The paradoxical antifibrinolytic effect of dabigatran and argatroban in the presence of soluble thrombomodulin is unrelated to protein C-dependent increase of thrombin generation

Background

Anticoagulants stimulate fibrinolysis in vitro, mainly by inhibiting thrombin-mediated TAFI activation. Surprisingly, however, direct thrombin inhibitors (DTIs) inhibit fibrinolysis and enhance thrombin generation in vitro when tested in the presence of high thrombomodulin (TM) concentrations. Because the paradoxical effect on thrombin generation was shown to be protein C (PC)-dependent, we investigated the role of PC in the antifibrinolytic effect of two DTIs, dabigatran and argatroban.

Methods and Results

In the presence of 10 nM TM, both dabigatran (0.5 μM) and argatroban (1 μM) prolonged clot lysis time and enhanced thrombin generation. This notwithstanding, the DTIs inhibited thrombin-mediated TAFI activation, peak TAFIa activity being reduced by > 60%. A specific feature of TAFI activation curve in the presence of DTIs was a much slower disappearance of TAFIa activity, which was likely the cause of fibrinolysis inhibition. The addition of an anti-PC antibody (αPC) nullified the paradoxical effect of DTIs on thrombin generation but influenced neither TAFI activation nor the fibrinolysis time.

Conclusions

Our results suggest that the inhibition of PC activation by DTIs in the presence of TM, while enhancing thrombin generation, has no effect on thrombin-mediated TAFI activation. The inhibition of fibrinolysis by DTIs can be explained by the prolonged activation of TAFI resulting from the sustained release of thrombin from thrombin-DTI complex. While the clinical relevance of these findings needs to be investigated by in vivo studies, our data might help understanding the role of the different players in the regulation of thrombin generation, TAFI activation and fibrinolysis resistance.     

Novel assays in the coagulation laboratory: a clinical and laboratory perspective

The ability to monitor Factor VIII (FVIII) and Factor IX (FIX) levels is integral to the clinical management of hemophilia A and B patients, respectively. Factor activity levels are checked during regular follow-up, post-infusion of factor concentrates, during pre- and post-operative assessments, and when the presence of an inhibitor is suspected. However, the ability to accurately and reproducibly measure factor activity levels with standard coagulation assays has been challenging due to the emergence of recombinant factor concentrates with extended half-lives. Similarly, special considerations must be given to the type of inhibitor assay used in patients with acquired hemophilia receiving recombinant porcine FVIII replacement. Alternative approaches to achieve hemostasis with clotting factor mimetics and interference of endogenous anticoagulants lack standardized assays for monitoring hemostatic efficacy. Laboratory assays measuring dynamic clotting parameters such as thrombin generation or whole blood viscoelasticity may provide a way forward, but have yet to enter routine clinical use. This review highlights the role of specialized coagulation assays in an era where multiple new hemostatic therapeutics for hemophilia are available, and underscores the need for clear communication between bedside and laboratory clinicians.     

Derivation and Validation of a Chronic Total Coronary Occlusion Intervention Procedural Success Score From the 20,000-Patient EuroCTO Registry: The EuroCTO (CASTLE) Score

Objectives

The aim was to establish a contemporary scoring system to predict the outcome of chronic total occlusion coronary angioplasty.

A comparison of two clinical scores for bronchiolitis. A multicentre and prospective study conducted in hospitalised infants

Background

There are a number of clinical scores for bronchiolitis but none of them are firmly recommended in the guidelines.

Ventricular fibrillation waveform measures combined with prior shock outcome predict defibrillation success during cardiopulmonary resuscitation

Aim

Amplitude Spectrum Area (AMSA) and Median Slope (MS) are ventricular fibrillation (VF) waveform measures that predict defibrillation shock success. Cardiopulmonary resuscitation (CPR) obscures electrocardiograms and must be paused for analysis. Studies suggest waveform measures better predict subsequent shock success when combined with prior shock success. We determined whether this relationship applies during CPR.

