fibrinopeptide-a and Coronary-Thrombosis

Coronary thrombosis is an important determinant of prognosis in patients with acute coronary syndromes (ACS). However, the identification of patients at high-risk for progression of coronary thrombosis is difficult partly because we currently lack clinically meaningful laboratory methods for its detection. The most promising approaches involve the measurement in plasma of markers of fibrin formation and degradation. Thrombin activity, as reflected by plasma or urine concentrations of fibrinopeptide A, is increased in patients with ACS and is associated with adverse outcome. However, the use of fibrinopeptide A as a marker of fibrin formation is limited by the very short half-life of the compound, by artifact due to sample acquisition, and by extremely long turnaround times. To overcome these limitations, measurement of soluble fibrin has been proposed. We have recently explored the prognostic value of a new fibrin-specific ELISA assay for soluble fibrin in patients with ACS and found that patients with the highest levels had a 2-fold increased risk of early and late cardiac events. Increases in plasma concentrations of cross-linked fibrin degradation products (XL-FDPs), which reflect increased fibrin turn-over, are a marker of risk for complications of myocardial infarction. However, until recently, assays for XL-FDPs lacked specificity, because they did not distinguish between fibrin and fibrinogen degradation products. Recently, fibrin-specific ELISAs have been described and a rapid whole blood assay for D-dimer has been developed. We recently validated the prognostic value of this whole blood agglutination assay in patients with ACS. These results suggest that: (1) The detection of significant activation of the coagulation and/or fibrinolytic system may be important for rapid risk stratification of patients with ACS; (2) patients with biochemical evidence of ongoing coronary thrombosis may particularly benefit from aggressive antithrombotic strategies; (3) sequential measurement of these markers may be useful to guide antithrombotic treatment during the unstable phase of coronary artery disease.

Topics: Angina, Unstable; Coronary Thrombosis; Fibrinopeptide A; Humans; Myocardial Infarction; Prognosis; Prothrombin; Risk Assessment; Sensitivity and Specificity; Time Factors

Topics: Angina Pectoris; Blood Coagulation; Coronary Thrombosis; Fibrinolysis; Fibrinopeptide A; Humans; Myocardial Infarction; Plasminogen Inactivators

The interaction between blood factors and the vessel wall is important in the development of common cardiovascular diseases. Clinical markers of these interactions should be sought to help in the understanding of the processes involved, and such markers should ideally be available to identify people at risk from the disease, screen relatives, help identify appropriate treatment, and monitor the outcome of the therapy. Various aspects of platelet interaction with the vessel wall can be used, as can some changes in levels of coagulation factors, fibrinolytic proteins, and natural anticoagulants. All have their advantages and disadvantages in terms of having the attributes of the ideal marker that would identify the pathophysiological processes and be reproducible, inexpensive, and easy to perform. This review will consider the value of various clinical markers, taking account of their advantages and disadvantages.

Topics: beta-Thromboglobulin; Blood Coagulation Factors; Blood Platelets; Coronary Disease; Coronary Thrombosis; Fibrinolysin; Fibrinolysis; Fibrinopeptide A; Humans; Muscle, Smooth, Vascular; Plasminogen; Platelet Aggregation; Platelet Factor 4; Thrombosis; Thromboxane B2

The blood coagulation system is frequently activated in the acute phase of unstable angina, but it is unknown whether the augmented function of the hemostatic mechanism may serve as a marker of increased risk for an early unfavorable outcome.. Plasma concentrations and 24-hour urinary excretion of fibrinopeptide A were prospectively determined in 150 patients with unstable angina. All patients underwent 24-hour Holter monitoring, during which time urine was collected; at the end of this period, a blood sample was taken and coronary arteriography was performed. The patients were followed up for the occurrence of cardiac events (death and myocardial infarction) until they underwent coronary revascularization or until they were discharged from the hospital. Fibrinopeptide A plasma levels and 24-hour urinary excretion were found to be abnormally elevated in 50% and 45% of the study population, respectively. During hospitalization, 11 patients developed myocardial infarction and 2 patients died. Kaplan-Meier analysis demonstrated a significantly higher probability of developing cardiac events in patients with abnormal rather than normal plasma levels of fibrinopeptide A (P<.01), whereas no difference in outcome was observed between patients with normal and those with abnormal 24-hour urinary excretion. Cox regression analysis showed that the only variables independently related to an early unfavorable outcome were the presence of persistent ischemia during 24-hour Holter monitoring (P<.0001), the presence of intracoronary thrombosis at angiography (P=.016), and abnormal fibrinopeptide A plasma levels (P=.038).. Patients with unstable angina pectoris and abnormal fibrinopeptide A plasma levels are at increased risk for an early unfavorable outcome.

