L. Drouet

Prasugrel compared with high-dose clopidogrel in acute coronary syndrome. The randomised, double-blind ACAPULCO study.

Compared with the approved dose regimen of clopidogrel (300-mg loading dose [LD], 75-mg maintenance dose [MD]), prasugrel has been demonstrated to reduce ischaemic events in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). In ACS, antiplatelet effects of a prasugrel MD regimen have not been previously compared with either a higher clopidogrel MD or after switching from a higher clopidogrel LD. The objective of this study was to evaluate the antiplatelet effect of a prasugrel 10-mg MD versus a clopidogrel 150-mg MD in patients with ACS who had received a clopidogrel 900-mg LD. Patients with non-ST elevation ACS, treated with aspirin and a clopidogrel 900-mg LD, were randomised within 24 hours post-LD to receive a prasugrel 10-mg or clopidogrel 150-mg MD. After 14 days of the initial MD, subjects switched to the alternative treatment for 14 days. The primary endpoint compared maximum platelet aggregation (MPA, 20 microM adenosine diphosphate [ADP]) between prasugrel and clopidogrel MDs for both periods. Responder analyses between treatments were performed using several platelet-function methods. Of 56 randomised subjects, 37 underwent PCI. MPA was 26.2% for prasugrel 10 mg and 39.1% for clopidogrel 150 mg (p<0.001). The prasugrel MD regimen reduced MPA from the post-900-mg LD level (41.2% to 29.1%, p=0.003). Poor response ranged from 0% to 6% for prasugrel 10 mg and 4% to 34% for clopidogrel 150 mg. Thus, in ACS patients a prasugrel 10-mg MD regimen resulted in significantly greater platelet inhibition than clopidogrel at twice its approved MD or a 900-mg LD.

24-hour time-dependent aspirin efficacy in patients with stable coronary artery disease

Aspirin-induced cyclooxygenase (COX)-1 acetylation is irreversible and it is assumed that the platelet thromboxane-A2 aggregation pathway is inhibited for at least 24 hours (h) after aspirin ingestion. However, time course of biological efficacy of daily low-dose aspirin has rarely been assessed in patients with coronary artery disease (CAD). We aimed to assess the 24-h biological efficacy of daily low-dose aspirin in CAD patients. The peak and trough (2 h-24 h) effect of a chronic treatment with once daily dose aspirin were studied in 150 consecutive stable CAD patients. The main outcome measure was light transmission aggregometry (LTA) triggered with 0.5 mg/ml arachidonic acid (AA). In the last 47 consecutive patients, additional tests were conducted at 6, 12, 16, 20 h after last aspirin administration. 4.7% of the patients had significant aggregation (>20% maximal intensity LTA-AA) 2 h after aspirin ingestion and 24.7% at 24 h (p<0.0001). The more precise assessments in the last 47 patients showed that significant platelet aggregation progressively reappeared with time after aspirin intake (2 h--4% of patients, 6 h-- 4%, 12 h--11%, 16 h--16%, 20 h--19% and 24 h--28%). Concordant results were observed using production of thromboxane-B2 and other techniques evaluating AA-induced platelet aggregation/activation. No significant differences were found between lower (75-100 mg/day) and higher (>100 mg/day) dose aspirin. Such aspirin «resistance» at 24 h after ingestion was related to biological inflammatory markers, current smoking and diabetes. In conclusion, once daily aspirin does not provide stable 24-h antiplatelet protection in a significant proportion of CAD patients. Any biological assessment of aspirin efficacy should take time since last aspirin intake into consideration.

