Laboratory Measurement of the Anticoagulant Activity of the Non–Vitamin K Oral Anticoagulants

AbstractBackgroundNon–vitamin K oral anticoagulants (NOACs) do not require routine laboratory monitoring. However, laboratory measurement may be desirable in special situations and populations.ObjectivesThis study’s objective was to systematically review and summarize current evidence regarding laboratory measurement of the anticoagulant activity of dabigatran, rivaroxaban, and apixaban.MethodsWe searched PubMed and Web of Science for studies that reported a relationship between drug levels of dabigatran, rivaroxaban, and apixaban and coagulation assay results. Study quality was evaluated using QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies 2).ResultsWe identified 17 eligible studies for dabigatran, 15 for rivaroxaban, and 4 for apixaban. For dabigatran, a normal thrombin time excludes clinically relevant drug concentrations. The activated partial thromboplastin time (APTT) and prothrombin time (PT) are less sensitive and may be normal at trough drug levels. The dilute thrombin time (R2 = 0.92 to 0.99) and ecarin-based assays (R2 = 0.92 to 1.00) show excellent linearity across on-therapy drug concentrations and may be used for drug quantification. For rivaroxaban and apixaban, anti-Xa activity is linear (R2 = 0.89 to 1.00) over a wide range of drug levels and may be used for drug quantification. Undetectable anti-Xa activity likely excludes clinically relevant drug concentrations. The PT is less sensitive (especially for apixaban); a normal PT may not exclude clinically relevant levels. The APTT demonstrates insufficient sensitivity and linearity for quantification.ConclusionsDabigatran, rivaroxaban, and apixaban exhibit variable effects on coagulation assays. Understanding these effects facilitates interpretation of test results in NOAC-treated patients. More information on the relationship between drug levels and clinical outcomes is needed

Dual and triple antithrombotic therapies: current patterns of practice and controversies

Dual antiplatelet therapy (DAPT) has been the cornerstone of antithrombotic management for patients undergoing percu­taneous coronary intervention (PCI). Despite low-quality evidence, triple antithrombotic therapy involving acetylsalicylic acid, clopidogrel, and warfarin or non-vitamin K antagonist oral anticoagulant (NOAC) has been recommended in patients with concomitant atrial fibrillation undergoing PCI, who require long-term oral anticoagulation, although such a strategy is associated with a substantially increased risk of bleeding compared with DAPT. NOAC combined with P2Y12 inhibitor alone appears to be safer and as effective as triple therapy with warfarin in patients with acute coronary syndromes based on the results of recent randomised trials on dabigatran and rivaroxaban. The present review summarises the current data on various combinations of antithrombotic agents in terms of their efficacy and safety

Elevated troponin and myocardial infarction in the intensive care unit: a prospective study

INTRODUCTION: Elevated troponin levels indicate myocardial injury but may occur in critically ill patients without evidence of myocardial ischemia. An elevated troponin alone cannot establish a diagnosis of myocardial infarction (MI), yet the optimal methods for diagnosing MI in the intensive care unit (ICU) are not established. The study objective was to estimate the frequency of MI using troponin T measurements, 12-lead electrocardiograms (ECGs) and echocardiography, and to examine the association of elevated troponin and MI with ICU and hospital mortality and length of stay. METHOD: In this 2-month single centre prospective cohort study, all consecutive patients admitted to our medical-surgical ICU were classified in duplicate by two investigators as having MI or no MI based on troponin, ECGs and echocardiograms obtained during the ICU stay. The diagnosis of MI was based on an adaptation of the joint European Society of Cardiology/American College of Cardiology definition: a typical rise or fall of an elevated troponin measurement, in addition to ischemic symptoms, ischemic ECG changes, a coronary artery intervention, or a new cardiac wall motion abnormality. RESULTS: We screened 117 ICU admissions and enrolled 115 predominantly medical patients. Of these, 93 (80.9%) had at least one ECG and one troponin; 44 of these 93 (47.3%) had at least one elevated troponin and 24 (25.8%) had an MI. Patients with MI had significantly higher mortality in the ICU (37.5% versus 17.6%; P = 0.050) and hospital (50.0% versus 22.0%; P = 0.010) than those without MI. After adjusting for Acute Physiology and Chronic Health Evaluation II score and need for inotropes or vasopressors, MI was an independent predictor of hospital mortality (odds ratio 3.22, 95% confidence interval 1.04–9.96). The presence of an elevated troponin (among those patients in whom troponin was measured) was not independently predictive of ICU or hospital mortality. CONCLUSION: In this study, 47% of critically ill patients had an elevated troponin but only 26% of these met criteria for MI. An elevated troponin without ischemic ECG changes was not associated with adverse outcomes; however, MI in the ICU setting was an independent predictor of hospital mortality

