Abstract
ATA is a novel anticoagulant polymetic anionic aromatic compound that inhibits von Willebrand factor binding to platelet glycoprotein Ib and thereby prevents ristocetin- and shear stress-induced platelet aggregation. To investigate its mechanism of action, ATA fractions of homogeneous Mr have been prepared by size exclusion chromatography. ATA fractions of Mr ≥ 2,500 are most effective at inhibiting vWF-mediated platelet aggregation, and ATA of Mr = 2,500 also inhibits thrombin-induced platelet activation. Paradoxical results were observed in studies of ATA with Mr = 6,400. This fraction of ATA stimulates aggregation of washed platelets or platelet-rich plasma. The dose/response of aggregation shows a bell-shaped curve with maximal aggregation at approximately 2 μg/ml. Platelet aggregation is associated with phosphoinositide turnover and protein kinase C- and calcium-dependent protein phosphorylation. Platelet signalling responses to ATA are inhibited by platelet pretreatment with PGI2 or dibutyryl-cyclic AMP, but are unaffected by inhibiting platelet cyclooxygenase with aspirin. These results suggest that Mr 6,400 ATA directly activates platelet phospholipase C to initiate platelet aggregation. This effect, unique to Mr 6,400 ATA, could potentially mitigate ATA's beneficial anti-thrombotic effect on vWF-mediated platelet responses, and should be considered when analyzing results of experiments that utilize unfractionated ATA.
Original language | English (US) |
---|---|
Pages (from-to) | 77-88 |
Number of pages | 12 |
Journal | Thrombosis Research |
Volume | 71 |
Issue number | 1 |
DOIs | |
State | Published - Jul 1 1993 |
Keywords
- aurin tricarboxylic acid
- cyclic nucleotides
- phospholipase
- protein kinases
- thrombosis
ASJC Scopus subject areas
- Hematology