Topics: Aged; Angina, Unstable; Coronary Thrombosis; Electrocardiography; Female; Fibrinopeptide A; Humans; Male; Middle Aged; Prognosis; Prospective Studies; Risk Factors

Tissue factor pathway inhibitor (TFPI) is the endogenous inhibitor of the extrinsic coagulation pathway; however, its involvement during thrombus formation in patients with acute coronary syndromes (ACS) is still unknown.. Transcardiac (aorta/coronary sinus) free and total TFPI (free + lipoprotein-bound form) levels, as well as TFPI/factor Xa (FXa) complex levels, were measured in plasma samples obtained from patients with acute myocardial infarction undergoing primary PTCA and patients with unstable angina undergoing urgent PTCA. Patients with stable angina undergoing elective PTCA served as controls. In addition, prothrombin fragment 1+2 and fibrinopeptide A plasma levels were measured. Samples were collected at baseline, after PTCA, and after stent deployment. In patients with ACS, both total and free TFPI plasma levels in the coronary sinus were significantly lower than the corresponding levels measured in the aorta at any time point of the study; conversely, a significant increase in TFPI/FXa complex plasma levels was observed in the coronary sinus as compared with the aorta. In contrast, in patients with stable angina, no differences were observed in TFPI and TFPI/FXa levels at baseline in the coronary sinus as compared with the aorta.. TFPI is involved in the process of thrombus formation in vivo in patients with ACS, which suggests a potential role for TFPI in modulating coronary thrombosis.

Topics: Aged; Angina Pectoris; Angina, Unstable; Angioplasty, Balloon, Coronary; Anticoagulants; Aorta; Coronary Circulation; Coronary Thrombosis; Coronary Vessels; Factor Xa; Female; Fibrinolysis; Fibrinopeptide A; Heparin; Humans; Lipoproteins; Male; Middle Aged; Myocardial Infarction; Peptide Fragments; Prothrombin; Stents; Thrombin; Thrombophilia

The purpose of this study was to determine whether the elevated levels of hemostatic markers in the early phase of myocardial infarction may serve as risk factors for subsequent cardiac mortality.. Increased plasma hemostatic markers were noted in acute myocardial infarction, indicating that the blood coagulation system is highly activated in those patients. However, there are few clinical data concerning the association between the elevated hemostatic markers and survival in patients with myocardial infarction.. Blood samples were obtained from 64 patients (mean age 67 +/- 11 years; 49 male) with acute myocardial infarction within 12 h after the onset of symptoms and before the initiation of any antithrombotic treatment. We measured plasma concentrations of fibrinopeptide A (FPA), prothrombin fragment 1+2 (F1+2) and thrombin-antithrombin complex (TAT) using the enzyme-linked immunosorbent assay method, and examined the associations between the level of these markers and survival with Cox proportional hazards models.. The follow-up time was 27 +/- 17 months, and 19 patients died of cardiac causes during the follow-up. Univariate survival analysis identified Killip class IV (hazard ratio 4.86; 95% confidence interval [CI] 1.55-15.19), left ventricular ejection fraction (hazard ratio 0.94; 95% CI 0.90-0.99), FPA (hazard ratio 1.54; 95% CI 1.13-2.10), F1+2 (hazard ratio 2.03; 95% CI 1.17-3.53) and TAT (hazard ratio 1.88; 95% CI 1.27-2.79) as significant factors associated with cardiac mortality. In multivariate analyses, only FPA level (hazard ratio 1.84; 95% CI 1.03-3.30) and left ventricular ejection fraction (hazard ratio 0.93; 95% CI 0.88-0.98) were independent predictors of cardiac mortality.. Elevated FPA in the early phase of myocardial infarction identifies patients with increased risk for subsequent cardiac death. This association appears to be independent of residual left ventricular function after infarction.

