Differential effects of conventional and low dose oral hormone therapy (HT), tibolone, and raloxifene on coagulation and fibrinolysis.

INTRODUCTION: We have recently reported that different hormone regimens given to healthy post-menopausal women had markedly different effects on activation of coagulation. Low-dose hormone therapy (HT) and raloxifene, as opposed to conventional-dose HT and tibolone, were associated with no or minor activation of coagulation. The aim of this study was to elucidate the mechanism(s) for differences in coagulation activation by analysing clotting and fibrinolytic factors and coagulation inhibitors. MATERIALS AND METHODS: 202 healthy women were randomly assigned to receive treatment for 12 weeks with either low dose HT containing 1 mg 17 beta-estradiol+0.5 mg norethisterone acetate (NETA) (n=50), conventional dose HT containing 2 mg 17 beta-estradiol and 1 mg NETA (n=50), 2.5 mg tibolone (n=51), or 60 mg raloxifene (n=51) in an open-label design. RESULTS: The conventional-and low-dose HT groups generally showed similar effects, i.e., reductions in both clotting factors and inhibitors, but the effects were markedly more pronounced in the conventional-dose HT group. Compared with the low-dose HT group those treated with tibolone showed more pronounced decreases in factor VII, less reduction of antithrombin and protein C and even increased levels in protein S and tissue factor pathway inhibitor. As opposed to the low-dose HT group the reductions in inhibitors in the raloxifene group were smaller. Moreover in those allocated to raloxifene reduced levels of fibrinogen were seen. CONCLUSIONS: Our study demonstrates that the different HT regimens and raloxifene exert differential effects on coagulation factors, inhibitors and fibrinolytic factors.

The effects of oral and transdermal hormone replacement therapy on C-reactive protein levels and other inflammatory markers in women with high risk of thrombosis.

INTRODUCTION: In the estrogen in venous thromboembolism (EVTET) study of 140 women with a history of venous thromboembolism (VTE), oral hormone replacement therapy (HRT) was associated with strong activation of coagulation markers and increased risk of recurrent VTE. No such associations were observed in the estrogen women atherosclerosis (EWA) study of 118 women with established coronary artery disease who were given transdermal HRT. OBJECTIVES AND METHODS: The aim of the present study was to evaluate the effects of oral and transdermal HRT on levels of C-reactive protein (CRP), which was assayed with a highly sensitive method. We also evaluated the effects on other inflammatory markers and the influence of possible confounding factors. RESULTS: Oral HRT was associated with a significant increase in CRP after 3 months as compared with placebo (median 79% [95% confidence interval 36-119%] versus -4% [-13 to 10%], p = 0.001). These changes sustained after 12 months. Among those allocated HRT, the median increase in CRP was higher in women who subsequently developed recurrent thrombosis (median 328%, n = 5, versus 54%, n = 60). TNF-alpha levels decreased significantly by mean -10% [-15 to -5%] versus 3% [-4 to 10%], p=0.004. Soluble VCAM-1 decreased in the HRT group compared to the placebo group (mean -13% [-18 to -8%] versus 1%, [-3 to 5%], p < 0.001). There were no significant changes in levels of IL-6, TGF-beta or P-selectin. On transdermal HRT no significant changes in CRP were observed after 3 and 12 months of treatment. CONCLUSIONS: Our findings substantiate that oral HRT containing estradiol is associated with a marked and rapid increase in CRP, whereas transdermal treatment is not. However, this increase on oral treatment was associated with no increases of other inflammatory markers.

Impaired circadian variations of haemostatic and fibrinolytic parameters in tetraplegia.

Spinal cord injured patients are at increased risk of developing deep vein thrombosis (DVT). Whether these patients have increased blood levels of prothrombotic markers remains to be clarified. In general, the risk of developing DVT is highest in the morning hours. In healthy humans, several haemostatic and fibrinolytic parameters exhibit circadian variations, but it is not known whether this also applies to those with spinal cord injury. The aim of the present study was to examine possible circadian variations in prothrombotic markers in tetraplegic patients. We studied six patients with complete tetraplegia and eight control subjects with repetitive blood sampling over a 24 h period. While the control subjects showed marked circadian variations in factor VIII activity, prothrombin fragments 1+2 and D-dimer levels, the tetraplegic patients did not (P < 0.05). Circadian variation in plasminogen activator inhibitor type-1 was present in both groups, being most marked (P < 0.05) in tetraplegia. We conclude that the circadian variations of several factors of the haemostatic and fibrinolytic systems are impaired in spinal cord injury. This could possibly reflect a deregulated autonomic nervous system, leading to a dysfunctional link between central and peripheral circadian oscillators.