Platelet Biology, Coagulation, and Fibrinolysis
Platelet Biology, Coagulation, and Fibrinolysis
We have demonstrated that the combination of hyperinsulinemia, hyperglycemia and increased concentrations of free fatty acids in blood of healthy subjects increases the concentration and activity of the primary inhibitor of fibrinolysis, plasminogen activator inhibitor type-1. Illustration: mechanisms of activation of platelets
In vitro studies delineated that increased concentrations in blood of insulin increase expression of PAI-1 through stabilization of mRNA. In addition, we demonstrated that free fatty acids increase expression of PAI-1 by increasing transcription of PAI-1 through a fatty acid response region in the 5’ untranslated region of the PAI-1 gene.
In addition, we have developed a semi-quantitative method to assess plaque morphology in mice. This approach has been implemented to determine the role of genetic modifications such as increased vascular smooth muscle expression of PAI-1 in the genesis of atherosclerotic lesions. We have developed and implemented a sensitive and specific means for assessment of platelet function that utilizes flow cytometry to characterize specific components of platelet reactivity. Our work has utilized this method to delineate the prognostic implications of platelet reactivity and to characterize the effects of selected treatment modalities on platelet function and prognosis.
Recent Grant Support
American Diabetes Association: "Mechanisms of Fatty Acid Induced Hypofibrinolysis in Diabetes" - 1/99-12/02
Schneider, Principal Investigator
NIH: (P20 RR1557) "Translational Research in Lung Biology and Disease" - 10/00 - 9/05, "Elucidation of the role of altered pulmonary proteolysis in the pathogenesis of asthma"
Charles Irvin, Principal Investigator, Schneider, Co-investigator
NIH: (U01 HL61744) "BARI 2D" - 1/01-12/07
Kathryn Detre, Principal Investigator, Schneider, Co-Investigator
Merck: "Early Inhibitory Properties of Tirofiban and Abciximab During PCI in Patients with Acute Coronary Syndromes" - 01/01 - 06/01
Schneider, Principal Investigator
NIH: (R01 HL69146) "Mechanisms of Pro-Thrombosis in Diabetes Mellitus" - 7/01/01 6/30/04
Schneider, Principal Investigator
Merck: "An Open-Label, Sequential, Dose-Finding Study of Tirofiban in Combination with Unfractionated Heparin in Patients with Acute Coronary Syndromes Undergoing Percutaneous Coronary Intervention" - 08/01 - 7/02
Schneider, Principal Investigator and Director of Core Laboratory
Centocor: "Platelet Function, GP IIIa Polymorphism, and PCI in BARI 2D An Ancillary Study to BARI 2D" - 1/02 - 12/04
Schneider, Principal Investigator
Fletcher Allen Health Care Research Development Fund: "Changes in Platelet Reactivity after Acute Coronary Syndromes" - 10/01 - 9/03
Schneider, Principal Investigator
Representative Publications
Schneider, D.J., Nordt, T.K., and Sobel, B.E.: Attenuated fibrinolysis and atherogenesis in noninsulin-dependent diabetic subjects. Diabetes 42:1, 1993.
Schneider, D.J., Absher, P.M., and Ricci, M.A.: Dependence of augmentation of arterial endothelial cell expression of plasminogen activator inhibitor type 1 by insulin on soluble factors released from vascular smooth muscle cells. Circulation, 96:2868-76, 1997.
Taatjes, D.J., Wadsworth, M.P., Schneider, D.J., Sobel, B.E.: Improved quantitative characterization of atherosclerotic plaque composition with immunohistochemistry, confocal fluorescence microscopy, and computer-assisted image analysis. Histochem. Cell Biol., 113:161-73, 2000
Holmes, M.B., Schneider, D.J., Hayes, M. Sobel, B.E., Mann K.G.: A novel bedside, tissue factor-dependent clotting assay permitting improved assessment of both antithrombotic and antiplatelet therapy. Circulation, 102:2051-7, 2000
Chen Y., Billadello J.J., Schneider D.J.: Identification and localization of a fatty acid response region in human plasminogen activator inhibitor-1 gene. Arterioscler Thrombos Vasc Biol, 20:2696-701, 2000
Schneider, D.J., Baumann, P.Q., Holmes, M.B., Taatjes, D.J., Sobel, B.E.: Time and dose dependent augmentation of inhibitory effects of abciximab by aspirin. Thromb Haemost 85:309-13, 2001
Kabbani, S.S., Watkins, M.W., Ashikaga, T., Terrien, E.F., Holoch, P.A., Sobel, B.E., Schneider, D.J.: Platelet reactivity characterized prospectively: a determinant of outcome 90 days after percutaneous coronary intervention. Circulation, 104:181-6, 2001
