Platelet Resistance to Prostacyclin. Enhancement of the Antiaggregatory Effect of Prostacyclin by Pentoxifylline

With regard to existence of high prostacyclin (PGI2) levels during atheromatosis and thrombus formation, resistance of platelets to prostacyclin and its analogues seems to play an important pathophysiologic key role for the clarifying of vasoocclusive phenomena. Platelet resistance to prostacyclin was studied in vitro and ex vivo in 160 atherosclerotic patients (assessed by objective diagnostic criteria) with and without thrombotic complications and in 50 controls. Prostacyclin resistance phenomena were more pronounced and frequent in patients with occlusive complications, the difference from controls being statistically significant. However, there was no significant difference between the controls and the nonthrombotic patient sample. The intraplatelet cAMP levels might be the metabolic basis of the PGI2 resistance phenomenon, because in the patient group, platelet cAMP levels were decreased by 50% after Ca2+ stimulation. Compared to controls β-thromboglobulin and thromboxane B2 plasma levels were significantly increased (30±9 to 87±26 ng/ml and 9±5 to 54±21 pg/ml, respectively), confirming the hyperreactivity state of resistant platelets. From the therapeutic point of view, patients with resistant platelets require PGI2 doses that cause, however, increased side effects. We were able to demonstrate in vivo that IV pretreatment with pentoxifylline—a known stimulator of cAMP formation in platelets—followed by a simultaneous and continuous IV infusion of PGI2 + pentoxifylline, permitted us to reduce significantly the mean PGI2 doses needed for triggering an antiplatelet effect, without inducing side effects. In ex vivo studies, PGI2 resistant platelets of atherosclerotic patients pretreated with pentoxifylline showed normalized stimulation response, and platelet cAMP levels increased from 7.8±2.7 to 15.2±1.9 pmol/108 platelets. Our data disclose a synergistic antiplatelet effect of PGI2 and pentoxifylline, which increases the antithrombotic potential and sheds light on the beneficial effects of pentoxifylline in the treatment of occlusive vascular disease.