Topics: Adult; Aged; Antithrombin III; Biomarkers; Coronary Thrombosis; Female; Fibrinopeptide A; Follow-Up Studies; Hemostasis; Humans; Male; Middle Aged; Myocardial Infarction; Peptide Fragments; Peptide Hydrolases; Prognosis; Prothrombin; Risk Assessment; Survival Rate

This study investigates the association between the concentration and function of plasma fibrinogen molecules measured at the time of hospital admission in patients with acute myocardial infarction (AMI), with reference to the risk of new coronary ischemic events during a three-day follow-up period of. Before starting fibrinolytic and anticoagulant treatment plasma fibrinogen, high molecular weight fibrinogen (HMW-fibrinogen), fibrin formation rate (FbFR) and phosphorous content in fibrinogen were determined in 90 AMI patients. During a three-day follow-up period 12 patients suffered new ischemic events. The 12 patients with coronary ischemia had higher concentrations of plasma fibrinogen (312+/-23 vs. 270+/-73 mg/dl, p<0.05) and HMW-fibrinogen (246+/-35 vs. 189+/-23 mg/dl, p<0.001) and a higher FbFR (65+/-30 vs. 40+/-25, p<0.001) than patients without these events. No association was found between the phosphorous content in fibrinogen and new coronary ischemic events. We conclude that after myocardial infarction an elevated plasma level of HMW-fibrinogen and a high FbFR value at the time of hospital admission are associated with new coronary ischemic events during a three-day follow-up period.

Topics: Aged; Biomarkers; Convalescence; Coronary Thrombosis; Female; Fibrin; Fibrinogen; Fibrinopeptide A; Follow-Up Studies; Humans; Male; Middle Aged; Molecular Weight; Myocardial Infarction; Phosphorus; Phosphorylation; Protein Processing, Post-Translational; Recurrence

Rethrombosis limits the efficacy of coronary thrombolysis and may result from surface-associated thrombin, de-novo prothrombin activation, or both. This study was designed to determine the relative roles of thrombin, factor Xa, and the complex of tissue factor and factor VIIa in the procoagulant activity on injured arteries with evolving thrombi.. Extensive vascular injury and platelet-rich thrombi were induced in the abdominal aorta of 25 anesthetized rabbits by applying anodal current through a transluminal electrode for 3 h. Injured vessel segments were excised and placed in a chamber permitting perfusion over the luminal surface and associated thrombus.. Vessel segments perfused with recalcified, citrated human plasma induced marked increases in the concentration of fibrinopeptide A, a marker of thrombin-induced fibrin formation, in the effluent plasma after 10 min (4636 +/- 1894% of fibrinopeptide A in the nonperfused plasma, n = 5). Perfusion with plasma depleted of vitamin K-dependent coagulation factors prevented the increase in fibrinopeptide A (122 +/- 30%, n = 4), indicating the lack of preformed functional thrombin. Furthermore, appearance of fibrinopeptide A was attenuated by perfusion with plasma containing 0.1 mumol/l recombinant tick anticoagulant peptide, a specific inhibitor of factor Xa (594 +/- 320%, n = 3), and by preincubation of vessel segments with a monoclonal antibody to rabbit tissue factor (438 +/- 220%, n = 3).. Procoagulant activity on injured vessels and associated thrombi is mediated by factor Xa, a product of the functional initiation of coagulation by factor VIIa associated with tissue factor. Accordingly, inhibition of tissue factor-mediated coagulation may be effective for attenuation of active thrombogenesis on injured vessels and during thrombolysis.

Topics: Animals; Aorta, Abdominal; Blood Coagulation; Coronary Thrombosis; Disease Models, Animal; Factor VIIa; Factor Xa; Fibrinopeptide A; Humans; Microscopy, Electron, Scanning; Prothrombin; Rabbits; Thrombin; Thrombolytic Therapy; Thromboplastin; Thrombosis

