ALBERT

Description: Introduction: Microalbuminuria (albuminuria 30–300 mg/24h) is a well known risk marker for arterial thromboembolism (ATE). It has been postulated that microalbuminuria is a reflection of generalized endothelial dysfunction that is associated with, among others, increased levels of several coagulation factors. The impact of coagulation disorders is more evident in the pathogenesis of venous thromboembolism (VTE), than in the pathogenesis of ATE. Therefore, we hypothesized that microalbuminuria might be an independent risk factor for VTE. Methods: In 1997, all inhabitants of the city of Groningen, aged between 28 and 75 years (n=85,421) were sent a postal questionnaire collecting information about risk factors for cardiovascular disease and a vial to collect a first morning urine sample for measurement of urinary albumin concentration (UAC). Of responded subjects (40,856), a cohort (8,592 subjects) enriched for higher levels of UAC was formed that completed screening at an outpatient clinic. Screening data were collected on albuminuria (assessed in two 24-h urine collections), and risk factors for atherosclerosis and renal disease. To identify subjects with VTE, we used the databases of the regional anticoagulation clinic, the national registry of hospital discharge diagnoses and the national registry of death certificates. Of identified subjects patient charts were drawn. Only symptomatic and objectively verified venous thromboembolic events were considered established. We evaluated the association between albuminuria and the incidence of VTE, using Cox-regression models. Results: Of 8592 subjects, 18 subjects were excluded because of missing data on albuminuria. Of the remaining 8574 subjects (mean age±SD, 49±13 years; 50% male), 129 subjects experienced VTE during a follow-up period of 8.6±1.8 years. In univariate analyses albuminuria, age, hypertension, smoking, body mass index (BMI), eGFR, triglycerides, C-reactive protein, tissue plasminogen activator, tissue plasminogen activator inhibitor 1 and cancer were associated with VTE (P300 mg/24h (n=134) conferred hazard ratios of 1.35 (95% CI, 0.83–2.19, P=0.23), 1.90 (1.02–3.53, P=0.04), 2.49 (1.56–3.99, P

Description: Abstract 25 Introduction: Accumulating evidence shows that venous and arterial thrombosis may be viewed as two diseases with similar pathophysiological entities. Both high factor VIII and low free protein S levels are risk factors for venous thrombosis, but if, and in what way, these thrombophilic factors also increase the risk of arterial thrombosis is unknown. Patients and Methods: In a single-center retrospective cohort study of families with thrombophilia, we performed a post-hoc analysis to identify if relatives with high factor VIII or low free protein S levels were at risk of arterial thrombosis. Clinical data were collected before laboratory testing. To avoid bias, all probands were excluded from the analyses. In addition, relatives with protein S deficiency type I were excluded from analysis when analyzing effects of free protein S. Factor VIII:C levels were measured by one-stage clotting assays and were considered increased at levels above 150 IU/dL. Free protein S antigen levels were measured by enzyme-linked immunosorbent assay after precipitation of protein S complexed with C4b-binding protein with polyethylene glycol. Free protein S antigen levels were considered decreased at levels below the normal range (〈 65 IU/dL). Coronary and peripheral arterial disease had to be symptomatic and angiographically proven, whereas myocardial infarction was diagnosed according to clinical, enzymatic and electrocardiographic criteria. Known risk factors for arterial thrombosis were recorded and included: hypertension, hyperlipidemia, the presence of diabetes mellitus, smoking habits or obesity. Absolute risks of first arterial thrombosis in relatives with high factor VIII or low free protein S levels were calculated. Linear regression was used to determine the relation between factor VIII levels and free protein S levels, respectively, combined with traditional arterial thrombotic risk factors. Adjustments were made for age and sex. Cumulative distribution functions were constructed to visualize a possible relationship between factor VIII and free protein S levels, respectively, and BMI Results: Of 1468 relatives tested for thrombophilia, 1399 were analyzed on factor VIII and 1143 on free protein