fibrinopeptide-a and Coronary-Artery-Disease

To characterize effects of bivalirudin compared with unfractionated heparin plus eptifibatide on inflammation, and thrombin generation and activity after percutaneous coronary intervention.. We measured the concentration in blood of fibrinopeptide A, prothrombin fragment 1+2, soluble CD40 ligand, interleukin 1 receptor antagonist, interleukin 6, and high sensitivity C-reactive protein in 63 patients treated with aspirin and clopidogrel and undergoing elective percutaneous coronary intervention, who were randomized to treatment with either bivalirudin (n=34) or unfractionated heparin plus eptifibatide (n=29).. Neither generation nor activity of thrombin increased 10 min after percutaneous coronary intervention in patients randomized to bivalirudin or unfractionated heparin plus eptifibatide. However, prothrombin fragment 1+2 increased modestly and comparably in both groups after 1 day. Inflammation, reflected by concentrations of interleukin 6 and high sensitivity C-reactive protein in blood, increased similarly 1 day after percutaneous coronary intervention in patients treated with either regimen. In a subset of patients (n=12 in each group) from whom blood was obtained 30 days after percutaneous coronary intervention, the concentration of high sensitivity C-reactive protein was lower in those who had been treated with bivalirudin (by 3.5 mg/l, P=0.002).. The early effects on inflammation and thrombin generation and activity are similar after treatment with bivalirudin alone compared with unfractionated heparin plus eptifibatide in patients treated with aspirin and clopidogrel who are undergoing percutaneous coronary intervention for symptoms of stable angina. The decreased concentration of high sensitivity C-reactive protein seen 30 days after percutaneous coronary intervention in those treated with bivalirudin is consistent with greater attenuation of inflammation that may have contributed to the trend toward reduced mortality 1 year later in those treated with bivalirudin in REPLACE-2.

Topics: Aged; Angioplasty, Balloon, Coronary; Anticoagulants; C-Reactive Protein; CD40 Ligand; Combined Modality Therapy; Coronary Artery Disease; Eptifibatide; Female; Fibrinopeptide A; Heparin; Hirudins; Humans; Interleukin-6; Male; Middle Aged; Peptide Fragments; Peptides; Platelet Aggregation Inhibitors; Protein Precursors; Prothrombin; Receptors, Interleukin-1; Recombinant Proteins; Thrombin; Treatment Outcome

Clinical trials evaluating direct thrombin inhibitors in unstable coronary artery disease (CAD) have been disappointing. The hypothesis tested in the present study was that these agents may inhibit the anticoagulant effect of thrombin to a further extent than the procoagulant effect of thrombin.. We studied both reversible and irreversible thrombin inhibitors and compared the effects of each inhibitor on activated protein C (APC) generation vs. the effect on fibrinopeptide A (FPA) generation. A mixture of protein C, thrombin inhibitor, fibrinogen, fibrin polymerisation blocker and thrombin was incubated with thrombomodulin (TM)-expressing human saphenous vein endothelial cells (HSVECs). The inhibitors investigated were melagatran, inogatran, hirudin, hirugen, D-Phe-D-Pro-D-arginyl chloromethyl ketone (PPACK), and antithrombin (AT) alone or in combination with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH).. All agents, except hirugen, inhibited APC and FPA generation in a dose-dependent manner. FPA inhibition/APC inhibition ratios, based on IC50 for inogatran, melagatran, hirudin, PPACK, AT, AT-UFH and AT-LMWH were 1.73, 0.85, 0.55, 2.1, 0.5, 0.65 and 3.1 respectively.. All agents, except hirugen, inhibited APC and FPA generation approximately to a similar extent. Thus, it can be inferred that the poor efficacy of thrombin inhibitors in recent clinical trials in patients with unstable CAD is unlikely to be a consequence of their effects on the protein C system.

Topics: Amino Acid Chloromethyl Ketones; Anticoagulants; Azetidines; Benzylamines; Clinical Trials as Topic; Coagulants; Coronary Artery Disease; Fibrinopeptide A; Glycine; Hirudins; Humans; Peptide Fragments; Piperidines; Protein C; Thrombin

Optimal anti-thrombotic therapy for acute coronary syndromes (ACS) should suppress pro-thrombotic activity at the site of plaque rupture. We sought to determine whether platelet reactivity is increased in blood in the immediate vicinity of a ruptured plaque and is apparent even when blood is obtained by sampling from a catheter placed proximal to the lesion.. Blood was obtained from a catheter placed in the aorta and from the same catheter after engaging the culprit coronary artery. Platelet reactivity was determined with the use of flow cytometry by surface expression of P-selectin.. In preliminary studies we demonstrated that a marker of thrombin activity, fibrinopeptide A, was similarly increased in blood taken from the coronary sinus and coronary arterial ostium of patients with ACS. Subsequently blood was obtained from the aorta and coronary arterial ostium through a coronary guide catheter for assessment of platelet reactivity in 23 subjects with ACS and 22 subjects with stable angina. The percentage of platelets expressing P-selectin in response to 0.2 microM adenosine diphosphate (ADP) was greater in coronary arterial samples from patients with ACS (aorta=6.1+/-1%, coronary artery=8.8+/-1.6%, p=0.02) compared with that in patients with stable symptoms (aorta=6.9+/-1.2, coronary artery=6.5+/-1.4, p=NS).. Coronary arterial blood obtained from the ostium through a coronary guide catheter can be used to determine whether thrombin activity and platelet reactivity are increased in the immediate vicinity of a ruptured atherosclerotic plaque. The simplicity of the approach developed should facilitate its use in future studies designed to determine the impact of optimal suppression of platelet reactivity and the pro-thrombotic state before coronary interventions on short- and long-term clinical outcomes.

Topics: Acute Disease; Aged; Aorta; Case-Control Studies; Coronary Artery Disease; Coronary Circulation; Coronary Vessels; Fibrinolytic Agents; Fibrinopeptide A; Humans; Male; Middle Aged; P-Selectin; Platelet Activation; Rupture, Spontaneous; Thrombophilia

Fibrinopeptide A was determined in 75 middle aged male patients, five control subjects and a control group of young medical students, divided into nine subsets. The FPA levels were significantly elevated in the patient group, particularly among the diabetics, when compared with the medical students and also age matched controls. Diabetic patients who smoked and had vascular pathology had high FPA levels even after they stopped smoking.

Topics: Angina Pectoris; Biomarkers; Coronary Artery Disease; Diabetic Angiopathies; Fibrinopeptide A; Humans; Male; Middle Aged; Smoking; Thrombosis