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Introduction: Sudden cardiac arrest (SCA) and cardiopulmonary resuscitation (CPR) are associated with activated coagulation and impairment of end-organ perfusion. Activated factor IX (FIXa) is part of the intrinsic coagulation system. FIX may also be activated by extrinsic tenase (tissue factor/activated factor VII), as well as through the intrinsic pathway, which may include thrombin-induced activation of factor XI, by which thrombin generation is sustained. Hypothesis: We hypothesized that the level of activated factor IX -antithrombin (FIXa-AT) complex, as a measure of coagulation activation, would be of prognostic value in SCA patients. Methods: From February 2007 until December 2010 blood samples in EDTA tubes were collected during or closely after termination of CPR from patients aged > 18 years with out-of-hospital cardiac arrest (OHCA) of assumed cardiac origin. Survivors had follow-up samples drawn 8-12 hours and 24-48 hours after admission. FIXa-AT was determined by ELISA. Patients were divided into quartiles (Q1-4) by FIXa-AT levels. Cox regression was used for analysis of death within 30 days. Results: A total of 115 OHCA patients were included. Of these, 71 patients (61,7%) died, of whom 35 died on scene and 36 in-hospital. Early-on FIXa-AT complex levels in the higher quartiles as compared to the lowest were significantly associated with increased risk of death (Figure 1). The hazard ratio (HR) for Q4 patients compared to Q1 was 6.79, (95% CI 2.04-22.61); p = 0.002, for Q3 4.48 (95% CI 1.33-15.16); p = 0,016, and for Q2 3.48 (95% CI 1.01-11.95); p = 0.048. Mean log e (FIXa-AT) in hospitalized non-survivors were higher than in survivors; 8-12 hours (p = 0.002) and 24-48 hours (p = 0.008). There was a positive correlation between the duration of advanced CPR and log e (FIXa-AT), r = 0.24, p = 0.012. Conclusion: Early-on FIXa-AT complex predicts 30-day mortality in OHCA-patients. Prolonged resuscitation seems to be associated with increased coagulation activation.

Background Preclinical data have indicated a link between use of vitamin K antagonists ( VKA ) and detrimental effects on vascular structure and function. The objective of the present study was to determine the relationship between VKA intake and different phenotypes of subclinical cardiovascular disease in the population. Methods and Results Clinical and laboratory data, as well as medical–technical examinations were assessed from 15 010 individuals aged 35 to 74 years during a highly standardized 5‐hour visit at the study center of the population‐based Gutenberg Health Study. In total, the study sample comprised 287 VKA users and 14 564 VKA nonusers. Multivariable analysis revealed an independent association between VKA intake and stiffness index (β=+2.54 m/s; [0.41/4.66]; P =0.019), ankle‐brachial index (β=−0.03; [−0.04/−0.01]; P P =0.0098), left ventricular ejection fraction (β=−4.02% [−4.70/−3.33]; P P =0.014) left ventricular mass (β=+5.34 g/m 2.7 [4.26/6.44]; P P P P P P VKA demonstrated consistent and robust results. Genetic variants in CYP 2C9 , CYP 4F2 , and VKORC 1 were modulating effects of VKA on subclinical markers of cardiovascular disease. Conclusions These data demonstrate negative effects of VKA on vascular and cardiac phenotypes of subclinical cardiovascular disease, indicating a possible influence on long‐term disease development. These findings may be clinically relevant for the provision of individually tailored antithrombotic therapy.

Introduction: Long-term exposure to air pollutants increases cardiovascular morbidity and mortality. Particulate matter (PM) derived from diesel exhaust has been documented to be pro-atherogenic in animal studies. Biodiesels are widely introduced as new fuels with improved emission characteristics. However, biodiesel contains relatively more polycyclic aromatic carbohydrates (PAH) compared to diesel. Therefore, we hypothesise that exposure to biodiesel as compared to diesel exhaust results in increased atherosclerosis. Methods and Results: In a carotid cuff atherosclerosis model, the effects of exposure to exhaust PM of biodiesel vs. diesel PM vs. saline (control) on atherosclerosis were evaluated. Both common carotid arteries in LDLR -/- mice were cuffed at week 2 in the course of an 8-week high-fat diet regimen. All mice were intratracheally instilled with saline, PM biodiesel or biodiesel once-weekly for 5 times. Immunohistochemistry and primary human vascular smooth muscle cells (hVSMC) were used for evaluation. Results: Exposure to both biodiesel and diesel didn’t exacerbate atherosclerosis development, however, biodiesel affected plaque composition towards a more vulnerable phenotype as compared to diesel with decreased total collagen content and hVSMC (respectively -100%, p=0.09 and -339%, p Conclusions: This study demonstrates that exposure to biodiesel exhaust PM dramatically modulates atherosclerotic plaque composition, resulting in an unstable plaque phenotype through enhanced pro-apoptotic mechanisms.

