Genome-wide analysis of genetic determinants of circulating factor VII-activating protease (FSAP) activity.

Essentials Knowledge of genetic regulators of plasma factor VII activating protease (FSAP) levels is limited. We performed a genome-wide analysis of variants influencing FSAP activity in Scandinavian cohorts. We replicated an association for Marburg-1 and identified an association for a HABP2 stop variant. We identified a novel locus near ADCY2 as a potential additional regulator of FSAP activity. SUMMARY: Background Factor VII-activating protease (FSAP) has roles in both coagulation and fibrinolysis. Recent data indicate its involvement in several other processes, such as vascular remodeling and inflammation. Plasma FSAP activity is highly variable among healthy individuals and, apart from the low-frequency missense variant Marburg-I (rs7080536) in the FSAP-encoding gene HABP2, determinants of this variation are unclear. Objectives To identify novel genetic variants within and outside of the HABP2 locus that influence circulating FSAP activity. Patients/Methods We performed an exploratory genome-wide association study (GWAS) on plasma FSAP activity amongst 3230 Swedish subjects. Directly genotyped rare variants were also analyzed with gene-based tests. Using GWAS, we confirmed the strong association between the Marburg-I variant and FSAP activity. HABP2 was also significant in the gene-based analysis, and remained significant after exclusion of Marburg-I carriers. This was attributable to a rare HABP2 stop variant (rs41292628). Carriers of this stop variant showed a similar reduction in FSAP activity as Marburg-I carriers, and this finding was replicated. A secondary genome-wide significant locus was identified at a 5p15 locus (rs35510613), and this finding requires future replication. This common variant is located upstream of ADCY2, which encodes a protein catalyzing the formation of cAMP. Results and Conclusions This study verified the Marburg-I variant to be a strong regulator of FSAP activity, and identified an HABP2 stop variant with a similar impact on FSAP activity. A novel locus near ADCY2 was identified as a potential additional regulator of FSAP activity.

Antiphospholipid Antibodies are Associated with Low Levels of Complement C3 and C4 in Patients with Systemic Lupus Erythematosus.

Complement activation and low complement levels are common in systemic lupus erythematosus (SLE). Antiphospholipid antibodies (aPL) are found in about 30-40% of patients with SLE. This study aimed to investigate the association between aPL and complement levels in patients with SLE. Serum samples were collected from 269 patients with SLE enrolled in the Norwegian Systemic Connective Tissue and Vasculitis Registry (NOSVAR) during 2003-2009, and from 353 controls. All samples were analysed for anti-ß2 glycoprotein 1 (anti-ß2GP1) and anticardiolipin antibodies (aCL), C-reactive protein (CRP) and complement components C3 and C4. Median CRP level was significantly higher in cases than in controls (2.06 versus 0.90 mg/l; P < 0.0001). No significant difference in CRP was found between SLE patients with or without aPL (2.09 versus 1.89; P = 0.665). Median C3 levels were similar in cases (1.03 g/l) and controls (1.00 g/l), whereas median C4 levels were 0.16 g/l in cases versus. 0.19 in controls (P < 0.0001). However, aPL-positive SLE patients had significantly lower median C3 levels (0.92 versus. 1.07 g/l; P = 0.001) and C4 levels (0.11 versus 0.16 g/l; P < 0.0001) compared to aPL-negative patients. Lower C3 and C4 values in aPL-positive SLE patients may reflect a higher consumption of C3 and C4 due to more pronounced complement activation in aPL-positive SLE patients compared to SLE patients without aPL.

Medication use and drug-related problems among women at maternity wards-a cross-sectional study from two Norwegian hospitals.

PURPOSE: There is a lack of knowledge about drug-related problems (DRPs) among pregnant and lactating women. The aim of this study was to determine the extent and type of DRPs among pregnant and lactating women in the maternity ward at two Norwegian hospitals. We also aimed to investigate which drugs were involved in the identified DRPs, and the outcome of solving the DRPs. METHODS: Patient-reported treatment reviews were performed to assess the prevalence and type of DRPs among women at the two maternity wards. RESULTS: In all, 212 women were included in the study, of which 89 (42 %) had experienced at least one DRP (105 DRPs in total). "Need for additional drug" (49 cases, 46.7 %) was the most frequent. The most frequent drug group involved in DRPs was drugs acting on the respiratory system, and the most common intervention was raising awareness/providing confidence/giving information during the patient-reported treatment review. CONCLUSIONS: Over four out of ten women in the maternity wards have DRPs, and many have questions about drug use during pregnancy and lactation. Many of the DRPs could probably be avoided by providing patient-reported treatment reviews to pregnant women as a part of antenatal care. Multidisciplinary collaboration including physicians, midwifes, and pharmacists in antenatal care and in maternity ward could possibly prevent DRPs and thereby promote patient safety for pregnant and lactating women.

