fibrin and Carcinoma--Small-Cell

Venous thromboembolism (VTE) is common in cancer patients, and is the second commonest cause of death associated with the disease. Patients with chronic inflammation, such as cancer, have been shown to have pathological clot structures with modulated mechanical properties. Fractal dimension (df) is a new technique which has been shown to act as a marker of the microstructure and mechanical properties of blood clots, and can be performed more readily than current methods such as scanning electron microscopy (SEM). We measured df in 87 consecutive patients with newly diagnosed lung cancer prior to treatment and 47 matched-controls. Mean group values were compared for all patients with lung cancer vs controls and for limited disease vs extensive disease. Results were compared with conventional markers of coagulation, fibrinolysis and SEM images. Significantly higher values of df were observed in lung cancer patients compared with controls and patients with extensive disease had higher values than those with limited disease (p< 0.05), whilst conventional markers failed to distinguish between these groups. The relationship between df of the incipient clot and mature clot microstructure was confirmed by SEM and computational modelling: higher df was associated with highly dense clots formed of smaller fibrin fibres in lung cancer patients compared to controls. This study demonstrates that df is a sensitive technique which quantifies the structure and mechanical properties of blood clots in patients with lung cancer. Our data suggests that df has the potential to identify patients with an abnormal clot microstructure and greatest VTE risk.

Topics: Aged; Algorithms; Biomarkers; Blood Coagulation; Blood Coagulation Tests; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Case-Control Studies; Female; Fibrin; Fractals; Hemorheology; Humans; Lung Neoplasms; Male; Microscopy, Electron, Scanning; Middle Aged; Neoplasm Staging; Prospective Studies; Risk; Single-Blind Method; Smoking; Thrombophilia; Venous Thromboembolism

Involvements of interleukin-6 (IL-6) and fibrinogen in cancer development have been independently studied. However, the association of these molecules in cancer patients remains uncertain. This study was conducted to clarify the association according to the clinicopathological characteristics of lung cancer patients.. Serum IL-6 levels assayed in 339 patients without pleural effusion were assessed according to clinical stage, histological type of the cancer and levels of fibrin (ogen) degradation products (FDP), and C-reactive protein (CRP).. Elevations of serum IL-6 levels more than 4 pg/ml were found in 37.8% of all patients. According to the clinical stage and histological type, the elevations were significantly more frequent in the advanced stage (44.7%), in squamous cell (49.1%) and large cell carcinomas (63.6%). Similarly, the frequency of the elevated cases (> 400 mg/dl) and the mean value of the fibrinogen level were also higher in the advanced stage (54.2%, 455.0 mg/dl) and large cell carcinoma (54.6%, 459.3 mg/dl), respectively. The elevations of fibrinogen, FDP and CRP levels were found to be related to those of the IL-6 level.. In lung cancer, serum IL-6 elevations are particularly frequent in the advanced stages of patients with squamous cell and large cell carcinoma, which are associated with the elevated levels of fibrinogen, suggesting a possibility that IL-6 was involved not only directly, but also indirectly, through regulating plasma fibrinogen with promotion of cancer development in vivo.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; C-Reactive Protein; Carcinoma, Large Cell; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinogen; Humans; Interleukin-6; Lung Neoplasms; Male; Middle Aged

Components of coagulation and fibrinolysis reactions were identified in situ by immunohistochemical staining in fresh frozen sections of small cell carcinoma of the lung tissue. Tumor cells stained positively for tissue factor, a protein that is capable of activating the extrinsic pathway of coagulation (the components of which have been seen within small cell carcinoma of the lung [SCCL] tissue), and for proteins C and S antigens. Fibrin was seen in a focal distribution at the host-tumor interface, indicating that thrombin had acted upon the fibrinogen found throughout the tumor stroma. Staining with a neoepitope-specific antibody, which does not discriminate between fibrinogen fragment D and fibrin fragment D-dimer, was similar to that of the fibrin antibody. High molecular weight urokinase-type and tissue-type plasminogen activators were seen in vascular endothelium, but neither existed within the tumor. Low molecular weight urokinase was found in rare isolated foci of tumor cells primarily adjacent to areas of necrosis. Plasminogen activator inhibitor-3 occurred in tumor cell cytoplasmic blebs and in necrotic tumor cells, but plasminogen activator inhibitors 1 and 2 were not seen. Our data suggest a mechanism for thrombin generation and fibrin formation within SCCL tissues that could support cell proliferation, stroma formation, and preservation. These features could be conductive to perpetuation of this tumor and conceivably could form the basis of the beneficial effects of antithrombotic therapy seen in SCCL.

