fibrinopeptide-a and Thromboembolism

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

Thromboembolic disease continues to plague mankind because it is often detected too late for effective management, because modern therapeutic measures are often inefficiently managed, and because new therapeutic agents and available laboratory tests are ignored. New investigations that continue to be reported in Seminars in Thrombosis and Hemostasis and other journals deserve greater recognition and appreciation. Physicians and other scientists have reached a point at which antithrombotic and hemorrhagic effects of therapeutic anticoagulants can become dissociated if they effectively work together at the many interfaces for research and development among them to harvest the yield of basic research for practical clinical application.

Topics: Antithrombins; Blood Coagulation Tests; Factor X; Factor Xa; Fibrinopeptide A; Heparin; Humans; Intracranial Embolism and Thrombosis; Myocardial Infarction; Oligosaccharides; Prothrombin; Pulmonary Embolism; Thromboembolism

There are many reports in the literature of blood test abnormalities occurring in patients with venous or arterial thrombosis. Most of these have not used acceptable criteria for establishing an association between thrombosis and blood tests and, therefore, their interpretation is questionable. Recently, sensitive and specific assays have been developed for the detection of products of intravascular thrombin formation, of plasmin digests of fibrin or fibrinogen and of platelet specific proteins that are released into the plasma when platelets react with stimuli. Blood abnormalities have been sought that can either predict or detect venous thrombosis. Many of the predictive tests evaluated are nonspecific acute phase reactant responses to inflammation; of these, only reduced fibrinolytic activity has been consistently reported to be associated with postoperative venous thrombosis. Hereditary antithrombin III deficiency has been consistently shown to predispose patients to venous thrombosis. Abnormalities of the plasminogen and fibrinogen molecule have also been described in patients with familial or recurrent venous thrombosis but these are rare and the association could be coincidental. Two blood tests, the fibrinopeptide A assay and the assay for fibrin/fibrinogen fragment E are highly sensitive to acute venous thromboembolism in symptomatic patients but both are nonspecific. Elevated levels of beta thromboglobulin and platelet factor 4 have been reported in patients with arterial thromboembolism but the sensitivity and specificity of these findings is presently unknown.

Topics: Antithrombin III; Arteries; Blood Coagulation Tests; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinolysis; Fibrinopeptide A; Humans; Inflammation; Platelet Adhesiveness; Platelet Aggregation; Risk; Thrombin; Thromboembolism; Thrombophlebitis; Thrombosis; Wounds and Injuries

Topics: Acetylcysteine; Aged; Analysis of Variance; Antithrombin III; Cell Aggregation; Cerebrovascular Disorders; Cytidine Diphosphate Choline; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Erythrocytes; Female; Fibrinogen; Fibrinopeptide A; Glutathione; Humans; Infusions, Intravenous; Leukocytes; Male; Middle Aged; Nootropic Agents; Reperfusion Injury; Rutin; Thromboembolism

A pilot investigation was performed with Innohep, a low molecular weight (LMWH) preparation (peak maximum molecular mass 3,000-6,000), to determine possible dose regimens for patients undergoing regular maintenance haemodialysis for chronic renal failure. Results from this study suggested that suppression of macroscopic clot formation and fibrinopeptide A (FPA), a marker of fibrin formation, could be achieved following bolus injections rather than bolus injections and an infusion. On the basis of these preliminary findings, a randomised crossover study was performed in eight patients undergoing regular maintenance haemodialysis for 5-7 h to determine the effective antithrombotic dose of this LMWH. Single i.v. bolus doses of 1,250 AFXa u, 2,500 AFXa u and 5,000 AFXa u (n = 7-8) were compared to an UFH regime of 5,000 iu + 1,500 iu/h. Excessive clot formation in the dialyser bubble trap, necessitating additional UFH to enable completion of a prolonged (up to 7 h) dialysis, was observed in all patients on the 1,250 AFXa u dose (mean duration of dialysis prior to UFH, 3 h) but in a single patient only receiving the other LMWH doses. A dose-related response in the AFXa activity, measured by chromogenic substrate (CS) assay was seen in the three LMWH groups, with levels declining significantly (p less than 0.05) from 1-7 h. This contrasted with the constant levels maintained during dialysis with UFH. FPA levels were significantly elevated after 2 h following the 1,250 AFXa u bolus and after 4 h following the 2,500 AFXa u bolus. There was no significant difference in FPA levels between the 5,000 AFXa u bolus and UFH.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Dose-Response Relationship, Drug; Fibrinopeptide A; Heparin; Humans; Kidney Failure, Chronic; Molecular Weight; Monitoring, Physiologic; Pilot Projects; Renal Dialysis; Thromboembolism

