A proportion of patients with mitral stenosis have increased left atrial thrombin generation, with elevated left atrial but normal peripheral venous levels of prothrombin fragment 1+2 (F1+2). Whether this pattern of left atrial and venous F1+2 levels is related to limited spillover of F1+2 from the left atrium into the systemic circulation, or to washout of increased left atrial F1+2 production into the arterial circulation with subsequent systemic clearance, is unclear. We examined the relationship between arterial and venous F1+2 levels in mitral stenosis patients without left atrial thrombus. The study group comprised 36 patients with either a normal (n=29) or prolonged (n=7) international normalized ratio (INR; a measure of clotting time) who were undergoing percutaneous balloon mitral valvuloplasty. Baseline arterial and venous blood samples were collected at the beginning of the valvuloplasty procedure, and left atrial and venous samples were collected after trans-septal puncture. The left atrial F1+2 level exceeded the corresponding venous level in patients with a normal INR (P<0.03); however, baseline arterial and venous F1+2 levels were similar. Arterial and venous F1+2 levels were also similar in the subgroup of patients with evidence of a regional increase in left atrial thrombin generation, and were not different from arterial and venous F1+2 levels in patients without such an increase. Baseline arterial and venous F1+2 levels were both lower in the presence of a prolonged INR. Thus the pattern of increased left atrial but normal venous F1+2 levels in mitral stenosis is due to limited spillover from the left atrium into the systemic circulation.

A proportion of mitral stenosis patients with left atrial spontaneous echo contrast but without thrombus exhibit a regional hypercoagulable state, characterized by increased left atrial levels, but normal venous levels, of prothrombin fragment 1+2 (F1+2), a marker of thrombin generation. Valve dilatation by balloon mitral valvuloplasty has beneficial effects on left atrial spontaneous echo contrast, but its effect on left atrial thrombin generation is unknown. We examined the effects of balloon mitral valvuloplasty on venous and left atrial levels of F1+2 in 37 patients with mitral stenosis, divided into those with normal (group 1; n=22) and those with increased (group 2; n=15) regional left atrial thrombin generation, as described previously. The mitral valve area increased by a similar degree after the valvuloplasty procedure in the two groups. In group 1, the venous (P<0.005) and left atrial (P<0.0005) levels of F1+2 increased similarly after valvuloplasty, and as a result the left-atrial-venous F1+2 difference was unchanged. The venous F1+2 level also increased after valvuloplasty in group 2 (P<0.005); however, in contrast with group 1, the left atrial level decreased (P<0.03) and as a result the left-atrial-venous difference fell (P<0.05). These results show that balloon mitral valvuloplasty results in an immediate increase in thrombin generation, but a decrease in the left-atrial-venous F1+2 difference, in patients with increased left atrial thrombin generation. The divergent changes in venous and left atrial levels of F1+2 further highlight the limitations of assessing regional changes in coagulation activity by measuring venous levels of coagulation markers.

Studies have recently demonstrated that long-term oestrogen therapy improves endothelium-dependent and endothelium-independent vasodilatation in the conductance vessels of biological males. We sought to determine if an acute single dose of oestrogen might similarly improve vasodilator function in young males. In a randomized, double-blind, placebo-controlled, crossover study, we compared the effects of 1 mg of sublingual 17beta-oestradiol (E(2)) and placebo on endothelium-dependent and endothelium-independent vasodilatation in the brachial artery using a non-invasive ultrasound technique. We recruited 30 young males based on a power calculation. Neither acute sublingual oestrogen nor placebo affected flow-mediated vasodilatation [5.32+/-0.78% and 5.28+/-0.60% respectively (mean+/-S.E.M.), P=0.94]. Responses to nitroglycerine were similar after oestrogen or placebo (16.01+/-0.86% and 15.29+/-1. 19%, P=0.47). Basal blood flow and flow during reactive hyperaemia did not differ after oestrogen or placebo. Heart rate and blood pressure were similar during both treatment phases of the study. The absolute change in serum oestradiol levels was greater after the oestrogen treatment phase than after placebo (1509+/-87 versus -13+/-4 pmol/l, P<0.0001). Despite achieving supra-physiological oestradiol levels, the acute administration of sublingual E(2) does not appear to improve endothelium-dependent or endothelium-independent vasodilatation, at least acutely, in the brachial artery of young males. In keeping with our previous study, these data suggest that a period of oestrogen 'priming' (possibly to induce receptor-mediated nitric oxide synthesis) may be required to yield an improvement in vascular function in males.