Dipyridamole decreases protease-activated receptor and annexin-v binding on platelets of post stroke patients with aspirin nonresponsiveness.
BACKGROUND
Although controversial, the phenomenon of aspirin resistance (AR) has been correlated in some small studies with poor clinical outcomes in patients with coronary artery disease. Even less is known regarding the role of AR in the post stroke population. The reason for and the underlying mechanism of AR is unknown. We hypothesized that excessive formation of thrombin on the platelet surface may contribute to this phenomenon and assessed how dipyridamole affects multiple platelet and thrombin generation biomarkers in AR patients after ischemic stroke.


METHODS
Whole blood samples from 20 post stroke AR patients were pretreated with dipyridamole, simulating the therapeutic range, and then incubated for 45 min at 37 degrees C. Platelet characteristics were assessed by aggregometry, cartridge-based analyzer, and receptor expression by flow cytometry. Markers of thrombin generation were measured in the autologous plasma by ELISA.


RESULTS
Pretreatment of blood with dipyridamole resulted in 22-26% diminished expression of intact PAR-1 receptor (p=0.021 and p=0.024) and 28-31% decrease of annexin V binding (p=0.031 and p=0.02) after incubation with 2 microg/ml and 4 microg/ml of dipyridamole, respectively. Platelet aggregation and thrombin generation markers were not affected in vitro by dipyridamole.


CONCLUSIONS
Dipyridamole may be capable of overcoming increased prothrombinase complex formation and be in part able to compensate for AR in patients with moderate carotid stenosis. This phenomenon may explain the clinical advantages of Aggrenox, known to reduce ischemic events in post stroke patients as proven in clinical trials, though an additional antithrombotic benefit beyond the platelet inhibition by aspirin alone.
Serebruany
Victor
V
Heart Drug Research Laboratories, Johns Hopkins University, Baltimore, Md 21204, USA. heartdrugs@aol.com
Malinin
Alex
A
Ziai
Wendy
W
Atar
Dan
D
Pokov
Alex
A
Jilma
Bernd
B
Hanley
Dan
D
D000368:Aged; D001241:Aspirin; D018929:Cell Culture Techniques; D004176:Dipyridamole / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D044463:Receptor, PAR-1 / Q000187:drug effects; D018000:Receptors, Peptide / Q000187:drug effects; D020521:Stroke / Q000503:physiopathology*
D010975:Platelet Aggregation Inhibitors; D044463:Receptor, PAR-1; D018000:Receptors, Peptide; C080707:annexin V receptor; D004176:Dipyridamole; D001241:Aspirin