Tirofiban (Aggrastat) protects platelets and decreases platelet-granulocyte binding in an extracorporeal circulation model.
OBJECTIVE
Extracorporeal circulation (ECC) induces platelet activation and inflammation with potentially life-threatening organ dysfunction. Short-acting GP IIb/IIIa inhibitors like tirofiban and eptifibatide protect platelets during ECC without increasing bleeding complications and may reduce inflammation. This study investigates anti-thrombotic and anti-inflammatory effects of different platelet inhibitors.


METHODS
Control (untreated) and treated (using either 150 ng/mL tirofiban, 2.5 microg/mL eptifibatide, 0.7 microg/mL milrinone, 15 microg/mL dipyridamol, or 300 KIU/mL aprotinin) heparinized blood of healthy volunteers (n = 6) was recirculated in a well-established ECC model (Chandler loop). Percentage of platelet aggregates, P-selectin-expressing (activated) platelets, CD15-positive aggregates (indicating proinflammatory platelet-granulocyte binding), and platelet counts were determined before (baseline) and after 30 minutes recirculation in unstimulated and ADP-stimulated samples using flow cytometry. Statistical analysis was performed using multifactor ANOVA after transforming the data (logarithms for counts and log odds for percentages). Least square means were backtransformed to obtain appropriate means and their 95 % confidence intervals. Multiple post-hoc comparisons were performed by Tukey's HSD test with a global alpha of 5 %.


RESULTS
Significant inhibition was observed for: 1) ECC-induced platelet aggregation by tirofiban (unstimulated: 2.2-fold/stimulated: 2.46-fold), eptifibatide (unstimulated: 1.96-fold/stimulated: 2.65-fold), and milrinone (unstimulated: 1.87-fold/stimulated: 1.37-fold); 2) ECC-induced P-selectin expression by tirofiban (unstimulated: 3.95-fold/stimulated: 2.54-fold), and eptifibatide (unstimulated: 5.87-fold/stimulated: 3.28-fold); 3) ECC-induced platelet loss by tirofiban (1.27-fold), and eptifibatide (1.25-fold); 4) ECC-induced platelet-granulocyte binding by tirofiban (unstimulated: 2.25-fold/stimulated: 1.59-fold), but not by eptifibatide.


CONCLUSIONS
Amongst the investigated drugs only GP IIb/IIIa inhibitors decreased activation, aggregation, and loss of platelets during ECC but acted differently on platelet-granulocyte interaction. A short-acting GP IIb/IIIa inhibitor with the potential to inhibit platelet activation and platelet-leukocyte interaction should be considered both for platelet protection and inhibition of platelet-mediated inflammation during ECC.
Straub
A
A
Department of Thoracic, Cardiac and Vascular Surgery, University of Tübingen, Tübingen, Germany. anstraub@nexgo.de
Azevedo
R
R
Beierlein
W
W
Wendel
H P
HP
Dietz
K
K
Ziemer
G
G
D007611:Aprotinin / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects*; D015415:Biomarkers / Q000097:blood; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D004176:Dipyridamole / Q000494:pharmacology; D000077542:Eptifibatide; D005112:Extracorporeal Circulation; D005434:Flow Cytometry; D006098:Granulocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008297:Male; D020105:Milrinone / Q000494:pharmacology; D019007:P-Selectin / Q000096:biosynthesis / Q000187:drug effects; D010455:Peptides / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D010976:Platelet Count; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D000077466:Tirofiban; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000494:pharmacology
D015415:Biomarkers; D019007:P-Selectin; D010455:Peptides; D010726:Phosphodiesterase Inhibitors; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D015842:Serine Proteinase Inhibitors; D014443:Tyrosine; D004176:Dipyridamole; D007611:Aprotinin; D000077466:Tirofiban; D020105:Milrinone; D000077542:Eptifibatide