Effect of the Thromboxane Prostaglandin Receptor Antagonist Terutroban on Arterial Thrombogenesis after Repeated Administration in Patients Treated for the Prevention of Ischemic Stroke

Background: The antithrombotic, antiplatelet and endothelial activity of terutroban, a specific thromboxane prostaglandin receptor antagonist, was assessed in patients previously treated with aspirin for the prevention of ischemic stroke. Methods: This double-blind, parallel-group, 10-day study included 48 patients (age = 70.5 ± 9.5 years) with cerebral ischemic event and/or carotid stenosis in 4 groups: terutroban 10 mg/day (n = 13), aspirin 300 mg/day (n = 12), terutroban 10 mg/day + aspirin 300 mg/day (n = 11) or clopidogrel 75 mg/day + aspirin 300 mg/day (n = 12). The measurements included parameters from an ex vivo model of thrombosis, platelet aggregation in platelet-rich plasma and plasma biomarkers of endothelial/platelet activation. Results: Between days 0 and 10, the mean cross-sectional surface of dense thrombus significantly decreased with terutroban (58%, p = 0.001), terutroban + aspirin (63%, p = 0.005) and clopidogrel + aspirin (61%, p < 0.05). On day 10, the value for terutroban was significantly lower than that for aspirin (p < 0.01) and was comparable to the dual therapy terutroban + aspirin or clopidogrel + aspirin. Similar results were found for total thrombus surface and platelet adhesion. Platelet aggregation induced by the specific thromboxane prostaglandin receptor agonist U46619 was almost completely inhibited on day 10 in both terutroban groups but not in the others. As regards markers of endothelial/platelet activation or lesions, thrombomodulin significantly increased and plasma soluble P selectin significantly decreased by day 10 in both terutroban groups, whereas the von Willebrand factor did not change significantly. Terutroban was found to be safe and well tolerated. Conclusions: Terutroban has demonstrated an antithrombotic activity that is superior to aspirin and similar to clopidogrel + aspirin; it induces a significant in vivo reduction in endothelial/platelet activation.

Prothrombin G20210A carriers the genetic mutation and a history of venous thrombosis contributes to thrombin generation independently of factor II plasma levels

Summary.  Background: The prothrombin (PT) G20210A gene mutation is a common risk factor for venous thrombosis (VT), which is mainly mediated through an increase in factor II (FII) plasma levels. High FII plasma levels may act through an increase in endogenous thrombin potential (ETP) a key step in hemostasis and thrombosis. While FII may be the main contributor to ETP in PT G20210A carriers, the knowledge of other environmental or genetic factors influencing ETP may help to better identify those at risk of VT. Aims: ETP was determined in 472 non‐carriers of PT G20210A (PT−) and in 325 unrelated carriers of PT G20210A (PT+) with (symptomatic n = 158) or without (asymptomatic, n = 167) a history of VT. All PT+ were heterozygous and free of other thrombophilic defects.Results: ETP was higher in asymptomatic PT+ than in PT− (2038 ± 371 vs. 1616 ± 267 nmol L−1 min; P < 0.0001). ETP was significantly higher in symptomatic PT+ than in controls PT+ (2129 ± 430 vs. 2038 ± 371 nmol L−1 min; P = 0.01). Multivariate analyses evidenced the importance of FII and fibrinogen plasma levels in determining ETP. Discussion: After taking these variables into account, a personal history of VT remained associated with ETP in PT+ carriers. Moreover, PTG20210A still contributes to ETP after consideration of FII levels. Conclusion: In conclusion, the increase in ETP observed in carriers is not entirely explained by higher FII or fibrinogen plasma levels but also by the history of VT.

Rationale for the use of antifactor Xa in the treatment and prevention of venous and arterial thromboembolic events

The design and synthesis of new antithrombotic agents have led to numerous recent clinical trials to investigate their efficacy and safety. Analysis of the data from these trials, especially when the results were not totally expected, has provided interesting information, allowing a better understanding of the pathophysiology of thrombosis in various clinical situations. The aim of the present manuscript is to present the hypotheses on thrombogenesis generated by some of these recent clinical trials, notably those investigating the antithrombotic efficacy of a new synthetic and selective factor Xa inhibitor, fondaparinux. The antithrombotic efficacy of fondaparinux was recently investigated in a number of trials in the prevention and treatment of venous and arterial thrombotic disorders. In each case, the concept of the clinical efficacy of a selective factor Xa inhibitor has been proven. These trials have also clarified the implication and mode of action of factor Xa in these various types of thrombotic events. In the light of these trials, we discuss the clinical efficacy of such a selective factor Xa inhibitor, and other specific points such as the apparent lack of dose‐dependency of its antithrombotic effect.

Role of serotonin in arteriolar thrombosis and secondary vasospasm

Platelets are implicated both in the thrombotic reaction to an intimal lesion of the arteriolar wall and to the resulting vasospasm even if the two phenomena are not linked directly. The spastic reaction is a consequence of the thrombotic process because without localized platelet activation (thrombus formation) there is no vasospastic reaction, but by pharmacological manipulation, the thrombotic reaction can develop without resulting vasospasm. We developed an original experimental model that allowed us to study the thrombotic reaction secondary to localized endothelial injury in arterioles of the mesentery of the rat, as well as the vasospastic reaction downstream to the site of thrombus formation. In this setting, we studied the reactivity of Sprague-Dawley rats treated with three 5-HT2 serotonergic antagonists (ketanserin, ritanserin, and naftidrofuryl) and that of Fawn-Hooded rats (a strain affected by a congenital reduction of platelet dense granules, with a resulting decrease in platelet content of serotonin, ADP, and catecholamines). Naftidrofuryl had antithrombotic properties similar to those of ritanserin but was less potent than ketanserin. It possessed antispastic activity against the reaction secondary to intravascular platelet activation. Its potency was similar to that of ketanserin but greater than that of ritanserin. Naftidrofuryl had no significant antispastic activity against platelet-derived agents reaching the arteriolar wall from the adventitial side. Compared to the Sprague-Dawley rat, Fawn-Hooded rats had a minimal reduction of the thrombotic process and of the intraluminal induced vasospasm but a similar response to adventitial stimulation of the arterial wall by vasoactive factors released from a neighboring hemostatic plug. These results suggest that the serotonin-induced release by endothelial cells of vasorelaxing factors partially antagonizes its direct vasconstrictor effect on vascular smooth muscle cells. This endothelium-mediated vasorelaxing action is unmasked by 5-HT2 serotonergic antagonists such as ketanserin (70 μM/kg) and naftidrofuryl (60 μM//kg). The small effect observed in the Fawn-Hooded rats is probably related to the fact that in this model the defect in platelet-dense granules and their content is partial.

Guidelines of the French Society of Otorhinolaryngology (SFORL). Managing epistaxis under coagulation disorder due to antithrombotic therapy

OBJECTIVE The authors present the guidelines of the French Society of Otorhinolaryngology concerning the management of epistaxis during antithrombotic therapy. METHODS A review of the literature was performed by a multidisciplinary work group. Guidelines were drafted, then re-edited by a reading group independent of the work group to produce the final text. The proposed recommendations were graded A, B, C or expert opinion, on decreasing levels of evidence. RESULTS Before any decision to modify antithrombotic treatment, it is recommended to screen for overdose and assess the risk of thrombosis. In stented patients, dual antiplatelet therapy must be maintained during the month following stenting and, if possible, for 3 months. In epistaxis with antivitamin K (AVK) overdose controlled by packing, corrective measures are based on the International Normalized Ratio (INR). In uncontrolled epistaxis, it is recommended to stop AVK, administer antidotes and regularly monitor INR. In case of intravascular embolization, it is not recommended to alter anticoagulant treatment.

Correlation between burst of thrombin and microvacular obstruction (no reflow) during ST Elevation Myocardial Infarction treated by primary percutaneous coronary Intervention

