fibrinopeptide-a and Neoplasms

Endothelial cells (EC) interact with fibrin at sites of vascular injury, thrombosis, inflammation and tumor growth, whereas they are quiescent when exposed to circulating fibrinogen. To determine the structural basis for specific interaction with fibrin we have characterized the response of EC to fibrin of varying structure. Fibrin was prepared with thrombin, which cleaves both fibrinopeptide A (FPA) and fibrinopeptide B (FPB), with Reptilase, which cleaves only FPA, and with contortrix procoagulant to cleave only FPB. Fibrin with FPB cleavage stimulated release of von Willebrand factor from EC Weibel-Palade bodies and also supported cell spreading. Involvement of the amino terminus of the fibrin beta chain in the response was shown by stimulation of von Willebrand factor release by the peptide beta 15-42. Also, fibrin prepared from a fibrinogen derivative lacking residues 15-42 of the beta chain failed to support EC spreading. EC adhesion was unaffected by the pattern of fibrinopeptide cleavage or by the removal of peptide beta 15-42 from fibrin. The results indicate that separate sites on the fibrin molecule mediate adhesion and spreading, and that the latter requires cleavage of FPB and the new amino terminus of the beta chain. They further suggest that cellular responses to fibrin are regulated by the proteolytic cleavages and conformational changes that convert fibrinogen to fibrin and may also be modulated by plasmic or elastase degradation.

Topics: Amino Acid Sequence; Animals; Cell Adhesion; Endothelium, Vascular; Fibrin; Fibrinogen; Fibrinopeptide A; Fibrinopeptide B; Humans; Inflammation; Macromolecular Substances; Molecular Sequence Data; Neoplasms; Platelet Adhesiveness; Thrombosis; von Willebrand Factor

Topics: Animals; Antibodies, Monoclonal; Antibody Specificity; Arteriosclerosis; Dogs; Enzyme-Linked Immunosorbent Assay; Epitopes; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinogen; Fibrinolysis; Fibrinopeptide A; Humans; Kidney Diseases; Neoplasms; Pregnancy; Pregnancy Complications; Radioimmunodetection; Thrombosis

The mutual relationships between malignant tumours and mechanisms of blood coagulation are presented in a brief survey. In this connection, the mechanisms of a tumour cell entering the circulation through the vessel well and its leaving into the tissues are discussed, the theory of microtrauma being used for explaining these processes. Subsequently, the alterations to be found in the count and function of thrombocytes after contact with a malignant cell and the impact on this cell by blood platelets are represented. As a third factor the activation of blood coagulation which is exercised by substances with a procoagulatory effect produced by the malignant tissue and the frequently observed thrombosis in the course of neoplastic diseases are dealt with in connection with blood level changes of some coagulation factors. In a fourth section the significance of fibrinolysis, its activation and inhibition as well as the production of fibrinolytic activators by neoplasms are discussed.

Topics: Animals; Blood Coagulation Factors; Blood Platelets; Disseminated Intravascular Coagulation; Fibrin Fibrinogen Degradation Products; Fibrinogen; Fibrinolysis; Fibrinopeptide A; Fibrinopeptide B; Humans; Neoplasms; Neoplastic Cells, Circulating; Plasminogen Activators; Platelet Aggregation; Thromboembolism

