Genetic determinants of activity and antigen levels of contact system factors.

Essentials Genetic variation may provide valuable insight into the role of the contact system in thrombosis. Explored associations of genetic variants with activity, antigen, and disease in RATIO study. Two novel loci were identified: KLKB1 rs4253243 for prekallikrein; KNG1 rs5029980 for HMWK levels. Contact system variants and haplotypes were not associated with myocardial infarction or stroke. SUMMARY: Background The complex, interdependent contact activation system has been implicated in thrombotic disease, although few genetic determinants of levels of proteins from this system are known. Objectives Our primary aim was to study the influence of common F11, F12, KLKB1, and KNG1 variants on factor (F) XI activity and FXI, FXII, prekallikrein (PK) and high-molecular-weight kininogen (HMWK) antigen levels, as well as the risk of myocardial infarction and ischemic stroke. Patients/methods We analyzed samples from all 630 healthy participants, 182 ischemic stroke patients and 216 myocardial infarction patients in the RATIO case-control study of women aged < 50 years. Forty-three tagging single nucleotide variants (SNVs) were genotyped to represent common genetic variation in the contact system genes. Antigen and activity levels were measured with sandwich-ELISA-based and one-stage clotting assays. We performed single variant, age-adjusted, linear regression analyses per trait and disease phenotype, assuming additive inheritance and determined conditionally independent associations. Haplotypes based on the lead SNV and all conditionally independent SNVs were tested for association with traits and disease. Results We identified two novel associations of KLKB1 SNV rs4253243 with PK antigen (ßconditional = -12.38; 95% CI, -20.07 to -4.69) and KNG1 SNV rs5029980 with HMWK antigen (ßconditional = 5.86; 95% CI, 2.40-9.32) and replicated previously reported associations in a single study. Further analyses probed whether the observed associations were indicative of linkage, pleiotropic effects or mediation. No individual SNVs or haplotypes were associated with the disease outcomes. Conclusion This study adds to current knowledge of how genetic variation influences contact system protein levels and clarifies interdependencies.

Impact of time since diagnosis and mortality rate on cancer-associated venous thromboembolism: the Scandinavian Thrombosis and Cancer (STAC) cohort.

Essentials Competing risk by death may lead to overestimation of venous thromboembolism (VTE) risk in cancers. We assessed the risk of VTE in cancer with and without accounting for competing risk by death. The risk of VTE was influenced by the mortality rate and the time since cancer diagnosis. Competing risk by death should be taken into account when exploring VTE risk in cancer. SUMMARY: Background Venous thromboembolism (VTE) is a common complication in cancer, and studies have suggested that aggressive cancers create the highest risk of VTE. However, competing risk by death may result in overestimation of VTE risk in patients with cancers associated with high mortality. Therefore, we estimated the risk of VTE by cancer site, accounting for the differential mortality between cancers. Methods The Scandinavian Thrombosis and Cancer cohort included 144 952 participants followed from 1993-1997 to 2008-2012. Incidence rates, cause-specific hazard ratios (HRs) and subdistribution HRs (SHRs) were assessed for overall cancer and by cancer site according to time intervals since cancer diagnosis. Results During follow-up, 14 272 subjects developed cancer, and 567 had cancer-related VTE. In cause-specific analyses, the VTE risk was highest in the first 6 months after cancer diagnosis (HR 17.5, 95% confidence interval [CI] 15.1-20.3), and declined rapidly thereafter. However, when mortality was taken into account, the risk was similar in the periods 6 months before (SHR 4.8, 95% CI 3.6-6.4) and 6 months after (SHR 4.6, 95% CI 3.9-5.4) cancer diagnosis. The range of the 2-year cumulative VTE incidence rates was substantially narrowed for all cancer sites after competing risk by death was taken into account (from 1-10% to 1-4%). Conclusion VTE risk by cancer site was influenced by the mortality rate and the time since cancer diagnosis. Our findings suggest that the cancer itself is a major contributor to VTE risk, and that competing risk by death should be taken into account when VTE risk in cancer is explored.

