piperidines and Thrombophilia

Unstable coronary artery disease is in most cases associated with plaque rupture, activation of the coagulation system and subsequent intracoronary thrombus formation which may cause myocardial cell damage. The aim of the present analysis was to assess the relation between troponin T, markers of coagulation activity, i.e. prothrombin fragment 1+2, thrombin-antithrombin complex, soluble fibrin and D-dimer, and ischemic events, i.e. death, myocardial (re-)infarction or refractory angina. 320 patients with unstable coronary artery disease were randomized to 72 hours infusion with inogatran, a low molecular weight direct thrombin inhibitor, or unfractionated heparin. Patients with elevated troponin levels had higher levels of prothrombin fragment 1+2, soluble fibrin and D-dimer before, during, and at 24 hours after cessation of anticoagulant treatment. These troponin-positive patients tended to have worse short-term clinical outcome, without relation to markers of coagulation activity. Troponin-negative patients with unchanged or early increased thrombin generation during treatment had a cluster of ischemic events within 24 hours after cessation of the study drug. The 30-day ischemic event rate was 19 % in troponin-negative patients with unchanged or early increased prothrombin fragment 1+2, and 5.7 % in patients with decreased prothrombin fragment 1+2, p=0.006, and similarly 15 % in troponin-negative patients with unchanged or early increased thrombin-antithrombin complex and 4.5 % in patients with decreased thrombin-antithrombin complex, p=0.02. In conclusion, in unstable coronary artery disease a troponin elevation indicates higher risk and higher coagulation activity. However, among the troponin negative patients, with a lower risk and lower coagulation activity, a part of the patients seem to be non-responders to treatment with a thrombin inhibitor expressed as unchanged or raised coagulation activity and a raised risk of ischemic events early after cessation of treatment.

Topics: Adult; Aged; Biomarkers; Blood Coagulation; Coronary Artery Disease; Glycine; Heparin; Humans; Middle Aged; Myocardial Ischemia; Piperidines; Predictive Value of Tests; Risk Factors; Thrombin; Thrombophilia; Treatment Failure; Treatment Outcome; Troponin T

Stress evokes lipolytic release of free fatty acid (FFA) and low-grade inflammation in visceral adipose tissue, mediated by increased adipokine secretion, and contributes to glucose metabolism disorder and prothrombotic state. We tested the hypothesis that alogliptin, a dipeptidyl peptidase-4 inhibitor, can ameliorate the biological effects of chronic stress in mice.. C57BL/6J mice were subjected to 2-week intermittent restraint stress and orally treated with vehicle or alogliptin (dose: 15 or 45mg/kg/day). Plasma levels of lipids, proinflammatory cytokines (monocyte chemoattractant protein-1, tumor necrosis factor-α, and interleukin-6), and 8-hydroxydeoxyguanosine were measured with enzyme-linked immunosorbent assay. Monocyte/macrophage accumulation in inguinal white adipose tissue (WAT) was examined by CD11b-positive cell count and mRNA expression of CD68 and F4/80 was examined by immunohistochemistry and RT-PCR, respectively. The mRNA levels of the above-mentioned proinflammatory cytokines, NADPH oxidase 4, adiponectin, and coagulation factors (plasminogen activation inhibitor-1 and tissue factor) in WAT were also assessed with RT-PCR. Glucose metabolism was assessed by glucose and insulin tolerance tests, plasma levels of DPP-4 activity, glucagon-like peptide-1, expression of DPP-4, insulin receptor substrate-1 and glucose transporter 4 in WAT and skeletal muscle. Alogliptin administration suppressed stress-induced FFA release, oxidative stress, adipose tissue inflammation, DPP-4 activation, and prothrombotic state in a dose-dependent manner, and improved insulin sensitivity in stressed mice.. The results indicate that alogliptin improves stress-induced prothrombotic state and insulin resistance; suggesting that alogliptin could have beneficial therapeutic effects against cardiovascular complications in diabetic patients under stress.