Aspirin has been shown to be beneficial in the prophylaxis of arterial thromboembolic disease. The rationale for its use as an antithrombotic drug lies in its inhibition of thromboxane A2-dependent platelet function. However, the effect of aspirin on coagulation and fibrinolysis during chronic therapy has not been studied. We have measured a range of haemostatic and platelet functions in 49 patients with transient ischaemic attacks randomly allocated to aspirin 300 mg a day, aspirin 1,200 mg a day or placebo. All had been taking their allocated treatment for between 9 months and 4 years prior to investigation. Bleeding time was prolonged, serum thromboxane diminished and platelet aggregation to arachidonic acid but not ADP was abolished by both 300 mg and 1,200 mg aspirin, in a non-dose dependent fashion. Serum salicylate increased with the dose of aspirin ingested. No effect was seen with either dose of aspirin on urinary thromboxane and 6-keto-PGF1 alpha excretion, or on coagulation. Patients taking 1,200 mg aspirin a day had a lower haemoglobin and packed cell volume, lower resting fibrinopeptide A concentration and lower basal plasminogen activator activity than those on placebo. Response to venous occlusion was normal in all groups. The results suggest 300 mg and 1,200 mg aspirin have an equivalent platelet inhibitory effect but 1,200 mg aspirin causes greater gastro-intestinal blood loss.

Topics: Aged; Aged, 80 and over; Aspirin; Bleeding Time; Blood Coagulation; Dose-Response Relationship, Drug; Female; Fibrinolysis; Fibrinopeptide A; Humans; Male; Middle Aged; Placebos; Plasminogen Activators; Platelet Aggregation; Platelet Aggregation Inhibitors; Salicylates; Thromboembolism; Thromboxane B2; Time Factors

The relationship between tumor stage and the concentration of circulating heparin achieved after subcutaneous administration and its effect on fibrin generation were studied in 24 women with gynecologic malignancy. A single subcutaneous injection of 5000, 7500, and 10,000/U of sodium heparin was given in random order on different days. Plasma specimens for antithrombin III, fibrinopeptide A, and heparin were obtained serially over an 11-hour interval. Women with a Stage III or IV malignancy had significantly lower circulating heparin after the 5000 and 10,000/U doses. There was a significant decline in fibrinopeptide A as the concentration of circulating heparin increased. Thirty-three percent of women with a Stage III or IV malignancy had no detectable circulating heparin at any point examined over the 11 hours after 5000/U of heparin. Likewise, 16.7% and 8.4% had no detectable circulating heparin after 7500 and 10,000/U, respectively. A similar percentage was noted in a smaller group of women with Stage II malignancy. Next, a known quantity of heparin was added to the plasma from these patients and the concentration of heparin was determined. A significant amount of heparin-neutralizing activity was documented. We conclude that a large percentage of women with an advanced gynecologic malignancy are able to neutralize heparin administered for the prevention of thromboembolic disease. This heparin-neutralizing activity may account for the failure of low-dose heparin to prevent thromboembolic complications in this patient population.

Topics: Antithrombin III; Female; Fibrin; Fibrinopeptide A; Genital Neoplasms, Female; Heparin; Humans; Thromboembolism

In 19 patients with unstable angina pectoris at rest, plasma levels of the platelet-derived proteins beta-thromboglobulin and platelet factor 4 were significantly elevated in blood samples obtained during or within 4 hours after episodes of angina, but were usually normal during quiescent intervals. Plasma levels of the arachidonic acid metabolite thromboxane B2 were less clearly related to angina, and there was no association of angina with levels of the coagulation product fibrinopeptide A. This demonstration of an association of platelet activation and secretion with unstable angina pectoris by radioimmunoassay of circulating platelet constituents offers a new approach to assessment of therapy in ischemic heart disease and suggests that agents that alter platelet function should be evaluated in patients with unstable angina.