Genetic variations in the annexin A5 gene and the risk of pregnancy-related venous thrombosis.

BACKGROUND: Annexin A5 is a natural anticoagulant assumed to have thrombomodulary functions as it shields phospholipid layers from coagulation complexes. It was recently shown that the M2 haplotype within the annexin A5 gene (ANXA5) promoter reduces the transcriptional activity of the gene. In a previous report, the M2 haplotype was found to be associated with pregnancy-related venous thrombosis (VT). OBJECTIVES: To investigate whether the M1 or M2 haplotypes or other genetic variations in ANXA5 are associated with pregnancy-related VT. PATIENTS/METHODS: We investigated samples from 313 cases and 353 controls included in the VIP study, which is a case-control study of pregnancy-related VT. We analyzed tag single nucleotide polymorphisms (SNPs) selected from the CEU population (Utah Residents with Northern and Western European Ancestry) of HapMap and the M1 and the M2 haplotypes of the promoter. Odds ratios for VT were calculated for each haplotype with the wild type as the reference and for each tag SNP with the most common genotype as reference. RESULTS: We did not find any association between genetic variants in ANXA5 and the risk of pregnancy related VT, but some of the genetic variants were not in Hardy-Weinberg equilibrium. CONCLUSION: Neither the M1/M2 haplotypes nor the tag SNPs in ANXA5 were convincingly associated with pregnancy related VT, but other studies in this field are needed.

Perforation of the Pregnant Uterus during Laparoscopy for Suspected Internal Herniation after Gastric Bypass.

We report perforations of a pregnant uterus during laparoscopy for suspected internal herniation after gastric bypass at 24 weeks of gestation. Abdominal access and gas insufflation were achieved by the use of a 12 mm optic trocar. An additional 5 mm trocar was positioned. The perforations were handled by suturing following laparotomy and mobilisation of the high located uterus. The uterine fundus was located in the subcostal area. Internal herniation was not verified. A cesarean section was made 6 weeks later due to acute low abdominal pain. During delivery the uterus was found normal. At 5 months of age the child has developed normal and seems healthy. Optical trocars should be used with caution for abdominal access during laparoscopy in pregnancy. Open access should probably be preferred in most cases. Accidental perforations of the uterine cavity may be handled in selected cases with simple closure even following the use of large trocars under close postoperative surveillance throughout the pregnancy.

Prevalence and predictors for post-thrombotic syndrome 3 to 16 years after pregnancy-related venous thrombosis: a population-based, cross-sectional, case-control study.

BACKGROUND: The long-term outcome of pregnancy-related venous thrombosis (VT) is not known. OBJECTIVES: To assess predictors and long-term frequency of post-thrombotic syndrome (PTS) after pregnancy-related VT. PATIENTS/METHODS: In 2006, 313 women with pregnancy-related VT during 1990-2003 and 353 controls answered a comprehensive questionnaire that included self-reported Villalta score as a measure of PTS. Cases were identified from 18 Norwegian hospitals using the Norwegian Patient Registry and the Medical Birth Registry of Norway. The latter was used to select as possible controls women who gave birth at the same time as a case. Thirty-nine patients and four controls were excluded because of VT outside the lower limbs/lungs or missing Villalta scores. Two hundred and four patients had DVT in the lower limb and 70 had pulmonary embolism (PE). The control group comprised 349 women naive for VT at the time of the index pregnancy. RESULTS: Forty-two per cent of cases with DVT in the lower limb, compared with 24% of cases with PE and 10% of controls, reported a Villalta score of ≥ 5. Severe PTS (Villalta score of ≥ 15) was reported among 7%, 4% and 1%. Proximal postnatal, but not antenatal, thrombosis was a strong predictor of PTS with an adjusted odds ratio of 6.3 (95% confidence interval, 2.0-19.8; P = 0.002). Daily smoking before the index pregnancy and age above 33 years at event were independent predictors for post-thrombotic syndrome. CONCLUSIONS: PTS is a common long-term complication after pregnancy-related DVT. Proximal postnatal thrombosis, smoking and higher age were independent predictors of the development of PTS.

Long-term quality of life after pregnancy-related deep vein thrombosis and the influence of socioeconomic factors and comorbidity.

BACKGROUND: Little is known about the long-term impact of pregnancy-related deep vein thrombosis (DVT) of the lower limbs. OBJECTIVES: To evaluate the long-term consequences of pregnancy-related DVT by assessment of self-reported, disease-specific quality of life (QOL) and symptom severity using the Venous Insufficiency Epidemiological and Economic Study (VEINES)-QOL/Sym questionnaire, and to investigate the influence of socioeconomic factors and comorbidity. PATIENTS/METHODS: In this cross-sectional case-control study, 313 women with validated pregnancy-related DVT and 353 controls completed a comprehensive questionnaire, including the disease-specific VEINES-QOL/Sym questionnaire. After exclusion of DVT outside the lower limbs and missing scores, the study population comprised 208 patients and 347 controls. A VEINES-QOL/Sym score < the 25th percentile was defined as a clinically relevant reduced outcome compared with scores ≥ the 50th percentile. Predictors for low scores were identified in multivariate logistic regression models. RESULTS: Cases reported lower mean VEINES-QOL/Sym scores than controls, 45.6/45.4 vs. 52.8/52.7, respectively (P < 0.001), and QOL among cases was still reduced compared with controls when adjusted for possible confounders. Low education was an independent predictor for both low VEINES-QOL and VEINES-Sym scores, and in addition being married/cohabitating predicted low VEINES-Sym scores. CONCLUSIONS: Long-term QOL and symptom scores as assessed with the VEINES-QOL/Sym questionnaire were lower in women with previous pregnancy-related DVT than in controls, and also when adjusted for possible confounders. By logistic regression, low education was an independent predictor for low scores. This supports the use of the VEINES-QOL/Sym questionnaire in studies on pregnancy-related DVT.

Risk of venous thrombosis in pregnancy among carriers of the factor V Leiden and the prothrombin gene G20210A polymorphisms.

BACKGROUND: Pregnancy is associated with a 10-fold increased risk of venous thrombosis (VT), with different risk profiles for the antenatal and postnatal periods. The purpose of this study was to assess the risk of pregnancy-related VT associated with the factor (F)V Leiden and prothrombin gene G20210A polymorphisms. MATERIALS AND METHODS: The study comprised 377,155 women with 613,232 pregnancies at 18 Norwegian hospitals from 1 January 1990 to 31 December 2003. Of a total 559 cases with a validated first lifetime diagnosis of VT in pregnancy or within 14 weeks postpartum, and 1229 controls naive for VT, 313 cases and 353 controls donated biological material. RESULTS: The odds ratios for VT during pregnancy or puerperium were 5.0 [95% confidence interval (CI) 3.1-8.3] and 9.4 (95% CI 2.1-42.4) for heterozygous carriers of the FV Leiden and the prothrombin gene polymorphisms, respectively. All homozygous carriers of the FV Leiden polymorphism (n = 8) and the prothrombin polymorphism (n = 1) developed VT, indicating a very high risk of VT. We estimated that pregnancy-related VT occurred in 1.1/1000 non-carriers, in 5.4/1000 heterozygous carriers of the FV Leiden polymorphism, and in 9.4/1000 heterozygous carriers of the prothrombin polymorphism. To avoid one VT, the number of pregnant women needed to be screened for these two polymorphisms and the number needed to be given thromboprophylaxis were 2015 and 157, respectively. CONCLUSIONS: Although the relative risk for VT during pregnancy and after delivery was increased among carriers of the FV Leiden and the prothrombin polymorphisms, the overall probability for pregnancy-related VT was low.

The association of antiphospholipid antibodies with pregnancy-related first time venous thrombosis--a population-based case-control study.

In this population-based case-control study we explored the association of antiphospholipid antibodies with pregnancy-related venous thrombosis. From 1990 through 2003 615 pregnant women were identified at 18 hospitals in Norway with a diagnosis of first time VT. In 2006, 531 of 559 eligible cases and 1092 of 1229 eligible controls were invited for further investigations. The final study population comprised 313 cases and 353 controls, who completed a comprehensive questionnaire and donated a single blood sample, 3-16 years after index pregnancy. We report the results on lupus anticoagulant, anticardiolipin antibodies, and anti-ss(2) glycoprotein-1 antibodies alone, in combination, and with the contribution of the factor V Leiden and the prothrombin gene G20210A polymorphisms. Cut-off values for APAs were chosen according to current international consensus. 29 (9.3%) of the cases and 24 (6.8%) of the controls had at least one positive test for APAs (OR 1.4; 95% CI 0.8-2.5). Nine cases (2.8%) and no controls had more than one positive test (multi-positivity) for APAs. After excluding women with factor V Leiden or prothrombin polymorphisms, still 6 cases were multi-positive for APAs. We conclude that multi-positivity, but not single-positivity, for APAs was weakly associated with a history of ante- and postnatal VT.

Ante- and postnatal risk factors of venous thrombosis: a hospital-based case-control study.

OBJECTIVE: To study ante- and postnatal risk factors of venous thrombosis (VT) in pregnancy. METHODS: A hospital-based case-control study. Cases were women with objectively verified VT during pregnancy or postpartum. Two controls were selected for each case. Validated risk factors were analyzed using chi-square test and logistic regression. RESULTS: In total 559 cases with no prior VT, 268 ante- and 291 postnatal cases were identified together with 1229 controls. Risk factors for antenatal VT were assisted reproduction technique (ART), antepartum immobilization, cigarette smoking, and slight weight gain (<7 kg). Conception after ART and multiple pregnancy had an additive effect, whereas antepartum immobilization and high body mass index (BMI) had a multiplicative effect on the risk for antepartum VT. No other interaction was found between risk factors for antepartum VT. Risk factors for postnatal VT were antepartum immobilization, cigarette smoking, intrauterine fetal growth restriction (IUGR), preeclampsia, emergency cesarean section, postpartum hemorrhage, infection, surgery, and age and parity. Antepartum immobilization, high BMI and reoperation on the indication of bleeding showed multiplicative effects on the risk of postnatal VT. CONCLUSIONS: Ante- and postpartum risk factors differed markedly. More attention should be paid to pregnant women of high BMI who are immobilized.

The EWA (estrogen in women with atherosclerosis) study: a randomized study of the use of hormone replacement therapy in women with angiographically verified coronary artery disease. Characteristics of the study population. Effects on lipids and lipoproteins.

OBJECTIVES: To evaluate the effects of hormone replacement therapy (HRT) on lipids and lipoproteins in postmenopausal women with coronary artery disease. SETTING: In this single-centre, controlled and randomized study taking place in a tertiary referral clinic, patients were examined at baseline, and after 3 and 12 months. All analyses were performed examiner-blind. SUBJECTS: Postmenopausal women (n = 118) with angiographically verified coronary artery disease were recruited consecutively from patients referred for investigational procedures due to coronary artery disease. INTERVENTIONS: The women were randomized to HRT, i.e. transdermal application of continuous 17-beta oestradiol with cyclic medroxyprogesterone actetate tablets every 3rd month for 14 days, or to a control group. MAIN OUTCOMES: Effects on lipids and lipoproteins. RESULTS: After 3 months of unopposed oestradiol, triglycerides decreased significantly compared to the control group (P = 0.006). Sequential administration of medroxyprogesterone caused a decrease in HDL cholesterol (P = 0.01), concomitantly with a decrease in ApoA1 lipoproteins (P = 0.007). No other changes in lipids or lipoproteins were observed. After 12 months of therapy, no significant differences were observed between the two groups in lipid or lipoprotein levels. Concomitant statin treatment did not alter the main findings. CONCLUSIONS: In postmenopausal women with established coronary artery disease in whom the majority is treated with statins, no additional effect of HRT on lipids or lipoproteins could be observed except for a transient decrease in triglycerides in the initial unopposed oestradiol phase. No deleterious effect could be observed during medroxyprogesterone administration except for a small transient decrease in HDL cholesterol and ApoA1 lipoproteins.