Examining the clinical use of hemochromatosis genetic testing

BACKGROUND: Hereditary hemochromatosis leads to an increased lifetime risk for end-organ damage due to excess iron deposition. Guidelines recommend that genetic testing be performed in patients with clinical suspicion of iron overload accompanied by elevated serum ferritin and transferrin saturation levels. OBJECTIVE: To evaluate guideline adherence and the clinical and economic impact of HFE genetic testing. METHODS: The electronic charts of patients submitted for HFE testing in 2012 were reviewed for genetic testing results, biochemical markers of iron overload and clinical history of phlebotomy. RESULTS: A total of 664 samples were sent for testing, with clinical, biochemical and phlebotomy data available for 160 patients. A positive C282Y homozygote or C282Y/H63D compound heterozygote test result was observed in 18% of patients. Patients with an at-risk HFE genotype had significantly higher iron saturation, serum iron and hemoglobin (P\u3c0.001), without higher ferritin or liver enzyme levels. Fifty percent of patients referred for testing did not have biochemical evidence of iron overload (transferrin saturation \u3e45% and ferritin level \u3e300μg/L). Patients were four times more likely to undergo phlebotomy if they were gene test positive (RR 4.29 [95% CI 2.35 to 7.83]; P\u3c0.00001). DISCUSSION: One-half of patients referred for testing did not exhibit biochemical evidence of iron overload. Many patients with biochemical evidence of iron overload, but with negative genetic test results, did not undergo phlebotomy. A requisition to determine clinical indication for testing may reduce the use of the HFE genetic test. Finally, improvement of current genetic test characteristics would improve rationale for the test. CONCLUSION: A significant proportion of hemochromatosis genetic testing does not adhere to current guidelines and would not alter patient management

The intracellular accumulation of polymeric neuroserpin explains the severity of the dementia FENIB

Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is an autosomal dominant dementia that is characterized by the retention of polymers of neuroserpin as inclusions within the endoplasmic reticulum (ER) of neurons. We have developed monoclonal antibodies that detect polymerized neuroserpin and have used COS-7 cells, stably transfected PC12 cell lines and transgenic Drosophila melanogaster to characterize the cellular handling of all four mutant forms of neuroserpin that cause FENIB. We show a direct correlation between the severity of the disease-causing mutation and the accumulation of neuroserpin polymers in cell and fly models of the disease. Moreover, mutant neuroserpin causes locomotor deficits in the fly allowing us to demonstrate a direct link between polymer accumulation and neuronal toxicity

Massive Stars in the Quintuplet Cluster

We present near-infrared photometry and K-band spectra of newly-identified massive stars in the Quintuplet Cluster, one of the three massive clusters projected within 50 pc of the Galactic Center. We find that the cluster contains a variety of massive stars, including more unambiguously identified Wolf-Rayet stars than any cluster in the Galaxy, and over a dozen stars in earlier stages of evolution, i.e., LBV, Ofpe/WN9, and OB supergiants. One newly identified star is the second ``Luminous Blue Variable'' in the cluster, after the ``Pistol Star.'' Given the evolutionary stages of the identified stars, the cluster appears to be about 4 \pm 1 Myr old, assuming coeval formation. The total mass in observed stars is \sim 10^3 \Msun, and the implied mass is \sim 10^4 \Msun, assuming a lower mass cutoff of 1 \Msun and a Salpeter initial mass function. The implied mass density in stars is at least a few thousand \Msun pc^{-3}. The newly-identified stars increase the estimated ionizing flux from this cluster by about an order of magnitude with respect to earlier estimates, to 10^{50.9} photons/s, or roughly what is required to ionize the nearby ``Sickle'' HII region (G0.18 - 0.04). The total luminosity from the massive cluster stars is $\approx 10^{7.5}$ \Lsun, enough to account for the heating of the nearby molecular cloud, M0.20 - 0.033. We propose a picture which integrates most of the major features in this part of the sky, excepting the non-thermal filaments. We compare the cluster to other young massive clusters and globular clusters, finding that it is unique in stellar content and age, except, perhaps, for the young cluster in the central parsec of the Galaxy. In addition, we find that the cluster is comparable to small ``super star clusters.'