Resistance to activated protein C in women using oral contraceptives.

Hereditary activated protein C (APC) resistance is an established risk factor for venous thromboembolism and a decreased sensitivity to APC is widely used to identify carriers of this mutation. The authors demonstrated differences in APC sensitivity between healthy men and women especially oral contraceptive (OC) users. To confirm an estrogen-related hormonal effect on acquired APC resistance the study was extended to healthy pregnant women. APC values obtained from 38 women at 36 weeks gestation were compared with those previously obtained in 43 healthy men 38 OC users and 42 women not using OCs. Values below the lower limit of the normal range (0.82-1.22) were found in 10% of nonusers of OCs 32% of OC users and 82% of pregnant women compared with 5% of men. The standard APR resistance test yielded false-positive results in 25% of OC users and 75% of pregnant women. When the modified sensitivity ratio was used there was no significant difference between pregnant women and men and lowered values were found in 5% of each of the study groups. Increased levels of fibrinogen and factors II VIII IX and X experienced during pregnancy and OC use could explain a lowered APC ratio by shortening the partial thromboplastin time. Clinical studies are recommended to assess the contribution of acquired APC resistance to the development of thrombosis in pregnant women and OC users either as an independent or concomitant risk factor.

In 1993, individuals with a hereditary predisposition to venous thromboembolism whose plasmas exhibited a poor response to activated protein C (APC) in an activated partial thromboplastin time assay were identified.1 The molecular basis for this laboratory phenotype of resistance to APC was a guanine to adenine mutation at nucleotide 1691 in the factor V gene.2 This results in the replacement of arginine (R) at position 506 by glutamine in the resulting protein, a defect which has been termed factor V Leiden. R506 is the first of three sites at which APC normally cleaves and inactivates procoagulant factor Va. The Q506 substitution causes factor Va to be inactivated approximately l0-fold more slowly than normal, thereby making the cofactor relatively resistant to the anticoagulant action of APC.3 This allows for increased factor Va availability within the prothrombinase complex, thereby enhancing thrombin generation and the development of a hypercoagulable state. See page 1012 Factor V Leiden is the most common inherited risk factor for venous thromboembolism, increasing the risk of venous thrombosis by 4- to 10-fold in heterozygotes and 50- to 100-fold in homozygotes.4,5⇓ Heterozygosity can be identified in 12% to 20% of unselected white patients presenting with venous thrombosis and 40% to 50% of patients with a strong positive family history. Approximately 3% to 7% of normal white patients are heterozygous carriers of factor V Leiden, but the mutation is rare in …

Cerebral venous thrombosis (CVT) is a rare disease. It has numerous and complex etiologies. Inherited or acquired prothrombotic states play a key role in the development of this disease, such as factor V G1691A mutation (FV Leiden). A 15-year-old girl presented to the Department of Neurology with a complaint of severe headache with visual blurring. The diagnosis of CVT was not initially suspected because of the patient's condition on presentation. An MRI showed thrombosis in the superior sagittal sinus, confirming venous stroke. Anticardiolipin and antiphospholipid antibodies were assessed. In addition, inherited prothrombotic defects, such as protein C, protein S, and antithrombin deficiencies, and genetic mutations for FV Leiden, prothrombin gene G20210A (FII G20210A), and methyltetrahydrofolate reductase C677T (MTHFR C677T) were studied. All results were unremarkable except for the unique homozygous FV Leiden mutation, which likely contributed to this prothrombotic situation. This study highlights the fact that FV Leiden may play a significant role in the onset of CVT in young patients.

Enhancement by factor V Leiden mutation of risk of deep-vein thrombosis associated with oral contraceptives containing a third-generation progestagen.

Impact of progestagens on activated protein C (APC) resistance among users of oral contraceptives

Effect of oral contraceptives containing 20 and 35 μg ethinyl estradiol on urinary prostacyclin and thromboxane levels in smokers and non-smokers

The development of venous thromboembolism is influenced by a variety of genetic and environmental risk factors. A few studies have ascertained whether thrombophilic defects are risk factors for venous thromboembolism in Latin American populations with a variable degree of admixture, such as the Colombian population. To address this issue, we conducted a case-control study involving 100 consecutive patients with deep vein thrombosis and 114 healthy controls from the Hospital Universitario San Vicente de Paúl, Medellín, Colombia. Activated protein C resistance (APC resistance) was detected in 25/99 patients vs. 6/114 controls (OR = 6.08, 95% CI = 2.23-17.47). Ten of 100 patients carried the factor V Leiden mutation vs. 1/114 controls (OR = 12.56, 95% CI = 1.61-267). APC resistance was associated with the factor V Leiden mutation in only 10/25 patients. The prothrombin G20210A mutation was found in 4/100 patients, but none of the controls (P < 0.05). There was no significant difference in the proportion of homozygous carriers of methylenetetrahydrofolate reductase C677T variant among patients and controls. In conclusion, in our studied population, factor V Leiden, APC resistance, and prothrombin G20210A were associated with an increased risk of deep vein thrombosis. However, the frequencies of these thrombophilic defects and of APC resistance associated with factor V Leiden was lower than the corresponding frequencies previously reported for Caucasian populations. Further study is required to assess the influence of ethnicity on thrombophilia.

