[Hemorrhagic stroke and new oral anticoagulants]. / Hémorragies cérébrales et nouveaux anticoagulants.

The recent release of new oral anticoagulants (NOAC) raises the question of the management of intracranial hemorrhage occurring during treatment with these molecules. Dabigatran, rivaroxaban and apixaban have different pharmacological characteristics that physicians need to know to adjust their prescription to each patient. Studies of efficacy and safety prior to the marketing of these molecules showed a decreased risk of intracranial hemorrhage compared with vitamin K antagonists. However, no reliable data are available regarding the prognosis of these hemorrhages occurring during NOAC treatment. In addition, there is no specific antidote and reversal protocol validated in humans. So, physicians are in a difficult situation when critical bleeding occurs. The timing of recovering normal hemostatic capacity is then a determinant factor of prognosis. Studies in animals or healthy volunteers showed a correction of the biological parameters using prothrombin complex concentrates activated or not, without reducing the volume of hematoma. On this basis, proposals have been issued by the french group of interest for perioperative hemostasis (GIHP) for the management of bleeding under NOAC treatment, which include management of intracranial hemorrhage.

[Use of rFVIIa in intractable hemorrhage in patients on central veno-arterial ECMO]. / Utilisation du facteur VIIa en cas d'hémorragie réfractaire sous ECMO centrale veino-artérielle.

OBJECTIVE: The purpose of our study is to describe the use of recombinant factor VIIa (rFVIIa) in patients on central veno-arterial ECMO with a particular attention on associated thrombotic complications. STUDY DESIGN: Monocentric retrospective study. PATIENTS AND METHODS: We examined 91 files of patients on ECMO between 2005 and 2010. During this period, eight patients presented refractory bleeding and benefited from rFVIIa treatment. RESULTS: In six of the eight patients, the bleeding stopped. A decrease of the bleeding was noticed after the treatment of rFVIIa (before rFVIIa: 40.1±33.1mL/kg per 3 hours after rFVIIa: 5.4±3.2mL/kg per 3 hours (P=0.01). The transfusional needs were decreased after administration of rFVIIa. No thrombotic event was detected. Fibrinogen, d-dimers, platelet count and lactate were not modified by the treatment. Two patients were weaned from ECMO. One patient died 17 days after the weaning. The other patient survived without neurological damages. CONCLUSION: The rFVIIa is a treatment of exception for patients on central veno-arterial ECMO and could be a last-resort treatment in the presence of a not curable massive bleeding.

Glomerular filtration rate estimated by Cockcroft-Gault formula better predicts anti-Xa levels than modification of the diet in renal disease equation in older patients with prophylactic enoxaparin.

OBJECTIVES: Older people have an increased risk of low molecular weight heparin accumulation leading to an increased bleeding risk. The objective of this study was to assess whether reduced glomerular filtration rate (GFR), estimated by the Cockcroft-Gault or modification of the diet in renal disease (MDRD) equations, indicates drug accumulation by increased anti-Xa levels in older subjects receiving prophylactic enoxaparin treatment. DESIGN: Cohort study. SETTING: Acute geriatric units in Nancy Hospital. PARTICIPANTS: Ninety-two consenting consecutive patients, 65 and older, confined to bed for an acute medical condition requiring enoxaparin for prevention of venous thromboembolism, and hospitalized for at least six days were enrolled. MEASUREMENTS: Serum creatinine and peak plasma anti-Xa levels 3 to 4 hours after the daily injection of enoxaparin were measured at days 3, 6, 9 and 12 (first dose of enoxaparin at day one). Analyses of variance for repeated measures were used to evaluate significant predictors of peak anti-Xa activity in univariate and multivariate analyses. RESULTS: A significant correlation was observed between anti-Xa activity and GFR estimated with the Cockcroft formula r=0.43. Following univariate analysis, the three factors associated with higher anti-Xa levels were a lower Cockcroft-Gault GFR (p=0.0002), female gender (p=0.0003) and a lower bodyweight (p<.0001). No significant association between anti-Xa levels and MDRD GFR (p=0.33) was observed. Following multivariate analysis, female gender (p=0.02), bodyweight (p=0.04) and Cockcroft GFR (p=0.05) remained independent determinants of anti-Xa levels. CONCLUSION: In hospitalized patients older than 65 years old, the Cockcroft-Gault equation, in contrast to the MDRD equation, is able to predict the risk of higher anti-Xa levels.

Laboratory effect on platelet activity within 24 h of the first 300-mg oral dose of aspirin given in hospital during the acute phase of ischemic cerebral events.

