Erythromelalgia, a characteristic
aspirin-responsive microvascular thrombotic complication in
essential thrombocythemia (ET), may develop despite oral
anticoagulant treatment or treatment with
heparin, suggesting that the generation of
thrombin is not a prerequisite for its development. To study this, a cross-sectional comparison of the plasma levels of
thrombomodulin (TM),
platelet factor 4 (PF4),
beta-thromboglobulin (beta-TG),
prothrombin fragment 1 + 2 (F1 + 2) and total degradation products of
fibrin(
ogen) (TDP) was made between 5 ET patients suffering from
erythromelalgia, 16 asymptomatic ET patients and 20 control subjects, and
after treatment with
aspirin, respectively. Furthermore, 2 ET patients with a history of
erythromelalgia were studied at regular time intervals after discontinuation of
aspirin until
erythromelalgia recurred. 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 paralleled by a significant decrease of beta-TG and TM levels. Histopathologic and immunohistochemical analysis of biopsies derived from erythromelalgic skin areas of 2 ET patients showed that erythromelalgic thrombi stained positively for
von Willebrand factor opposed to only a weak
fibrin 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 generation of
thrombin appears not to be essential for the formation of these platelet thrombi, thereby giving a plausible explanation for the inefficacy of
coumadin derivatives and
heparin in the prevention and treatment of
erythromelalgia in
essential thrombocythemia.