Determinants of impaired renal and vascular function are associated with elevated levels of procoagulant factors in the general population.

Essentials Why venous thrombosis is more prevalent in chronic kidney disease is unclear. We investigated whether renal and vascular function are associated with hypercoagulability. Coagulation factors showed a procoagulant shift with impaired renal and vascular function. This suggests that renal and vascular function play a role in the etiology of thrombosis. SUMMARY: Background Impaired renal and vascular function have been associated with venous thrombosis, but the mechanism is unclear. Objectives We investigated whether estimated glomerular filtration rate (eGFR), urinary albumin-creatinine ratio (UACR), and pulse wave velocity (PWV) are associated with a procoagulant state. Methods In this cross-sectional analysis of the NEO Study, eGFR, UACR, fibrinogen, and coagulation factors (F)VIII, FIX and FXI were determined in all participants (n = 6536), and PWV was assessed in a random subset (n = 2433). eGFR, UACR and PWV were analyzed continuously and per percentile: per six categories for eGFR (> 50th [reference] to < 1st) and UACR (< 50th [reference] to > 99th), and per four categories (< 50th [reference] to > 95th percentile) for PWV. Linear regression was used and adjusted for age, sex, total body fat, smoking, education, ethnicity, total cholesterol, C-reactive protein (CRP) and vitamin K antagonists use (FIX). Results Mean age was 55.6 years, mean eGFR 86.0 (12SD) mL 1.73 m- ² and median UACR 0.4 mg mmol-1 (25th, 75th percentile; 0.3, 0.7). All coagulation factors showed a procoagulant shift with lower renal function and albuminuria. For example, FVIII was 22 IU dL-1 (95% CI, 13-32) higher in the eGFR < 1st percentile compared with the > 50th percentile, and FVIII was 12 IU dL-1 (95% CI, 3-22) higher in the UACR > 99th percentile compared with the < 50th percentile. PWV was positively associated with coagulation factors FIX and FXI in continuous analysis; per m/s difference in PWV, FIX was 2.0 IU dL-1 (95% CI, 0.70-3.2) higher. Conclusions Impaired renal and vascular function was associated with higher levels of coagulation factors, underlining the role of renal function and vascular function in the development of venous thrombosis.

Occult cancer-related first venous thromboembolism is associated with an increased risk of recurrent venous thromboembolism.

Essentials Recurrence risk after an occult cancer-related incident venous thromboembolism (VTE) is unknown. We compared the risk of VTE recurrence in occult-, overt- and non-cancer related first VTE. Patients with occult-cancer related first VTE had the highest risk of VTE recurrence. The high recurrence risk in occult cancer is likely due to the advanced cancers. SUMMARY: Background Although venous thromboembolism (VTE) is associated with a high recurrence rate, the absolute recurrence rates for cancer-related VTE, particularly occult cancer, are not well known. Objectives To investigate the risk of VTE recurrence in patients with occult and overt cancer-related VTE. Methods Incident VTE events among participants of the first to sixth Tromsø surveys occurring in the period 1994-2012 were included. Occult cancer was defined as cancer diagnosed within a year following a VTE, and overt cancer was defined as cancer diagnosed within the 2 years before a VTE. Results Among 733 patients with incident VTE, 110 had overt cancer and 40 had occult cancer. There were 95 recurrent VTE events during a median of 3.2 years of follow-up. The 1-year cumulative incidence of VTE recurrence was 38.6% in subjects with occult cancer, 15.5% in subjects with overt cancer, and 3.8% in non-cancer subjects. The 1-year risk of recurrence was 12-fold (hazard ratio [HR] 12.4, 95% confidence interval [CI] 5.9-26.3) higher in subjects with occult cancer and four-fold (HR 4.3, 95% CI 2.0-9.2) higher in subjects with overt cancer than in non-cancer subjects. The occult cancers associated with VTE recurrence were typically located at prothrombotic sites (i.e. lung and gastrointestinal) and presented at advanced stages. The majority (69%) of recurrences in subjects with occult cancer occurred before or shortly after cancer diagnosis, and were therefore not treatment-related. Conclusion Our findings suggest that the increased risk of recurrence in patients with occult cancer is mainly attributable to the advanced cancers in these patients.

