Direct oral anticoagulants (DOACs) are tending to supplant antivitamin K inhibitors (VKAs) in their common indications, dominated in elderly patients by atrial fibrillation and venous thromboembolism. Nevertheless, it remains necessary to know how best to use VKAs for which there are still indications. It is also important not to assume that AODs can be prescribed without risk, while ignoring certain particularities in their handling, particularly in the most fragile patients with co-morbidities and multiple medications.

Antivitamin K agent (AVK) reversal in patients with cirrhosis awaiting liver transplantation (LT) is not defined in guidelines. We investigated the effect of reversion with prothrombin complex concentrate (PCC) on intraoperative transfusion, bleeding, and safety in LT patients on AVK.
In 511 patients undergoing LT, we identified 25 patients treated with AVK (AVK group) and 13 patients with incidental portal vein thrombosis (PVT) without AVK (incidental PVT group). Fifty patients who underwent LT without PVT or AVK matched by age, model for end stage of liver disease (MELD), body mass index (BMI), and cirrhosis etiology were selected as the control group.
There were no significant differences between the three groups in intraoperative blood loss, transfusion, and postoperative bleeding. In the AVK group, there were no differences between patients who received PCC and those who did not in intraoperative blood loss, red blood cells, fibrinogen, and platelet transfusion, or postoperative bleeding. PCC use had no effect on RBC transfusion in patients who had international normalized ratio or clotting time above versus below median values of the two parameters at baseline (2.3 and 103 s, respectively). No thrombotic events were detected in patients who received PCC.
These data suggest that systematic administration of PCC to revert AVK prior to LT should be reconsidered.

AVK could be prescribed in elderly patients over 75 years for the prevention of thromboembolic complications of atrial fibrillation (AF). The objective of this study was to study the quality of the anticoagulation balance by AVK and its determinants. Inclusion of all patients ≥ 75 years of age treated with AVK for an AF hospitalized in the acute geriatric department of the University hospital of Dijon. The balance of the AVK treatment was determined by the input INR and the calculation of the TTR. The last four INRs prior to admission were retrospectively collected for its calculation. Each patient had a standardized geriatric evaluation (EGS): lifestyle, MMSE, nutritional status (albumin), polypathology (Charlson), level of dependence (ADL-IADL). Bleeding complication were collected. 155 patients aged over 75 years (87±5.6 years, 88 women and 67 men) were included. The mean TTR was 55.4±31.2%. Only 46% of patients had a correct TTR (≥ 75%). The balance was significantly worse in women than in men (49.3±29.5 vs 60.1±31.8%; p=0.0326), and in case of haematological pathology (41.7±27.1 vs 57.2± 9.8; p=0.047) but better with high BMI (r=0.416, p=0.001). No EGS parameters were associated with the quality of anticoagulation. The control of AVK therapy is insufficient in geriatric elderly subjects. No modifiable explicative geriatric factor has been identified. If AVK remains a therapeutic option, direct oral anticoaulants should be considered as the first choice.

In 2008, we decided to enter the era of direct oral anticoagulants (DOACS). Was that the right decision to make? The answer will depend on how well we meet the conditions of proper use. This means avoiding underdosing and overdosing as well as understanding how DOACS were validated so that our prescriptions fulfill their role in the management of thrombotic disease.

BACKGROUND: Antivitamin K anticoagulant (AVK) rodenticides are commonly used to control rodent pests worldwide. They specifically inhibit the VKORC1 enzyme essential for the recycling of vitamin K, and thus prevent blood clotting and cause death by haemorrhage. Numerous mutations or polymorphisms of the Vkorc1 gene were reported in rodents, and some led to resistance to rodenticides. In house mice (Mus musculus domesticus), adaptive introgression of the Vkorc1 gene from the Algerian mouse (Mus spretus) was reported. This adaptive introgression causes the substitution of four amino acids in M. musculus domesticus.
RESULTS: The consequences of introgression were assessed by (i) the characterisation of the in vivo resistant phenotype of adaptive Vkorc1spr -introgressed mice, (ii) the characterisation of the ex vivo resistance phenotype of the liver VKOR activity and (iii) the comparison of these results with the properties of recombinant VKORC1spr protein expressed in yeast. The resistance factor (from 1 to 120) induced by the four introgressed polymorphisms obtained using these three approaches was dependent on the AVKs used but were highly correlated among the three approaches.
CONCLUSIONS: The four introgressed polymorphisms were clearly the cause of the strong resistant phenotype observed in the field. In the context of strong selection pressure due to the extensive use of AVKs, this resistant phenotype may explain the widespread distribution of this genotype from Spain to Germany. © 2016 Society of Chemical Industry.