Topics: Adult; Aged; Angina Pectoris; beta-Thromboglobulin; Blood Platelets; Electrocardiography; Female; Fibrinopeptide A; Heparin; Humans; Male; Middle Aged; Myocardial Infarction; Platelet Factor 4; Thromboembolism; Thromboxane B2

To investigate the association of left atrial (LA) spontaneous echo contrast with the hemostatic state in nonrheumatic atrial fibrillation (AF), we examined the plasma levels of prothrombin fragment 1+2 and fibrinopeptide A in 73 patients with chronic nonrheumatic AF undergoing transesophageal echocardiography and 38 age-matched normal subjects. The results support the theory that LA spontaneous echo contrast in nonrheumatic AF is associated with a hypercoagulable state, especially in patients with marked LA spontaneous echo contrast.

Topics: Adult; Aged; Aged, 80 and over; Atrial Fibrillation; Cardiomyopathy, Hypertrophic; Case-Control Studies; Echocardiography, Transesophageal; Female; Fibrinopeptide A; Heart Atria; Humans; Hypertension; Male; Middle Aged; Peptide Fragments; Protein Precursors; Prothrombin; Thromboembolism

Topics: Adaptation, Physiological; Adult; Antibodies, Antiphospholipid; Antiphospholipid Syndrome; Antithrombin III; Case-Control Studies; Female; Fibrinolysis; Fibrinopeptide A; Humans; Lupus Erythematosus, Systemic; Male; Peptide Fragments; Prothrombin; Thrombin; Thromboembolism

Given that the restoration of sinus rhythm after chronic atrial fibrillation is associated with embolic events, anticoagulation is prescribed before and after pharmacological and electrical cardioversion. However, the need for anticoagulation in patients with acute atrial fibrillation (lasting <48 hours) who undergo cardioversion is less clear. In addition, it is not known whether cardioversion to sinus rhythm determines a hypercoagulable state in these patients.. In 21 patients with acute nonvalvular atrial fibrillation, plasma median concentrations of thrombin-antithrombin complex, a marker of thrombin generation, significantly increased from 2.8 ng/mL (interquartile range, 2.1 to 4.0 ng/mL) on hospital admission to 3.5 ng/mL (interquartile range, 2.9 to 6.0 ng/mL) after cardioversion to sinus rhythm obtained by means of infusion of antiarrhythmic drugs and decreased to 2.5 ng/mL (interquartile range, 2.0 to 3.5 ng/mL) at the 1-month follow-up visit (P=.04). Similarly, the levels of fibrinopeptide A, a marker of thrombin activity, increased from 1.1 nmol/L (interquartile range, 0.7 to 1.5 nmol/L) at baseline to 1.8 nmol/L (interquartile range, 1.1 to 3.0 nmol/L) after cardioversion and returned to 0.8 nmol/L (interquartile range, 0.6 to 1.1 nmol/L) at the 1-month follow-up visit (P=.02).. A significant increase in plasma levels of the markers of thrombin generation and activity was observed in patients with acute atrial fibrillation early after pharmacological cardioversion to sinus rhythm. This is the first biochemical evidence that cardioversion of recent-onset atrial fibrillation determines a hypercoagulable state.

Topics: Acute Disease; Amiodarone; Anti-Arrhythmia Agents; Antithrombin III; Atrial Fibrillation; Biomarkers; Disease Susceptibility; Female; Fibrinopeptide A; Flecainide; Hemostasis; Humans; Male; Middle Aged; Peptide Hydrolases; Propafenone; Thrombin; Thromboembolism

The existence of a phenomenon of rebound hypercoagulability after cessation of oral anticoagulant therapy is controversial. The sensitive procoagulant markers for in vivo thrombin and fibrin formation are potential tools for the reassessment of the presence of each a phenomenon. We examined 19 patients anticoagulated for 6 +/- 2 months (SD, range 3-12) because of venous thromboembolism or myocardial infarction as follows: twice during stable, oral anticoagulation (INR 3.1-3.7) and then on days 1, 2, 3, 4, 5, 7, 9, 11, 13, 15, and > 30 after cessation of oral anticoagulation. Thrombin-antithrombin III complexes (TAT) and fibrinopeptide A (FPA) were measured in addition to the prothrombin times and factors II, V, VII, and X. None of the 19 patients developed clinically manifest thromboembolism within the following 9-18 months. However, the patients' TAT levels increased transiently: rising from 1.5 +/- 0.1 ng/ml (SEM) to 3.0 +/- 0.2 ng/ml on day 4 (P < 0.001), and returned to 1.7 +/- 0.1 ng/ml after day 30 (normals 1.8 +/- 0.33). 17/19 patients showed TAT peak levels above the upper limit of normal between days 3 and 11 (average: day 4), which normalized again after 30 d. 8/19 patients also had transient FPA levels above the upper normal limits ( < 1.81). We conclude that our patients increased their thrombin and fibrin formation transiently and that a subpopulation reached values consistent with a prethrombotic state.

