Haemostatic abnormalities in Raynaud's Phenomenon and the potential for treatment with manipulation of the arachidonic acid pathway.

Abstract

It has been 130 years since Raynaud first described the `strange and remarkable phenomenon' of cold/emotional stress induced intense digital vasospasm. However, the aetiology of this common disorder is still poorly understood and treatment for this condition is unsatisfactory. The objectives of this thesis are (1) to determine the pathophysiological role of the haemostatic systems in Raynaud's phenomenon (RP) and (2) to explore the potential for treatment with manipulation of the arachidonic acid (AA) pathway in favour of anti-thrombotic and vasodilatory effects.

Blood flow is dependent on the blood vessel tone, an intact functioning endothelium and the various coagulation factors and cellular elements in the blood. Laser Doppler flowmetry technique to assess digital skin vasomotor response, and blood tests to determine other haemostatic abnormalities were performed in patients with various forms of RP (Chapters 4 and 5). Particular attention was paid to delineate the role of white cells in RP which has not been studied before. Results were compared to age and sex matched controls. All studies were performed in the winter months. To determine whether the abnormalities found were induced by vasospasm, clinical disease severity was also measured. The results obtained demonstrated the key aetiological role of abnormal haemostasis in RP, particularly those with the secondary form - Raynaud's syndrome (RS). These patients had endothelial dysfunction in addition to platelet and white cell activation which occurred in all RP patients. It was likely that most of these abnormalities were a consequence rather than a cause of RP. Nevertheless such changes might worsen the condition by further decreasing digital blood flow.

In conclusion, work documented in this thesis has demonstrated the pathophysiological importance of abnormal haemostasis in RP. Drug treatment such as PGI₂ which improves these changes may be useful. A search for a stable analogue of PGI₂ is currently underway and I am hopeful that such an agent will become available soon.