The abrupt cessation of heparin and other thrombin inhibitors when used to treat acute coronary syndromes has been accompanied by a clustering of thrombotic events. It is unknown whether these events are the result of inadequate antithrombin therapy or whether they represent a rebound increase in thrombin activity. This study was designed to determine whether there is a true rebound, as defined by an increase followed by a subsequent decrease, in thrombin activity after discontinuation of intravenous heparin therapy.. Thirty-five patients with recent acute myocardial infarction or unstable angina who had received at least 48 hours of intravenous heparin were studied. Patients underwent ST-segment monitoring, and blood samples for determination of thrombin generation and activity were drawn at 0, 3, 6, 10, and 24 hours after heparin discontinuation. Median aPTT was 65 seconds before heparin discontinuation. Median fibrinopeptide A increased from 9.5 to 16.9 ng/mL at 3 hours (P < .0004) and returned to 10.5 by 24 hours. Prothrombin fragment 1.2 likewise transiently increased, from 0.34 to 0.51 nmol/L at 6 hours (P < .0002). Modified antithrombin III decreased over time (P < .002), and activated protein C increased from 2.3 to 4.5 ng/mL at 3 hours (P < .001). Although there were no clinical thrombotic events in the first 24 hours, 4 patients had evidence of ischemia by ST-segment monitoring at a median of 12 hours after heparin discontinuation. The degree of increase in fibrinopeptide A and prothrombin fragment 1.2 was not found to be associated with baseline diagnosis, duration of heparin therapy, baseline level of antithrombin III, or activated protein C.. This study demonstrates a transient rebound increase in thrombin activity as well as in activated protein C upon abrupt discontinuation of intravenous heparin. Clinicians should be vigilant for associated thrombotic events. Further investigation of the significance, mechanism, and possible prevention of this rebound phenomenon is needed.

Topics: Aged; Angina, Unstable; Blood Coagulation Factors; Blood Coagulation Tests; Coronary Thrombosis; Electrocardiography; Female; Fibrinopeptide A; Heparin; Humans; Infusions, Intravenous; Male; Monitoring, Physiologic; Myocardial Infarction; Myocardial Ischemia; Protein C; Substance Withdrawal Syndrome; Thrombin; Thrombosis

Fibrinopeptide A (FPA) is a small polypeptide cleaved from fibrinogen by thrombin, has a short half-life, and is considered a sensitive biochemical marker of thrombin activity, fibrin generation, and ongoing thrombosis. Increased plasma levels of FPA have been reported in various procoagulable and thrombotic medical and cardiovascular disorders, including acute myocardial infarction, unstable angina, and sudden cardiac death. However, activation of thrombosis by the arterial injury incurred during coronary angioplasty has not been systematically examined with use of plasma FPA measurements. To detect and monitor activation of thrombosis by coronary angioplasty, plasma levels of FPA were obtained by venipuncture and measured by radioimmunoassay before, immediately after, 24 to 48 h later, and 1 and 3 months after uncomplicated coronary angioplasty. From December 1990 through June 1991, FPA was measured in 30 patients (28 men and 2 women, aged 54 +/- 9 years) with coronary artery disease who were undergoing coronary angioplasty. The mean left ventricular ejection fraction was 55 +/- 7%. The dilated vessel was the left anterior descending coronary artery in 20 patients (together with a second vessel in 2), the right coronary artery in 9, and the left circumflex in 1. The procedure was successful and free of major complications in all patients. Before angioplasty the FPA levels averaged 6.50 +/- 1.18 ng/ml. Shortly after angioplasty they rose to 20.20 +/- 7.91 ng/ml (p = 0.08) despite intravenous heparin. At 24 to 48 h and after heparin had been discontinued for at least 4 h, the mean FPA levels were significantly higher (32.33 +/- 10.86 ng/ml) compared with baseline values (p = 0.025).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angioplasty, Balloon, Coronary; Coronary Disease; Coronary Thrombosis; Female; Fibrinopeptide A; Humans; Male; Middle Aged; Radioimmunoassay; Risk Factors; Thrombin; Time Factors

