thromboplastin and Pulmonary-Disease--Chronic-Obstructive

Statins are widely used to lower lipids and reduce cardiovascular events. In vitro studies and small studies in patients with hyperlipidemias show statins inhibit tissue factor (TF) and blood coagulation mechanisms. We assessed the effects of simvastatin on TF and coagulation biomarkers in patients entered in STATCOPE, a multicenter, randomized, placebo-controlled trial of simvastatin (40 mg daily) versus placebo on exacerbation rates in patients with chronic obstructive pulmonary disease (COPD).. In 227 patients (114 simvastatin, 113 placebo; mean [± standard error of the mean] age 62 ± 0.53 years, 44.5% women) we measured (baseline, and 6 and 12 months): whole blood membrane TF-procoagulant activity (TF-PCA) and plasma factors VIIa, VII, VIII, fibrinogen, TF antigen, tissue factor pathway inhibitor (TFPI), thrombin-antithrombin complexes (TAT), and D-dimer. We excluded patients with diabetes, cardiovascular disease, and those taking or requiring a statin.. In the statin group, there was a small increase in TF-PCA (from 25.18 ± 1.08 to 30.36 ± 1.10 U/ml; p = .03) over 12 months; factors VIIa and VIII, fibrinogen, TAT, and D-dimer did not change. Plasma TFPI (from 52.4 ± 1.75 to 44.7 ± 1.78 ng/ml; p < .0001) and FVIIC (1.23 ± 0.04 to 1.15 ± 0.03 U/ml; p = .03) decreased and correlated with total cholesterol levels. No changes in biomarkers were observed with placebo.. In contrast to previous studies on statins, in COPD patients without diabetes, cardiovascular disease, or requiring a statin treatment, simvastatin (40 mg per day) did not decrease TF or factors VIIa and VIII, fibrinogen, TAT, or D-dimer. The decreases in TFPI and factor VII reflect the decrease in serum lipids.

Topics: Blood Coagulation; Factor VIIa; Female; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Simvastatin; Thromboplastin

ESSENTIALS: Thrombosis is a major comorbidity in patients with chronic obstructive pulmonary disease (COPD). Roflumilast is a selective phosphodiesterase type-4 (PDE4) inhibitor approved for treatment of severe COPD. PDE4 blockade by roflumilast inhibits prothrombotic functions of neutrophils and monocytes. PDE4 inhibitors may reduce thrombotic risk in COPD as well as in other vascular diseases.. Roflumilast, an oral selective phosphodiesterase type 4 inhibitor, is approved for the treatment of severe chronic obstructive pulmonary disease (COPD). A recent meta-analysis of trials on COPD revealed that treatment with roflumilast was associated with a significant reduction in the rate of major cardiovascular events. The mechanisms of this effect remain unknown.. We tested the hypothesis that roflumilast N-oxide (RNO), the active metabolite of roflumilast, curbs the molecular mechanisms required for leukocyte-platelet (PLT) interactions and prevents the prothrombotic functions of polymorphonuclear leukocytes (PMNs) and monocytes (MNs).. Using well-characterized in vitro models, we analysed the effects of RNO on: (i) PMN adhesiveness; (ii) the release of neutrophil extracellular traps (NETs); and (iii) tissue factor expression in MNs. Key biochemical events underlying the inhibitory effects of RNO were defined.. In PMNs, RNO prevented phosphoinositide 3-kinase (PI3K)-dependent phosphorylation of Akt on Ser473, and Src family kinase (SFK)-mediated Pyk2 phosphorylation on Tyr579-580, while inducing protein kinase A-mediated phosphorylation of C-terminal Src kinase, the major negative regulator of SFKs. Modulation of these signaling pathways by RNO resulted in a significant impairment of PMN adhesion to activated PLTs or human umbilical vein endothelial cells, mainly mediated by inhibition of the adhesive function of Mac-1. Moreover RNO curbed SFK/PI3K-mediated NET release by PMNs adherent on fibrinogen-coated surfaces. In MNs interacting with activated PLTs, RNO curbed PI3K-mediated expression of tissue factor. The efficacy of RNO was significantly potentiated by formoterol, a long acting β-adrenergic receptor agonist. This study reveals novel antithrombotic activities by which roflumilast may exert protective effects against cardiovascular comorbodities in COPD.