Bone marrow lesions on magnetic resonance imaging in hand osteoarthritis are associated with pain and interact with synovitis.

OBJECTIVE: To determine the association between bone marrow lesions (BMLs) and (teno)synovitis as assessed on magnetic resonance (MR) imaging in patients with pain in hand osteoarthritis (OA). METHODS: In 105 consecutive primary hand OA patients (83% women, mean age 59 years), who were diagnosed by rheumatologists and included in the HOSTAS (Hand OSTeoArthritis in Secondary care) cohort, contrast enhanced MR imaging of right distal and proximal interphalangeal joints were obtained. In 92 patients joint site specific pain upon palpation was assessed within 3 weeks of magnetic resonance imaging (MRI) examination. MR features were scored (0-3) following the Oslo hand OA score: BMLs, synovitis, cysts, flexor tenosynovitis (FTS). Additionally, extensor tendon inflammation (ETI) (0-3) was scored. Odds ratios (OR, 95% confidence interval (CI)) were calculated using generalized estimating equations for MR features with joint pain, adjusted for putative confounders. Stratified analyses were performed to investigate interaction. RESULTS: BMLs, synovitis, cysts, FTS and ETI were demonstrated in 56%, 90%, 22%, 16% and 30% of patients, respectively. BMLs (grade 2/3 vs 0: 3.5 (1.6-7.7)) and synovitis (3 vs 0: OR 3.6 (95% CI 1.9-6.6)) were severity-dependent associated with joint pain, but FTS and ETI were not. Stratified analyses showed that BMLs did not associate with pain in the absence of synovitis, whereas synovitis was associated with pain in the absence of BMLs. Interaction was seen between BMLs and synovitis grade 2 or 3. CONCLUSION: In hand OA patients severe synovitis is associated with joint pain, which is worsened when BMLs co-occur, suggesting synovitis as primary target of treatment.

Bone marrow lesions and synovitis on MRI associate with radiographic progression after 2†years in hand osteoarthritis.

OBJECTIVE: To study the association of magnetic resonance (MR) features with radiographic progression of hand osteoarthritis over 2 years. METHODS: Of 87 primary patients with hand osteoarthritis (82% women, mean age 59 years), baseline distal and proximal interphalangeal joint contrast-enhanced MR images were scored 0-3 for bone marrow lesions (BMLs) and synovitis following the Oslo score. Baseline and 2-year follow-up radiographs were scored following Kellgren-Lawrence (KL) (0-4) and OsteoArthritis Research Society International (OARSI) scoring methods (0-3 osteophytes, joint space narrowing (JSN)). Increase ≥1 defined progression. Associations between MR features and radiographic progression were explored on joint and on patient level, adjusting for age, sex, body mass index, synovitis and BML. Joints in end-stage were excluded. RESULTS: Of 696 analysed joints, 324 had baseline KL=0, 28 KL=4 and after 2 years 78 joints progressed. BML grade 2/3 was associated with KL progression (2/3 vs 0: adjusted risk ratio (RR) (95% CI) 3.3 (2.1 to 5.3)) and with osteophyte or JSN progression, as was synovitis. Summated scores were associated with radiographic progression on patient level (RR crude BML 1.08 (1.01 to 1.2), synovitis 1.09 (1.04 to 1.1), adjusted synovitis 1.08 (1.03 to 1.1)). CONCLUSIONS: BMLs, next to synovitis, show, already after 2 years, graded associations with radiographic progression, suggesting that both joint tissues could be important targets for therapy.

Cross-sectional association of endogenous steroid hormone, sex hormone-binding globulin, and precursor steroid levels with hemostatic factor levels in postmenopausal women.