Topics: Blood Coagulation; Carcinoma, Small Cell; Factor V; Fibrin; Fibrinogen; Fibrinolysis; Glycoproteins; Humans; Immunohistochemistry; Lung Neoplasms; Plasminogen Activators; Plasminogen Inactivators; Protein C; Protein S

Erythrocyte CR1, a C3b/C4b-binding complement-regulatory protein, is sensitive to proteolysis in vitro. To test the hypothesis that in vivo erythrocyte CR1 reduction results from intravascular proteinase activities, we used enzyme-linked immunosorbent assays to measure gamma-crosslinked fibrin degradation products (D-dimers) as indicators of coagulation/fibrinolytic activity, and complexes of neutrophil elastase with alpha 1 proteinase inhibitor (E/A) as indicators of neutrophil enzyme release in malignant and inflammatory disorders. Erythrocyte CR1, measured by monoclonal anti-CR1 antibody binding, was inversely related to disease activity and blood proteinase markers. Levels of erythrocyte CR1 were significantly lower for patients with active versus remittent squamous and small cell lung cancers, Hodgkin's and diffuse large cell lymphomas, and acute myelogenous leukemias. In patients with active thoracic cancers, elevated D-dimer levels correlated with reduction of CR1. In patients with rheumatoid arthritis, CR1 reduction was correlated with elevated levels of elastase complexes. Our findings substantiate the relationship of acquired CR1 reduction to the activity of certain diseases and provide circumstantial support for the hypothesis that erythrocyte CR1 is lost to proteolysis in vivo. Although heritable differences in CR1 expression reduce the interpretability of single measurements of erythrocyte CR1 levels, disease-associated CR1 reduction may be a useful indicator of disorders with chronically increased blood proteinase activity.

Topics: Adult; Aged; Arthritis, Rheumatoid; Biomarkers; Carcinoma, Small Cell; Erythrocyte Membrane; Fibrin; Humans; Lung Neoplasms; Middle Aged; Peptide Hydrolases; Receptors, Complement

Thrombin-generated cleavage sites of human fibrinogen have been identified adjacent to viable tumor cells in fresh frozen sections of small cell carcinoma of the lung (SCCL) by means of immunohistochemical techniques using mouse monoclonal antibodies to the N-terminal peptides of the fibrinogen alpha and beta chains. These results indicate that thrombin is generated in situ in this tumor type. Based on previous evidence for the existence of an initiator of coagulation together with coagulation factor intermediates associated with viable SCCL tumor cells in situ, and also for the favorable effects of anticoagulant therapy with warfarin in SCCL, we postulate that local tumor cell-induced thrombin formation may contribute to self-regulated progression of SCCL through deposition of fibrin and stimulation of cell proliferation. These results suggest novel treatment strategies for this particular tumor type and justify efforts to identify other tumor types in which similar mechanisms exist.

Topics: Antibodies, Monoclonal; Carcinoma, Small Cell; Fibrin; Fibrinogen; Humans; Immunoenzyme Techniques; Lung Neoplasms

Fibrin was detected by specific immunofluorescence in tissue obtained from five of six cases of small cell carcinoma of the lung. Dense specific fluorescence was observed in the connective tissue stroma surrounding metastatic tumor nodules and frequently in the scant extracellular stroma surrounding individual viable tumor cells and small tumor cell clusters. When observed by electron microscopy, the fibrin hugged tumor cell plasma membranes and, in some areas, seemed to envelop the cells. Fluorescent staining of tumor cells, but not the stroma, was observed with an antibody to tissue factor. These findings suggest that local activation of coagulation occurs in small cell carcinoma of the lung. Deposited fibrin may contribute to the growth and spread of this particular type of cancer.

Topics: Antigens; Carcinoma, Small Cell; Fibrin; Fluorescent Antibody Technique; Humans; Lung Neoplasms; Microscopy, Electron; Thromboplastin

Topics: Adenocarcinoma; Adult; Aged; Alpha-Globulins; Blood Coagulation Disorders; Blood Protein Electrophoresis; Bronchial Neoplasms; Carcinoma; Carcinoma, Bronchogenic; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Female; Fibrin; Fibrinogen; Fibrinolysin; Fibrinolysis; Heparin; Humans; Infusions, Parenteral; Lung Neoplasms; Macroglobulins; Male; Middle Aged; Time Factors