Topics: Aminopyridines; Animals; Benzamides; Blood Platelets; Cardiovascular Diseases; Cyclic Nucleotide Phosphodiesterases, Type 4; Cyclopropanes; Extracellular Traps; Fibrinogen; Humans; Leukocytes; Macrophage-1 Antigen; Mice; Microscopy, Confocal; Monocytes; Neutrophils; P-Selectin; Phosphatidylinositol 3-Kinases; Phosphodiesterase 4 Inhibitors; Phosphorylation; Platelet Adhesiveness; Pulmonary Disease, Chronic Obstructive; Risk; Thromboplastin; Thrombosis

This study was conducted to investigate the variation of monocyte chemoattrant protein-1 (MCP-1) and tissue factor (TF) in elderly patients with acutely exacerbated chronic obstructive pulmonary disease (AECOPD) and their clinical significance.. Serum specimens were obtained from 49 AECOPD. Patients and 30 health controls, with mean age of 76.1 ± 10.2 and 62.8 ± 6.5 years. Patients in AECOPD group were further grouped into two subgroups, with high or normal procaletonin (PCT) levels. Plasma TE, MCP-1 and PCT were qualified by enzyme-linked immunosorbent assay (ELISA).. TF and MCP-1 were found to be higher in AECOPD patients than in health people (p < 0.01), and TF was linearly and positively related to MCP-1. In the subgroups TF was significantly higher in patients with higher PCT than those with normal PCT (p < 0.05).. In AECOPD patients blood cells are activated to hypercoagulation state, particularly when their PCT level is high. Extrinsic pathway activated by TE plays important role in development of the hypercoagulation state. Our results indicate that plasma TF level was positively correlated to the level of MCP-1. This suggests that monitoring of plasma TF and MCP-1 levels in AECOPD patients could be a very useful way to prevent and cure blood hypercoagulability, cardiovascular and cerebrovascular thrombotic diseases.

Topics: Acute Disease; Age Factors; Aged; Aged, 80 and over; Case-Control Studies; Chemokine CCL2; Cross-Sectional Studies; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Thromboplastin

Increased cardiovascular mortality and risk of venous thromboembolism are serious extra-pulmonary complications of chronic obstructive pulmonary disease (COPD). Previously, circulating active tissue factor (TF) and factor XIa (FXIa) have been reported to be associated with acute coronary syndromes.. To measure plasma FXIa and active TF, prothrombin fragment 1.2 (F1.2), and markers of systemic inflammation (C-reactive protein [CRP], interleukin-6 [IL-6], tumor necrosis factor α [TNFα] and matrix metalloproteinase 9 [MMP-9]) in 60 patients with documented stable COPD free of previous thromboembolic events.. In-house clotting assays using inhibitory monoclonal antibodies against FXIa and TF.. FXIa was detected in 9 (15%) and TF activity in 7 (11.7%) COPD patients. Subjects positive for FXIa and/or TF (n=10; 16.7%) had higher F1.2 (median [interquartile range], 398 [216] vs 192 [42] pM, p<0.000001), fibrinogen (5.58 [2.01] vs 3.97 [2.47] g/L, p=0.0007), CRP (14.75 [1.20] vs 1.88 [2.95] mg/L, p<0.000001), IL-6 (8.14 [4.74] vs 2.45 [2.24] pg/mL, p=0.00002), and right ventricular systolic pressure (47 [15] vs 38 [12] mmHg, p=0.023), and lower vital capacity (66 [15] vs 80 [17] % predicted, p=0.04) than COPD patients without detectable FXIa and TF. COPD severity was not associated with the presence of circulating FXIa and active TF.. This is the first study to show that active FXIa and TF are present in stable COPD patients, who exhibit enhanced systemic inflammation and thrombin generation. Our findings suggest a new prothrombotic mechanism which might contribute to elevated risk of thromboembolic complications in COPD.

Topics: Aged; Factor XIa; Female; Humans; Inflammation; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Thrombin; Thromboplastin

To explore the changes and clinical significances of plasma D-dimer, factor X and tissue factor in acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and analyze the in-depth changes of these indicators in AECOPD with co-current deep venous thrombosis (DVT).. A total of 56 AECOPD patients were divided into the DVT and non-DVT subgroups (n = 28 each). And 60 normal control subjects were recruited according to age and gender. For each subject, 2.7 ml whole blood was drawn and then the plasma levels of D-dimer, factor X and tissue factor were detected. The results were statistically analyzed with the software SPSS 13.0. And the analysis of variance was performed between the groups.. There was no significant difference between the distribution of the AECOPD group and the control group by gender and age. Therefore two groups were comparable. And in the AECOPD group, there was no significant difference between the distribution of DVT and non-DVT subgroups by gender and age. Therefore these two subgroups were comparable as well. The value of D-dimer in the AECOPD patients was significantly higher than that in the normal control [(0.76 ± 0.30) vs (0.29 ± 0.11) mg/L, P < 0.01]; and in the AECOPD group, the value of D-dimer in the DVT subgroup was significantly higher than that in the non-DVT subgroup [(0.85 ± 0.29) vs (0.67 ± 0.28) mg/L, P < 0.05]. In the AECOPD group, the value of tissue factor was (238 ± 68) mg/L and the value of factor X (1181 ± 337) mg/L. While in the normal control group, the values were (124 ± 30) and (998 ± 260) mg/L respectively. As for tissue factor and factor X, there were significant differences between two groups (all P < 0.01). Yet in AECOPD patients, neither indicator had significant differences between the DVT and non-DVT subgroups (all P > 0.05).. The blood of AECOPD patients is in a hypercoagulatory state. And an obvious rise in their plasma level of D-dimer suggests that it may be complicated with DVT.

Topics: Acute Disease; Aged; Aged, 80 and over; Blood Coagulation; Case-Control Studies; Factor X; Female; Fibrin Fibrinogen Degradation Products; Humans; Male; Middle Aged; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Thromboplastin; Venous Thrombosis

To explore the relationship between coagulation/anticoagulation imbalance and oxidative stress in the patients with chronic obstructive pulmonary disease during acute exacerbation (AECOPD) before and after treatment.. Plasma tissue factor (TF) and tissue factor pathway inhibitor (TFPI) activity was detected by chromogenic assay in 28 AECOPD patients before and after treatment as well as in 30 healthy controls. The total antioxidative capacity (TAC), malondialdehyde (MDA) and glutathione peroxidase (GSH-PX) in plasma were measured in both groups.. The levels of plasma TF and TFPI, and their ratio (TF/TFPI) in AECOPD patients before treatment were significantly higher than those after treatment (all P < 0.01), the latter were still higher than those in the healthy persons (all P < 0.01). The levels of the TAC and GSH-PX in plasma in AECOPD patients before treatment were significantly lower than those after treatment (all P < 0.01), the latter were still lower than those in the healthy persons (all P < 0.01). The plasma MDA in AECOPD patients before treatment was significantly higher than that after treatment (P < 0.01), which was still higher than that in the healthy persons (P < 0.05). There were negative correlations between TF/TFPI ratio and TAC (r = -0.518, P < 0.01), GSH-PX (r = -0.454, P < 0.05), PaO2 (r = -0.511, P < 0.01) respectively and a positive correlation between TF/TFPI ratio and the percentage of neutrophils (r = 0.379, P < 0.05) in AECOPD patients before treatment. There still were negative correlations between TF/TFPI ratio and TAC (r = -0.420, P < 0.05), FEV(1)% to predicted (r = -0.480, P < 0.05) respectively, and a positive correlation between TF/TFPI ratio and MDA (r = 0.451, P < 0.05) in AECOPD patients after treatment.. There existed coagulation/anticoagulation imbalance and oxidation/antioxidation imbalance before and after treatment in AECOPD patients and their relationship was explored.

Topics: Aged; Aged, 80 and over; Blood Coagulation; Case-Control Studies; Female; Glutathione Peroxidase; Humans; Lipoproteins; Male; Malondialdehyde; Middle Aged; Oxidative Stress; Pulmonary Disease, Chronic Obstructive; Thromboplastin

Fibrinogen-like protein 2 (FGL2)/fibroleukin has been reported to play a vital role in the pathogenesis of some critical inflammatory diseases by possessing immunomodulatory activity through the mediation of "immune coagulation" and the regulation of maturation and proliferation of immune cells. We observed upregulated FGL2 expression in alveolar macrophages from peripheral lungs of chronic obstructive pulmonary disease (COPD) patients and found a correlation between FGL2 expression and increased macrophage activation markers (CD11b and CD14). The role of FGL2 in the activation of macrophages was confirmed by the detection of significantly decreased macrophage activation marker (CD11b, CD11c, and CD71) expression as well as the inhibition of cell migration and inflammatory cytokine (IL-8 and MMP-9) production in an LPS-induced FGL2 knockdown human monocytic leukemia cell line (THP-1). Increased FGL2 expression co-localized with upregulated phosphorylated p38 mitogen-activated protein kinase (p38-MAPK) in the lung tissues from COPD patients. Moreover, FGL2 knockdown in THP-1 cells significantly downregulated LPS-induced phosphorylation of p38-MAPK while upregulating phosphorylation of c-Jun N-terminal kinase (JNK). Thus, we demonstrate that FGL2 plays an important role in macrophage activation in the lungs of COPD patients through MAPK pathway modulation.

