Association of the antagonism of von Willebrand factor but not fibrinogen by platelet alphaIIbbeta3 antagonists with prolongation of bleeding time.
BACKGROUND
The alphaIIbbeta3 antagonists inhibit platelet aggregation and are used as antithrombotic agents for cardiothrombotic disease. The present study investigates the correlation of inhibition of fibrinogen and von Willebrand factor (VWF) binding by alphaIIbbeta3 antagonists with the inhibition of platelet aggregation and prolongation of bleeding time (BT).


METHODS
Inhibition of fibrinogen and VWF binding were assessed in a purified alphaIIbbeta3-binding assay. As an in vitro cell-based assay, platelet aggregation and VWF-mediated adhesion studies were performed using human platelets. In vivo effects on BT were measured using a template device in dogs at the same time as an ex vivo aggregation study was performed.


RESULTS
In vitro studies demonstrated that the antiaggregatory effects of alphaIIbbeta3 antagonists correlate with their inhibition of fibrinogen binding, but not VWF. Interestingly, the effects of alphaIIbbeta3 antagonists on BT could be differentiated from the inhibition of platelet aggregation. Furthermore, this differentiation was strongly correlated with the different inhibitory potencies between fibrinogen and VWF binding, as well as that between VWF-mediated adhesion and aggregation.


CONCLUSIONS
Our study provides novel evidence showing that the inhibitory effect of alphaIIbbeta3 antagonists on VWF, but not fibrinogen binding, correlates with their ability to prolong BT.
Aoki
T
T
Medicinal Biology, Research Laboratories, Fujisawa Pharmaceutical Co., Ltd, Kashima, Yodogawa-ku, Osaka, Japan. toshiaki_aoki@po.fujisawa.co.jp
Tomiyama
Y
Y
Honda
S
S
Mihara
K
K
Yamanaka
T
T
Okubo
M
M
Moriguchi
A
A
Mutoh
S
S
D000818:Animals; D001780:Blood Coagulation Tests; D001792:Blood Platelets / Q000502:physiology*; D004285:Dogs; D005340:Fibrinogen / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006470:Hemorrhage / Q000209:etiology*; D006801:Humans; D007700:Kinetics; D010973:Platelet Adhesiveness / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D011485:Protein Binding / Q000187:drug effects; D014841:von Willebrand Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism
D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D014841:von Willebrand Factor; D005340:Fibrinogen