The effects of thromboxane receptor blockade on platelet aggregation and digital skin blood flow in patients with secondary Raynaud's syndrome

Abstract

Raynaud's syndrome (RS) is characterized by intense blood vessel spasm resulting in finger blanching. Treatment primarily involves vasodilation. Thromboxane A2 (TXA2) has been shown to be a potent vasoconstrictor and platelet aggregant. It may be possible to produce a vasodilatory and anti-thrombotic effect by blockade of the TXA2 receptors. ICI 192,605 is a potent TXA2 receptor antagonist and we studied its effects on platelet aggregation and digital blood flow in patients with RS. Sixteen patients with RS completed this double-blind, randomized, placebo controlled study. Each patient was seen on three separate occasions and was given ICI 192,605 (100 mg orally) on one occasion and matching placebo tablets on the other two. We measured platelet aggregation using platelet rich plasma (PRP) stimulated by U46619, a thromboxane (TX) mimetic. The concentration of U46619 required to cause just over 50% platelet aggregation before the administration of either ICI 192,605 or placebo (pre-dose) was noted. The same concentration of U46619 was used to stimulate the PRP sample at 1 h after the administration of ICI 192,605 or placebo (post-dose) and the percentage of platelet aggregation was again noted. Fingertip skin blood flow was also measured 1.25 h post-dose using a laser Doppler flowmeter. Patients were seated in a temperature controlled chamber which was initially heated to 40 °C to induce centrally mediated vasodilatation. The temperature was then lowered to 12 °C followed by rewarming to 40 °C. Steady blood flow values at these temperatures were measured and the rates of cooling and rewarming were also noted. There was significant inhibition of platelet aggregation 1 h following the administration of ICI 192,605 {post-dose % platelet aggregation [mean (standard deviation)] = 4.8 (12.7)% vs control values of 65.6 (10.5)% and 62.7 (21.3)%, P < 0.0001 (Analysis of covariance)}. No demonstrable evidence of improved fingertip skin blood flow was observed and it may be that more prolonged dosing is required. As platelet aggregation is increased in Raynaud's phenomenon further evaluation of this group of drugs in patients with RS is required.