ABSTRACT
Background: High D-dimer levels have been detected in patients with chronic obstructive pulmonary disease (COPD) exacerbation, irrespective of presence of venous thromboembolism. On the other hand, there is a continuing debate about the diagnostic efficiency of D-dimer tests in patients with stable COPD. Objectives: We aimed to investigate if basic laboratory investigations suggest hypercoagulability state in stable COPD patients, and if there is an association with D-dimer levels and pulmonary function tests. Methods: We conducted a case-control study. COPD patients and controls were matched for sex and age in a 2:1 matching ratio. D-dimer levels and pulmonary function tests were performed in COPD patients and controls. Results: A total of 58 COPD patients and 30 controls met the inclusion criteria and were included in the analysis. The median of D-dimers was 0.24 ng/mL (IQR: 0.21-0.36 ng/mL) in COPD group and 0.17 ng/mL (IQR: 0.12-0.24 ng/mL) in control group. This difference was not statistically significant (p = 0.102). Using bivariate correlations, we found significant positive correlations between BMI and D-dimers in COPD patients (r = 0.3, p = 0.024). Conclusions: We found that levels of D-dimers in stable COPD were not different as compared to control subjects. Our results also suggest that BMI could lead to disturbances in coagulation system.
INTRODUCTION
Chronic obstructive pulmonary disease (COPD) is a major global health problem, accounting for more than 3 million deaths annually (Citation1). Recent data indicates that COPD is often associated with a wide variety of systemic consequences, including the presence of systemic inflammation (Citation2). A hypercoagulable state can be triggered by inflammation, which promotes tissue-factor gene expression in endothelial cells (Citation3,4).
D-dimer levels, an end product of degradation of cross-linked fibrin by plasmin, have been shown to be increased in patients with COPD exacerbation, irrespective of presence of venous thromboembolism (VTE) (Citation5,6). The combination of an unlikely clinical decision rule and a normal D-dimer appears to have a similar safety in excluding pulmonary embolism irrespective of the presence of COPD (Citation7). On the other hand, there is a continuing debate about the VTE diagnostic efficiency of D-dimers tests in patients with stable COPD.
A similar distribution of D-dimer results was found in 313 patients with and without COPD, suggesting that the presence of COPD had no influence on the diagnostic performance of the test for thromboembolic disease (Citation8). However, some case-control studies (Citation9,10) have showed that plasma levels of fibrinogen and other markers of coagulation are significantly higher in stable COPD patients than in healthy subjects, which may have important diagnostic and therapeutic implications.
Given the conflicting results of prior studies, we aimed to investigate if D-dimer levels are increased in stable COPD patients, and if there is an association with D-dimer levels and pulmonary function tests.
METHODS
We conducted a case-control study in a general, tertiary care, university-affiliated hospital. COPD patients and controls were matched for sex and age in a 2:1 matching ratio. COPD was confirmed by a ratio of forced expiratory volume in the first second (FEV1) to forced vital capacity (FVC) of less than 0.7, measured 20 minutes after the administration of salbutamol. COPD severity was classified according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria (Citation11). Outpatients with COPD were enrolled consecutively. The control group consisted of individuals without symptoms or previous respiratory diseases and with normal spirometry.
They were recruited among relatives of patients in outpatient clinics or in pulmonary function laboratory in the same hospital. COPD patients with exacerbation in the last 4 weeks were excluded. We also excluded patients and controls with asthma, cancer diagnosis in the last 5 years, previous or actual episodes of venous thromboembolism, immobilization for more than 3 days, current or former smokers with an abstinence time less than 6 months, suspected diagnosis of acute inflammatory or infectious disease, use of anticoagulant therapy, diabetes mellitus, heart failure, chronic renal failure, liver disease, disseminated intravascular coagulation, sickle cell disease, pregnancy, hormone replacement therapy, stroke, and acute coronary syndrome. The local ethics committee approved the study, and all subjects gave written informed consent to participate.
