fibrinopeptide-a and Lung-Neoplasms

Small cell carcinoma of the lung (SCCL) responds commonly to combination chemotherapy but resistance to therapy follows. Prior reports have suggested that a relationship may exist between plasma fibrinogen levels and response to therapy in SCCL. This study was designed to determine the possible predictive value of the fibrinogen level for tumor response (chemoresistance) in SCCL. Pretreatment fibrinogen levels were correlated with outcome and response to therapy in a cohort of 119 previously untreated patients with SCCL who were admitted to VA Cooperative Study 188. Higher pretreatment fibrinogen levels at diagnosis correlated significantly with more advanced stage of disease at entry (P < 0.001) and with reduced overall survival (P = 0.030). In addition, higher pretreatment fibrinogen levels were correlated significantly with a reduced likelihood of achieving subsequent disease regression with combination chemotherapy (P = 0.005). Because several clinical trials have shown that anticoagulant therapy improves tumor response rates and survival of SCCL, we postulate that tumor cell thrombin generation not only promotes SCCL growth but may also be primarily responsible for both increased fibrinogen levels and for resistance to chemotherapy. These findings provide incentive for studies of thrombin effects on the development of multidrug resistance, and for new clinical trials of more potent and specific inhibitors of thrombin that may further improve tumor response and survival in SCCL.

Topics: Carcinoma, Small Cell; Cohort Studies; Drug Resistance; Fibrinogen; Fibrinolysin; Fibrinopeptide A; Fibrinopeptide B; Humans; Lung Neoplasms; Mopidamol; Randomized Controlled Trials as Topic; Regression Analysis; Thrombin

After the administration of cytostatic drugs, an increase in thromboembolic phenomena has been described in cancer patients. The authors studied the changes in plasmatic coagulation and fibrinolysis in 40 patients with nonoperable Stage III and IV lung cancer after cytostatic chemotherapy. The results show significant postchemotherapy increases in fibrinopeptide A levels, as well as a decrease in fibrinolytic activity reflected by a drop in functional tissue activator. Also the authors studied the potential accumulative effect of three chemotherapy cycles. A significant increase in functional plasminogen activator inhibitor has been noted. Chemotherapy is apparently capable of conditioning a decrease in fibrinolytic activity in these cancer patients that could be related to the enhanced tendency to developing thromboembolic phenomena after cytostatic chemotherapy.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Blood Coagulation; Female; Fibrinolysis; Fibrinopeptide A; Glycoproteins; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Plasminogen Inactivators; Tissue Plasminogen Activator

Disorders of haemostasis and altered platelet activity have been documented in patients with malignant disease but their relation to response to treatment and prognosis are not known. Thrombin activity (fibrinopeptide A (FpA), plasmin mediated fibrinolysis (B beta 15-42) antigen), and platelet alpha granule release (beta thromboglobulin) were studied in 37 patients with small cell lung cancer to find out whether these indices show a relationship to chemoresponse. There was evidence of considerably increased thrombin activity, with a median fibrinopeptide A concentration of 13.2 (normal less than 4) pmol/ml, but only modestly increased fibrinolysis, with a median B beta 14-42 antigen concentration of 5.6 (normal less than 3) pmol/ml. Thus the ratio of fibrinopeptide A to B beta 15-42 concentration (FpA:B beta) was raised, with a median value of 2.2 (normal less than 1.33). In addition, 57% of patients had increased platelet alpha granule release, the median beta thromboglobulin concentration being 50 (normal less than 50) ng/ml. There was a significant association between increased thrombin generation and lack of response to chemotherapy. Furthermore, non-responders had higher FpA:B beta ratios. The same haemostatic markers were studied in nine patients who have been in complete remission for at least two years after chemotherapy for small cell lung cancer. There was a significant difference in thrombin activity and also in the ratio of thrombin activity to lysis between the pretreatment group and the group of two year survivors. Lack of response to chemotherapy appears to be related to increased thrombin activity. Such an association has not previously been reported in patients with malignant disease.

Topics: Antineoplastic Combined Chemotherapy Protocols; beta-Thromboglobulin; Blood Platelets; Carcinoma, Small Cell; Fibrinolysis; Fibrinopeptide A; Hemostasis; Humans; Lung Neoplasms; P-Selectin; Platelet Membrane Glycoproteins

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Blood Proteins; Breast Neoplasms; Digestive System Neoplasms; Fibrinopeptide A; Humans; Immunoenzyme Techniques; Lung Neoplasms; Middle Aged; Partial Thromboplastin Time; Protein C; Protein C Deficiency; Protein C Inhibitor

Hemostatic analyses were carried out on 43 patients with small and non-small cell lung cancer, malignant lymphomas and plasmacytomas prior to, 4 h and 24 h after application of chemotherapy. The fibrinopeptide A (FPA) level and the FPA in vitro generation rate (delta FPA) increased significantly only in the small cell lung cancer and malignant lymphomas after 4 h. This supports the thesis of the clotting activation after cytostatic-induced exposition of the tumour cell thromboplastins. An increase in the FPA was observed in those tumor patients, where a high therapy-induced cell destruction was expected. An increase in the activity of factor VIII, as was seen in acute phase reactions, also led to hypercoagulability. Fibrinogen and plasminogen decreased significantly after chemotherapy. Evidence of relevant contact activation was not found in the missing deviation of the C1 inhibitor. The increase in protein C may possibly be attributed to the high-dose corticoid therapy.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Blood Coagulation; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Female; Fibrinogen; Fibrinopeptide A; Hodgkin Disease; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasms; Plasmacytoma

