Augmentation of inhibitory effects of glycoprotein IIb-IIIa antagonists in patients with diabetes.
BACKGROUND
Patients with diabetes mellitus and acute coronary syndromes (ACS) derive enhanced benefit from treatment with glycoprotein (GP) IIb-IIIa inhibitors. To determine mechanisms potentially responsible we characterized the binding of fibrinogen to platelets from patients with and without diabetes in the presence and absence of GP IIb-IIIa antagonists.


METHODS
GP IIb-IIIa antagonists (tirofiban, eptifibatide, and abciximab) were added in vitro to blood from patients with and without diabetes. Binding of fibrinogen to activated GP IIb-IIIa was assessed with the use of flow cytometry. The kinetics of binding of I(125)-abciximab and I(125)-fibrinogen to washed platelets from subjects with and without diabetes mellitus were determined. Glycation of platelet membrane proteins was measured with the fructosamine assay.


RESULTS
In the presence of GP IIb-IIIa antagonists, activation-induced binding of fibrinogen to platelets was reduced to a greater extent (p<0.02) in blood from patients with diabetes. The greater inhibition in blood from patients with diabetes was seen with pharmacologic concentrations of tirofiban (50 ng/ml, by 27%), eptifibatide (1.5 microg/ml, by 24%), and abciximab (2 mg/ml, by 12%). Whereas the binding of I(125)-abciximab was similar to platelets from patients with diabetes and those without, the rate of binding of I(125)-fibrinogen was decreased with platelets from patients with diabetes. Binding after 5 min was reduced by 46% in those with diabetes (p<0.05). Platelet membrane proteins from patients with diabetes were glycated to a greater extent compared with those without diabetes.


CONCLUSIONS
GP IIb-IIIa antagonists inhibit platelet activation to a greater extent in blood from patients with diabetes. The decreased rate of binding of fibrinogen early after activation of platelets appears to be a consequence of glycation and may promote inhibition by GP IIb-IIIa antagonists.
Keating
F K
FK
Cardiology Unit, Department of Medicine, Fletcher Allen Health Care, McClure 1, University of Vermont, 111 Colchester Avenue, Burlington, VT 05401, USA. friederike.keating@vtmednet.org
Whitaker
D A
DA
Sobel
B E
BE
Schneider
D J
DJ
D000077284:Abciximab; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000493:pharmacokinetics; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000188:drug therapy / Q000209:etiology; D005260:Female; D005340:Fibrinogen / Q000378:metabolism / Q000493:pharmacokinetics; D006031:Glycosylation; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008565:Membrane Proteins / Q000187:drug effects / Q000378:metabolism; D008875:Middle Aged; D010974:Platelet Aggregation / Q000187:drug effects / Q000502:physiology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D011485:Protein Binding / Q000187:drug effects; D013997:Time Factors
D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments; D008565:Membrane Proteins; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D005340:Fibrinogen; D000077284:Abciximab