798 - Platelets Exhibit Enhanced Activation and Aggregation in Rheumatoid Arthritis

Donald L. Kimpel, Krishnaswamy Kannan, Renata Polanowska-Grabowska, Marek Marcinkiewic, Adrian Gear. University of Virginia, Charlottesville, VA
Presentation Number: 798

Purpose: Platelet activation and increased platelet number are consequences of inflammation, and platelets play a critical role in atherosclerosis and thrombosis. We have previously demonstrated enhanced platelet-dependent leukocyte adhesion in joint vasculature of arthritic animals, suggesting altered platelet function. Autoimmune diseases, especially rheumatoid arthritis (RA) and systemic lupus erythematous (SLE), are associated with enhanced cardiovascular mortality, but phenotypic and functional changes in platelets have not been well characterized in autoimmune inflammatory diseases. These changes could be important because platelets have been shown to modulate the immune response and participate in leukocyte adhesion. In this study we evaluated phenotypic and functional changes of platelets in a rat model of arthritis.
Methods: Chronic inflammatory arthritis mimicking RA was induced by a single intraperitoneal injection of the streptococcal cell wall component peptidoglycan-polysaccharide and platelets were obtained on day 18 of arthritis. The functional capacity of the platelets was assessed by measuring aggregation by two separate methods in response to standard stimuli (ADP, thrombin, collagen), and by measuring dense-granule (serotonin) release. Platelets were then analyzed for surface expression of CD62P (P-selectin), CD63 (LAMP-3), and CD40.
Results: Using platelets derived from arthritic animals (“arthritic platelets”) aggregation induced by the primary agonist ADP (0.125-10.0 μM) occurred 2-3 times more rapidly than control platelets from normal rats, as determined by single-platelet counting and by aggregometry. Release of serotonin, a measure of dense granule release, was enhanced by greater than 50% for arthritic platelets relative to controls. In addition, serotonin release occurred immediately in arthritic platelets, while normal platelets demonstrated a 30 second lag. Only slight differences were observed between freshly isolated arthritic platelets compared to controls in terms of expression of CD62p, CD63, and CD40. However, when exposed to a mild activation stimulus (thrombin 5 U/ml) ‘arthritic’ platelets exhibited a pronounced increase in surface expression of these molecules compared to control platelets. Arthritic platelet CD40 and CD63 expression increased more than two-fold compared to control platelets.
Conclusions: During inflammatory arthritis, important functional changes occur in platelets giving rise to enhanced surface expression of adhesion and immuno-modulatory molecules, and increased responsiveness to aggregation and degranulation stimuli. These findings have important implications for increased cardiovascular risk observed in autoimmune inflammatory disorders, and for our choices of medications in treatment of these disorders.

 D.L. Kimpel, None.