Topics: Aged; Bronchoalveolar Lavage Fluid; Female; Fibrinogen; Gene Knockdown Techniques; Humans; Lipopolysaccharides; Macrophage Activation; Macrophages, Alveolar; Male; Middle Aged; p38 Mitogen-Activated Protein Kinases; Pulmonary Disease, Chronic Obstructive; Thromboplastin

Chronic obstructive pulmonary disease (COPD) patients have increased risk for cardiovascular mortality and venous thromboembolism. Tissue factor (TF) is the physiological initiating mechanism for blood coagulation and is pro-inflammatory.. We have studied circulating blood-borne TF-procoagulant activity (TF-PCA), plasma coagulation factors (F) VIIa and FVIII, and thrombin-antithrombin (TAT) complexes in 11 stable, moderate-severe COPD patients, 10 free of exacerbation for >3 weeks.. TF-PCA was increased in COPD patients (52.3+/-5.6 U/ml, (SE)) compared to control subjects (20.7+/-1.5, n=45, p<0.0001). TAT levels were increased (COPD patients: 2.99+/-0.65 ug/l; control subjects: 1.31+/-0.13, n=53, p<0.0001), indicating enhanced thrombin generation. Plasma FVIIa (the activated form of FVII) was higher in COPD (83+/-11 mU/ml; controls, 64+/-5 mU/ml, n=20) but did not reach statistical significance. Plasma FVIIc and FVIII were not increased. TF-PCA levels were inversely related to plasma FVIIa (r=-0.80, p=0.003) and FVIIc (r=-0.76, p=0.007).. Blood-borne TF-PCA is elevated and constitutes a prothrombotic and proinflammatory state in stable but moderate-severe COPD, and may contribute to the increased risk for vascular events.

Topics: Biomarkers; Female; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Reproducibility of Results; Sensitivity and Specificity; Thromboplastin

Pulmonary hypertension is common in patients with chronic obstructive pulmonary disease (COPD), but the precise mechanism of vascular impairment in these patients is unknown. We, therefore, decided to investigate whether endothelial cell dysfunction is present in patients with COPD with a wide range of chronic airflow obstruction before the development of severe pulmonary hypertension. Selected plasma markers of endothelial cell activity were studied: nitrate+nitrite (NO-(2)/NO-(3)), thrombomodulin (TM), tissue factor pathway inhibitor (TFPI), soluble selectins (endothelium sES, leukocyte sLS, platelet sPS), soluble intercellular adhesion molecule-1 (sICAM-1), and soluble platelet endothelial cell adhesion molecule-1 (sPECAM-1). Twenty-five patients with COPD (forced expiratory volume in one second/vital capacity [FEV(1)/VC] < 88% predicted) and 29 healthy control subjects were recruited to the study. Among patients nine had a pulmonary artery systolic pressure (PASP) between 15 and 30 mmHg, 13 between 32 and 38 mmHg, 2 had a PASP of 41 and 42 mmHg, respectively. One patient had severe pulmonary hypertension with a PASP of 70 mmHg. The average FEV(1) of patients with COPD was 46 +/- 4% predicted. As compared to control subjects, patients with COPD showed a significant increase in plasma levels of TM and TFPI, indicating that their endothelial cells are still able to produce potent coagulation inhibitors. Levels of NO-(2)/NO-(3) were similar in the two groups of subjects examined, further suggesting preserved endothelial function in patients with COPD. In regard to adhesion molecules, patients with COPD showed a reduction in sLS, sPS, and sPECAM-1, and an increase in sICAM-1. This study shows that endothelial cell activity is largely preserved in patients with COPD without severe pulmonary hypertension, suggesting that these patients, despite quite severe airway obstruction, retain reasonably normal endothelial function until they develop severe pulmonary hypertension.

Topics: Cell Adhesion; Endothelial Cells; Female; Humans; Hypertension; Male; Nitrates; Nitrites; Pulmonary Disease, Chronic Obstructive; Signal Transduction; Solubility; Thrombomodulin; Thromboplastin