Patients receiving chemotherapy for cancer are at increased risk for venous thromboembolism. Limited data support the clinical benefit of antithrombotic prophylaxis.. In this double-blind, multicenter trial, we evaluated the efficacy and safety of the ultra-low-molecular-weight heparin semuloparin for prevention of venous thromboembolism in patients receiving chemotherapy for cancer. Patients with metastatic or locally advanced solid tumors who were beginning to receive a course of chemotherapy were randomly assigned to receive subcutaneous semuloparin, 20 mg once daily, or placebo until there was a change of chemotherapy regimen. The primary efficacy outcome was the composite of any symptomatic deep-vein thrombosis, any nonfatal pulmonary embolism, and death related to venous thromboembolism. Clinically relevant bleeding (major and nonmajor) was the main safety outcome.. The median treatment duration was 3.5 months. Venous thromboembolism occurred in 20 of 1608 patients (1.2%) receiving semuloparin, as compared with 55 of 1604 (3.4%) receiving placebo (hazard ratio, 0.36; 95% confidence interval [CI], 0.21 to 0.60; P<0.001), with consistent efficacy among subgroups defined according to the origin and stage of cancer and the baseline risk of venous thromboembolism. The incidence of clinically relevant bleeding was 2.8% and 2.0% in the semuloparin and placebo groups, respectively (hazard ratio, 1.40; 95% CI, 0.89 to 2.21). Major bleeding occurred in 19 of 1589 patients (1.2%) receiving semuloparin and 18 of 1583 (1.1%) receiving placebo (hazard ratio, 1.05; 95% CI, 0.55 to 1.99). Incidences of all other adverse events were similar in the two study groups.. Semuloparin reduces the incidence of thromboembolic events in patients receiving chemotherapy for cancer, with no apparent increase in major bleeding. (Funded by Sanofi; ClinicalTrials.gov number, NCT00694382.).

Topics: Adult; Antineoplastic Agents; Double-Blind Method; Fibrinolytic Agents; Fibrinopeptide A; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Incidence; Kaplan-Meier Estimate; Neoplasms; Risk Factors; Venous Thromboembolism

Topics: Fibrinolytic Agents; Fibrinopeptide A; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Venous Thromboembolism

Topics: Fibrinolytic Agents; Fibrinopeptide A; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Venous Thromboembolism

Although most time-of-flight (TOF) mass spectrometers come equipped with vacuum matrix-assisted laser desorption/ionization (MALDI) sources, the atmospheric pressure MALDI (API-MALDI) source is an attractive option because of its ability to be coupled to a wide range of analyzers. This article describes the use of an API-MALDI source coupled to a TOF mass spectrometer for evaluation of the effects of medium- and long-term storage on peptidomic profiles of cryopreserved serum samples from healthy women. Peptides were purified using superparamagnetic beads either from fresh sera or after serum storage at -80°C for 18 months or at -20°C for 8 years. Data were preprocessed using newly developed bioinformatic tools and then were subjected to statistical analysis and class prediction. The analyses showed a dramatic effect of storage on the abundance of several peptides such as fibrinopeptides A and B, complement fractions, bradykinin, and clusterin, indicated by other authors as disease biomarkers. Most of these results were confirmed by shadow clustering analysis, able to classify each sample in the correct group. In addition to demonstrating the suitability of the API-MALDI technique for peptidome profiling studies, our data are of relevance for retrospective studies that involve frozen sera stored for many years in biobanks.

Topics: Atmospheric Pressure; Bradykinin; Clusterin; Complement System Proteins; Cryopreservation; Female; Fibrinopeptide A; Fibrinopeptide B; Humans; Neoplasms; Peptides; Specimen Handling; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

This investigation was carried out to evaluate fibrin formation and degradation in various types of solid neoplasms by measuring fibrinopeptide A (fpA) in the plasma with a radioimmunoassay and D-dimer (DD) with an enzyme-linked immunosorbent assay in 176 cancer patients; 77 of them showed signs of distant metastasis (M1). FpA and DD were abnormally elevated in 81 and 143 patients respectively. FpA and DD were significantly correlated and unrelated to plasma fibrinogen. Both fpA and DD levels were more elevated in M1 than M0 patients. Coumarin anticoagulants, administered to 32 patients of our series with the aim of preventing cancer growth and dissemination, caused a significant decrease both in fpA and DD levels. Our data provide evidence of increased in vivo fibrin formation and degradation in solid neoplasms: oral anticoagulants can modulate cancer-related hypercoagulation.