Fibrinopeptide A (FPA) levels have been followed sequentially in a three-year study of 50 patients with advanced carcinoma. Evidence for activation of blood coagulation was found in 26 of 43 subjects (60%) at the time of entry into the study. Serial FPA determinations revealed an upward trend which paralleled the progression of clinical disease. Persistent elevation of the FPA level suggested treatment failure and a poor prognosis. Anticoagulation with sodium warfarin significantly reduced the FPA level in subjects with cancer. Short-term anticoagulation with heparin decreased FPA levels in two patients with thromboembolic disease but failed to reduce FPA to the normal range in any of the three patients with cancer so tested. These data suggest that most patients with advanced cancer have evidence for activation of blood coagulation and suggest that serial FPA determinations may be useful in following tumor progression or response to therapy in patients with cancer.

Topics: Aged; Blood Coagulation; Fibrinogen; Fibrinopeptide A; Heparin; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasms; Prognosis; Prothrombin Time; Warfarin

This study was made to know the significance of fibrinopeptide A(FPA) as an indicator for coagulative analysis in thrombotic diseases. In normal control subjects (n=21), values of FPA by the radioimmunoassay were 0.5 +/- 1.4 ng/ml (mean +/- SD). In animal models, using Lyoplastin (tissue thromboplastin, n=5) or Ancrod (n=5) to piglets, plasma FPA levels elevated rapidly as a reflection of fibrin formation, and these changes of FPA were found to be most rapid and sensitive among the indicators for coagulation and fibrinolysis. In patients with thrombosis (n=32), elevated FPA levels (14.7 +/- 13.8 ng/ml) and beta-thromboglobulin (beta-TG)(86.1 +/- 65.6 ng/ml) were found. FPA levels in these patients positively correlated to beta-TG (r=0.5539, P less than 0.05) and inversely to fibrinogen (fbg) (r= -0.3622, P less than 0.05). In patients with acute myelocytic leukemia (AML, n=112), acute promyelocytic leukemia (APL, n=18) and acute lymphocytic leukemia (ALL, n=15), mean FPA levels in patients with active signs and symptoms were significantly higher (AML: 13.5 ng/ml, APL: 20.8 ng/ml, ALL: 12.4 ng/ml) than those examined during remission states (AML: 7.7 ng/ml, P less than 0.02, APL: 3.9 ng/ml, P less than 0.01, ALL: 2.7 ng/ml, P less than 0.01). FPA levels in patients with APL inversely correlated to fbg (r= -0.6399, P less than 0.01). In patients with lung cancer (n=75), mean FPA level in advanced stage (17.7 ng/ml, n=67) were significantly higher than those examined in early stage 6.5 ng/ml, n=8, P less than 0.001). In patients with acute disseminated intravascular coagulation (n=12), prolonged prothrombin time and activated partial thromboplastin time, severely reduced fbg and platelets, and remarkably elevated fibrin degradation product were found. Elevated FPA and beta-TG levels were also found (FPA: 23.5 +/- 15.0 ng/ml, beta-TG: 100.0 +/- 63.0 ng/ml). In five patients with thrombotic diseases who were treated successfully with 12500 IU of heparin per 12 hours (subcutaneous injection), plasma FPA levels were reduced to near normal levels quicker than changes of other indicators. These clinical and experimental data suggested that FPA was an useful indicator for active coagulation process.

Topics: Adult; Animals; Blood Coagulation; Disseminated Intravascular Coagulation; Female; Fibrin; Fibrinogen; Fibrinopeptide A; Heparin; Humans; Leukemia, Lymphoid; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Lung Neoplasms; Male; Radioimmunoassay; Swine; Thrombosis

Activation of blood coagulation, as characterized by the occurrence of disseminated intravascular coagulation, increased levels of plasma FPA, and the local deposition of fibrin, is common in both experimental animals and patients with malignant tumors. Many mechanisms have been proposed for the mediation of this response to tumors, including tumor-associated proteases, platelet adherence to tumors, surface activation of blood coagulation by tumor cells, and activation of coagulation by tissue factor derived from either tumor tissue or reactive leukocytes. We have investigated the hypothesis that MTF generation may contribute to increased fibrin generation in cancer patients. Plasma FPA levels and in vitro unstimulated MTF generation were measured simultaneously in samples obtained from 35 patients with lung cancer. FPA levels were significantly elevated in these patients as compared to a group of 20 normal volunteers (p = 0.03). Although unstimulated MTF generation showed considerable variability in both the patients and the normal volunteers, a high degree of correlation was observed between simultaneous levels of FPA and MTF regardless of whether MTF was expressed per cell (r = 0.83), per monocyte (r = 0.95), or per volume of peripheral blood (r = 0.96). MTF generation was also significantly decreased in a group of patients receiving sodium warfarin (p less than 0.001). These results suggest a potential role for MTF generation in the activation of blood coagulation in neoplasia and also suggest the possibility that inhibition of MTF generation by warfarin may be partially responsible for the decreased FPA values previously reported in anticoagulated cancer patients.

Topics: Aged; Blood Coagulation Disorders; Cells, Cultured; Fibrinopeptide A; Humans; Lung Neoplasms; Middle Aged; Mitogens; Monocytes; Reference Values; Warfarin