TY - JOUR
T1 - Recombinant GPVI-Fc added to single or dual antiplatelet therapy in vitro prevents plaque-induced platelet thrombus formation
AU - Munoz, Ann-Katrin Mojica
AU - Jamasbi, Janina
AU - Uhland, Kerstin
AU - Degen, Heidrun
AU - Muench, Goetz
AU - Ungerer, Martin
AU - Brandl, Richard
AU - Megens, Remco
AU - Weber, Christian
AU - Lorenz, Reinhard
AU - Siess, Wolfgang
PY - 2017/8
Y1 - 2017/8
N2 - The efficiency of current dual antiplatelet therapy might be further improved by its combination with a glycoprotein (GP) VI-targeting strategy without increasing bleeding. GPVI-Fc, a recombinant dimeric fusion protein binding to plaque collagen and concealing binding sites for platelet GPVI, acts as a lesion-focused antiplatelet drug, and does not increase bleeding in vivo. We investigated, whether GPVI-Fc added in vitro on top of acetylsalicylic acid (ASA), the P2Y(12) antagonist ticagrelor, and the fibrinogen receptor antagonist abciximab alone or in combination would increase inhibition of platelet activation by atherosclerotic plaque. Under static conditions, GPVI-Fc inhibited plaque-induced platelet aggregation by 53%, and increased platelet inhibition by ASA (51%) and ticagrelor (64%) to 66% and 80%, respectively. Under arterial flow, GPVI-Fc inhibited plaque-induced platelet aggregation by 57%, and significantly increased platelet inhibition by ASA (28%) and ticagrelor (47%) to about 81% each. The triple combination of GPVI-Fc, ASA and ticagrelor achieved almost complete inhibition of plaque-induced platelet aggregation (93%). GPVI-Fc alone or in combination with ASA or ticagrelor did not increase closure time measured by the platelet function analyzer (PFA)-200. GPVI-Fc added on top of abciximab, a clinically used anti fibrinogen receptor antibody which blocks platelet aggregation, strongly inhibited total (81%) and stable (89%) platelet adhesion. We conclude that GPVI-Fc added on top of single or dual antiplatelet therapy with ASA and/or a P2Y12 antagonist is likely to improve anti-atherothrombotic protection without increasing bleeding risk. In contrast, the strong inhibition of platelet adhesion by GPVI-Fc in combination with GPIIb/Illa inhibitors could be harmful.
AB - The efficiency of current dual antiplatelet therapy might be further improved by its combination with a glycoprotein (GP) VI-targeting strategy without increasing bleeding. GPVI-Fc, a recombinant dimeric fusion protein binding to plaque collagen and concealing binding sites for platelet GPVI, acts as a lesion-focused antiplatelet drug, and does not increase bleeding in vivo. We investigated, whether GPVI-Fc added in vitro on top of acetylsalicylic acid (ASA), the P2Y(12) antagonist ticagrelor, and the fibrinogen receptor antagonist abciximab alone or in combination would increase inhibition of platelet activation by atherosclerotic plaque. Under static conditions, GPVI-Fc inhibited plaque-induced platelet aggregation by 53%, and increased platelet inhibition by ASA (51%) and ticagrelor (64%) to 66% and 80%, respectively. Under arterial flow, GPVI-Fc inhibited plaque-induced platelet aggregation by 57%, and significantly increased platelet inhibition by ASA (28%) and ticagrelor (47%) to about 81% each. The triple combination of GPVI-Fc, ASA and ticagrelor achieved almost complete inhibition of plaque-induced platelet aggregation (93%). GPVI-Fc alone or in combination with ASA or ticagrelor did not increase closure time measured by the platelet function analyzer (PFA)-200. GPVI-Fc added on top of abciximab, a clinically used anti fibrinogen receptor antibody which blocks platelet aggregation, strongly inhibited total (81%) and stable (89%) platelet adhesion. We conclude that GPVI-Fc added on top of single or dual antiplatelet therapy with ASA and/or a P2Y12 antagonist is likely to improve anti-atherothrombotic protection without increasing bleeding risk. In contrast, the strong inhibition of platelet adhesion by GPVI-Fc in combination with GPIIb/Illa inhibitors could be harmful.
KW - Antiplatelet agents
KW - Atherothrombosis
KW - GP VI
KW - GP IIb/IIIa
KW - Ischaemic heart disease
KW - MULTIPLE ELECTRODE AGGREGOMETRY
KW - GLYCOPROTEIN-VI
KW - ATHEROSCLEROTIC PLAQUES
KW - RECEPTOR ANTAGONISTS
KW - FLOWING BLOOD
KW - WHOLE-BLOOD
KW - COLLAGEN
KW - AGGREGATION
KW - FUTURE
KW - INHIBITION
U2 - 10.1160/TH16-11-0856
DO - 10.1160/TH16-11-0856
M3 - Article
SN - 0340-6245
VL - 117
SP - 1651
EP - 1659
JO - Thrombosis and Haemostasis
JF - Thrombosis and Haemostasis
IS - 8
ER -