Topics: Adult; Aged; Aged, 80 and over; Coumarins; Enzyme-Linked Immunosorbent Assay; Female; Fibrin; Fibrinopeptide A; Humans; Male; Middle Aged; Neoplasm Metastasis; Neoplasms; Radioimmunoassay

The influence of Extrinsic pathway inhibitor (EPI) on global clotting times of plasma was studied using activity-blocking IgG antibodies. Dilute tissue thromboplastin (TP) clotting times in plasma collected after intravenous injection of heparin were dramatically shortened by the addition of anti-EPI IgG. Anti-EPI IgG shortened the TP times to a lesser degree in plasma heparinized in vitro. Compared to plasma heparinized in vitro, the TP clotting times were markedly prolonged in post-heparin plasma of equal heparin concentration. Addition of anti-antithrombin IgG reduced the clotting times somewhat more than did anti-EPI IgG, particularly in normal plasma. In plasma from patients with cancer, about equal effect was obtained by blocking either EPI or antithrombin. These clotting time studies suggested that much of the anticoagulant effect caused by injection of heparin depended on EPI. This was confirmed by recording the release of fibrinopeptide A (FPA), as marker of thrombin generation, following addition of TP and CaCl2 to citrated blood. Thrombin generation was delayed and markedly reduced in post-heparin blood compared to that in normal blood. After incubating post-heparin citrated blood with anti-EPI IgG, the generation of FPA was more rapid; the amounts released 30 seconds after addition of TP were 6 times greater (36 vs 6 ng/ml) than in post-heparin blood without anti-EPI IgG. The subsequent FPA values were midway between pre-injection and post-heparin values. In conclusion, between one third and one half of the inhibition of TP-initiated coagulation in post-heparin plasma depends on EPI. This inhibition is mainly due to inactivation of the factor VIIa-TP complex. A small, but distinct contributing effect observed in the APTT assay (and hence no TP) indicates that even increased inactivation of activated factor X contributes. In cancer patients, these EPI-heparin interactions contribute even more to the anticoagulant effects of heparin.

Topics: Antithrombins; Dose-Response Relationship, Drug; Factor VII; Fibrinopeptide A; Heparin; Humans; Lipoproteins; Neoplasms; Partial Thromboplastin Time; Thromboplastin

The mean levels of fibrinopeptide A (FPA), thrombin-antithrombin complex (TAT), and soluble fibrin (tPA method) in cancer patients (n = 32) were intermediate between those of patients with cerebral infarction and pancreatitis who had the most abnormal results and patients with myocardial infarction and pneumonia who had the least abnormal results. Patients with disseminated malignancies (n = 16) had significantly higher mean levels of FPA (10.6 vs. 5.3 nmol/l) and TAT (11.0 vs. 4.4 pmol/l) than patients with limited malignancies (n = 16). The difference in soluble fibrin (fibrin monomer, FM; 22.1 vs. 18.0 nmol/l) was not significant. The values of FPA, FM, and TAT in the patient population correlated significantly. There was a negative correlation between the level of antithrombin and test results for FPA (-0.69), FM (-0.48), and TAT (-0.38) in the cancer patients. Even cancer patients with locally limited disease may have elevated FPA, FM, and TAT test results, indicating a state of definite hypercoagulation.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Antithrombin III; Blood Coagulation Disorders; Blood Coagulation Tests; Cerebral Infarction; Female; Fibrin; Fibrinopeptide A; Humans; Male; Middle Aged; Myocardial Infarction; Neoplasms; Pancreatitis; Peptide Hydrolases; Pneumonia; Predictive Value of Tests; Reference Values