We examined the relation between the level of urinary fibrinopeptide A and the presence of angiographic intracoronary thrombus in patients with unstable angina to determine whether this marker predicts active thrombus formation.. Although it is known that thrombus plays a role in acute ischemic syndromes, a noninvasive method to predict its presence in individual patients with unstable angina has not been determined. Fibrinopeptide A is a polypeptide cleaved from fibrinogen by thrombin and thus is a sensitive marker of thrombin activity and fibrin generation.. Angiographic thrombus, graded 0 to 4, and the presence of ST segment depression or T wave inversions, or both, on the electrocardiogram (ECG) were related to fibrinopeptide A levels in 24 patients with rest angina of new onset, 18 with crescendo angina, 19 with stable angina and 9 with chest pain but without coronary artery disease. All patients had chest pain within the 24 h of sample acquisition.. The angiographic incidence of thrombus was significantly higher in patients with new onset of rest angina (67%, p < 0.001) and crescendo angina (50%, p < 0.001) as were fibrinopeptide A levels (p = 0.002). Fibrinopeptide A levels correlated significantly (p < 0.001) with the presence of a filling defect (grade 4 intracoronary thrombus) or contrast staining (grade 3). All patients with fibrinopeptide A > or = 8 ng/mg creatinine showed grade 3 to 4 thrombus and 15 of 16 patients with levels > or = 6.0 ng/mg creatinine exhibited angiographic evidence of thrombus (13 with grades 3 to 4). Patients with reversible ST changes on the ECG had significantly higher levels of fibrinopeptide A (p < 0.001), and ST changes correlated significantly with the presence of angiographic thrombus (p < 0.001). Nonetheless, a significant minority of patients with unstable angina had neither angiographic nor biochemical evidence of thrombus.. Elevated fibrinopeptide A levels in unstable angina reflected active intracoronary thrombus formation and were present in patients with angina of new onset as well as crescendo angina. Reversible ST changes are accompanied by thrombin activity and angiographic thrombus formation. However, a sizable percentage of patients with unstable angina had no evidence of thrombus and these patients may have had transient platelet aggregation without fibrin thrombus formation.

Topics: Angina, Unstable; Coronary Angiography; Coronary Thrombosis; Electrocardiography; Female; Fibrinopeptide A; Humans; Male; Middle Aged; Predictive Value of Tests; Regression Analysis

Topics: Aspirin; Coronary Thrombosis; Fibrinolytic Agents; Fibrinopeptide A; Heparin; Humans; Myocardial Infarction; Thrombin; Tissue Plasminogen Activator

In a majority of instances, both unstable angina and acute myocardial infarction occur secondary to plaque disruption and thrombus formation. Although the pathogenetic substrates are similar the clinical presentations are quite different. It is hypothesized in this editorial review that the amount of acute thrombus formation and specifically fibrin deposition is greater in myocardial infarction than in unstable angina. Both angiographic studies and studies analyzing the response to thrombolytic agents suggest more thrombus in myocardial infarction than in unstable angina. These data have recently been substantiated by angioscopic observations in these acute syndromes suggesting that more platelet-rich (whitish) thrombus occurs in unstable angina and more red thrombus in myocardial infarction. The red thrombus presumably would be more responsive to thrombolytic agents. Furthermore, it is proposed that these differences between syndromes in acute thrombus formation can be explained by the interplay of vessel wall injury, coagulation variables or stasis of blood flow occurring at or after the time of presentation. Therefore, acute myocardial infarction is associated with occlusive, fibrin-rich thrombus, whereas in unstable angina, the thrombus is nonocclusive, mural and possibly more platelet-rich. However, the clinical syndrome that ultimately develops after plaque disruption is dependent not only on the amount of acute thrombus formation but on the net result of all factors that influence the balance between coronary blood supply and myocardial oxygen demand.

Topics: Angina, Unstable; Blood Platelets; Coronary Angiography; Coronary Thrombosis; Endoscopy; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinopeptide A; Humans; Myocardial Infarction; Plasminogen Inactivators; Thrombolytic Therapy

