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 Livesey1,2,
- Richard A Manning3,
- John H Meek4,
- James E Jackson5,
- Elena Kulinskaya6,
- Michael A Laffan3,7,
- Claire L Shovlin8,9
- 1Imperial College School of Medicine, Imperial College, London, UK
- 2NHLI Respiratory Sciences, Imperial College, London, UK
- 3Department of Haematology, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK
- 4Department of Clinical Biochemistry, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK
- 5Department of Imaging, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK
- 6School of Computing Sciences, University of East Anglia, UK
- 7Investigative Sciences, Imperial College, London, UK
- 8NHLI Cardiovascular Sciences, Imperial College, London, UK
- 9Department of Respiratory Medicine, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK
- Correspondence to Claire L Shovlin, Respiratory Medicine, Hammersmith Hospital, Du Cane Rd, London W12 0NN, UK;
Contributors JAL generated the series 2 database to mid 2010; performed interim statistical analyses using Stata, performed the SIRES searches; and wrote the first manuscript draft. RAM and MAL made all factor VIII (FVIII) measurements, and advised on thrombotic and FVIII concepts. JM advised on iron measurements, and measured iron indices in the patients and in the diurnal study. JEJ reviewed patients with pulmonary arteriovenous malformations, and performed all angiography with associated measurements including pulmonary artery pressure. EK performed initial statistical analysis of series 1; advised on final statistical methodology; and contributed to final statistical interpretation. CLS designed the study including diurnal assessments; reviewed the patients; generated the series 1 database; validated and extended the series 2 database; performed all statistical analyses presented; generated the figures; and wrote the final manuscript. All authors contributed to manuscript review, and approved the final version.
- Received 7 September 2011
- Accepted 17 November 2011
- Published Online First 14 December 2011
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.
- pulmonary hypertension
- von Willebrand factor
- pulmonary embolism
- rare lung diseases
- COPD mechanisms
- COPD exacerbations
- airway epithelium
- cystic fibrosis
- cytokine biology
- innate immunity
- interstitial fibrosis
- lung proteases
- lung transplantation
Funding This study received support from the NIHR Biomedical Research Centre Funding Scheme (MAL, CLS), the National Heart and Lung Institute's Undergraduate Teaching Funds (JAL), and donations from families and friends of British HHT patients. The study sponsors played no part in study design, in the collection, analysis and interpretation of data, in the writing of the report, or in the decision to submit the paper for publication.
Competing interests None.
Ethics approval Hammersmith, Queen Charlotte's, Chelsea, and Acton Hospital Research Ethics Committee.
Provenance and peer review Not commissioned; externally peer reviewed.