Topics: Adult; Anticoagulants; Antithrombin III; Female; Fibrinopeptide A; Humans; Male; Middle Aged; Peptide Hydrolases; Prothrombin Time; Recurrence; Thromboembolism; Time Factors

Recombinant human erythropoietin (EPO) therapy in uremic patients raises the hematocrit (Hct) and increases physical exercise capacity (1,2) and quality of life (1). In general, partial correction of anemia to subnormal levels in uremic patients has proven to be safe with few serious adverse effects apart from hypertension (3). Ever since the advent of EPO the prospect of abuse of the hormone by sportsmen has been subject to scrutiny. Both maximal oxygen uptake and endurance capacity are increased after EPO treatment in healthy subjects (4). Moreover, EPO treatment in healthy subjects has been found to induce an accentuated blood pressure reaction after submaximal exercise (5). Previous studies have shown that extreme physical exertion can predispose to an increased intravascular coagulation (6). Moreover there is a significantly increased risk of thrombosis in patients with myeloproliferative disorders, particularly in polycythemia vera (7). An enhanced risk of cardiovascular events may therefore arise should sportsmen abuse EPO as a blood doping agent. The aim of this study was to examine the effects of an EPO-induced increase in Hct on the coagulation system in healthy subjects.

Topics: Adult; Antithrombin III; Blood Coagulation Tests; Erythropoietin; Fibrinopeptide A; Hematocrit; Humans; Male; Peptide Hydrolases; Recombinant Proteins; Reference Values; Risk; Sports Medicine; Substance-Related Disorders; Thromboembolism

The combined use of coumarin and low-dose aspirin appears to reduce the risk of systemic embolism at a low risk of bleeding. The remaining incidence of embolism of approximately 2%/y is still high. Methods for real-time detection of embolic events have not been used thus far to monitor the efficacy of therapeutic strategies. They might permit individually tailored, effective treatments.. The frequency of embolic signals in both middle cerebral arteries was monitored using a two-channel 2-MHz transcranial Doppler system. We examined five patients with mechanical prosthetic heart valves suffering from recurrent cerebral ischemic symptoms despite adequate anticoagulant therapy (international normalized ratio, 3.0 to 4.3). Measurements were performed on coumarin alone (four baseline values) and subsequent to the addition of intravenous (500 mg bolus) and oral (100 mg/d for 10 days) aspirin or intravenous (5000 IU bolus) heparin. The prothrombotic markers thrombin-antithrombin III complex, fibrinopeptide A, D-dimer, and platelet beta-thromboglobulin were measured simultaneously.. None of the combined drug regimens led to a significant reduction of the emboli count. The values of thrombin-antithrombin III complex, fibrinopeptide A, and D-dimer were already within normal limits with coumarin alone. The beta-thromboglobulin levels, however, were increased, and additional aspirin or heparin did not reduce them. There was no correlation between the emboli count and the prothrombotic markers or between the prothrombotic markers and the different drug regimens.. The rate of cerebral emboli measured with transcranial Doppler in the group of high-risk patients studied was not influenced by additional antiplatelet therapy. The emboli are likely to be composed at least in part of platelets, and their generation seems not dependent on thrombin or cyclooxygenase. There is an apparent discrepancy between the unchanged rate of emboli during Doppler monitoring found in this and other studies and the partial efficacy of combined treatment with coumarin and aspirin in clinical long-term studies. This may be explained by differences in the composition or size of the emboli.

Topics: Administration, Oral; Adult; Antithrombin III; Aspirin; beta-Thromboglobulin; Biomarkers; Coumarins; Drug Therapy, Combination; Female; Fibrin Fibrinogen Degradation Products; Fibrinolytic Agents; Fibrinopeptide A; Heart Valve Prosthesis; Heparin; Humans; Injections, Intravenous; Male; Middle Aged; Peptide Hydrolases; Postoperative Complications; Thromboembolism; Ultrasonography, Doppler, Transcranial

