax.bmj.com on December 21, 2011 - Published by group.bmj.com Orphan lung disease delineated environmental factors that elevate plasma FVIII, and included from 2006, after elevated FVIII levels were identified in these parallel clinical risk factors for VTE.1 Thus FVIII levels are series 1.4 All patients underwent a screen for pulmonary AVMs higher with increased age,8 and are acutely elevated in the that included standardised measurements of oxygen saturation setting of an acute phase inflammatory response.9 in the erect posture, and for patients with pulmonary AVM Patients with HHT provide a good group to further study the undergoing subsequent embolisation, mean pulmonary artery association between high FVIII and VTE because inflammation pressure, measured routinely at angiography.12 Pulmonary is not a prominent disease feature, yet patients display high rates emboli and deep venous thromboses were included as VTE of thrombotic events at relatively young ages.4 To identify novel endpoints only if confirmed by Doppler ultrasound, CT biomarkers associated with elevated FVIII, stringently pheno- pulmonary angiography, other contrast studies, or ventilation- typed HHT populations were examined. We hypothesised that perfusion scanning resulting in mismatched perfusion defects this might facilitate a better understanding of why FVIII is not explained by the presence of pulmonary AVMs. ‘Commu- elevated in patients with HHT, test the causal chain of nity-restricted VTE’ were defined as any spontaneous deep biomarker-high FVIII-VTE, and importantly, allow the devel- venous thromboses or pulmonary emboli that were not related opment of a strategy to reduce FVIII levels, and thereby also to current or recent (within 6 weeks) hospitalisation. prevent pulmonary emboli and deep venous thromboses. Statistical methods fi METHODS The distribution of patient-speci c variables was assessed using The online supplement provides full details of patient assess- one-way tables and data plots using Stata statistical software, fi ments, power calculations and statistical methods. release 11 (Statacorp, 2009, College Station, TX, USA). Identi ed outliers (prothrombin time>16 s; CRP >40 iu/ml) were excluded. The distribution of FVIII:Ag was skewed and normalised by Ethical approvals logarithmic transformation (data not shown). Log-transformed A case notes review of patients with hereditary HHT was ethi- FVIII (lnFVIII) was used as the dependent variable for multiple ’ cally approved by the Hammersmith, Queen Charlotte s, regression analyses as previously.4 Levels were compared with Chelsea, and Acton Hospital Research Ethics Committee (LREC concurrent indices and other parameters of clinical status. For 00/5792), and the approval remains valid. The study is also each series, automated and manual stepwise forward and registered on the National Clinical Trials Database as backwards linear regression analyses were performed using NCT00230685 (PI Shovlin). Stata 11 (Statacorp, TX, USA). Age-standardised VTE incidence rates were calculated by STUDY PARTICIPANTS allocating VTE cases to the decade of life in which they occurred. Patients were reviewed between 1 May 1999 and 7 January 2011 Incidence rates in each decade were calculated using the total at the Hammersmith Hospital HHT/pulmonary AVM service in number of person years per decade provided by the cohorts, London, UK, a centre that receives nationwide referrals for these using (Stata 11). Incidence rates were compared with previously conditions. The sole eligibility criterion for this study was published rates for the general population,2 and graphed using adefinite diagnosis of HHT, assigned in the presence of at least an exponential growth programme (GraphPad Prism 5.00, San three of four recognised international criteria of nosebleeds, Diego,