Coagulation disorders and the IPF puzzle.

While idiopathic pulmonary fibrosis (IPF) remains a frustrating mystery for patients and their physicians, growing evidence from a number of different sources provides potentially clinically relevant clues to the puzzle of this largely untreatable and highly fatal disorder. 2 Answers to frequently asked questions from patients of ‘why me?’ ‘what is the cause?’ ‘what can be done?’ and ‘what can I expect?’ are gradually emerging from studies of pathogenesis, clinical trials and epidemiological investigations. For over three decades, the majority of IPF research has focused on pathogenesis and clinical trials of various therapeutic agents. Available evidence on pathogenic mechanisms suggests that pulmonary fibrosis results from a number of exposures that cause alveolar epithelial injury (eg, cigarette smoke, asbestos fibres, viruses) followed by activation of a complex set of abnormal, genetically determined biological pathways that result in fibrosis. Altering the course of the disease remains a challenge partly because of the complexity of the pathogenesis of IPF, and time needed for discovery and clinical trials of new agents to determine efficacy. Moreover, despite the growing number of clinical trials among patients with symptomatic IPF the results have been disappointing. Therefore, parallel research approaches are needed on interventions to prevent the occurrence (ie, primary prevention) or progression of subclinical pulmonary fibrosis (ie, secondary prevention). For any disease, the ultimate goal is primary prevention through elimination of exposures that cause the disease. While epidemiological evidence suggests this may be a possible approach for IPF, there are also major challenges. Exposure to a number of environmental and occupational agents may cause IPF, and control of these exposures offers the potential to prevent the development of IPF. For example, based on the prevalence of smoking and risk of IPF associated with smoking an estimated 49% of IPF cases may be prevented through elimination of this exposure. However, the relatively low occurrence of IPF and challenges with control of multiple exposures limits the feasibility of conducting trials of primary prevention. Interventions may become feasible with the use of biomarkers of IPF to identify high-risk individuals. Secondary prevention or early detection combined with interventions to prevent progression of subclinical disease may be accomplished through advances in diagnostic sensitivity and accuracy with highresolution CT (HRCT) scans and other biomarkers. The feasibility of this approach is supported by recent findings of subclinical interstitial lung abnormalities by HRCT scanning among several different populations. 9 While the relationship between these abnormalities and IPF remains to be established, clinical and radiographic characteristics suggest patterns similar to IPF. For example, Doyle et al found that among smokers 8% had interstitial lung abnormalities and among these 75% had a subpleural or mixed pattern consistent with the radiographic distribution of IPF. Moreover, subclinical interstitial lung abnormalities were associated with clinically relevant impairment of spirometry and 6 min walking distance (Doyle et al). In addition to HRCT for early detection the use of biomarkers has the potential to detect high-risk individuals with subclinical disease. 7 9 Navaratnam et al add to the epidemiological evidence relevant to biomarkers and identification of high-risk individuals. They conducted a population-based, case– control study in the Greater Trent Region of the UK to examine the risk of IPF associated with a prothrombotic state. The investigators enrolled 211 incident cases of clinically stable patients with IPF diagnosed by a respiratory physician. To confirm the diagnosis and further categorise cases as definite or probable, HRCT scans were reviewed by two experienced thoracic radiologists. Age-matched and gender-matched population-based controls (n=256) were identified from 10 primary care practices from the same geographic region as the patients with IPF. The thrombotic state was characterised with a panel of 11 laboratory tests that included seven inherited and four acquired clotting defects. In a multivariate model adjusting for age, sex, smoking status and highly sensitive C-reactive protein (CRP), the risk (OR) of IPF associated with at least one abnormality of coagulation was substantially increased (OR=4.78 (95% CI 2.93 to 7.80)). Moreover, there was a dose– response increase in the risk of IPF associated with the number of thrombotic abnormalities. Other clinically relevant findings included associations between prothrombotic state and greater impairment of forced vital capacity and diffusing capacity for carbon monoxide (DLCO) and increased mortality. The investigators carefully designed and executed this study to minimise potential biases and strengthen both external and internal validity. Specific study design characteristics and results that support robust external validity of this investigation include (1) enrolment of a broadly representative sample of patients with newly diagnosed IPF from different types of hospitals, including five teaching and eight district general hospitals, (2) high response rate (86%) of eligible patients, (3) control subjects from the same geographic region and (4) patient characteristics of age, gender, distribution of severity of impairment and mortality similar to other investigations and (5) an increased risk of smoking similar to previous studies. In addition, several study design characteristics support strong internal validity. These characteristics include (1) minimisation of potential diagnostic misclassification of IPF by the use of standardised diagnostic criteria, independent verification by experienced thoracic radiologists and stratified analysis of definite and probable cases, (2) use of a panel of 11 objective measures of a prothrombotic state, (3) control of major potential confounding factors, including age, gender, smoking and highly sensitive CRP and (4) sufficient power to examine dose–response relationships. While the results of this investigation establish a strong association between a prothrombotic state and IPF, alone they do not prove causation. However, when evaluated in the context of other epidemiological and biological evidence these results provide a compelling case for a causal role of coagulation disorders in the development of IPF. Causal inference is a complex process that is based on the quality of evidence from multiple sources and an evaluation of that evidence using nine criteria, including magnitude of risk, dose– response, consistency, plausibility, coherence, temporality, analogy, experiment Correspondence to Dr David B Coultas, Department of Medicine, The University of Texas Health Science Center-Tyler, Tyler, TX 75708 USA; david.coultas@ uthct.edu