Blood coagulation abnormalities are common in patients with cancer, particularly after treatment with chemotherapeutic agents. Chemotherapy has been associated with an increased incidence of thromboembolic events, and patients treated with chemotherapy often develop evidence of local phlebitis, which may lead to loss of venous access. We have utilized the radioimmunoassay for plasma fibrinopeptide A (FPA) and in vitro FPA generation to assess the rate of in vivo blood coagulation and the level of plasma thrombin activity in 16 cancer patients treated with chemotherapy. Eight patients were treated twice, once with chemotherapy alone and once with chemotherapy after an intravenous infusion of heparin (5,000 U).. Our results confirm that FPA levels are elevated in most cancer patients. Following chemotherapy, FPA levels were further increased within 45 minutes (mean FPA = 5.2 ng/mL before chemotherapy versus 8.3 ng/mL after chemotherapy, p less than 0.01) and were accompanied by an increase in the FPA generation rate. Infusion of heparin prior to chemotherapy significantly lowered plasma FPA levels and abolished post-chemotherapy FPA generation.. These data suggest that patients receiving chemotherapy express thrombin-like activity in plasma and, therefore, may be at risk for clinically significant intravascular activation of coagulation. Heparin diminished the laboratory evidence of this chemotherapy-related coagulopathy and may have a role in the prevention of thromboembolic disorders in some cancer patients undergoing cytotoxic therapy.

Topics: Antineoplastic Agents; Fibrinogen; Fibrinopeptide A; Heparin; Humans; Neoplasms; Partial Thromboplastin Time

Different coagulation and fibrinolysis parameters were investigated in 149 patients with metastatic and non-metastatic tumours and results were compared with those obtained in a healthy population. Results showed a significant increase of thrombin-antithrombin complexes, fibrinopeptide A (FPA) and fibrin monomers in the group of patients (p less than 0.001). There was also a significant prolongation of euglobulin lysis time (p less than 0.005) and an increase of plasminogen activator inhibitor activity (p less than 0.0001), fibrinogen degradation products (p less than 0.001), and D-dimer (p less than 0.05) in the group of patients as compared to controls; FPA levels were also increased in patients with metastases (p less than 0.005). This study demonstrates clotting activation, at the level of fibrinogen to fibrin conversion, and impairment of fibrinolysis in patients with malignancy.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Blood Coagulation; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinolysis; Fibrinopeptide A; Humans; Male; Middle Aged; Neoplasms; Tissue Plasminogen Activator

Topics: Aged; Blood Coagulation; Cerebral Infarction; Fibrin Fibrinogen Degradation Products; Fibrinogen; Fibrinopeptide A; Fibrinopeptide B; Humans; Middle Aged; Myocardial Infarction; Neoplasms; Peptide Fragments

Several investigators have reported that tumor necrosis factor (TNF) can alter the hemostatic properties of vascular endothelial cells in vitro. We have examined the in vivo effects on the hemostatic mechanism of recombinant human TNF administered as a continuous intravenous infusion to 23 cancer patients with active disease. A battery of sensitive and specific immunochemical techniques were used to monitor changes in blood coagulability. Serial determinations of F1 + 2, the protein C activation peptide (PCP), and fibrinopeptide A (FPA) were obtained prior to the initiation of the TNF infusions and at three and 24 hours after the start of therapy in 12 individuals who received greater than 3 x 10(5) U/m2/24h. The mean levels of F1 + 2, PCP, and FPA were significantly elevated at both time points as compared to the baseline values. The metabolic behavior of 125I-F1 + 2 in an animal model was not affected by infusions of the cytokine. We therefore conclude that the observed elevations in the concentration of this marker in humans receiving TNF result from hemostatic system hyperactivity. In 11 subjects infused with 1 x 10(5) to 2.4 x 10(5) U/m2/24 h of the cytokine, the mean levels of F1 + 2, PCP, and FPA were not significantly greater at 24 hours as compared with the baseline values, indicating that there is a threshold dose at which the cytokine can exert a biochemical effect on the coagulation system. Our studies demonstrate that TNF is able to provide a substantial net procoagulant stimulus to the hemostatic mechanism, and suggest that this cytokine may be a mediator of certain hypercoagulable states in humans.