Essentials Endogenous hormone levels' influence on hemostatic factor levels is not fully characterized. We tested for associations of endogenous hormone with hemostatic factor levels in postmenopause. Estrone levels were inversely associated with the natural anticoagulant, protein S antigen. Dehydroepiandrosterone sulfate levels were inversely associated with thrombin generation. SUMMARY: Background Oral use of exogenous estrogen/progestin alters hemostatic factor levels. The influence of endogenous hormones on these levels is incompletely characterized. Objectives Our study aimed to test whether, among postmenopausal women, high levels of estradiol (E2), estrone (E1), testosterone (T), dehydroepiandrosterone sulfate (DHEAS), dehydroepiandrosterone (DHEA), and androstenedione, and low levels of sex hormone-binding globulin (SHBG), are positively associated with measures of thrombin generation (TG), a normalized activated protein C sensitivity ratio (nAPCsr), and factor VII activity (FVIIc), and negatively associated with antithrombin activity (ATc) and total protein S antigen (PSAg). Methods This Heart and Vascular Health study cross-sectional analysis included 131 postmenopausal women without a prior venous thrombosis who were not currently using hormone therapy. Adjusted mean differences in TG, nAPCsr, FVIIc, ATc and PSAg levels associated with differences in hormone levels were estimated using multiple linear regression. We measured E2, E1, total T, DHEAS, DHEA and androstenedione levels by mass spectrometry, SHBG levels by immunoassay, and calculated the level of free T. Results One picogram per milliliter higher E1 levels were associated with 0.24% lower PSAg levels (95% Confidence Interval [CI]: -0.35, -0.12) and 1 µg mL-1 higher DHEAS levels were associated with 40.8 nm lower TG peak values (95% CI: -59.5, -22.2) and 140.7 nm×min lower TG endogenous thrombin potential (ETP) (95% CI: -212.1, -69.4). After multiple comparisons correction, there was no evidence for other associations. Conclusions As hypothesized, higher E1 levels were associated with lower levels of the natural anticoagulant PSAg. Contrary to hypotheses, higher DHEAS levels were associated with differences in TG peak and ETP that suggest less generation of thrombin.

Causes of venous thrombosis.

Venous thrombosis which mainly manifests as deep vein thrombosis of the leg or pulmonary embolism occurs in 1 per 1000 per year. It occurs due to interacting genetic, environmental and behavioral risk factors. The strongest risk factors are certain types of surgery and malignancies. Over the last decade many new risk factors for venous thrombosis have been identified. Venous thrombosis has a high recurrence rate, of around 5 % per year. Whereas clinically it would be most important to identify patients at risk of recurrence, only male sex and a previous unprovoked thrombosis are established determinants of recurrent thrombosis.

Genetic risk factors for venous thrombosis in the elderly in a case-control study.

UNLABELLED: Essentials Risk of venous thrombosis (VT) related to common genetic variants in those aged 70+ is unknown. We studied Factor V Leiden, prothrombin mutation, non-O blood group and family history (FH) of VT. Risk of VT was increased 2.2-, 1.4-, 1.3- and 2.1-fold respectively. FH is easy to obtain and can be implemented in clinical decision rules of VT risk in the elderly. Click to hear Prof. Reitsma discuss genetic risk factors of arterial and venous thrombosis SUMMARY: Background As the incidence of venous thrombosis (VT) increases steeply with age and the number of elderly people is on the rise, studies of VT in this age group are important. Objectives We aimed to study the associations of common genetic risk factors (i.e. the factor V Leiden and prothrombin G20210A mutations, non-O blood group and family history of VT) with risk of a first VT in older age (> 70 years). Methods Four hundred and one consecutive cases with a first-time thrombosis and 431 controls (all ≥ 70 years) were included in the AT-AGE case-control study. Information on risk factors for VT, including family history of VT in first-degree relatives, was obtained by interview. Unprovoked VT was defined as thrombosis not related to surgery, fracture, plaster cast or immobility within 3 months prior to VT. Results The risk of VT was 2.2-fold increased in factor V Leiden carriers (95% confidence interval [CI], 1.2-3.9), 1.4-fold increased in prothrombin mutation carriers (95% CI, 0.5-3.9), and 1.3-fold increased in those with non-O blood group (95% CI, 1.0-1.8). Positive family history of VT was associated with a 2.1-fold increased risk of VT (95% CI, 1.5-3.1). The highest risk of VT was found in individuals who had both a positive family history and were carriers of one of the two prothrombotic mutations. Conclusions Genetic factors clearly related to VT in younger populations were also risk factors in older age and a positive family history was also important in this age group.