Background: The thrombotic burden at the acute phase of STEMI is a consequence of platelet and coagulation activation. Objective: To evaluate the generation of thrombin during acute phase of STEMI. In order to study the consequence, thrombin generation was correlated with other markers of coagulation activation, markers of cellular activation, microvascular injury and infarct size. Methods: Thirty six STEMI patients admitted for primary Percutaneous Coronary Intervention (PCI) were enrolled. Blood samples were collected before angioplasty, at the end of angioplasty and 2, 6, 12 and 24 hours after angioplasty. Plasma thrombin antithrombin complexes and d-dimers were evaluated by ELISA methods, fibrinogen by clothing test. Platelets and endothelial microparticles were determined by flow cytometry analysis. Microvascular obstruction was assessed by the myocardial blush grade. Myocardium at risk was determined on angiography and infarct size was assessed by area under the curve of plasma troponin and CK-MB. Results: A burst of thrombin occurred during PCI in 69% of patients and was associated with increased fibrinogen, d-dimer, circulating platelets and endothelials microparticles, when compared with patient without burst (p<0.05). Prolonged ischemic time and significant myocardium at risk were correlated with a higher level of thrombin generation (p<0.05). Thrombin generation was correlated with alteration of myocardial blush (p<0.05) and higher troponin I and CK levels (p<0.05). Conclusion: This study showed a burst of thrombin at the time of primary PCI during STEMI in two third of patients. When present, this burst was associated with more cellular, myocardial and micro-vascular damage.

Les effets pléiotropes d’un inhibiteur réversible de récepteurs P2Y12

Resume Le cangrelor actif par voie injectable a ete le premier inhibiteur reversible des recepteurs P2Y12, et maintenant, le ticagrelor, premier inhibiteur reversible actif par voie orale, ouvre une ere nouvelle dans l’inhibition de la voie de l’ADP: en effet, ils n’ont ni la meme pharmacocinetique ni la meme pharmacodynamie que les inhibiteurs irreversibles que sont les metabolites actifs des thienopyridines auxquels nous etions accoutumes. La molecule agit par sa concentration plasmatique et non par son affinite pour son recepteur. L’activite de la molecule va donc pouvoir se porter: - sur des sites P2Y12 extra-plaquettaires qui n’etaient que peu ou pas accessibles aux inhibiteurs irreversibles, et ainsi devoiler au niveau vasculaire des effets vasodilatateurs; - sur des sites recepteurs transporteurs de moindre affinite. C’est ainsi que le ticagrelor inhibe l’« erythrocyte equilibrative nucleoside transporter », transporteur situe a la membrane des globules rouges et responsable de l’incorporation rapide et active de l’adenosine dans les globules. L’inhibition de l’ENT induit une accumulation d’adenosine avec toute une serie d’effets possibles, « les effets adenosine », qui peuvent potentiellement renforcer l’effet primaire: l’adenosine a une activite directe d’anti-agregant plaquettaire et pas seulement inhibitrice de l’agregation plaquettaire; l’adenosine a des effets vasculaires: vasodilatateurs mais aussi de pre- et de post-conditionnement en protection contre l’ischemie-reperfusion, et des effets anti-inflammatoires au niveau local. Mais c’est aussi cet effet adenosine qui peut expliquer certains effets secondaires notes lors des etudes avec le ticagrelor (dyspnee, augmentation des taux plasmatiques d’acide urique et de creatinine, bradycardie en particulier). L’observation que ces patients presentant ces effets secondaires tirent un benefice meme superieur du traitement est un argument fort pour indiquer que l’effet adenosine participe de maniere significative au benefice global net du traitement par le ticagrelor.

Differences Between Upper and Lower Limbs in Venous Endothelial Reactivity in Humans

Objective: To determine the variability of endothelial reactivity to venostasis in the upper and lower limbs of healthy subjects. Participants: Ten healthy volunteers were investigated twice, at an interval of 1-week. Main outcome measures: Plasma concentrations of substances released from endothelial cells were determined in each limb after 10 min of venostasis in a sequential manner. Tissue plasminogen activator (tPA), plasminogen activator inhibiting factor (PAI-1), thrombin–antithrombin complexes (TAT) and D-dimers (D-Di) were used as indicators of the thrombotic process and its reactions; angiotensin converting enzyme (ACE) and endothelin-1 (ET1) were related to endothelial cell activity involved in vascular tone regulation. Results: No difference was observed in endothelial cell recovery following venostasis after an interval of 1 week. A significant difference in endothelial cell release was found between the upper and lower limbs and between the right and left legs. Conclusions: Excellent reproducibility of measurements was observed. In keeping with the higher frequency of venous thrombosis in the lower limbs, the left leg seemed to be less reactive after venostasis, and the endothelium was more reactive in the upper than in the lower limbs.