Topics: Blood Coagulation Tests; Drug Evaluation; Fibrinogen; Fibrinopeptide A; Hemostasis; Humans; Neoplasms; Protein C; Recombinant Proteins; Tumor Necrosis Factor-alpha

Increased fibrinopeptide A (FPA) levels have been reported in various non-thrombotic disorders, including cancer, acute myocardial infarction, liver cirrhosis and collagen vascular diseases. To investigate the significance of these findings, the present study combined the radioimmunoassay of FPA with that of fibrinogen/fibrin degradation fragment E (FgE) in the aforementioned disorders and compared the results with those observed in healthy subjects as well as in patients with thromboembolism and overt disseminated intravascular coagulation (DIC). Mean FPA and FgE in malignancy were 6.3 and 305 ng/ml, in myocardial infarction 5.6 and 98 ng/ml, in liver cirrhosis 2.7 and 132 ng/ml and in collagen vascular diseases 5.6 and 142 ng/ml. All these values were significantly higher than in healthy controls (mean FPA 1.6 ng/ml, mean FgE 49 ng/ml) but significantly lower than in thromboembolism (mean FPA 10.7 ng/ml, mean FgE 639 ng/ml). and DIC (mean FPA 22.0 ng/ml, mean FgE 1041 ng/ml). The overall correlation between FPA and FgE was highly significant. However, different disorders showed peculiar patterns in FPA, FgE and fibrinogen levels. In malignancy, a definite increase of FPA, FgE and plasma fibrinogen levels was observed. This finding probably indicates a compensated state of (intra- or extravascular) fibrin formation and lysis. Acute myocardial infarction was characterized by a high FPA to FgE ratio, which is interpreted to reflect acute thrombin generation and fibrin formation. FPA in cirrhosis was only marginally elevated with most single values within the normal range, indicating that intravascular coagulation was infrequent and unimportant in quantitative terms.

Topics: Collagen Diseases; Disseminated Intravascular Coagulation; Fibrin Fibrinogen Degradation Products; Fibrinogen; Fibrinopeptide A; Humans; Liver Cirrhosis; Myocardial Infarction; Neoplasms; Thromboembolism

Routine blood coagulation tests were performed on 431 consecutive patients enrolled in a study of the role of anticoagulation in cancer treatment (VA Cooperative Study #75). Two hundred sixteen control patients were treated with standard therapy, and 215 patients were treated with standard therapy plus sodium warfarin. At the time of entry into the study, the most common abnormalities were elevated fibrinogen levels, platelet counts, and fibrinopeptide A levels. Serial studies demonstrated a steady increase in platelet count and fibrinogen levels before death. Anticoagulation lowered FPA levels but had no significant effect on fibrinogen levels, platelet counts, or euglobulin clot lysis times. An unexpected finding was a dramatic increase in fibrin split product levels after institution of anticoagulation (means +/- SEM = 42.6 +/- 116.4 vs. 2.9 +/- 7.0 mg/L in control subjects; P less than 0.02). This study supports the presence of subclinical activation of blood coagulation in most patients with cancer. Moreover, the preferential activation of fibrinolysis in anticoagulated patients suggests a role for a vitamin K-dependent factor(s) in the regulation of fibrinolysis in patients with cancer.

Topics: Blood Coagulation Tests; Cardiovascular Diseases; Fibrinogen; Fibrinopeptide A; Humans; Neoplasms; Platelet Count; Thrombin; Warfarin