Bakers' cyst and tibiofemoral abnormalities are more distinctive MRI features of symptomatic osteoarthritis than patellofemoral abnormalities.

OBJECTIVE: To investigate which structural MR abnormalities discriminate symptomatic knee osteoarthritis (OA), taking co-occurrence of abnormalities in all compartments into account. METHODS: The Netherlands Epidemiology of Obesity (NEO) study is a population-based cohort aged 45-65 years. In 1285 participants (median age 56 years, 55% women, median body mass index (BMI) 30 kg/m(2)), MRI of the right knee were obtained. Structural abnormalities (osteophytes, cartilage loss, bone marrow lesions (BMLs), subchondral cysts, meniscal abnormalities, effusion, Baker's cyst) at 9 patellofemoral and tibiofemoral locations were scored following the knee OA scoring system. Symptomatic OA in the imaged knee was defined following the American College of Rheumatology criteria. Logistic ridge regression analyses were used to investigate which structural abnormalities discriminate best between individuals with and without symptomatic OA, crude and adjusted for age, sex and BMI. RESULTS: Symptomatic knee OA was present in 177 individuals. Structural MR abnormalities were highly frequent both in individuals with OA and in those without. Baker's cysts showed the highest adjusted regression coefficient (0.293) for presence of symptomatic OA, followed by osteophytes and BMLs in the medial tibiofemoral compartment (0.185-0.279), osteophytes in the medial trochlear facet (0.262) and effusion (0.197). CONCLUSIONS: Baker's cysts discriminate best between individuals with and without symptomatic knee OA. Structural MR abnormalities, especially in the medial side of the tibiofemoral joint and effusion, add further in discriminating symptomatic OA. Baker's cysts may present as a target for treatment.

The association of statin therapy with the risk of recurrent venous thrombosis.

UNLABELLED: Essentials A lowered risk of recurrent venous thrombosis (VT) with statin treatment is controversial. Among observational inception cohort of 2,798 adults with incident VT, 457 had recurrent VT. Time-to-event models with time-varying statin use and adjustment for potential confounders was used for analysis. Compared to nonuse, current statin use was associated with 26% lower risk of recurrent VT. Click to hear Prof. Büller's perspective on Anticoagulant Therapy in the Treatment of Venous Thromboembolism SUMMARY: Background Meta-analyses of randomized controlled trials suggest that treatment with hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) lowers the risk of incident venous thrombosis (VT), particularly among those without prevalent clinical cardiovascular disease (CVD). Whether this is true for the prevention of recurrent VT is debated. We used an observational inception cohort to estimate the association of current statin use with the risk of recurrent VT. Methods and Results The study setting was a large healthcare organization with detailed medical record and pharmacy information at cohort entry and throughout follow-up. We followed 2798 subjects 18-89 years of age who experienced a validated incident VT between January 1, 2002, and December 31, 2010, for a first recurrent VT, validated by medical record review. During follow-up, 457 (16%) developed a first recurrent VT. In time-to-event models incorporating time-varying statin use and adjusting for potential confounders, current statin use was associated with a 26% lower risk of recurrent VT: hazard ratio 0.74, 95% confidence interval 0.59-0.94. Among cohort members free of CVD (n = 2134), current statin use was also associated with a lower risk (38%) of recurrent VT: hazard ratio 0.62, 95% confidence interval 0.45-0.85. We found similar results when restricting to new users of statins and in subgroups of different statin types and doses. Conclusions In a population-based cohort of subjects who had experienced an incident VT, statin use, compared with nonuse, was associated with a clinically relevant lower risk of recurrent VT. These findings suggest a potential secondary benefit of statins among patients who have experienced an incident VT.