Plasma levels and 24-hour urine excretion of fibrinopeptide A were measured in a consecutive series of 179 patients with angina pectoris. Sixty-four patients had stable angina and 115 patients had unstable angina. Urine was collected over 24 hours the day before coronary arteriography, and blood samples were taken at the end of urine collection. When the values of fibrinopeptide A in plasma and in the 24-hour urine specimens were compared, no significant correlation was found in patients with either stable (rs = 0.16, difference not significant) and unstable (rs = 0.07, difference not significant) angina. The concentrations of fibrinopeptide A in the plasma did not differ significantly when patients with stable angina (range 0.1 to 82.6, median 7.4 ng/mL) were compared with patients with unstable angina (range 0.2 to 61.7, median 14 ng/mL, p = 0.055), whereas fibrinopeptide A 24-hour urinary excretion was significantly higher in patients with unstable angina (range 0.3 to 38.1, median 11.8 micrograms/24 hr) than in patients with stable angina (range 0.4 to 38.1, median 3.8 micrograms/24 hr, p less than 0.001). Twenty-four-hour urine excretion of fibrinopeptide A in patients with unstable angina and angiographically documented intracoronary thrombi were higher than the corresponding values in patients with unstable angina without such angiographic characteristic (p less than 0.001). The largest increase in plasma and urine concentration of fibrinopeptide A was observed in patients whose first episode of angina at rest occurred within the previous 48 hours. We conclude that the cumulative thrombin activity, assessed by 24-hour urinary excretion of fibrinopeptide A, is a more useful index, compared with single fibrinopeptide A measurement in plasma, for discriminating between patients with stable and with unstable angina pectoris.

Topics: Angina Pectoris; Angina Pectoris, Variant; Angina, Unstable; Coronary Angiography; Coronary Thrombosis; Female; Fibrinogen; Fibrinopeptide A; Humans; Male; Middle Aged; Prevalence; Prospective Studies; Thrombin

This study was designed to determine in patients with unstable angina whether specific electrocardiographic abnormalities associated with ischemia, the presence of coronary lesions consistent with thrombosis on angiography or the presence of recurrent ischemia reflects increases in thrombin activity as manifested by increased plasma concentrations of fibrinopeptide A. The concentration of fibrinopeptide A in plasma was increased to 6.7 +/- 3.1 nM for the group as a whole (n = 29). Increases were greater in the 17 patients who exhibited reversible ST segment shifts (10.2 +/- 5.2 nM) than in the 12 patients exhibiting reversible T wave abnormalities alone (1.6 +/- 0.2 nM) (p less than 0.01). Nine of the 17 patients with reversible ST segment shifts who underwent coronary angiography had lesions with morphologic characteristics consistent with atherosclerotic plaque complicated by thrombosis compared with only 2 of 9 patients with T wave changes only (p less than 0.05). Plasma concentrations of fibrinopeptide A were markedly elevated in 7 of the 11 patients in whom complex lesions were noted on angiographic examination. Thus, the occurrence of reversible ST segment shifts identifies a group of patients with unstable angina in whom ongoing thrombosis is likely and who may be particularly likely to benefit from antithrombotic therapy.

Topics: Angina, Unstable; Coronary Angiography; Coronary Thrombosis; Electrocardiography; Enzyme-Linked Immunosorbent Assay; Fibrin Fibrinogen Degradation Products; Fibrinopeptide A; Humans; Middle Aged; Recurrence

Topics: Antithrombin III; Coronary Thrombosis; Fibrinolysis; Fibrinolytic Agents; Fibrinopeptide A; Humans; Reagent Kits, Diagnostic; Thrombin

Elevated levels of fibrinopeptide A, a marker of thrombin activity associated with acute myocardial infarction, have been found to decrease after administration of streptokinase when reperfusion occurs. In contrast, in patients without reperfusion and those with reocclusion after streptokinase therapy, fibrinopeptide A remains elevated. In the present study early serial measurements of fibrinopeptide A were used to further characterize this paradoxic increase in thrombin activity after streptokinase and to characterize its response to heparin. In 19 patients with acute myocardial infarction fibrinopeptide A was elevated to 82.3 +/- 43.5 ng/ml (mean +/- SE) before therapy. Thirty minutes after the initiation of streptokinase, fibrinopeptide A increased to 300.1 +/- 117.4 ng/ml (p less than 0.01), consistent with extensive thrombin activity. Fibrinopeptide A remained elevated until 15 minutes after a heparin bolus injection when levels decreased to 15% of the poststreptokinase value (49.2 +/- 13.3 ng/ml) (p less than 0.001). These data document a prompt paradoxic increase in thrombin activity after administration of streptokinase that may be responsible for failure of therapy in some patients.

Topics: Cardiomyopathies; Coronary Circulation; Coronary Disease; Coronary Thrombosis; Fibrinogen; Fibrinolysis; Fibrinopeptide A; Humans; Streptokinase