Raz, Limor

White matter hyperintensities (WMHs) are associated with cerebral microvascular disease. Our objective was to investigate changes in volume of WMH in relationship to conventional cerebrovascular risk factors in recently menopausal women (within 6 months – 3 yrs of their last menses) enrolled in the Kronos Early Estrogen Prevention Study (KEEPS). Platelet activation, numbers of platelet‐derived microvesicles and conventional risk factors for cerebrovascular disease were determined in women (105) enrolled in KEEPS at Mayo Clinic. Each woman underwent MRI of the brain and WMH volumes were derived from the segmented Fluid Attenuated Inversion Recovery images at baseline and 36 months after randomization to treatment. Parametric, nonparametric and log transformation statistical analyses were conducted appropriately. Blood pressure and lipid profiles at baseline were not associated with changes in WMHs. However, baseline platelet micro‐aggregates, annexin V positive microvesicles and plasma activated protein C significantly correlated with increases in WMHs at 36 months. In conclusion, this correlation of increase in WMH with markers of platelet activation measured at baseline suggests that activated platelets and factors contributing to platelet activation may be causal to development of WMH. Supported by the Aurora Fnd, NIH HL90639, NS066147, HD65987 and the Mayo Fnd.

Estrogen modulates the prostanoids prostacyclin (PGI 2 ) and thromboxane A 2 (TXA 2 ) which contribute to vascular hemostasis in endothelium and platelets. Estrogen decreases in women at menopause, and menopausal hormone therapy (MHT) may increase risk of thrombosis. This study aimed to determine effects of MHT on serum prostanoid levels and on prostanoid‐related platelet functions in healthy, recently‐menopausal women. Women (age 52.3±2.3 yrs; n=115) enrolled in the Kronos Early Estrogen Prevention Study (KEEPS) were randomized to either: 1) oral conjugated equine estrogen, 2) transdermal 17β estradiol each with intermittent oral progesterone or 3) placebo, for 48 months. Serum PGI 2 and TXA 2 levels were assessed by quantification (ng/ml) of their stable metabolites 6‐k‐PGF 1α and TXB 2 , respectively. Initial TXB 2 levels (46.9±7.5) were unchanged (P>; 0.05) after 48 months in each treatment group. However, 6‐k‐PGF 1α decreased from 2.1±0.2 to 1.4±0.1 at 48 months in combined groups, but was statistically significant (1.5±0.3) only in the transdermal group. Inhibition of platelet ATP secretion by PGE 1 did not correlate with serum 6‐k‐PGF 1α levels. These results suggest that serum PGI 2 levels decrease with age in menopausal women and are unaffected by MHT. Factors other than changes in serum prostanoids may impose thrombotic risk associated with MHT. (Supported by the Aurora Fnd, NIH HL88988 and Mayo Clinic).