Oral Contraceptives Highlight the Genotype-Specific Association Between Serum Phospholipids and Activated Factor VII

Abstract

Abstract-The present analysis was undertaken to study the effect of oral contraceptive (OC) use on activated factor VII (FVIIa) in subjects characterized by FVII genotypes, with the further aim of evaluating the role of lipids in this pharmacological interaction. In OC users (nϭ42) and nonusers (nϭ130) Key Words: factor VII Ⅲ activated factor VII Ⅲ phospholipids Ⅲ factor VII genotype S ince the introduction of oral contraceptives (OCs) in the 1960s, epidemiological studies have revealed an association between their use and an increase in the risk of cardiovascular disease (CVD). [1][2][3][4][5][6] The most important cardiovascular complications noted were venous thromboembolism, myocardial infarction, and thrombotic stroke, 6 -11 with higher risk and susceptibility in female smokers in the 35ϩ age range. 12 The increased CVD risk has been attributed to the estrogenic component 7,13 : in fact, it was found to be reduced after the introduction of OCs containing a lower estrogen dose, [13][14][15][16][17][18] but recently venous thromboembolism was found to be higher in women using contraceptives containing third-generation compared with second-generation progestogens. 19 -22 The effect of OCs on hemostatis is an increase in the levels of some coagulation factors (factors II, VII [FVII], IX, X, XI, and VIII; von Willebrand factor; and fibrinogen), of protein C, and of protein complexes and fragments related to the activation of coagulation (thrombin-antithrombin complexes and D-dimer); these enhance fibrinolysis and decrease the levels of antithrombin III, protein S, and C4b-binding protein. [23][24][25][26][27][28][29][30][31] Concerning FVII, a relationship between FVII levels, the dose of estrogen, [23][24][25][26][27][28]31 and progestogen (norethisterone but not D-norgestrel 32 ) was consistently found. It is difficult, though, to pinpoint whether these changes are due to the estrogen or the progestative compound, and it is still a matter of debate whether the excess CVD risk after the use of OCs is related to the resulting dyslipidemia, the hemostasis changes, or both. Recently, a meta-analysis 33 pointed out the absence of an association between the duration of OC administration and CVD risk; the same analysis showed that the increased risk was limited to the period of OC administration.Because FVII has attracted attention owing to its association with lipids (namely triglycerides [TGs] and cholesterol

Plasma Lipoproteins, Hemostasis and Thrombosis

“…Hence, it was suggested that hyperlipidemia causes activation of factor X by factor IXa with subsequent activation of Factor VII by Factor Xa in reactions that occur on phospholipids carried on plasma lipoproteins. These in vitro findings from studies using purified proteins mirror the epidemiologic finding that levels of circulating factor VIIa are best correlated with circulating choline-containing phospholipids (10,11). Although they are minor plasma components, negatively charged phospholipid levels are approximately correlated with levels of choline-containing phospholipids, and it seems possible that factor VII activation on lipoprotein surfaces involves negatively charged lipids.…”

“…As a measure of relative risk, the odds ratio for deep vein thrombosis in subjects with GlcCer levels below the 10th percentile of controls was 5.7 (95% CI 2. [3][4][5][6][7][8][9][10][11][12][13][14]. In contrast to GlcCer, no significant difference between patients and controls was seen for mean plasma PE levels (p = 0.48) that were 71 g/ml and 65 g/ml, respectively (D).…”

“…Based on a variety of epidemiologic studies of atherothrombosis and markers of the hemostatic system, hypercoagulability is associated with hyperlipidemia and with an increased risk for arterial thrombosis. Many previous studies have sought to establish connections between systemic markers of hypercoagulability and abnormalities of serum lipids or lipoproteins with respect to increased risk of thrombosis [see for examples (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)]. However, correlations and statistical associations never establish causal relationships.…”

Apolipoprotein C-III Strongly Correlates with Activated Factor VII–Anti-Thrombin Complex: An Additional Link between Plasma Lipids and Coagulation

“…It could be argued that apolipoproteins could remodel the phospholipid distribution in cellular membranes, 46,47 which in turn influences TF-FVIIa activity at the cell surface. [48][49][50] However, our work does not provide any proof about the molecular mechanisms potentially linking ApoC-III and TF-FVIIa interaction. It could be not excluded that ApoC-III plasma levels may merely alter either directly or indirectly the clearance of FVIIa-AT complex (e.g.…”

Coagulation and Clinical Features Associated with the Arg304gln Mutation (Factor VII Padua) in the Irf7 Study Group Response to Letter to the Editor Regarding “Factor VII Deficiency (Semin Thromb Hemost 2009;35(4):400–406)”

“…7 In fact, the laboratory response to infused rFVIIa is rather variable, and FVII:C assays, which are not specific for the infused factor, might contribute to this variability. 8 In addition, the FVIIa assay can be easily standardized on coagulometers as pointed out by several groups, including ours, 9,10 in population-based studies.…”