The patients were interviewed and the following data were collected in a standardized questionnaire: demographic data, smoking habits, presence of co-morbidities, and inhaled and oral corticosteroid use. Pulmonary function tests (spirometry, lung volumes, and diffusing capacity of the lung for carbon monoxide (DLCO)) were performed using a computerized spirometer (Jäeger, Würzburg, Germany), according to the American Thoracic Society/European Respiratory Society guidelines (Citation12–14), and with previously published reference values (Citation15–17). We described post-bronchodilator values for COPD patients. Spirometry without bronchodilator was performed in control subjects.
Blood sample was collected from all patients and D-dimer level was obtained by the automated STA LIATEST immunoturbidimetric D-dimer assay performed on the STA-Compact analyzer (Liatest D-Dimer Diagnostica Stago, Asnières, France). C-reactive protein, hematocrit, and hemosedimentation velocity were determined to exclude subclinical inflammatory states.
Data analysis was performed using SPSS 16.0 (Statistical Package for the Social Sciences, Chicago, Illinois). Data were presented as number of cases, mean ± standard deviation (SD), or median with interquartile range. Categorical comparisons were carried out by chi-square test using Yates's correction if indicated or by Fisher's exact test. Continuous variables were compared using the t-test or Wilcoxon test. Pearson's (or Spearman's when indicated) correlations was performed to evaluate for potential relationships. To find a correlation (at least r = 0.60) between D-dimers and other variables, with a power of 80% and significance at 5%, 19 patients would be needed. A two-sided p-value < 0.05 was considered significant for all analyses.
RESULTS
A total of 60 COPD patients and 30 controls met the inclusion criteria. As there were only 2 patients with disease stage I according to GOLD criteria, we decided to exclude them from the analysis. Therefore, 58 COPD patients and 30 controls were included in the analysis, after have gave signed, informed consent. The characteristics of the study population are shown in .
Table 1. Characteristics of patients with COPD and control subjects
The study subjects had a mean age of 65.1 ± 8.4 years in COPD group and 64.3 ± 9.2 years in control group (p = 0.687). Patients with COPD had a lower BMI compared with control subjects (25.2 ± 4.5 kg/m2 vs 28.1 ± 4.3 kg/m2, p = 0.003). The number of ex-smokers was higher in COPD group (58 (96.7%)) than in control group (9 (30.0%)) (p<0.0001). The number of never smokers was higher in control group (21 (70.0%)) than in COPD group (2 (3.3%)) (p<0.0001). The amount of cigarette smoked was higher in COPD group (median = 48.5 pack-years) than in control group (median = 30.0 pack-years), but this difference was not statistically significant (p = 0.174). In COPD group, 20 (33.3%) patients had at least one co-morbid condition (17 systemic arterial hypertension; 9 dyslipidemia; 2 osteoporosis; 1 obstructive sleep apnea syndrome). In control group, 4 (13.3%) patients had co-morbidities (2 dyslipidemia; 1 systemic arterial hypertension; 1 hypothyroidism).
As expected, patients diagnosed with COPD had values of FEV1 (% of predicted) and FVC (% of predicted) lower than subjects in control group (p<0.0001). According to the GOLD criteria, there were 20 (34.5%), 21 (36.2%) and 17 (29.3%) patients, respectively with disease stage II, III, and IV disease.
The median of D-dimers was 0.24 ng/mL (IQR: 0.21-0.36 ng/mL) in COPD group and 0.17 ng/mL (IQR: 0.12-0.24 ng/mL) in control group. This difference was not statistically significant (p = 0.102). There were 10 (17.2%) patients in COPD group and 7 (23.3%) patients in control group with D-dimers greater than the normal value (p = 0.493). shows the characteristics of patients and controls with normal and abnormal D-dimer levels. The presence of co-morbidities was more frequent in COPD patients with abnormal D-dimer levels (7 (70.0%)) than in those with normal D-dimer levels (13 (26.0%)) (p = 0.012). The number of ex-smokers was not statistically different between patients with normal and abnormal D-dimer levels, in both COPD and control groups.
Table 2. Characteristics of patients and controls with normal and abnormal D-dimer levels
Using bivariate correlations, we found significant positive correlations between BMI and D-dimers in COPD patients (r = 0.3, p = 0.024) (). D-dimers were not correlated with BMI in control group (p = 0.958). In COPD patients, there was no correlation between D-dimers and DLCO (% of predicted) (p = 0.462). In both COPD and control groups, FEV1 (% of predicted) and CVF (% of predicted) were not correlated with D-dimers (p = 0.717 and p = 0.836 for COPD group; p = 0.114 and p = 0.325 for control group).
Table 3. Bivariate correlations with D-dimers in COPD patients and controls
DISCUSSION
In this case-control study, we aimed to evaluate if D-dimer levels were different in COPD and control subjects, and if there was an association between pulmonary function tests and D-dimers. We demonstrated that D-dimer levels were not statistically different between COPD patients and controls.
D-dimers result from the breakdown of fibrin and can serve as a marker for fibrinolytic system activity. D-dimer levels have been shown to be increased in a variety of diseases (Citation18,19). Some studies have provided evidence for the presence of a hypercoagulable state in COPD patients (Citation9,10,Citation20). In a case-control study with 51 stable COPD patients and 30 controls, an increase in fibrinogen, D-dimer, factor VIII and von Willebrand factor was found in COPD group compared with control group (Citation20). Plasma levels of thrombin antithrombin complex, fibrinopeptide A, tissue plasminogen activator-plasminogen activator inhibitor, and β-thromboglobulin were measured in a study with 40 stable COPD patients and in 20 control subjects, and showed higher concentrations in COPD patients than in controls (Citation10).
Another case-control study with 37 stable COPD patients and 30 controls, demonstrated hypercoagulability in COPD patients by measurement of F1+2 fragments and D-dimers (Citation9). On the other hand, Hartmann and colleagues (Citation8) reported in a large study that the distribution of D-dimer results was not influenced by the presence of COPD. However, the diagnosis of COPD in this study was based on clinical information, and perhaps some misclassifications of COPD might have occurred. In our study, we confirmed that D-dimer levels were not altered by the presence of a COPD diagnosis based on spirometric data.
In our study, we could not find a significant correlation between D-dimers and FEV1. There are evidences that reduced lung function is associated with increased levels of systemic inflammatory markers in subjects with stable COPD (Citation21,22). Moreover, fibrinogen, possibly a marker for chronic low-grade inflammation, is associated with modest deterioration of lung function in healthy young adults (Citation23,24). In a previous study, changes in FEV1 (% of predicted) at the 12-month follow-up period were significantly greater in COPD patients with high thrombin antithrombin complex or tissue plasminogen activator-plasminogen activator inhibitor levels (Citation10). In agreement with our findings, another case-control study did not find a correlation between severity of obstruction and D-dimers (Citation20).
Another finding in this study was a positive correlation between BMI and D-dimer levels. It is well known that low-grade systemic inflammation occurs in obese individuals (Citation25,26). Development of obesity is associated with adipogenesis, angiogenesis and extracellular matrix proteolysis, processes in which the fibrinolytic system plays an important role (Citation27). The relationship between adiposity and D-dimer is of clinical interest, as D-dimer and body mass index (BMI) are recognized risk factors for venous thromboembolism (Citation28–32). A previous study demonstrated that plasma leptin, a circulating peptide hormone produced by adipocytes and whose levels increase with BMI, was significantly associated with increase of inflammatory markers (C-reactive protein, interleukin-Citation6, fibrinogen) and increased coagulation activation (D-dimers, factor VIII) (Citation33).
We found that the presence of co-morbidities was more common in COPD group than in control group, and, in COPD patients, they were more frequent in those with abnormal D-dimer levels. Although co-morbidities can contribute to systemic inflammation and possibly interfere in D-dimer levels, we excluded patients with the most common co-morbidities related to chronic inflammation, as cardiovascular disease, diabetes mellitus, cancer, and current smoking (Citation34,35).
Our study has some limitations. First, the investigation was done in a single center. Second, it must be considered that this study was conducted with a small sample size. Finally, we have only two patients with COPD stage I, so that our results might not be valid to this subgroup of patients. Despite these limitations, these results are in agreement with a previous and larger study, and provide additional evidence of absence of fibrinolysis in patients with stable COPD, diagnosed on the basis of spirometric findings.