Thromboembolism is an important complication of heart failure. To test the hypothesis that heart failure may be associated with hemostatic dysfunction, we studied hemostatic function in 21 patients with stable chronic heart failure and related these measures to the severity of heart failure as assessed by clinical evaluation, neuroendocrine activation, radionuclide ventriculography, and cardiopulmonary exercise testing. Plasma and blood viscosity were elevated; all patients showed evidence of platelet activation, and many had elevated plasma concentrations of fibrinopeptide A, D-dimer, and von Willebrand factor. The plasma concentrations of these variables were poorly interrelated and related poorly to the severity of heart failure. Plasma concentrations of angiotensin II and endothelin were correlated, and the latter was also correlated with the plasma concentration of von Willebrand factor. Patients with chronic heart failure have hemostatic abnormalities that may predispose them to thromboembolic events and may be in part due to neuroendocrine activation.

Topics: Adult; Aged; Angiotensin II; Blood Coagulation; Blood Viscosity; Chronic Disease; Endothelins; Exercise Test; Female; Fibrin Fibrinogen Degradation Products; Fibrinopeptide A; Heart Failure; Humans; Male; Middle Aged; Neurosecretory Systems; Platelet Activation; Radionuclide Ventriculography; Thromboembolism; von Willebrand Factor

To test the hypothesis that disseminated intravascular coagulation contributes to hemostatic failure in liver cirrhosis, fibrinopeptide A and fibrin(ogen) degradation fragment E were measured in 69 patients with stable liver cirrhosis and compared with fibrinopeptide A and fibrin(ogen) degradation fragment E in 32 healthy subjects, 33 patients with thromboembolism, and 10 patients with hypofibrinogenemic disseminated intravascular coagulation. Mean fibrinopeptide A in cirrhosis was slightly increased compared with healthy subjects (2.4 vs. 1.8 ng/ml, p < 0.005), but fourfold lower than in thromboembolism (mean fibrinopeptide A 9.7 ng/ml; p < 0.0001), and tenfold lower than in disseminated intravascular coagulation (mean FPA 24.3 ng/ml; p < 0.0001). Single fibrinopeptide A levels in cirrhosis were within the normal range in 75% of the patients, marginally increased in 9%, and definitely increased in 16%. A definite increase in both fibrinopeptide A and fibrin(ogen) degradation fragment E, which characterized the groups of patients with thromboembolism and disseminated intravascular coagulation, was found in 10% of the cirrhotic patients. Among 17 patients with cirrhosis and hypofibrinogenemia, mean fibrinopeptide A (2.7 ng/ml) was tenfold lower compared with mean fibrinopeptide A in patients with hypofibrinogenemic disseminated intravascular coagulation (p < 0.0001), whereas the frequency of increased single fibrinopeptide A levels (29%) was not significantly different compared with the 52 cirrhotic patients without hypofibrinogenemia (single levels elevated in 23% of the cases). Moreover, the frequency of hypofibrinogenemia, thrombocytopenia, or abnormal clotting times was not significantly different in cirrhotic patients with normal fibrinopeptide A level when compared with cirrhotic patients with increased fibrinopeptide A. These findings do not support an important contribution of disseminated intravascular coagulation to coagulopathy of liver cirrhosis.

Topics: Adult; Aged; Blood Coagulation Disorders; Blood Coagulation Tests; Disseminated Intravascular Coagulation; Female; Fibrin Fibrinogen Degradation Products; Fibrinopeptide A; Humans; Liver Cirrhosis; Male; Middle Aged; Reference Values; Thromboembolism

Topics: Angiography; Blood; Catheterization; Contrast Media; Fibrinopeptide A; Humans; Microscopy, Electron, Scanning; Thromboembolism

Topics: Adult; Aged; Aged, 80 and over; Erythrocyte Aggregation; Fibrin; Fibrinogen; Fibrinopeptide A; Humans; Methods; Middle Aged; Pulmonary Embolism; Thromboembolism