S. Forty-six percent were male. Mean age at enrollment was 45 years. Mean factor VIII level was 146 IU/dL and mean free protein S level 80 IU/dL. High factor VIII levels were observed in 39% of relatives and low free protein S levels in 23% of relatives. First arterial thrombotic events were documented in 86 relatives at a mean age of 57 years. Annual incidence of arterial thrombosis in relatives with high factor VIII levels was 0.29% (95%CI, 0.22-0.38) compared to 0.13% (95%CI, 0.09-0.19) in relatives with normal factor VIII levels. In relatives with low free protein S levels, this risk was 0.26% (95%CI, 0.16-0.40), compared to 0.14% (95%CI, 0.10-0.20) in relatives with normal free protein S levels. Relatives with hypertension, diabetes mellitus, and obesity had mean factor VIII levels (age and sex adjusted) that were 11 IU/dL, 18 IU/dL, and 21 IU/dL higher than relatives without these arterial thrombotic risk factors, which were statitically significant findings. In addition, a dose response relation could be demonstrated between increasing factor VIII and body mass index (Figure). None of these associations were shown for free protein S. Conclusions: Both high factor VIII and low free protein S levels were a risk factor for arterial thrombosis in thrombophilic families. High factor VIII levels were particularly observed in relatives with traditional arterial thrombotic risk factors, suggesting that increase of these levels were acquired. Free protein S levels were not influenced by these arterial thrombotic risk factors which assumes that low free protein S levels were genetically determined. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction: Hereditary deficiencies of protein S, protein C or antithrombin are strong risk factors for venous thromboembolism (VTE). Whether these deficiencies are associated with arterial thromboembolism (ATE) and whether history of VTE in these subjects predisposes to subsequent ATE has yet to be determined. Methods: Based on pedigree analysis we enrolled a total 552 subjects (52% women; mean age, 46±17 years), belonging to 84 different kindreds, in this retrospective family-cohort study. Detailed information on previous episodes of VTE, ATE, anticoagulants use and atherosclerosis risk factors (i.e. diabetes, hypertension, hyperlipidemia, and smoking) were collected. In addition to the index deficiencies participants were also tested for other thrombophilic defects; including factor V Leiden, prothrombin G20210A, increased FVIII and lupus anticoagulants. Primary study outcome was objectively verified symptomatic ATE. As the assumption for proportional hazards for the final model was not met over the entire observation period, we opted for a piecewise Cox model with a cut off point set at 55 years of age. Results: Of 552 subjects (mean age±SD, 46±17 years; 52% women), 308 had either protein S (35%), protein C (39%) or antithrombin deficiency (26%). Age, atherosclerosis risk factors and other thrombophilic defects were similar (P〉0.23) between deficient and non-deficient subjects. A total of 44 arterial thromboembolic events had occurred, corresponding to an overall annual incidences of 0.34% (95% CI, 0.23–0.49) in deficient and 0.17% (0.09–0.28) in non-deficient subjects, hazard ratio 2.3 (1.2–4.5; P=0.01). However, the risk hazards varied over lifetime; while risk of ATE conferred by these deficiencies was 5.4 (1.6–18.4; P=0.006) before age 55 years, it was 1.3 (0.6–2.9; P=0.51) thereafter. After adjusting for atherosclerosis risk factors and clustering of ATE within families, deficient subjects had 4.7-fold (1.5–14.2; P=0.007) higher risk of ATE before age 55 years, versus 1.1 (0.5–2.6; P=0.84) thereafter, compared to non-deficient family members. For separate deficiencies these were 4.6 (1.1 – 18.3), 6.9 (2.1 – 22.2) and 1.1 (0.1 – 10.9) in protein S-, protein C- and antithrombin-deficient subjects, respectively, before age 55 years. History of VTE was not related to subsequent ATE, hazard ratio 1.1 (0.5 – 2.2). Conclusions: Compared to non-deficient family members, subjects with protein S or protein C deficiencies but not antithrombin deficiency have an increased risk for ATE before age 55 years, independent of prior VTE. After age 55 years conventional atherosclerosis risk factors accounted for ATE. In thrombophilic families, deficiencies of protein S and protein C should be considered in atherothrombotic risk assessment before age 55 years.