BACKGROUND AND PURPOSE: Aspirin is the most commonly used antiplatelet treatment during the acute phase of cerebral ischemic events. It inhibits the production of thromboxane (TX) A(2), a powerful platelet activator. Despite this protection, early ischemic recurrences are frequent and considered clinical failures of this therapy. Only a few trials have focused on the use of antiplatelet therapy during this phase, and none has described the laboratory effect of the first dose of aspirin given after an ischemic cerebral event. However, this study may help clinicians to understand the mechanisms of early recurrences, and to design new therapeutic strategies, in particular for patients already treated with a daily dose of aspirin. METHOD: We studied laboratory parameters of the first 300-mg oral dose of aspirin given within 48 h after an ischemic cerebral event. Two blood samples were taken from all of the patients: the first during the third hour following aspirin intake (T1) and the second during the twenty-fourth hour (T2). For patients already treated with a daily dose of aspirin, a supplementary sample was taken before aspirin intake (T0). Platelet reactivity was studied on the basis of serum TXB(2) levels, a metabolite of TXA(2), and light transmission aggregometry after stimulation of platelet-rich plasma by arachidonic acid and by two concentrations of collagen, i.e. 2 µg/ml (Col2), dependent on the TXA(2) pathway, and 20 µg/ml (Col20), independent of the TXA(2) pathway. Results with Col2 were related to results with Col20 (Col2/20 ratio) to limit the impact of variations induced by the effects of preanalytical conditions. RESULTS: Fifty patients were included. TXB(2) values (p < 0.001) and relative values of the Col2/20 ratio (p = 0.037) were significantly higher at T2 compared to T1. For patients already treated with aspirin, TXB(2) levels (p < 0.001) were significantly lower at T1 compared to T0, and the Col2/20 ratio tended to decrease (p = 0.096). CONCLUSION: Platelet reactivity recovers within 24 h following the first 300-mg oral dose of aspirin during the acute phase of a cerebral ischemic event as demonstrated by an increase in TXB(2) levels, and the Col2/20 ratio, at T2 compared to T1. This would favor early ischemic recurrences. However, for patients already treated with aspirin, this dose is able to decrease TXB(2) levels and to complete the inhibition of the TXA(2) pathway, which shows the utility of this prescription in this case.

[Anticoagulants drugs direct trombin inhibitors]. / Les anticoagulants inhibiteurs directs de la thrombine.

The aim of this review is to explain the central role of thrombin in haemostasis and the main pharmacological features of the anticoagulants that are direct inhibitors of thrombin, with emphasis on orally active small molecules. Owing to the complexity of the clotting system only well designed and conducted studies can tell us which drug is the most useful, safe and convenient to limit each type of thrombosis and what are the appropriate dosage and management. Parenterally administered direct thrombin inhibitors require laboratory monitoring, whereas dabigatran, orally active, does not.

[Variable platelet response to aspirin and new therapeutic targets]. / Variabilité de réponse plaquettaire à l'aspirine et nouvelles cibles thérapeutiques.

Aspirin is the first-line oral antiplatelet drug to prevent thromboembolic arterial occlusions. Aspirin irreversibly inhibits cyclooxygenase (COX) 1 involved in the platelet production of thromboxane (TX) A(2), an inducer of vasoconstriction and a platelet activating agent. Recurrent vascular events despite aspirin intake, combined with laboratory evidence of poor antiplatelet effect, suggested what has been called "aspirin resistance". For clarity's sake a real aspirin resistance would be the absence of COX1 inhibition due to intrinsic platelet factors (which has never been reported). What has been described is (expected) variability. COX1 inhibition can be insufficient to modify TX-dependent platelet behaviour. Other agonists, the production of which does not involve COX1, can stimulate TX-receptors. The antiplatelet effect of aspirin can be insufficient for pharmacokinetic or pharmacodynamic reasons, the latter being further classified as TX-dependent or not. If platelets are so reactive that responses are more TX-independent than normally, then neither aspirin nor any drugs acting on this pathway can do the job. These mechanisms should be better understood and diagnosed, and this is the prerequisite for the development of newer antiplatelet agents.

Biological response of human aortic endothelial cells exposed to acellular hemoglobin solutions developed as potential blood substitutes.

The cardiovascular effects of hemoglobin-based oxygen carriers (HBOCs) are mainly related to their nitric oxide (NO) scavenging properties but other effects such as the impact of these hemoglobins on the endothelial cell (EC) biology are not well understood. We hypothesized that HBOCs could modify EC functions by altering gene expression, in particular the endothelial NO synthase (NOS3) and/or by activating EC. Cultured human aortic endothelial cells (HAEC) were incubated for 3 hours with purified cell-free Hb, Dex-BTC-Hb or alpha alpha-Hb (16 g/L). Expression of NOS3 mRNA and protein were assessed by semi-quantitative RT-PCR and Western blot respectively immediately after and 24 hours after incubation. The expression and localization of the adhesion molecule ICAM-1 were detected by fluorescence microscopy. None of the solutions tested modified NOS3 mRNA and protein expression despite adequate controls that up- or down-regulate NOS3 expression. The expression and the localization of ICAM-1 on the cell membrane were modified after 3 hours of incubation with all the hemoglobin solutions tested in a manner similar to tumor necrosis factor-alpha. In conclusion, HAEC incubation with clinically relevant concentrations of HBOCs induced changes in the pattern of ICAM-1 expression consistent with cell activation/cell signaling mechanisms. However, HBOCs did not alter NOS3 gene expression.