Fibrinopeptide A is a good marker of in vivo thrombin formation. The aim of oral anticoagulants (OA) is to lower in vivo thrombin formation. We therefore assessed FpA levels on several occasions in 38 patients receiving OA for artificial heart valve prostheses and in 20 patients receiving OA for biological heart valve prostheses. The mean FpA level, 1.82 ng ml-1 (SEM 0.14, n = 176), in patients with artificial valves was significantly higher than the mean, 1.02 ng ml-1 (SEM 0.4), obtained in 41 healthy subjects (P = 0.01). FpA mean value for biological valves was 1.41 ng ml-1 (SEM 0.14, n = 76), which was not significantly higher than controls (P = 0.08). A decrease in FpA levels, for both artificial and biological heart valve prostheses, was associated with a parallel increase in the intensity of anticoagulation. When considering FpA values obtained in the optimal therapeutic range for oral anticoagulant treatment, (International Normalized Ratio [INR] between 3 and 4.5), the mean level for artificial valves, 1.87 ng ml-1 (SEM 0.18, n = 102), was significantly higher than the mean value, 1.25 ng ml-1 (SEM 0.16, n = 55), obtained for biological valves. From a biological point of view, this indicates that artificial valves should be kept at a higher intensity of anticoagulation.

Topics: Administration, Oral; Adult; Aged; Anticoagulants; Bioprosthesis; Female; Fibrinogen; Fibrinopeptide A; Heart Valve Prosthesis; Humans; Male; Middle Aged; Thrombin; Thromboembolism

Twenty-six pregnant women were given prophylactic heparin treatment because of previous thromboembolic complications. The mean duration of treatment was 25 weeks (range, 6 to 32 weeks). The amount of heparin was adjusted to a plasma concentration of 0.08 to 0.15 IU/ml, measured as anti-factor Xa activity. This effect was compared with that on activated partial thromboplastin time. The average dose was 16,400 IU/24 hours or 225 IU/kg of body weight per 24 hours. When the plasma concentration was within the stipulated range, the dose was 234 IU/kg of body weight/24 hours. No significant prolongation of activated partial thromboplastin time was found in two thirds of the samples. Blood coagulation was either not activated or only slightly activated, as verified by a low level of fibrinopeptide A. Platelet counts and antithrombin III levels were generally not depressed. No thromboembolic complications occurred during the pregnancies or puerperium. Bleeding during delivery was not increased. No fractures of the spine caused by osteoporosis were found on radiologic examination post partum.

Topics: Adult; Antithrombin III; Factor Xa; Female; Fibrinopeptide A; Heparin; Humans; Injections, Subcutaneous; Partial Thromboplastin Time; Platelet Count; Pregnancy; Pregnancy Complications, Cardiovascular; Self Administration; Serine Proteinase Inhibitors; Thromboembolism

Topics: beta-Thromboglobulin; Blood Coagulation Disorders; Fibrinopeptide A; Hemostasis; Humans; Receptors, Cell Surface; Receptors, Thrombin; Thromboembolism; Tissue Plasminogen Activator

In five patients with venous thromboembolic disease treated with recombinant tissue-type plasminogen activator (rt-PA), there was a marked increase in the mean concentrations of fibrinopeptide A (from 0.6 to 5.9 nM; P less than 0.0001) and desarginine fibrinopeptide B (from 5.6 nM to 24.1 nM; P less than 0.01) 30 min after a bolus of rt-PA (0.6 mg/kg). Thrombin was unlikely to be responsible because the levels of desarginine fibrinopeptide B exceeded those of fibrinopeptide A and the changes occurred despite concomitant heparin therapy. The purpose of this study therefore, was to determine whether rt-PA directly releases the fibrinopeptides from fibrinogen. Incubation of rt-PA with heparinized plasma or purified fibrinogen resulted in time and dose-dependent release of both fibrinopeptide A and B. Contaminating thrombin was not responsible for this activity by the following criteria: the rate of rt-PA mediated fibrinopeptide B release was considerably faster than that of fibrinopeptide A, and fibrinopeptide release was unaffected by heparin, hirudin, or a monospecific antithrombin IgG. Aprotinin also had no effect on fibrinopeptide release, indicating that this activity was not plasmin mediated. Fibrinopeptide release was shown to be due to rt-PA because this activity was completely blocked by a monoclonal antibody against the enzyme. Further, the specificity of rt-PA for the thrombin cleavage sites on fibrinogen was confirmed by the demonstration that rt-PA released fibrinopeptide A or fibrinopeptide B from fibrinopeptide A or B-containing substrates, respectively. These studies thus demonstrate that (a) rt-PA releases fibrinopeptides A and B from fibrinogen thereby indicating that this enzyme is not specific for plasminogen, and (b) plasma fibrinopeptide A and desarginine fibrinopeptide B levels are not specific markers of thrombin action on fibrinogen in patients receiving rt-PA.

