women with sphingomyelin levels of Ն60 mg/dL than in women with sphingomyelin levels of Ͻ39 mg/dL. This association did not remain significant after multivariant adjustment for standard cardiovascular risk factors. Men with sphingomyelin levels of Ͼ60 mg/dL had higher calcium scores (135 vs 99 Agatston units, P ϭ .01) than men with sphingomyelin levels Ͻ39 mg/dL. Comment: Sphingomyelin accumulates in atheromas in animal models and in human atheroma. Much sphingomyelin found in arteries arises from synthesis within the arterial tissue (Circulation 1961;23:370-5). However, synthesis of sphingomyelin within arterial tissue appears slow compared with the total amount accumulated, suggesting plasma levels of sphingomyelin may also contribute to accumulation of sphingomyelin within arterial tissue. The unadjusted data from this study provide some support that plasma sphingomyelin is a component of a pathway that mediates risk for subclinical disease attributable to traditional cardiovascular risk factors.

Essentials Currently, DOACs are given at fixed doses and do not require laboratory monitoring.Direct oral anticoagulant‐specific measurements were performed at trough and peak.Patients who developed bleeding events showed higher DOAC plasma levels at peak.This study suggests the need of a more accurate DOAC dose assessment. BackgroundDirect oral anticoagulants (DOACs) are administered at fixed dose. The aim of the study was to evaluate the relationship between DOAC C‐trough or C‐peak plasma levels and bleeding complications in patients with non‐valvular atrial fibrillation (NVAF).MethodsFive hundred sixty five consecutive naive NVAF patients were enrolled. The DOAC measurements at C‐trough and at C‐peak (available in 411 patients) were performed at steady state, within the first month of treatment. Major bleeding (MB), clinically relevant non‐major bleeding (CRNMB), and minor bleeding (MinB), occurring during 1 year of follow‐up after blood sampling, were recorded. For each DOAC, interval of C‐trough and C‐peak levels was subdivided into four equal classes and results were attributed to these classes; the median values of results were also calculated.ResultsTwo hundred eight patients were on apixaban, 185 on dabigatran, and 172 on rivaroxaban. For 1‐[qqqdeletezzz] year follow up for all patients, we observed: 19 MB (3.36%), 6 CRNMB (1.06%), and 47 MinB (8.31%). The prevalence of bleeding patients with anticoagulant levels in the upper classes of C‐peak activity (II + III + IV) was higher than that in the lowest class. Normalized results of C‐peak levels were higher in patients with bleeding than in those without bleeding.ConclusionsBleeding complications during DOAC treatment were more frequent among atrial fibrillation (AF) patients with higher C‐peak anticoagulant levels. In addition to a previous study that showed an increased risk of thrombotic complications in the patients with low C‐trough levels, this study seems to indicate that patients with NVAF on DOACs would need a more accurate definition of their optimal therapeutic window.

Long-term risk for major bleeding during extended oral anticoagulant therapy for first unprovoked venous thromboembolism: A systematic review and meta-analysis / Khan, F.

The molecular genetic analysis of protein S deficiency has been hampered by the complexity of the protein S (PROS) gene and by the existence of a homologous pseudogene. In an attempt to overcome these problems, a reverse transcript-polymerase chain reaction (RT-PCR) mutation screening procedure was developed. However, the application of this mRNA-based strategy to the detection of gene lesions causing heterozygous type I protein S deficiency appears limited owing to the high proportion of patients exhibiting absence of mRNA derived from the mutation-bearing allele (“allelic exclusion”). Nevertheless, this strategy remains extremely effective for rapid mutation detection in type II/III protein S deficiency. Using the RT-PCR technique, a G-to-A transition was detected at position +1 of the exon IV donor splice site, which was associated with type I deficiency and resulted in both exon skipping and cryptic splice site utilization. No abnormal protein S was detected in plasma from this patient. A missense mutation (Asn 217 to Ser), which may interfere with calcium binding, was also detected in exon VIII in a patient with type III protein S deficiency. A further three PROS gene lesions were detected in three patients with type I deficiency by direct sequencing of exon-containing genomic PCR fragments: a single base-pair (bp) deletion in exon XIV, a 2-bp deletion in exon VIII, and a G0to-A transition at position-1 of the exon X donor splice site all resulted in the absence of mRNA expressed from the disease allele. Thus, the RT-PCR methodology proved effective for further analysis of the resulting protein S-deficient phenotypes. A missense mutation (Met570 to Thr) in exon XIV of a further type III-deficient proband was subsequently detected in this patient's cDNA. No PROS gene abnormalities were found in the remaining four subjects, three of whom exhibited allelic exclusion. However, the father of one such patient exhibiting allelic exclusion was subsequently shown to carry a nonsense mutation (Gly448 to Term) within exon XII.

A nonsignificant trend was noted toward a higher rate of both bleeding and thrombotic complications in elderly vs matched younger patients. Intracranial bleeding and fatal thrombotic events were significantly more frequent in the elderly. Our results also indicate that lower than 2.0 INRs do not preclude bleeding in the elderly nor offer adequate protection from thrombotic events. Moderate anticoagulation (2.0-3.0 INRs) in elderly patients seems the safest and most effective.