In conclusion, in this study we found that levels of D-dimers in stable COPD were not different as compared to control subjects. Our results suggest that BMI could lead to disturbances in fibrinolytic system. However, the small sample size may have lacked sufficient statistical power to reveal an association between D-dimers and some of the variables, as FEV1 and smoking pack-years. A larger and more homogeneous study population, including only COPD stage II and III may clarify this topic.
Declaration of Interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
REFERENCES
- Barnes PJ. Chronic obstructive pulmonary disease. N Engl J Med 2000; 343(4): 269–280.
- Stone AC, Nici L. Other systemic manifestations of chronic obstructive pulmonary disease. Clin Chest Med 2007; 28(3):553–557, vi.
- Esmon CT Does inflammation contribute to thrombotic events? Haemostasis 2000; 30 Suppl 2:34–40.
- Libby P, Simon DI. Inflammation and thrombosis: the clot thickens. Circulation 2001; 103(13):1718–1720.
- Akgun M, Meral M, Onbas O, Araz O, Koplay M, Aslan S, Mirici A. Comparison of clinical characteristics and outcomes of patients with COPD exacerbation with or without venous thromboembolism. Respiration 2006; 73(4):428–433.
- Karwat K, Kosciuch J, Chazan R. (Is microembolism present and is it important element of COPD exacerbation?). Pol Merkur Lekarski 2005; 18(106):385–388.
- Sohne M, Kruip MJ, Nijkeuter M, Tick L, Kwakkel H, Halkes SJ, Accuracy of clinical decision rule, D-dimer and spiral computed tomography in patients with malignancy, previous venous thromboembolism, COPD or heart failure and in older patients with suspected pulmonary embolism. J Thromb Haemost 2006; 4(5):1042–1046.
- Hartmann IJ, Hagen PJ, Melissant CF, Postmus PE, Prins MH. Diagnosing acute pulmonary embolism: effect of chronic obstructive pulmonary disease on the performance of D-dimer testing, ventilation/perfusion scintigraphy, spiral computed tomographic angiography, and conventional angiography. ANTELOPE Study Group. Advances in New Technologies Evaluating the Localization of Pulmonary Embolism. Am J Respir Crit Care Med 2000; 162(6):2232–2237.
- Alessandri C, Basili S, Violi F, Ferroni P, Gazzaniga PP, Cordova C. Hypercoagulability state in patients with chronic obstructive pulmonary disease. Chronic Obstructive Bronchitis and Haemostasis Group. Thromb Haemost 1994; 72(3):343–346.
- Ashitani J, Mukae H, Arimura Y, Matsukura S. Elevated plasma procoagulant and fibrinolytic markers in patients with chronic obstructive pulmonary disease. Intern Med 2002; 41(3):181–185.
- Rabe KF, Hurd S, Anzueto A, Barnes PJ, Buist SA, Calverley P Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 2007; 176(6):532–555.
- MacIntyre N, Crapo RO, Viegi G, Johnson DC, van der Grinten CP, Brusasco V Standardisation of the single-breath determination of carbon monoxide uptake in the lung. Eur Respir J 2005; 26(4):720–735.
- Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A Standardisation of spirometry. Eur Respir J 2005; 26(2):319–338.
- Wanger J, Clausen JL, Coates A, Pedersen OF, Brusasco V, Burgos F Standardisation of the measurement of lung volumes. Eur Respir J 2005; 26(3):511–522.
- Crapo RO, Morris AH, Gardner RM. Reference spirometric values using techniques and equipment that meet ATS recommendations. Am Rev Respir Dis 1981; 123(6): 659–664.
- Crapo RO, Morris AH. Standardized single breath normal values for carbon monoxide diffusing capacity. Am Rev Respir Dis 1981; 123(2):185–189.
- Crapo RO, Morris AH, Clayton PD, Nixon CR. Lung volumes in healthy nonsmoking adults. Bull Eur Physiopathol Respir 1982; 18(3):419–425.