Topics: Chromatography, High Pressure Liquid; Fibrinogen; Fibrinopeptide A; Fibrinopeptide B; Heparin; Humans; Recombinant Proteins; Thrombin; Thromboembolism; Tissue Plasminogen Activator

Low-dose oral contraceptives when tested for vascular or thrombotic effects not only show no risk of venous thromboembolic disease, but this method could possibly reduce the chance of thromboembolic disease as compared with pills which have a higher estrogen dose. It has also been found that pills containing lower doses of estrogen have no effect on the coagulatory system. Concerns raised about the connection between oral contraceptive use and the risk of cardiovascular disease called for testing in the late 1960s. Epidemiological studies confirmed the risk of oral contraceptive use and cardiovascular disease especially venous thromboembolism. A further association was identified between the amount of estrogens contained in oral contraceptives and the risk of disease. Estrogens affect the hemostatic system; decreases in antithrombin III activity in addition to platelet adhesiveness and blood viscosity have been observed in oral contraceptive users. Although both a decreased influence on the hemostatic system and the risk of thromboembolic disease have been found in pills with lower doses of estrogen, further research on the effect of the clotting system by low-dose oral contraceptives is needed.

Topics: Contraceptives, Oral, Hormonal; Estrogens; Ethinyl Estradiol; Female; Fibrinopeptide A; Humans; Risk; Thromboembolism

In an earlier study on post-operative thromboembolism in neurosurgery the incidence of deep vein thromboses (DVT) diagnosed by the fibrinogen uptake test and phlebography was reduced to the same extent by two different prophylactic methods (low dose heparin or calf muscle stimulation + dextran). However, patients with lower limb paresis due to a brain lesion experienced relatively often a less successful prophylaxis compared to patients with spinal lesions. There are few reports on successful clinical methods for haematological screening of post-operative DVT. The aim of this study was to examine possible haematological indicators for post-operative thromboembolism and secondarily to elucidate whether there exist some special coagulatory or fibrinolytic characteristics in patients who had been operated upon for brain lesions. We have studied two specific coagulatory factors (FPA reflecting thrombin generation and B beta 15-42 reflecting plasmin activity) in connection with neurosurgical operations. Patients in the above-mentioned study on post-operative DVT operated upon for malignant cerebral tumours or intracranial vascular disease exhibited post-operatively higher values for FPA compared to other neurosurgical diagnoses. B beta 15-42 was higher in the malignant tumour group and almost significantly higher in the intracranial vascular group (p less than 0.065). These differences could not be ascribed to the occurrence of DVT. Another 15 patients divided into a minor and a major lesion group were investigated with determination of both parameters pre- and post-operatively. Concerning FPA an increase was noticed post-operatively compared to pre-operatively in the major lesion group.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Brain Diseases; Brain Neoplasms; Dextrans; Fibrin Fibrinogen Degradation Products; Fibrinogen; Fibrinopeptide A; Heparin; Humans; Peptide Fragments; Postoperative Complications; Spine; Thromboembolism

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

RIAs for hemostatic system activation were employed to study patients who were anticoagulated with warfarin. The mean prothrombin fragment F1 + 2 concentration in stably anticoagulated individuals without an inherited thrombotic diathesis (mean prothrombin time [PT] ratio [PT of patient/PT of normal plasma pool] = 1.74) was 0.231 nM as compared with a mean plasma F1 + 2 level of 1.68 nM for a nonanticoagulated control group (P less than 0.0001). The initiation of oral anticoagulants in two subjects who did not exhibit protein C deficiency led to a paradoxical increase in F1 + 2 levels during the first day of therapy. We have also shown that a relatively low intensity regimen of warfarin (PT ratio less than 1.2) may reduce elevated concentrations of F1 + 2 into the normal range in patients with a history of recurrent thromboembolism. The mean F1 + 2 level in antithrombin-deficient individuals on warfarin was significantly elevated (mean = 0.714 nM) as compared with that in anticoagulated subjects with protein C deficiency (mean = 0.205 nM) or in those without an inherited thrombotic disorder (P less than 0.01) at equivalent levels of intensity of oral anticoagulation. We therefore conclude that the effect of warfarin on hemostatic system activation is modulated by the endogenous heparan sulfate-antithrombin mechanism.