Background: Thrombin formation is one of the key enzymatic processes that direct the activity of the hemostatic system. Thrombin generation (TG), a method addressing the overall potential of a given plasma sample to form thrombin, may be a potential tool to improve risk stratification for cardiovascular diseases (CVD). This study aims to explore the relation between TG and cardiovascular risk factors (CVRFs), CVD, and total mortality. Methods: For this study, N=5000 subjects from the population-based Gutenberg Health Study were analyzed in a highly standardized setting. TG was measured by the Calibrated Automated Thrombogram method at 1 and 5 pM tissue factor (TF) trigger in platelet poor plasma. Lag time, endogenous thrombin potential (ETP), and peak height were derived from the TG curve. Sex-specific multivariable linear regression analysis adjusted for age, CVRFs, CVD and therapy (vitamin K antagonists, oral contraceptives and hormonal replacement therapy), was used to analyze the determinants of TG. Cox regression models adjusted for age, sex, CVRFs and vitamin K antagonists investigated the association between TG parameters and total mortality. Results: Lag time (at 1 and 5 pM TF) was positively associated with obesity and dyslipidemia for both sexes (p Conclusion: This large-scale study provides important insights in the effects of traditional CVRFs, particularly obesity, on TG in males and females. Lag time and ETP were found as potentially relevant predictors of increased mortality in the general population, which deserves further investigation.

Introduction: The reversal of the new oral anticoagulants in severely bleeding patients with prothrombin complex concentrates remains uncertain with conflicting evidence. This study assessed the ability of a four-factor PCC and activated PCC (aPCC) to reverse dabigatran anticoagulation in a porcine polytrauma model. Methods: After ethical approval, male pigs (n=30) were given dabigatran etexilate for 3 days (30 mg/kg bid PO), the sham group (n=6) received placebo. To accomplish supratherapeutic anticoagulation, dabigatran was infused for 90 min (30 min: 0.77 mg/kg/h; 60 min 0.52 mg/kg/min) prior to injury on day 4 in anaesthetized pigs. A standardized blunt liver injury and bilateral femur fractures were induced. Following hemorrhagic shock, resuscitation was started 5 min after trauma and blood loss (BL) was recorded 12 min post trauma. Randomized animals (n=6/group) received a single injection of PCC or aPCC (25 and 50 IU/kg), or vehicle (control). BL and hemodynamic variables were monitored over 5 h or until time of death. Data were analyzed by ANOVA (± SD). Results: After infusion and prior to injury dabigatran levels were 559 ± 36 ng/mL and remained elevated throughout. In contrast to sham animals (BL: 601 ± 137 mL), BL in in all anticoagulated animals was significantly elevated 12 min post injury (BL : 791 ± 54 mL). Anticoagulation with dabigatran without PCC therapy resulted in a total BL of 3774 ± 628 mL) with 100% mortality (survival time: 65-146 min; p Conclusions: This porcine model demonstrates that high doses of PCC and aPCC application of PCC may be a reasonable intervention for dabigatran-treated patients with life-threatening haemorrhage, though these data need clinical confirmation.

Abstract —Matrix Gla protein (MGP) is synthesized in a vitamin K–dependent way in smooth muscle cells of the healthy vessel wall, and its mRNA transcription is substantially upregulated in atherosclerotic lesions. Here we report the preparation of a monoclonal antibody against human MGP and its use in an enzyme-linked immunosorbent assay. The intra-assay and interassay coefficients of variation in serum samples were 5.4% and 12.6%, respectively, and the lower detection limit was 8.5% of the normal serum value. Individual within-day variations were