- Ginsberg JS, Wells PS, Brill-Edwards P, Donovan D, Panju A, van Beek EJ, Patel A. Application of a novel and rapid whole blood assay for D-dimer in patients with clinically suspected pulmonary embolism. Thromb Haemost 1995; 73(1):35–38.
- Raimondi P, Bongard O, de MP, Reber G, Waldvogel F, Bounameaux H. D-dimer plasma concentration in various clinical conditions: implication for the use of this test in the diagnostic approach of venous thromboembolism. Thromb Res 1993; 69(1):125–130.
- Aibar M, Laborda K, Conget F, Cornudella R. Hipercoagulability state and endotelial injury in stable chronic obstructive pulmonary disease patients. An Sist Sanit Navar 2010; 33:43–50.
- Gan WQ, Man SF, Senthilselvan A, Sin DD. Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis. Thorax 2004; 59(7): 574–580.
- Papaioannou AI, Mazioti A, Kiropoulos T, Tsilioni I, Koutsokera A, Tanou K, Systemic and airway inflammation and the presence of emphysema in patients with COPD. Respir Med 2010; 104(2):275–282.
- Engstrom G, Lind P, Hedblad B, Wollmer P, Stavenow L, Janzon L, Lindgarde F. Lung function and cardiovascular risk: relationship with inflammation-sensitive plasma proteins. Circulation 2002; 106(20):2555–2560.
- Thyagarajan B, Jacobs DR, Apostol GG, Smith LJ, Lewis CE, Williams OD. Plasma fibrinogen and lung function: the CARDIA Study. Int J Epidemiol 2006; 35(4):1001–1008.
- Garcia-Rio F, Miravitlles M, Soriano JB, Munoz L, Duran-Tauleria E, Sanchez G, Systemic inflammation in chronic obstructive pulmonary disease: a population-based study. Respir Res 2010;11:63.
- Sin DD, Man SF, Marciniuk DD, Ford G, FitzGerald M, Wong E, The effects of fluticasone with or without salmeterol on systemic biomarkers of inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2008; 177(11):1207–1214.
- Lijnen HR. Role of fibrinolysis in obesity and thrombosis. Thromb Res 2009; 123 Suppl 4: S46–S49.
- Abdollahi M, Cushman M, Rosendaal FR. Obesity: risk of venous thrombosis and the interaction with coagulation factor levels and oral contraceptive use. Thromb Haemost 2003; 89(3):493–498.
- Cushman M, Folsom AR, Wang L, Aleksic N, Rosamond WD, Tracy RP, Heckbert SR. Fibrin fragment D-dimer and the risk of future venous thrombosis. Blood 2003; 101(4):1243–1248.
- Goldhaber SZ, Grodstein F, Stampfer MJ, Manson JE, Colditz GA, Speizer FE, A prospective study of risk factors for pulmonary embolism in women. JAMA 1997; 277(8):642–645.
- Hansson PO, Eriksson H, Welin L, Svardsudd K, Wilhelmsen L. Smoking and abdominal obesity: risk factors for venous thromboembolism among middle-aged men: “the study of men born in 1913”. Arch Intern Med 1999; 159(16):1886–1890.
- Pomp ER, le CS, Rosendaal FR, Doggen CJ. Risk of venous thrombosis: obesity and its joint effect with oral contraceptive use and prothrombotic mutations. Br J Haematol 2007; 139(2):289–296.
- Wannamethee SG, Tchernova J, Whincup P, Lowe GD, Kelly A, Rumley A, Plasma leptin: associations with metabolic, inflammatory and haemostatic risk factors for cardiovascular disease. Atherosclerosis 2007; 191(2):418–426.
- Corsonello A, Antonelli Incalzi R, Pistelli R, Pedone C, Bustacchini S, Lattanzio F. Comorbidities of chronic obstructive pulmonary disease. Curr Opin Pulm Med 201; 17(Suppl 1):S21–28.
- Nussbaumer-Ochsner Y, Rabe KF. Systemic manifestations of COPD. Chest 2011; 139(1):165–173.