Topics: Administration, Oral; Adult; Anticoagulants; Depression, Chemical; Fibrinopeptide A; Hemostasis; Humans; Middle Aged; Oligopeptides; Peptide Fragments; Prothrombin; Thromboembolism; Warfarin

Topics: Adolescent; Adult; Aged; beta-Thromboglobulin; Female; Fibrinopeptide A; Fibrinopeptide B; Humans; Leg; Lung; Male; Middle Aged; Platelet Factor 4; Postoperative Complications; Radionuclide Imaging; Thrombin; Thromboembolism; Thrombophlebitis; Thromboplastin

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 effect of discontinuation of a long term oral anticoagulant therapy with phenprocoumon on blood clotting parameters has been evaluated in patients in a controlled prospective trial. After termination of phenprocoumon the prothrombin time normalized within 15 days and the thrombotest coagulation value within 57 days. Fibrinopeptide A (FPA) increased significantly during the observation period. FPA release in vitro also rose after discontinuation of anticoagulants. In control patients on a phenprocoumon maintenance therapy no alterations of the above mentioned parameters occurred within the same period. The data indicate that plasma hypercoagulability is found in many patients, orally anticoagulated because of myocardial infarction, when the anticoagulant therapy is discontinued.

Topics: 4-Hydroxycoumarins; Administration, Oral; Aged; Anticoagulants; Blood Coagulation; Fibrinogen; Fibrinopeptide A; Humans; Middle Aged; Myocardial Infarction; Phenprocoumon; Prothrombin Time; Thromboembolism; Time Factors

The prompt reduction of elevated fibrinopeptide A (FPA) levels (normal less than 1.3 pmole/ml) by heparin therapy in patients with thromboembolism suggests that measuring the FPA level may provide a good index of disease activity and be a useful method of monitoring therapy. Sepsis or malignancy may elevate FPA levels and coexist with thromboembolism. FPA levels were surveyed in 51 patients with thromboembolism (including 15 with concurrent sepsis or malignancy) during heparin treatment in an attempt to distinguish the effects of coexistent disease and the progression of thromboembolism. The anticoagulant effect of heparin was within the therapeutic range for 81% of the study period. In patients with thromboembolism alone and marked resolution of emboli on repeat lung scan, the mean daily FPA levels were lower than the values in patients with minimal resolution (p less than 0.005). In patients with marked resolution of pulmonary embolism or venous thrombosis and a concurrent disorder, the mean FPA level remained elevated compared to normal values in patients with thromboembolism alone. These results suggest that FPA levels monitored during heparin therapy of thromboembolism may be useful as an index of disease activity except in the presence of coexisting sepsis or malignancy.

Topics: Adenocarcinoma; Adult; Aged; Anticoagulants; Carcinoma, Squamous Cell; Female; Fibrinogen; Fibrinopeptide A; Heart Failure; Heparin; Humans; Leukemia, Lymphoid; Lupus Erythematosus, Systemic; Male; Middle Aged; Polycythemia Vera; Pulmonary Embolism; Sepsis; Thromboembolism

Topics: beta-Thromboglobulin; Fibrinopeptide A; Humans; Platelet Factor 4; Radioimmunoassay; Thromboembolism

Topics: Blood Coagulation Tests; Bradykinin; Disseminated Intravascular Coagulation; Fibrinogen; Fibrinopeptide A; Humans; Thromboembolism; Thrombophlebitis

A qualitatively abnormal fibrinogen was detected in the plasma of a 53 year old woman with severe arterial thrombotic disease. The concentrations of plasma fibrinogen and serum fibrinogen related material were normal. The abnormal fibrinogen was electrophoretically normal. The defects detected were an abnormality of polymerization of fibrin monomers and a decreased rate of release of fibrinopeptide A. The absorption of radiolabelled partially degraded plasminogen on to fibrin prepared from purified fibrinogen Copenhagen was normal.

Topics: Adsorption; Blood Coagulation Tests; Electrophoresis, Polyacrylamide Gel; Female; Fibrin; Fibrinogen; Fibrinopeptide A; Humans; Middle Aged; Pedigree; Plasminogen; Polymers; Thromboembolism

Topics: Adult; Aged; Fibrinogen; Fibrinopeptide A; Heparin; Humans; Lung; Middle Aged; Radionuclide Imaging; Recurrence; Thromboembolism; Thromboplastin; Time Factors

Topics: Animals; Anticoagulants; Disseminated Intravascular Coagulation; Dogs; Epitopes; Fibrinogen; Fibrinopeptide A; Fibrinopeptide B; Heparin; Humans; Radioimmunoassay; Thrombin; Thromboembolism; Thrombosis