Topics: Adipose Tissue; Animals; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Inflammation; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Piperidines; Stress, Psychological; Thrombophilia; Uracil

Platelets are hyperactive in Type 2 diabetes mellitus (T2DM), and antiplatelet treatment with glycoprotein (GP) IIb/IIIa inhibitors provides better thrombotic protection in DM than in non-diabetic subjects.. We hypothesized that diabetic platelets are hyperprocoagulant, and that this hyperactivity can be inhibited by GPIIb/IIIa blockade.. Patients with T2DM and gender/age/body mass index-matched non-diabetic controls were recruited (n = 12 for both) to study the effect of GPIIb/IIIa blockade on platelet procoagulant activity. Platelet phosphotidylserine (PS), factor (F) Va expression, and platelet-derived microparticle (PDMP) generation were measured by whole blood flow cytometry. Platelet-dependent thrombin generation and plasma clotting time were monitored in recalcified platelet-rich plasma.. Compared to controls, basal platelet activation was similar, while thrombin receptor activating peptide stimulated activation was enhanced in patients with T2DM. Diabetic platelets also displayed more profound elevations of platelet PS exposure, FVa binding, and PDMP generation upon stimulation. These alterations resulted in a hyperprocoagulant state, as evidenced by a marked increase in the platelet procoagulant index, enhanced thrombin generation, and a shortened plasma clotting time. GPIIb/IIIa blockade by c7E3 or SR121566 decreased platelet PS exposure and FVa binding, and diminished platelet procoagulant activity in patients with T2DM.. Platelets have increased procoagulant activity in patients with T2DM. The hyperprocoagulant activity is counteracted by GPIIb/IIIa blockade.

Topics: Benzylamines; Blood Platelets; Case-Control Studies; Diabetes Mellitus, Type 2; Humans; Phosphatidylserines; Piperidines; Platelet Activation; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Receptors, Thrombin; Thiazoles; Thrombophilia

Coagulation abnormalities, including an increased platelet turnover, are frequently found in patients with cancer. Because platelets secrete angiogenic factors on activation, this study tested the hypothesis that platelets contribute to angiogenesis. Stimulation with vascular endothelial growth factor (VEGF, 25 ng/mL) of human umbilical vein endothelial cells (HUVECs) promoted adhesion of nonactivated platelets 2.5-fold. In contrast, stimulation of HUVECs with basic fibroblast growth factor (bFGF) did not promote platelet adhesion. By blocking tissue factor (TF) activity, platelet adhesion was prevented and antibodies against fibrin(ogen) and the platelet-specific integrin, alpha(IIb)beta(3), inhibited platelet adhesion for 70% to 90%. These results indicate that VEGF-induced platelet adhesion to endothelial cells is dependent on activation of TF. The involvement of fibrin(ogen) and the alpha(IIb)beta(3) integrin, which exposes a high-affinity binding site for fibrin(ogen) on platelet activation, indicates that these adhering platelets are activated. This was supported by the finding that the activity of thrombin, a product of TF-activated coagulation and a potent platelet activator, was required for platelet adhesion. Finally, platelets at physiologic concentrations stimulated proliferation of HUVECs, indicative of proangiogenic activity in vivo. These results support the hypothesis that platelets contribute to tumor-induced angiogenesis. In addition, they may explain the clinical observation of an increased platelet turnover in cancer patients. Platelets may also play an important role in other angiogenesis-dependent diseases in which VEGF is involved, such as diabetes and autoimmune diseases. (Blood. 2000;96:4216-4221)

Topics: Adult; Blood Platelets; Cell Division; Cells, Cultured; Endothelial Growth Factors; Endothelium, Vascular; Fibroblast Growth Factor 2; Flow Cytometry; Humans; Lymphokines; Microscopy, Fluorescence; Neoplasms; Neovascularization, Pathologic; Phenylalanine; Piperidines; Platelet Activation; Platelet Adhesiveness; Platelet Aggregation Inhibitors; Thrombin; Thrombophilia; Umbilical Veins; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors