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.     

Factor V Leiden and prothrombin G20210A polymorphisms as risk factors for miscarriage during a first intended pregnancy: the matched case–control ''NOHA first'' study

Factor V Leiden (FVL) and prothrombin G20210A (FIIG20210A) mutations are associated with a higher risk of miscarriage: we sought to understand whether this association differs by clinical time of unexplained miscarriage, and by ethnic origin, among women with no previous thrombotic episode, during the first intended pregnancy. We performed a case-control study nested in a cohort of 32 683 women. We analyzed 3496 pairs of women matched for classical confounding factors. The FVL and FIIG20210A mutations were associated with an increased risk of miscarriage in Caucasian women [odds ratio (OR) 3.19, 95% confidence interval (CI) 2.37-4.30, P < 0.001 and OR 2.36, 95% CI, 1.72-3.24, P < 0.001, respectively]. Among non-Caucasian women, the mutations were rare and the associations with risk of miscarriage less clear. FVL and FIIG20210A mutations were independent risk factors for miscarriages only for women with related clinical signs occurring from the 10th week of gestation on (OR 3.46, 95% CI 2.53-4.72, P < 0.001 and OR 2.60, 95% CI 1.86-3.64, P < 0.001, respectively). These results indicate that FVL and FIIG20210A mutations are associated with a significant risk of spontaneous abortion which clinical signs occur from the 10th week on of the first intended pregnancy.     

High platelet reactivity is associated with myocardial infarction in premenopausal women: a population‐based case–control study

Summary. Background: Platelets are involved in the occlusion of coronary arteries after rupture of an atherosclerotic plaque. Furthermore, activated platelets release large quantities of growth factors, chemokines and interleukines that regulate inflammatory reactions. Therefore, we hypothesized that high basal platelet reactivity may contribute to an increased risk of myocardial infarction (MI) in premenopausal women. Methods: We assessed the relation between high platelet reactivity and MI in a population‐based case–control study among premenopausal women (aged < 50 years). We used multivariable logistic regression to quantify the effect of high platelet reactivity, adjusted for potential confounders. Platelet reactivity was estimated by plasma levels of neutrophil activating peptide 2 (NAP‐2), CXC chemokine ligand (CXCL)4, soluble glycoprotein 1b (sGPIb) and soluble P‐selectin. Results: High platelet reactivity (i.e. levels ≥ 90th percentile control subjects) was associated with a 2‐ to 3‐fold increased incidence of MI: the adjusted odds ratios (ORs) were 3.0 [95% confidence interval (CI) 1.4–6.4] for NAP‐2, 2.2 (0.9–5.1) for CXCL4, 1.9 (0.7–4.6) for sP‐selectin and 2.5 (1.1–5.7) for sGPIb. The incidence of MI dose‐dependently increased when more markers were elevated. High platelet reactivity according to both NAP‐2 and sGPIb was associated with an up to tenfold increased incidence (9.9, 95% confidence interval 2.0–48.3). Conclusions: High basal platelet reactivity was associated with a 2‐ to 3‐fold higher incidence of MI compared with normal platelet reactivity in premenopausal women. Our results suggest that high basal platelet reactivity may contribute to a higher risk of MI.     

The risk of first venous thromboembolism during pregnancy and puerperium in double heterozygotes for factor V Leiden and prothrombin G20210A

Background : The risk of venous thromboembolism (VTE) during pregnancy in double heterozygous carriers of factor (F) V Leiden and prothrombin G20210A is not established. Hence, whether or not these women deserve antithrombotic prophylaxis when pregnant is unknown. Patients and methods : In the frame of a multicenter family study, 52 double heterozygous carriers of FV Leiden and prothrombin G20210A who had remained pregnant at least once before knowledge of thrombophilia, were retrospectively investigated with respect to the occurrence of first VTE during pregnancy and puerperium. They were compared with 104 heterozygous carriers of FV Leiden, 104 of prothrombin G20210A and 104 women without thrombophilia. Results : Double heterozygotes were similar to single heterozygous carriers and non-carriers for the age at first pregnancy, age at testing and rate of full-term pregnancies. No VTE during pregnancy was observed in the four groups of women, whereas in the puerperium it occurred in two double carriers (1.8% of pregnancies, 95% CI: 0.5–6.3), three single FV Leiden carriers (1.5%, 0.5–4.3), two single prothrombin G20210A carriers (1%, 0.2–3.6) and one non-carrier (0.4%, 0–2.5). Conclusions : The risk of first VTE during pregnancy and puerperium in double heterozygous carriers of FV Leiden and prothrombin G20210A is low and similar to that of single carriers. As for single heterozygotes, antithrombotic prophylaxis in asymptomatic double heterozygous carriers appears to be justified only in puerperium.     

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.     

Factor V Leiden is associated with pre‐eclampsia but not with fetal growth restriction: a genetic association study and meta‐analysis

Summary. Background: Adverse pregnancy outcomes have been related to environmental and/or genetic factors. Of interest are genes associated with the clotting system as any perturbation in the balance of thrombotic and thrombolytic cascades could affect the placental circulation and hence the viability of the developing fetus. Several previous reports using relatively small numbers of cases and controls have suggested that there is a relationship between poor pregnancy outcomes and two polymorphisms, one in the factor V gene, the 1691G to A change (rs6025) located on chromosome 1q23 (factor V Leiden, FVL), and the other in the prothrombin gene, 20210G to A change (rs1799963) on chromosome 11p11‐q12 (PT). These results, however, are conflicting. Methods: We genotyped 6755 mother/infant pairs from the Avon Longitudinal Study of Parents and Children (ALSPAC) to determine whether maternal or fetal FVL or PT, either alone or in combination, are associated with fetal growth restriction (FGR) or pre‐eclampsia (PE). We also added the present results to previous cohort studies using meta‐analysis. Results: Smoking, primiparity and lower body mass index (BMI) were all associated with FGR, but neither maternal nor fetal FVL or PT, singly or in combination, were associated with FGR in the ALSPAC cohort. Meta‐analysis confirmed the lack of association between maternal FVL and FGR with a pooled odds ratio (OR) of 1.15 [95% confidence interval (CI) 0.95–1.39]. High BMI, primiparity, diabetes and chronic hypertension were all associated with pre‐eclampsia. Combining ALSPAC results with previous studies in a meta‐analysis indicated that maternal FVL is significantly associated with pre‐eclampsia, with a pooled OR of 1.49 (95% CI 1.13–1.96). Conclusion: Neither maternal nor fetal FVL or PT, singly or in combination, are associated with FGR; this contradicts previous case–control studies and meta‐analyses based on these studies. In a meta‐analysis of all published cohort studies to date, maternal FVL appears to increase the risk of pre‐eclampsia by almost 50%. This result is robust, homogeneous and does not appear to be affected by publication bias.     

Autoimmune skin and connective tissue diseases and risk of venous thromboembolism: a population‐based case‐control study

Summary. Background: Systemic inflammation is associated with vessel wall damage, upregulation of procoagulants, downregulation of anticoagulants, and suppression of fibrinolysis. Autoimmune diseases may therefore increase the risk of venous thromboembolism (VTE). Objectives: To examine whether autoimmune skin and connective tissue diseases are associated with increased VTE risk. Methods: We conducted this population‐based case–control study in northern Denmark, using administrative databases. From 1999 to 2009, we identified 14 721 VTE cases and 147 210 birth year‐matched, sex‐matched and county‐matched population controls. The date of diagnosis/matching was considered to be the index date for cases and controls. For all study subjects, we identified hospital diagnoses of autoimmune skin or connective tissue diseases between 1977 and the index date. We used conditional logistic regression with adjustment for VTE risk factors to calculate odds ratios and 95% confidence intervals (CIs) for patients with vs. without autoimmune disease. Given the risk‐set sampling design, odds ratios estimate incidence rate ratios (IRRs). Results: Autoimmune skin disease was not associated with VTE (IRR 1.0; 95% CI 0.9–1.2). Patients with connective tissue disease had an increased VTE risk within 90 days (IRR 2.3; 95% CI 1.5–3.7) and 91–365 days (IRR 2.0; 95% CI 1.5–2.8) after diagnosis, but not thereafter (IRR 1.1; 95% CI 1.0–1.2). Among connective tissue diseases, the greatest overall risk increases were found for juvenile rheumatoid arthritis (IRR 3.0; 95% CI 1.4–6.4) and systemic lupus erythematosus (IRR 2.8; 95% CI 1.7–4.7). Conclusions: Autoimmune connective tissue disease was associated with an increased risk of VTE within 1 year after diagnosis, whereas skin diseases were not.     

