ERYTHROMELALGIA IN ESSENTIAL THROMBOCYTHEMIA IS CHARACTERIZED BY PLATELET ACTIVATION AND ENDOTHELIAL-CELL DAMAGE BUT NOT BY THROMBIN GENERATION

Erythromelalgia, a characteristic aspirin-responsive microvascular thr ombotic complication in essential thrombocythemia (ET), may develop de spite oral anticoagulant treatment or treatment with heparin, suggesti ng that the generation of thrombin is not a prerecuisite for its devel opment. To study this, a cross-sectional comparison of the plasma leve ls of thrombomodulin (TM), platelet factor 4 (PF4), beta-thromboglobul in (beta-TG), prothrombin fragment 1+2 (F1+2) and total degradation pr oducts of fibrin(ogen) (TDP) was made between 5 ET patients suffering from erythromelalgia, 16 asymptomatic ET patients and 20 control subje cts, and after treatment with aspirin, respectively. Furthermore, 2 ET patients with a history of erythromelalgia were studied at regular ti me intervals after discontinuation of aspirin until erythromelalgia re curred. As compared with asymptomatic ET patients and control subjects erythromelalgia was characterized by significantly higher beta-TG and TM levels but no significant differences were detected in either F1+2 or TDP levels. Treatment of erythromelalgia with aspirin resulted in disappearance of erythromelalgic signs and symptoms, which was paralle led by a significant decrease of beta-TG and TM levels. Histopathologi c and immunohistochemical analysis of biopsies derived from erythromel algic skin areas of 2 ET patients showed that erythromelalgic thrombi stained positively for von Willebrand factor opposed to only a weak fi brin staining, Our data suggest that erythromelalgia is caused by the intravascular activation and aggregation of platelets with subsequent sludging or occlusion of the acral arterial microvasculature. The gene ration of thrombin appears not to be essential for the formation of th ese platelet thrombi, thereby giving a plausible explanantion for the inefficacy of coumadin derivatives and heparin in the prevention and t reatment of erythromelalgia in essential thrombocythemia.