Correlates of oral contraceptive use in Italian women, 1991–1993

Epidemiological studies evaluating the potential association between oral contraceptive (OC) use and melanoma risk have reported conflicting results. We assessed the association of OC use with melanoma risk in a large prospective cohort. The Nightingale Study comprises 59 944 Dutch female nurses at ages 19-65 years (mean, 46.9 years; SD, 11.0) who completed a baseline questionnaire in 2011, including information on lifetime OC use. Melanoma incidence was retrieved through linkage with the Netherlands Cancer Registry. Associations between lifetime OC use and risk of melanoma were assessed by using Cox proportional hazard models. Women who used OCs at baseline were considered current users and women who had used OCs but stopped before baseline were considered former users. Never OC users were defined as the reference. During 10 years of follow-up, 447 women were diagnosed with melanoma. Melanoma risk was not increased among women who used OCs for a duration of <9, 10-15, or ≥16 years compared with never CO users. Melanoma risk was increased for current OC users [hazard ratio (HR), 1.53; 95% confidence interval (CI), 1.03-2.29], without a trend with duration of use (P-trend = .42) and age at cohort entry (P-trend = .05). Melanoma risk was not increased among former OC users (HR, 0.99; 95% CI, 0.72-1.38) nor when they had last used OC <2 years before baseline (HR, 0.69; 95% CI, 0.36-1.32). Current OC use was associated with increased melanoma risk, irrespective of the duration or recency of use.

In Brief OBJECTIVE To assess the effect of oral contraceptive (OC) use during adolescence on body composition parameters and cardiovascular disease risk factors. METHODS We used 9 years of longitudinal data from 66 non-Hispanic white females who were 12 years old at study entry in 1990, and who were subsequently classified either as OC users or nonusers. The OC users (n = 39) used OCs for a minimum of 6 months, were still using at age 21, and had used OCs, on average, for 28 months. The nonusers (n = 27) never used OCs. Individuals who started and then stopped using OCs before age 21 or used OCs for less than 6 months were excluded from these analyses. Cardiolipoprotein profiles were obtained from fasting blood samples (from age 16 to 21), and body composition measurements were made by dual energy x-ray absorptiometry (from age 12.5 to 21). Longitudinal models were used to examine changes in body composition patterns and in cardiolipoprotein patterns. RESULTS Between ages 12.5 and 21, gains by OC users and nonusers in height, weight, body mass index (BMI), and percent body fat were not significantly different. However, between ages 16 and 21, the OC users had significantly greater increases in total serum cholesterol, serum low-density cholesterol, and serum triglycerides than did the nonusers. CONCLUSION The use of OCs in young women is associated with less favorable blood lipid patterns, but is not associated with weight gain or increased body fat. The long-term effects of the alteration in the lipid profiles are unknown. Oral contraceptive use by teenage women increases total serum cholesterol, high-density lipoprotein cholesterol, and serum triglycerides but does not alter body weight or percent body fat.

Use of oral contraceptives in Germany: Prevalence, determinants and use-associated health correlates: Results of National Health Surveys from 1984 to 1999

The effect of kind of carbohydrate in the diet and use of oral contraceptives on metabolism of young women. I. Blood and urinary lactate, uric acid, and phosphorus

One hundred and seventy four (81% of all) pathologically confirmed new incident cases of female breast cancer identified from a medical center in Taipei from February, 1993 to June, 1994 were selected as the case group. Four hundred and fifty three inpatient controls who were without obstetric-gynecological, breast, or malignant diseases were individually matched for each case by age and date of admission. Information was obtained through direct interview and review of medical records. Conditional logistic regression was used to estimate the effects of each risk factor. After adjusting for education level, body mass index, age at menarche and first full-term pregnancy, parity, menopausal status and age at menopause, lifetime lactation, use of lactation inhibition hormones, and family history of breast cancer, breast cancer risk significantly elevated in use of OC before 25 years old and before 1971. In stratified analysis, significantly higher risk were found in OC use before 25 years old and in duration of use less than one year among post-menopausal subjects. Our results support the notion that OC use in early life for younger women and in early calendar years increase breast cancer risk.

In der Literatur wurde konsistent bei Nutzung oraler Contraceptiva (OCs) ein reduziertes Risiko von Uterus- und Ovarialtumoren berichtet. Der Effekt von niedrigdosierten OCs ist weniger klar.

Introduction: While oral contraceptive (OC) use is generally safe, women at higher risk for vascular disease are advised to use alternative forms of contraception. Smoking, a prothrombotic factor, is a contraindication for OC use in women over age 35. ABO blood group, specifically the non-O blood types, has also been associated with thrombosis risk. We therefore hypothesized that the effects of smoking and OC use on stroke risk would be accentuated in women with non-O blood groups. Methods: Using data from the Genetics of Early Onset Stroke Study, we used 3 polymorphisms within the ABO locus to classify blood group type in women under age 50, including 347 cases and 383 controls. Logistic regression was used to assess the stroke risk of current OC use, defined as use within 30 days, adjusted for other risk factors, and stratified by O and non-O blood group type. Results: Of the 347 women with early-onset stroke, 45% had African ancestry, 51% had European ancestry, and 4% had other ancestry. The median age was 42 years. After adjusting for race, age, hypertension, diabetes, migraines and aura, and smoking status, the odds ratio (OR) for stroke for smoking alone and OC use alone were 3.0 (95% CI 2.1-4.2) and 3.7 (95% CI 1.7-8.4), respectively in this population. Blood group (O vs non-O) did not appreciably alter the magnitude of these associations. However, the joint risk of smoking and OC use was substantially higher in women with blood group non-O (OR = 9.5, 95% CI 3.2-34.9) vs in women with blood group O (OR=4.9, 95% CI 0.4-110.2). Conclusions: Our findings are consistent with the possibility that non-O type blood group confers an increased risk of early onset stroke among OC users who smoke. Further studies are needed to confirm or refute this possibility and to determine whether non-O blood type should be considered in assessing the risk of OC use.