Tissue factor non‐coagulant signaling – molecular mechanisms and biological consequences with a focus on cell migration and apoptosis

Tissue factor (TF), a transmembrane glycoprotein, is the main initiator of the blood coagulation cascade. TF is also recognized as a true signaling receptor. There is accumulating evidence that the downstream signaling effects of the TF complexes are transduced by several mechanisms, including: activation of protease‐activated receptor (PAR)‐1 and PAR‐2, and the PAR‐dependent pathways, via the TF cytoplasmic domain and by transactivation of receptor tyrosine kinases. Triggering of signaling cascades such as the mitogen‐activated protein kinase and phosphoinositide 3‐kinase/AKT pathways couples TF to a multitude of functions within the cell, such as proliferation, cell migration, and survival. Thus, TF has a Janus face; on the one hand, it has vital life‐maintaining functions, and on the other it has harmful effects, exemplified by inflammation, the acute coronary syndromes, and cancer. TF mediates a broad spectrum of signaling mechanisms. Learning more about these different mechanisms/pathways will lead to new treatment strategies, which can ultimately be personalized.     

Heparin‐induced thrombocytopenia – therapeutic concentrations of danaparoid,unlike fondaparinux and direct thrombin inhibitors,inhibit formation of platelet factor 4–heparin complexes

Summary. Background: Treatment of heparin‐induced thrombocytopenia (HIT), a disorder in which anti‐platelet factor 4 (PF4)–heparin antibodies cause platelet activation and hypercoagulability, requires alternative (non‐heparin) anticoagulation. Treatment options include direct thrombin inhibitors [lepirudin and argatroban (approved), and bivalirudin], danaparoid (approved) (mixture of anticoagulant glycosaminoglycans), or fondaparinux (synthetic heparin‐mimicking pentasaccharide). PF4–heparin complexes form at optimal stoichiometric ratios. Objectives: To compare the effects of these various non‐heparin anticoagulants in disrupting the formation of PF4–heparin complexes, and PF4‐containing immune complexes. Patients/methods: Sera were obtained from patients with serologically confirmed HIT. The effects of the alternative anticoagulants on PF4 and PF4–heparin complex interactions with platelets, as well as HIT antibody binding and platelet activation, were investigated. Results: Danaparoid at very low concentrations increased PF4 binding to platelets. In therapeutic concentrations, however, it decreased PF4 binding to platelets (P = 0.0004), displaced PF4–heparin complexes from platelets (P = 0.0033) and PF4 from the surface of a PF4‐transfected HEK‐293 EBNA cell line expressing the PF4 receptor CXCR3‐B (P = 0.0408), reduced PF4–heparin complex size (P = 0.025), inhibited HIT antibody binding to PF4–heparin complexes (P = 0.001), and prevented platelet activation by HIT antibodies (P = 0.046). Although fondaparinux also interfered with PF4 binding to platelets, HIT antibody binding to PF4–heparin complexes, and activation of platelets by HIT antibodies, these effects occurred only at supratherapeutic concentrations. The direct thrombin inhibitors had no effect at any concentrations. Conclusions: Danaparoid uniquely interferes with the pathogenesis of HIT by disrupting PF4‐containing immune complexes at therapeutic dose concentrations. It is possible that these effects contribute to its therapeutic efficacy.     

Unintentional injuries among older adults in northern Sweden – a one‐year population‐based study

Scand J Caring Sci; 2011; 25; 185–193
Unintentional injuries among older adults in northern Sweden – a one‐year population‐based study Aim: To study the epidemiology of unintentional injuries in a population of 21 000 Swedish older adults (65+) and to compare the injury incidence with similar data collected two decades earlier. Method: This is a retrospective epidemiologic cross‐sectional study based on a 1‐year data set of all the 1753 registered injury events from a well‐defined population. Result: The injury rate per 1000 individuals was three times higher in the 85+ age group than in the 65–74 age group. The rate was also higher in women than in men aged 75 and older. Fractures, especially on lower and upper extremities, were the most common injuries. Falls in residential care facilities caused the most serious injuries. In transport areas, pedestrian falls and bicyclist crashes were much more common than car crashes. Of the 1753 people injured, 42% were treated as inpatients for a total of 11 569 days; 86% of these days were caused by injury events in the home (57%) or in residential care facilities (29%). Our 65+ age group occupied 69% of all hospital bed‐days for trauma in all ages (0–102 years). Conclusion: Over the last two decades, the injury and fracture rate per 1000 individuals has increased by 40–50%, especially in the older age groups. During this time, the nursing strategy for older adults has changed in Sweden. As a result, more people live in their homes nowadays. This increase is distressing especially when we consider the current knowledge of preventive measures. The high number and proportion (>2/3) of inpatient trauma days for these age groups are a heavy burden for the medical sector. These facts call for more effective preventive measures, especially in the home and in residential care facilities, to minimize the negative health effects and the rising health costs.