Isolation from commercial aurintricarboxylic acid of the most effective polymeric inhibitors of von Willebrand factor interaction with platelet glycoprotein Ib. Comparison with other polyanionic and polyaromatic polymers.
Solutions of commercial aurintricarboxylic acid (ATA) inhibit ristocetin- or shear stress-induced, von Willebrand factor (vWF)-mediated platelet aggregation by interacting with vWF and blocking its attachment to platelet membrane glycoprotein Ib. ATA has also been shown to prevent cyclic platelet clumping in a dog model of coronary artery thrombosis. Because these ATA solutions are actually a heterogeneous mixture of polyanionic, polycarboxylic polyaromatic polymers of molecular weight (Mr) 200 to greater than 6,000, we separated the most effective inhibitory components of commercial ATA using exclusion chromatography. ATA polymers larger than Mr 700 inhibited ristocetin-induced, vWF-mediated platelet aggregation more effectively than smaller ATA polymers, whereas shear-induced, vWF-mediated platelet aggregation was optimally inhibited by ATA polymers of Mr greater than or equal to 2,500. Platelet aggregation mediated by vWF was not inhibited by a nonphenolic, polyanionic polymer (polyglutamic acid) or by a polyphenolic ATA-like polymer (aurin) devoid of carboxyl groups. Polyanionic, polysulfonated aromatic polymers (polystyrene sulfonate) of Mr 35, 17.4, 8, and 4.6 x 10(3) inhibited ristocetin- and shear-induced, vWF-mediated aggregation with less potency on a mass/volume basis than large polymers of ATA. We conclude that a polyanionic, polycarboxylated, polyphenolic ATA polymer of Mr 2,500 is optimally potent as an inhibitor of shear- and ristocetin-induced, vWF-mediated platelet aggregation and is likely to be more effective than solutions of commercial ATA as an anti-arterial thrombotic agent.
Boston University School of Medicine, MA 02118.
M
M
Weinstein
E
E
Vosburgh
M
M
Phillips
N
N
Turner
L
L
Chute-Rose
J
J
Moake
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000838:Anions; D016718:Arachidonic Acid / Q000494:pharmacology; D001312:Aurintricarboxylic Acid / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D003094:Collagen / Q000494:pharmacology; D015394:Molecular Structure; D008970:Molecular Weight; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism*; D011108:Polymers / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D012310:Ristocetin / Q000494:pharmacology; D014841:von Willebrand Factor / Q000378:metabolism* / Q000494:pharmacology
D000838:Anions; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D011108:Polymers; D014841:von Willebrand Factor; D012310:Ristocetin; D016718:Arachidonic Acid; D001312:Aurintricarboxylic Acid; D000244:Adenosine Diphosphate; D003094:Collagen