Hypercoagulability and the risk of myocardial infarction and ischemic stroke in young women.

BACKGROUND: Myocardial infarction (MI) and ischemic stroke (IS) are acute forms of arterial thrombosis and share some, but not all, risk factors, indicating different pathophysiological mechanisms. OBJECTIVE: This study aims to determine if hypercoagulability has a differential effect on the risk of MI and IS. PATIENTS AND METHODS: We reviewed the results from the Risk of Arterial Thrombosis in Relation to Oral Contraceptives study, a population-based case-control study involving young women (< 50 years) with MI, non-cardioembolic IS and healthy controls. From these data, relative odds ratios (ORIS /ORMI ) and their corresponding confidence intervals for all prothrombotic factors that were studied in both subgroups were calculated. RESULTS: Twenty-nine prothrombotic risk factors were identified as measures of hypercoagulability. Twenty-two of these risk factors (21/29, 72%) had a relative odds ratios > 1; for 12 (41%), it was > 2; and for 5 (17%), it was > 2.75. The five risk factors with the largest differences in associations were high levels of activated factor XI (FXI) and FXII, kallikrein, the presence of lupus anticoagulans, and a genetic variation in the FXIII gene. CONCLUSION: In young women, prothrombotic factors are associated more with the risk of IS than with MI risk, suggesting a different role of hypercoagulability in the mechanism leading to these two diseases.

Risk of venous thrombosis after arthroscopy of the knee: results from a large population-based case-control study.

BACKGROUND: From the currently available evidence, the risk of venous thrombosis after knee arthroscopy remains unclear. OBJECTIVES: To estimate the risk of venous thrombosis after arthroscopy of the knee, and to identify high-risk groups. PATIENTS AND METHODS: We used data from a large population-based case-control study (the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis [MEGA] study) on the etiology of venous thrombosis (4416 cases; 6150 controls). Odds ratios (ORs) with 95% confidence intervals (CIs), adjusted for age, sex, body mass index, rheumatic disease, and regular exercise, were calculated. RESULTS: One hundred and three patients and 24 controls had a knee arthroscopy in the year before the index date, resulting in a six-fold increased risk (OR 5.9, 95% CI 3.7-9.3). Ligament reconstructions led to a higher risk (OR 17.2, 95% CI 2.2-136) than meniscal surgery, diagnostic arthroscopy, or chondroplasty (OR 5.4, 95% CI 3.4-8.7). An additionally increased risk was found for combinations with genetic and acquired risk factors: with oral contraceptives (OR 46.6, 95% CI 6.1-353); and with factor V Leiden, factor II G20210A mutation, or non-O blood type (OR 15.3, 95% CI 8.1-28.5). The risk of venous thrombosis was particularly high in the first 3 months after knee arthroscopy, with an 18-fold increased risk (OR 16.2, 95% CI 7.8-33.7). CONCLUSIONS: We observed a strongly increased risk of venous thrombosis after knee arthroscopy, especially in the first months after the procedure. The risk was particularly high in the presence of other acquired or genetic risk factors, making knee arthroscopy a high-risk intervention in certain individuals.

Mortality in osteoarthritis patients.

OBJECTIVES: To investigate whether all-cause mortality and deaths due to cardiovascular disease are increased in patients who have consulted primary or secondary health care with symptoms and signs of osteoarthritis (OA). METHOD: This study included 383 patients with symptomatic OA at multiple sites from the Genetics ARthrosis and Progression (GARP) study (mean age 60 years, 82% women, 3693 person-years of follow-up) and 459 patients with primary hand, knee, or hip OA from the Osteoarthritis Care Clinic (OCC) study (mean age 61 years, 88% women, 1890 person-years of follow-up). Standardized mortality ratios (SMRs) with 95% confidence intervals (CIs) were calculated for all-cause mortality and causes of deaths in comparison to the general population. Cox proportional hazard ratios (HRs) with 95% CIs were used to associate baseline characteristics with all-cause mortality. RESULTS: In the GARP study, 26 patients died whereas 48 deaths were expected (SMR 0.54, 95% CI 0.37-0.79). The SMR was 0.47 (95% CI 0.29-0.76) in women and 0.73 (95% CI 0.39-1.35) in men. Similar results were found in the OCC study (SMR 0.45, 95% CI 0.25-0.82). Malignancy and cardiovascular disease were the main causes of deaths in GARP. Male sex (HR 3.04, 95% CI 1.38-6.69), increasing age (HR 1.10, 95% CI 1.05-1.16), and self-reported cancer (HR 8.29, 95% CI 3.12-22.03) were associated with increased mortality in GARP. CONCLUSIONS: Patients consulting health care for their OA are not at higher risk of death than the general population. These results suggest that the management of OA patients may not need to focus specifically on the treatment of cardiovascular risk factors and comorbidities.

The relative contribution of mechanical stress and systemic processes in different types of osteoarthritis: the NEO study.

OBJECTIVE: To study the relative contribution of surrogates for mechanical stress and systemic processes with osteoarthritis (OA) in weight-bearing and non-weight-bearing joints. METHODS: The Netherlands Epidemiology of Obesity study is a population-based cohort including 6673 participants (range 45-65 years, 56% women, median body mass index 26 kg/m(2)). Weight (kg) and fat mass (kg) were measured, fat-free mass (kg) was calculated. The metabolic syndrome was defined following the Adult Treatment Panel III criteria. Knee and hand OA were defined according to the American College of Rheumatology clinical criteria.Logistic regression analyses were performed to associate surrogates for mechanical stress (such as weight, fat-free mass) and systemic processes (such as metabolic syndrome) with OA in knees alone, knees and hands or hands alone, adjusted for age, sex, height, smoking, education and ethnicity, and when appropriate for metabolic factors and weight. RESULTS: Knee, knee and hand, and hand OA were present in 10%, 4% and 8% of the participants, respectively. Knee OA was associated with weight and fat-free mass, adjusted for metabolic factors (OR 1.49 (95% CI 1.32 to 1.68) and 2.05 (1.60 to 2.62), respectively). Similar results were found for OA in knees and hands (OR 1.51 (95% CI 1.29 to 1.78) and 2.17 (95% CI 1.52 to 3.10) respectively). Hand OA was associated with the metabolic syndrome, adjusted for weight (OR 1.46 (95% CI 1.06 to 2.02)). CONCLUSIONS: In knee OA, whether or not in co-occurrence with hand OA, surrogates for mechanical stress are suggested to be the most important risk factors, whereas in hand OA alone, surrogates for systemic processes are the most important risk factors.

Below-knee cast immobilization and the risk of venous thrombosis: results from a large population-based case-control study.

BACKGROUND: From the available evidence, the risk of venous thrombosis in patients with below-knee cast immobilization remains unclear. OBJECTIVES: To estimate the risk of venous thrombosis after below-knee cast immobilization and to identify high-risk groups. PATIENTS AND METHODS: We used data from a large population-based case-control study (MEGA study) on the etiology of venous thrombosis (4418 cases; 6149 controls). Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated, and adjusted for age, sex, body mass index, and regular exercise. Absolute risks were estimated from the ORs. RESULTS: One hundred and thirty-four patients and 23 controls had below-knee plaster cast immobilization in the year before the index date, resulting in an eight-fold increased risk (OR 8.3 [95% CI 5.3-12.9]). Traumatic indications led to a higher risk than non-traumatic indications: OR 12.7 (95% CI 6.6-24.6) vs. OR 7.6 (95% CI 0.9-66.4). An additionally increased risk was found for combinations with genetic or acquired risk factors: oral contraceptives (OR 18.2 [95% CI 6.2-53.4]); obesity (OR 17.2 [95% CI 5.4-55.2]); factor V Leiden, factor II 20210A mutation, and/or non-O blood group (OR 23.0 [95% CI 11.5-46.0]); all for a period of 1 year. Ninety per cent of the events occurred in the first 3 months after cast application. This led to a 56-fold increased risk (OR 56.3 [95% CI 17.9-177.3]) in this period. CONCLUSIONS: Below-knee cast immobilization strongly increases the risk of venous thrombosis. We found distinct differences in intrinsic risk between individuals with respect to indication for cast immobilization and the presence of genetic or acquired risk factors.

No effect of isolated long-term supine immobilization or profound prolonged hypoxia on blood coagulation.

BACKGROUND: Long-distance air travel is associated with an increased risk of venous thrombosis. The most obvious factor that can explain air travel-related thrombosis is prolonged seated immobilization. In addition, hypobaric hypoxia has been shown to affect coagulation, and the lowered atmospheric pressures present in the cabin during the flight may therefore play an etiologic role. Because immobilization and hypoxic conditions are usually present simultaneously in airplanes or hypobaric chambers, their separate effects on the coagulation system or on thrombosis risk have not been studied extensively. OBJECTIVES: To investigate the separate effects of long-term immobilization and profound prolonged hypoxia on blood coagulation. PATIENTS AND METHODS: We performed two studies in collaboration with European Space Agency/European Space Research and Technology Centre. In the first study, 24 healthy, non-smoking, adult women underwent 60 days of -6° head-down bed rest. In the second study, we took blood samples from 25 healthy men who participated during their stay in the Concordia station in Antarctica, where, due to the atmospheric conditions, continuous severe hypobaric hypoxia is present. In both studies, we measured markers of blood coagulation at baseline and at several time points during the exposures. RESULTS AND CONCLUSIONS: We observed no increase in coagulation markers during immobilization or in the hypobaric environment, compared with baseline measurements. Our results indicate that neither immobilization nor hypoxia per se affects blood coagulation. These results implicate that a combination of risk factors is necessary to induce the coagulation system during air travel.

Differential associations of oral estradiol and conjugated equine estrogen with hemostatic biomarkers.

BACKGROUND: The risk of venous thrombosis (VT) associated with oral hormone therapy (HT) may differ by type of estrogen compound. OBJECTIVE: To compare the thrombotic profile of women using oral conjugated equine estrogens (CEE) with that of women using oral estradiol (E2). METHODS: In postmenopausal, female, health maintenance organization (HMO) members with no history of VT, we measured thrombin generation, levels of factor VII activity, antithrombin activity and total protein S antigen. Mean levels of hemostasis biomarkers were cross-sectionally compared by use and type of estrogen using multiple linear regressions. The type of estrogen used was determined primarily by the HMO formulary, which changed its preferred estrogen from CEE to E2 during the study period. RESULTS: The sample included 92 E2 users and 48 CEE users, with a mean age of 64.1 years and mean BMI of 29.1 kg m(-2) . Twenty-seven per cent of HT contained medroxyprogesterone acetate. Compared with E2 users, CEE users had greater thrombin generation peak values and endogenous thrombin potential, and lower total protein S (multivariate adjusted differences of 49.8 nm (95% CI, 21.0, 78.6), 175.0 nm × Min (95% CI, 54.4, 295.7) and -13.4% (95% CI, -19.8, -6.9), respectively). Factor VII and antithrombin levels were not different between E2 and CEE users. Results were similar in subgroups of users of unopposed HT, opposed HT, low-dose estrogen and standard dose estrogen. CONCLUSION: The hemostatic profile of women using CEE is more prothrombotic than that of women using E2. These findings provide further evidence for a different thrombotic risk for oral CEE and oral E2.