fibrin and Pleural-Effusion--Malignant

We have shown that the thrombin G-protein coupled receptors (GPCR) designated as protease-activated receptors (PAR-1) are expressed in primary cancer cells isolated from peritoneal and pleural malignant effusions. Here, our main goal was to evaluate several coagulation and thrombin activation effectors and markers in a series of 136 malignant effusions from cancer patients with gastrointestinal, lung and mammary carcinomas. All these patients present a highly activated coagulation system in blood and their malignant effusions, as indicated by high levels of prothrombin F1.2 fragments and D-dimers. Notably, we detected in the effusions all the coagulation factors of the tissue factor pathway inducing thrombin activation, namely factors VII, V, X and II, as well as high VEGF levels and IGF-II in mature and precursor forms. Fibrin clot formation also correlated with higher levels of free ionized calcium (iCa), suggesting that iCa and its binding protein albumin are regulatory factors for fibrinogenesis in effusions. Consequently, thrombin, VEGF and IGFII appear to converge in the promotion of survival and invasivity of the metastatic cancer cells from blood to the malignant effusions. Thus, we add new insights on the interconnections between blood coagulation disorders in cancer patients and thrombin activation in malignant effusions, including their functional interaction with PAR in metastatic cancer cells. Based on these data we propose to counteract the metastatic cascades by targeted invalidation of key effectors of the coagulation system. Therefore, potential therapeutic approaches include the application of thrombin protease inhibitors, VEGF-blocking antibodies, and drugs targeting the VEGF and thrombin signaling pathways, such as tyrosine kinase or GPCR inhibitors.

Topics: Aged; Antineoplastic Agents; Antithrombins; Ascitic Fluid; Blood Coagulation; Blood Coagulation Factors; Breast Neoplasms; Calcium; Case-Control Studies; Factor V; Factor VII; Factor X; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Gastrointestinal Neoplasms; Humans; Insulin-Like Growth Factor II; Lung Neoplasms; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms; Peptide Fragments; Pericardial Effusion; Pleural Effusion, Malignant; Proteins; Prothrombin; Serum Albumin; Thrombin; Thromboplastin; Vascular Endothelial Growth Factor A

To evaluate the effect of repeated thoracenteses on the fluid characteristics and the levels of various cytokines, including tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-5, IL-6, and IL-8, and of plasminogen activator inhibitor type 1 (PAI-1) and tissue type plasminogen activator in malignant pleural effusion and its clinical significance.. A prospective study.. Twenty-six patients with symptomatic and a large amount of free-flow malignant pleural effusions were studied. Thoracentesis with drainage of 500 mL of pleural fluid per day was performed for 3 continuous days (days 1 to 3). The effusion samples were collected to evaluate the changes of fluid characteristics, cytokine levels, and fibrinolytic activity. Chest ultrasonography was done on day 6 to observe the presence of fibrin strands. The result of pleurodesis was evaluated in the patients classified into groups based on chest ultrasonographic findings.. The values of TNF-alpha, PAI-1, IL-8, and neutrophil count in pleural fluid increased significantly during repeated thoracenteses in 26 patients studied. A positive correlation was found between the concentrations of TNF-alpha and PAI-1 and between the values of IL-8 and neutrophils. On day 6, fibrin strands were observed in the pleural effusion on chest ultrasonography in 11 patients (42%, fibrinous group) but were absent in the remaining 15 patients (nonfibrinous group). During repeated thoracenteses, a significant increase of effusion PAI-1 and TNF-alpha was observed in the fibrinous group but not in the nonfibrinous group. In addition, the levels of effusion PAI-1 and TNF-alpha obtained from day 2 and day 3 were significantly higher in the fibrinous group than in the nonfibrinous group. The success rate of pleurodesis was significantly higher in the fibrinous group (11 of 11 patients, 100%) than in the nonfibrinous group (8 of 12 patients, 67%).. Repeated thoracenteses may cause pleural inflammation and induce local release of proinflammatory cytokine as TNF-alpha, which may subsequently enhance the release of PAI-1 and lead to fibrin formation in malignant effusion. The presence of fibrin strands after repeated thoracenteses may be of considerable value in predicting the success of subsequent pleurodesis in patients with malignant pleural effusions.

Topics: Adult; Aged; Aged, 80 and over; Cytokines; Female; Fibrin; Humans; Inflammation; Interleukins; Male; Middle Aged; Neutrophils; Paracentesis; Plasminogen Activator Inhibitor 1; Pleural Effusion, Malignant; Prospective Studies; Retreatment; Tumor Necrosis Factor-alpha

Cancer-related fibrin deposition and fibrinolysis were investigated by two-dimensional gel electrophoresis of human solid tumor and effusion specimen in addition to plasma samples. Fibrinogen gamma-chain dimer indicating fibrin deposition and plasmin-generated fibrinogen beta-chain fragments were identified in various solid tumor types by amino acid sequencing, mass spectrometry analysis and Western blotting. In tumor-associated effusions, these techniques allowed to observe plasmin-generated fragments of fibrinogen alpha, beta and gamma-chains in addition to elevated levels of acute-phase proteins. Similar observations were made in case of inflammation-associated effusions. No fibrin degradation product was observed in plasma samples, however, high amounts of fibrinogen gamma-chain dimer crosslinked by transglutaminase were detected in plasma from tumor patients, but not in plasma from controls and patients suffering acute infections and/or inflammations. This finding demonstrated that high transglutaminase activity may be associated with cancer. The presented data indicate that the amount of crosslinked fibrinogen gamma-chain dimer in plasma may correlate with tumor-associated fibrin deposition. The tumor-biological relevance of this potential marker protein is discussed.

Topics: Biomarkers, Tumor; Case-Control Studies; Cross-Linking Reagents; Dimerization; Electrophoresis, Gel, Two-Dimensional; Fibrin; Fibrinogen; Fibrinolysis; Hemostasis; Humans; Neoplasm Proteins; Neoplasms; Pleural Effusion, Malignant; Proteome; Tissue Distribution

The potential importance of pleural fibrin deposition in the pathogenesis of pleural injury is supported by both clinical and experimental observations. We hypothesized that the local equilibrium between procoagulant and fibrinolytic activities is disrupted to favor fibrin deposition in exudative pleuritis. To test this hypothesis, we characterized procoagulant and fibrinolytic activities in pleural exudates from patients with pneumonia, lung cancer, or empyema and transudates from patients with congestive heart failure. Procoagulant activity was generally increased in exudative processes and was due mainly to tissue factor. All effusions contained antithrombin III and inhibited factor Xa and thrombin, but endogenous prothrombinase or thrombin activities were variably detected. Pleural fluid fibrinolytic activity was increased in congestive heart failure and was due to both tissue plasminogen activator and urokinase. Depressed fibrinolytic activity was found in pleural exudates despite increased concentrations of plasminogen, mainly glu-1-plasminogen, and was due to inhibition of plasminogen activation by plasminogen activator inhibitors 1 and 2 and of plasmin, in part by alpha 2-antiplasmin. Concentrations of PAI-1 in exudative pleural fluids were increased up to 913-fold, compared with normal pooled plasma. Exudative pleural effusions are characterized by increased procoagulant and depressed fibrinolytic activity, favoring fibrin deposition in the pleural space. The balance of these activities is reversed and favors fibrin clearance in congestive heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Blood Coagulation; Blood Coagulation Factors; Empyema; Fibrin; Fibrinolysis; Heart Failure; Humans; Pleura; Pleural Effusion; Pleural Effusion, Malignant; Pneumonia