Over a 2-month period, 40 patients with untreated malignancy were studied for protein-C (PRC), antithrombin-III (AT-III), fibrinopeptide A (FPA), routine hemostatic screens, and presence of liver metastases to determine pretreatment changes of hemostasis and relate them to subsequent development of thrombotic or hemorrhagic complications. These patients were observed for a mean period of 18 months. There were 23 males and 17 females with a median age of 64 years. Nine patients had lung carcinoma, 8 colon carcinoma, 7 lymphoma, 5 breast carcinoma, 5 head and neck carcinoma, 2 acute leukemia, 2 prostate carcinoma, 1 adenocarcinoma of unknown primary, and 1 sarcoma. Eight patients had liver metastases. PRC was measured by ELISA, AT-III by radial immunodiffusion, and FPA by RIA. Four patients had decreased AT-III, 28 had decreased levels of PRC, and 39 had elevated levels of FPA. All patients with liver metastases had low PRC. Albumin levels were lower in patients with low PRC (mean 3.3 g/dL v 4.0 g/dL for others). Eight patients, five with liver metastases, developed thrombotic (4), hemorrhagic (3), or both (1) complications. Statistically significant associations were found between (1) presence of liver metastases and development of thrombotic and hemorrhagic complications (P less than .001), (2) presence of liver metastases and decreased PRC (P = .001), and (3) lower albumin levels and decreased PRC (P = .0001). Our study documents early changes of hemostasis in untreated malignancy. We extend previous observations that decreased PRC levels in malignancy may be due to poor synthetic functions of liver. Presence of liver metastases was the only factor associated with subsequent development of thrombotic and hemorrhagic complications. Biochemical markers of hemostatic abnormalities, even though encountered frequently at the time of presentation, are of little predictive value for development of thrombotic and hemorrhagic complications.

Topics: Adult; Aged; Aged, 80 and over; Antithrombin III; Female; Fibrinopeptide A; Hemorrhage; Hemostasis; Humans; Liver Neoplasms; Male; Middle Aged; Neoplasms; Protein C; Prothrombin Time; Thrombosis

Topics: Blood Coagulation Disorders; Fibrinopeptide A; Heparin; Humans; Neoplasms; Thrombophlebitis

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

In tumor cell thrombosis thrombin does not only act as clotting enzyme but also as tissue hormone stimulating the proliferation of malignant cells indicated by an increase of cell count and thymidine uptake in cell cultures. Spontaneous and by cytostatic treatment induced decay of tumor cells induces the release of tumor cell thromboplastins which activate locally the clotting system and liberate thrombin. This local liberation of thrombin in tumor cell thrombosis stimulates again tumor cell proliferation and represents a biochemical substrate of tumor spread and growth in tumor cell thrombosis.

Topics: Cell Division; DNA Replication; Fibrinopeptide A; Growth Substances; Humans; Neoplasms; Thrombin; Thromboplastin; Thrombosis; Thymidine; Tritium

Coagulation parameters were initially monitored in 8 patients receiving whole body hyperthermia (WBH). Patients were heated by the warm water blanket technique to 41.8 degrees C (Tmax), maintained at this temperature for 2 hours, then allowed to cool. A fall in platelets was apparent by the time Tmax was achieved and continued during the 18 hours after WBH. Levels of beta-thromboglobulin (BTG) and platelet factor 4 rose by 56% and 191% by the end of treatment but returned to baseline 18 hours later. Fibrinogen, plasminogen and alpha 2-antiplasmin levels declined and FDP and fibrinopeptide A (FPA) levels increased during WBH. Factor XII and Factor VIII:C fell moderately during WBH while Factors VIII R:Ag, VIII:RC and V did not change or showed a late rise. Factor VII levels fell in 7 of 8 patients, reaching levels of 30% of normal in four. To better define the sequence of these coagulations perturbations, earlier and more frequent timepoints were studied in an additional 3 patients. This revealed that decreases in fibrinogen and plasminogen and increases in FPA and BTG occur very early (by the time the patient reaches 39 degrees C). On the other hand, a decrease in Factor VII activity was not apparent until patients had reached Tmax. WBH is therefore associated with a consumption coagulopathy. Possible mechanisms are discussed and extrapolations to the situation seen in heat stroke are suggested.