Appropriateness Ratings of Percutaneous Coronary Intervention in Japan and Its Association With the Trend of Noninvasive Testing

ObjectivesThe aim of this study was to evaluate the appropriateness of percutaneous coronary intervention (PCI) in Japan and clarify the association between trends of pre-procedural noninvasive testing and changes in appropriateness ratings.BackgroundAlthough PCI appropriateness criteria are widely used for quality-of-care improvement, they have not been validated internationally. Furthermore, the correlation of appropriateness ratings with implementation of newly developed noninvasive testing is unclear.MethodsWe assigned an appropriateness rating to 11,258 consecutive PCIs registered in the Japanese Cardiovascular Database according to appropriateness use criteria developed in 2009 (AUC/2009) and the 2012 revised version (AUC/2012). Trends of pre-procedural noninvasive testing and appropriateness ratings were plotted; logistic regression was performed to identify inappropriate PCI predictors.ResultsIn nonacute settings, 15% of PCIs were rated inappropriate under AUC/2009, and this percent increased to 30.7% under AUC/2012 criteria. This was mostly because of the focused update of AUC, in which the patients were newly classified as inappropriate if they lacked proximal left anterior descending lesions and did not undergo pre-procedural noninvasive testing. However, these cases were simply not rated under AUC/2009. The amount of inappropriate PCIs increased over 5 years, proportional to the increase in coronary computed tomography angiography use. Use of coronary computed tomography angiography was independently associated with inappropriate PCIs (odds ratio: 1.33; p = 0.027).ConclusionsIn a multicenter, Japanese PCI registry, approximately one-sixth of nonacute PCIs were rated as inappropriate under AUC/2009, increasing to approximately one-third under the revised AUC/2012. This significant gap may reflect a needed shift in appropriateness recognition of methods for noninvasive pre-procedural evaluation of coronary artery disease.     

Adiposity measurements in association with metabolic syndrome in older men have different clinical implications

Obesity is a major public health problem, and measuring adiposity accurately and predicting its future comorbidities are important issues. Therefore, we hypothesized that 4 adiposity measurements, body mass index (BMI), waist circumference (WC), waist-to-height ratio, and body fat percentage, have different physiological meanings and distinct associations with adverse health consequences. This study aimed to investigate the relationship of these 4 measurements with metabolic syndrome (MetS) components and identify the most associated factor for MetS occurrence in older, non-medicated men. Cross-sectional data from 3004 men, all 65 years of age and older, were analyzed. The correlation and association between adiposity measurements and MetS components were evaluated by Pearson correlation and multiple linear regression. Based on multivariate logistic regression, BMI and WC were significantly associated with MetS and were selected to build a combined model of receiver operating characteristic curves to increase the diagnosis accuracy for MetS. The results show that BMI is independently associated with systolic and diastolic blood pressure; WC and body fat percentage are associated with fasting plasma glucose and log transformation of triglyceride; BMI and WC are negatively associated with high-density lipoprotein cholesterol (HDL-C); and WC is a better discriminate for MetS than BMI, although the combined model (WC + BMI) is not significantly better than WC alone. Based on these results, we conclude that the 4 adiposity measurements have different clinical implications. Thus, in older men, BMI is an important determinant for blood pressure and HDL-C. Waist circumference is associated with the risk of fasting plasma glucose, HDL-C, triglyceride, and MetS occurrence. The combined model did not increase the diagnosis accuracy.     

Blends of hydrophobic and swelling agents in the swelling layer in the preparation of delayed-release pellets of a hydrophilic drug with low MW: Physicochemical characterizations and in-vivo evaluations

In this study, a hydrophobic material, ethylcellulose, which was used as its aqueous suspension Surelease^®, was combined with a swelling agent as the swelling layer to prepare delayed-release pellets for Danshensu, which is a hydrophilic drug with low MW. A rupturable, delayed-release pellet consists of a drug core, a swelling layer containing a swelling agent (cross-linked sodium carboxymethyl cellulose) with a hydrophobic agent (Surelease^®), and a controlled layer composed by an insoluble, water-permeable polymeric coating (aqueous ethylcellulose dispersions) was developed in a fluidised bed. Results showed that blending Surelease^® into the swelling layer could effectively extend the release of Danshensu from the pellets, which may be attributed to the slowed swelling rate by reduction of water penetration and improvement of mechanical integrity of the swelling layer. Drug in the delayed pellets showed sustained release in beagle dogs after oral administration with comparable in-vivo exposure to the uncoated drug pellets. In conclusion, blends of hydrophobic and swelling agents in the swelling layer in double-membrane pellets could achieve a delayed drug-release profile in vitro, as well as delayed and sustained absorption in vivo for highly soluble, low-MW drug. The present study highlighted the potential use of a delayed-release system for other hydrophilic, low-MW drugs to meet the formulation requirements for chronopharmacological diseases.     

Central vein sign detected by SWI at 3 T MRI as a discriminator between multiple sclerosis and leukoaraiosis

Background

MRI is an essential tool for diagnosing multiple sclerosis; however, overlap with nonspecific white matter lesions still exists. The central vein sign as detected by MR susceptibility weighted imaging has been proposed to improve the diagnostic accuracy of MRI in MS.