Inhibition and reversal of platelet aggregation by alphaIIbbeta3 antagonists depends on the anticoagulant and flow conditions: differential effects of Abciximab and Lamifiban.
Shear influences platelet aggregate formation and stability, as well as the inhibitory capacities of antithrombotic drugs. We compared the inhibitory and disaggregating properties of two distinct alphaIIbbeta3 antagonists, Abciximab and Lamifiban, on platelet aggregation induced by adenosine diphosphate (ADP) (5 micromol/l) in platelet-rich plasma (PRP), in an aggregometer (poorly defined low shear, <100/s) and in a microcouette at arterial shear rate (1,000/s). Platelet aggregation was detected by changes in light transmission in the aggregometer (TA), and by particle counting with a flow cytometer (PA). Lamifiban (1 mumol/l) completely inhibited TA or PA induced by ADP in citrated PRP in the aggregometer or microcouette. In contrast, Abciximab (2 micromol/l) only partially inhibited PA in the microcouette while blocking both TA and PA in the aggregometer. Moreover, Abciximab did not reverse platelet aggregates formed either in the microcouette or in the aggregometer, whereas Lamifiban caused complete reversal. On the contrary, Abciximab completely inhibited platelet aggregation induced by ADP in hirudin/d-Phe-Pro-Arg-chloromethylketone PRP in the microcouette. Our results demonstrate a marked dependence of inhibitory capacity of Abciximab on shear conditions, with citrate anticoagulant responsible for the residual aggregation, in contrast to Lamifiban, another alphaIIbbeta3 antagonist interacting with a distinct site on beta3.
Frojmovic
Mony
M
INSERM U553, Institut Universitaire d'Hématologie Paris VII, Hôpital Saint-Louis, Paris, France.
Labarthe
Benoit
B
Legrand
Chantal
C
D000077284:Abciximab; D000085:Acetates / Q000494:pharmacology*; D000244:Adenosine Diphosphate; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000925:Anticoagulants / Q000494:pharmacology; D001792:Blood Platelets / Q000378:metabolism; D001800:Blood Specimen Collection / Q000379:methods; D005340:Fibrinogen / Q000378:metabolism; D018056:Hemorheology; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology*; D019007:P-Selectin / Q000097:blood; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D010979:Platelet Function Tests / Q000379:methods; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000494:pharmacology
D000085:Acetates; D000911:Antibodies, Monoclonal; D000925:Anticoagulants; D007140:Immunoglobulin Fab Fragments; D019007:P-Selectin; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D014443:Tyrosine; D000244:Adenosine Diphosphate; D005340:Fibrinogen; C084062:lamifiban; D000077284:Abciximab