Topics: Adult; Aged; Blood Coagulation; Blood Coagulation Factors; Disseminated Intravascular Coagulation; Female; Fibrin Fibrinogen Degradation Products; Fibrinolysis; Fibrinopeptide A; Humans; Hyperthermia, Induced; Male; Middle Aged; Neoplasms; Platelet Count

Topics: Adult; Anticoagulants; Antineoplastic Combined Chemotherapy Protocols; Blood Coagulation Disorders; Female; Fibrinogen; Fibrinopeptide A; Humans; Male; Middle Aged; Neoplasms

A simple nonisotopic method for the quantitation of FPA in biologic samples has been developed utilizing a competitive enzyme immunoassay technique. The performance characteristics of these assays have been investigated in both the experimental and clinical settings and were found to be satisfactory for the routine clinical application. This method is comparable to a commercially available RIA kit (Mallinckrodt, St. Louis, MO) in both the clinical and normal samples. This assay can be used in the diagnosis of hypercoagulable states associated with various diseases. Subclinical activation of coagulation can be readily assessed when the global tests, such as the prothrombin time, partial thromboplastin time, and thrombin time, have no value. This test is of value in the monitoring of the newer antithrombotic agents, such as the low molecular weight heparin fractions that do not effect the global assays, such as the partial thromboplastin time. Similarly, the risk of thrombosis associated with the use of procoagulant therapy, such as the activated prothrombin complex concentrates, can be readily assessed using this assay. It is proposed that the FPA measurement may also provide useful information on the quality control of various plasma-based therapeutic products, such as plasma concentrates or activated prothrombin complex concentrates. FPA generation tests are currently proposed for the screening of antithrombotic and prohemostatic agents.

Topics: Blood Coagulation Tests; Cardiovascular Diseases; Evaluation Studies as Topic; Fibrinogen; Fibrinopeptide A; Humans; Immunoenzyme Techniques; Neoplasms; Radioimmunoassay; Reference Values; Thrombosis

Topics: Antineoplastic Agents; Fibrinogen; Fibrinopeptide A; Humans; Neoplasms; Thrombin

Topics: Antibodies; Aspirin; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Platelets; Cell Adhesion; Cell Communication; Cyclooxygenase Inhibitors; Disseminated Intravascular Coagulation; Epoprostenol; Fibrin Fibrinogen Degradation Products; Fibrinogen; Fibrinopeptide A; Humans; Indomethacin; Monocytes; Neoplasm Transplantation; Neoplasms; Syndrome; Thrombocytopenia; Thrombocytosis; Thromboembolism; Thromboplastin

The relationship between FPA level and fibrinogen turnover rate as well as fibrinolytic activity was studied in 18 patients with malignant diseases. It was found that the FPA levels were significantly elevated and were correlated with fibrinogen turnover rate (r = 0.74, p less than 0.001) and FDP (r = 0.58, p less than 0.02). The estimated FPA turnover rate was also correlated with fibrinogen turnover rate (r = 0.70, p less than 0.001). These results suggest that fibrinogen catabolism in patients with malignant disease is related to thrombin proteolysis. However, ratios of 1/2 FPA turnover rate to fibrinogen turnover rate suggest that intravascular thrombin proteolysis is not the major determinant of fibrinogen catabolism. It is suspected that extravascular thrombin proteolysis is responsible for the elevation of plasma FPA level which is correlated with acceleration of fibrinogen catabolism.

Topics: Adult; Aged; Disseminated Intravascular Coagulation; Female; Fibrinogen; Fibrinolysis; Fibrinopeptide A; Humans; Male; Middle Aged; Neoplasms; Thrombin