BACKGROUND: In spite of intensive use of bromadiolone, rodent control was inefficient on a farm infested by rats in Zaragoza, Spain. While metabolic resistance was previously described in this rodent species, the observation of a target resistance to antivitamin K rodenticides had been poorly documented in Rattus rattus.
RESULTS: From rats trapped on the farm, cytochrome b and Vkorc1 genes were amplified by PCR and sequenced in order to identify species and detect potential Vkorc1 mutations. VKORC1-deduced amino acid sequences were thus expressed in Pichia pastoris, and inhibition constants towards various rodenticides were determined. The ten rats trapped on the farm were all identified as R. rattus. They were found to be homozygous for the g.74A>T nucleotide replacement in exon 1 of the Vkorc1 gene, leading to p.Y25F mutation. This mutation led to increased apparent inhibition constants towards various rodenticides, probably caused by a partial loss of helical structure of TM4.
CONCLUSIONS: The p.Y25F mutation detected in the Vkorc1 gene in R. rattus trapped on the Spanish farm is associated with the resistance phenotype to bromadiolone that has been observed. It is the first evidence of target resistance to antivitamin K anticoagulants in R. rattus.

Prescribing anticoagulant therapy when the CHA₂DS₂-VASc score is ≥ 1 prevents strokes secondary to non-valvular atrial fibrillation (AF). However, it is important to remember that whether the aged population has the highest risk of stroke in case of AF, under anticoagulant therapy this population is also at the highest risk of bleeding. Vitamin K antagonists were for decades the molecules of reference with benefits even after 75 years of age. The direct oral anticoagulants have overcome the biological constraints inherent to monitoring vitamin K antagonists and provide a more stable pharmacological action with a limited number of drug-drug interactions. However, the widespread use of these molecules in the older population remains controversial. In this review article, indications and modalities of administration of anticoagulant therapy in the elderly will be detailed and discussed on the basis of the most recent recommendations proposed in particular by the European Society of Cardiology. Particular attention will be paid to new oral anticoagulant therapies compared with vitamin K antagonists and antiplatelet agents.

The benefits of anti-vitamin K (AVK) drugs have been acknowledged in several indications. Such indications increasing with increasing age, AVK prescriptions also increases with age. At the same time, conditions involving significant bleeding are common in this elderly population. It is thus essential to recognize the determining factors. This study included all patients taking AVK drugs aged 75 years and older who sought emergency care at the Cochin Hospital from January to December 2011 for significant bleeding. These patients were compared with a cohort of patients aged 75 years or older who were taking AVK drugs and who were admitted to the same unit during the same time period for other reasons. The case-control comparison included demographic data, comorbidity factors, multiple medications, emergency measured INR, and CHA2DS2VASC level. The hemorrhagic risk was evaluated by HEMORR2HAGES and HAS-BLED. A total of 34 patients were studied and compared with 70 case-controls. The Charlson comorbidity index was higher in patients than case-controls (P<0.05), with a much higher hemorrhagic risk for scores ≥ 9 (OR=2.5; P<0.05). Multiple medication was also more predominant in patients (P<0.05). The risk of serious hemorrhage was also higher when the hemorrhagic scores were high, especially for HEMORR2HAGES (P<0.0001) and HAS-BLED (P<0.001). The risk of serious hemorrhage in elderly outpatients taking AVK drugs is related to their higher comorbidity and hemorrhagic levels which need to be evaluated before starting or stopping AVK treatment.

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