Aurin tricarboxylic acid: a novel inhibitor of the association of von Willebrand factor and platelets.
Shear stress activated platelets undergo aggregation in the presence of large or unusually large von Willebrand factor (vWF) multimers without the addition of ristocetin or any other exogenous chemical. This phenomenon may be analogous to the platelet aggregation that leads to thrombosis in the narrowed arteries and arterioles of patients with atherosclerosis or vasospasm. A triphenyl-methyl compound, aurin tricarboxylic acid (ATA), inhibits shear-induced, vWF-mediated platelet aggregation in platelet-rich plasma (PRP) in concentrations above 200 mumol/L and in buffer suspensions of washed platelets at a concentration of 0.1 mumol/L. In a concentration-dependent manner, ATA also inhibits ristocetin-induced, vWF-mediated platelet clumping in both fresh and formaldehyde-fixed platelet suspensions. This inhibition can be overcome by increasing the concentration of vWF, following the kinetics of first order competitive inhibition. ATA prevents the attachment to platelets of the largest vWF multimeric forms found in normal plasma and of the unusually large vWF multimers derived from endothelial cells. The rate of aggregation and degree of inhibition by ATA is not accounted for by the binding of ristocetin or calcium. Arachidonic acid- and adenosine diphosphate (ADP)-induced aggregation are not inhibited by ATA. Platelets incubated with ATA can be easily separated from the compound. However, ATA binds to large vWF multimeric forms and inhibits their ristocetin-induced interaction with platelet glycoprotein Ib. Because ATA also inhibits shear-induced, vWF-mediated platelet aggregation in vitro in the absence of ristocetin, it may be a useful prototype compound to impede the development of arterial thrombosis in vivo.
Phillips
M D
MD
Baylor College of Medicine, Methodist Hospital, Houston, TX 77030.
Moake
J L
JL
Nolasco
L
L
Turner
N
N
D001312:Aurintricarboxylic Acid / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology*; D006801:Humans; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism; D012310:Ristocetin / Q000494:pharmacology; D013314:Stress, Mechanical; D014841:von Willebrand Factor / Q000378:metabolism*
D003509:Cyclohexanecarboxylic Acids; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D014841:von Willebrand Factor; D012310:Ristocetin; D001312:Aurintricarboxylic Acid