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

To provide more information on the pathways of fibrinogen catabolism in generalized cancer, the effect of heparin on fibrinopeptide A (fpA) and on 125I-fibrinogen kinetics was studied in 15 patients with disseminated neoplasia. Three patients had evidence of venous thrombosis and in 2 additional patients a low fibrinogen level together with increased amounts of FDP/fdp and a positive ethanol test indicated disseminated intravascular coagulation (DIC). The plasma levels of fpA were grossly elevated (4.6--20, mean 11.4 ng/ml, normal values 1.01 +/- 0.45 ng/ml) in patients with thrombosis or DIC, and normal to grossly elevated (0.4--10.4, mean 6.1 ng/ml) in the other patients. Intravenous heparin bolus lowered the fpA level in 11/11 patients, and continuous heparin treatment led to an impressive suppression or complete normalization of the plasma fpA in 5/6 patients. This finding is thought to reflect heparin suppression of thrombin activity on fibrinogen. In some cases, the fpA fall after heparin bolus was slow and/or incomplete, suggesting fpA generation at sites not easily accessible to heparin or insufficient heparin dosage. The 125I-fibrinogen kinetics were characterized by a significantly shorter half-life (t1/2: 2.5 days), increased catabolic rate constant (j: 0.44 days-1), and increased absolute turnover (68.9 mg fibrinogen/kg/day) as compared to 4 normal subjects (t1/2: 4.2 days; j: 0.26 days-1; turnover 21.7 mg fibrinogen/kg/day). As estimated from the fpA generation rates, intravascular thrombin action on fibrinogen contributed only in minor part to increase the turnover of 125I-fibrinogen. In particular, the turnover was greatly accelerated in heparin-treated patients despite impressive suppression or normalization of the fpA levels in 5/6 cases.

Topics: Adult; Aged; Disseminated Intravascular Coagulation; Female; Fibrin Fibrinogen Degradation Products; Fibrinogen; Fibrinopeptide A; Heparin; Humans; Iodine Radioisotopes; Kinetics; Male; Middle Aged; Neoplasm Metastasis; Neoplasms

Topics: Adolescent; Adult; Aged; Animals; Brain Abscess; Burns; Child; Circadian Rhythm; Dogs; False Positive Reactions; Female; Fibrinogen; Fibrinopeptide A; Hemoglobinuria; Humans; Hydrogen-Ion Concentration; Liver Cirrhosis, Alcoholic; Male; Middle Aged; Myocardial Infarction; Neoplasms; Thrombin

FPA level, fibrinogen turnover rate, and fibrinolytic activity were studied on 18 patients with malignant disease. It was found that the FPA levels were significantly elevated and were correlated with fibrinogen turnover rate (r = 0.74, p less than 0.001) and FDP (r - 0.58, p less than 0.02). Estimated FPA turnover rate was also correlated with fibrinogen turnover rate (r = 0.70, p less than 0.001). These results suggest that fibrinogen catabolism in patients with malignant disease is related with thrombin proteolysis. However, ratios of 1/2 FPA turnover rate to fibrinogen turnover rate suggest that intravascular thrombin proteolysis is not the major determinant of fibrinogen catabolism. It is suspected that extravascular thrombin proteolysis is responsible for the elevation of plasma FPA level which is correlated with acceleration of fibrinogen catabolism.

Topics: Adolescent; Adult; Aged; Female; Fibrinogen; Fibrinolysis; Fibrinopeptide A; Humans; Kinetics; Male; Middle Aged; Neoplasms; Thrombin

FPA immunoreactivity was elevated in 14 out of 15 patients with disseminated neoplasia. Two of the patients showed signs of DIC, two had clinically evident thrombosis and one a positive 125I-fibrinogen uptake test suggesting thrombosis. Infusion of heparin produced a prompt fall in FPA levels. FPA immunoreactivity correlated well with the turnover of intravasal 125I-fibrinogen. The results confirm that the RIA of FPA provides a specific and quantitative index of the conversion of fibrinogen into fibrin and indirectly of the thrombin action in vivo.

Topics: Disseminated Intravascular Coagulation; Fibrinogen; Fibrinopeptide A; Heparin; Humans; Iodine Radioisotopes; Neoplasms; Radioimmunoassay; Thrombosis

Topics: Blood Preservation; Blood Specimen Collection; Burns; Disseminated Intravascular Coagulation; Fibrinogen; Fibrinopeptide A; Freezing; Humans; Immune Sera; Neoplasms; Plasma; Radioimmunoassay; Streptokinase; Thrombin; Thrombophlebitis; Uremia; Venous Pressure; Wounds and Injuries