To cite this article: Altman R, Scazziota A, de Lourdes Herrera M, Gonzalez C. Recombinant factor VIIa reverses the inhibitory effect of aspirin or aspirin plus clopidogrel on in vitro thrombin generation. J Thromb Haemost 2006; 4: 2022-7. Summary. Background: Antiplatelet drugs constitute the therapy of choice for acute coronary syndromes, but bleeding can be a side-effect requiring treatment. Restoration of normal platelet activity is also mandatory before urgent surgery. This study investigated: (a) whether a regimen of aspirin or clopidogrel plus aspirin significantly inhibited platelet thrombin generation (TG); and (b) the reversal of this inhibition by recombinant activated factor VII (rFVIIa). Methods and results: TG was evaluated by the lag time, time to peak, peak of TG, and area under the curve after 35 min of assay (AUC 0 fi 35 min ). These measures were examined by the calibrated automated thrombography method in 22 healthy volunteers, 22 volunteers after a 100 mg day )1 aspirin intake (200 mg first day) for 5-7 days, and 22 healthy volunteers after aspirin 100 mg day )1 (200 mg first day) plus clopidogrel 75 mg day )1 (300 mg first day) for 4-7 days. The TG parameters were measured under basal conditions and after platelet stimulation by sodium arachidonate (AA), adenosine 5¢-diphosphate (ADP), collagen and rFVIIa in normal nonaspirinated as well as in vivo aspirinated platelet-rich plasma (PRP) or aspirin plus clopidogrel PRP. Lag time was shorter (P < 0.05), and peak of TG and AUC 0 fi 35 min were significantly greater (P < 0.01 for both), in PRP activated with ADP, collagen, AA or FVIIa than in non-activated PRP from normal subjects. Both non-activated PRP and activated PRP prepared from platelets obtained from volunteers after aspirin intake showed significant prolongation of the time parameters but there was less effect on peak of TG and AUC 0 fi 35 min . For most parameters, aspirin plus clopidogrel administration showed to be more effective compared with the effect obtained by aspirin alone. When rFVIIa was added to ASA-PRP or ASA + Clop PRP, lag time (P < 0.001 for all) and time to peak (P < 0.001-0.017) were significantly shortened, indicating that rFVIIa reverses the inhibitory effect of these anti-aggregating agents. Conclusion: Platelets activated by AA, ADP, collagen or FVIIa triggered TG. This effect was inhibited by aspirin plus clopidogrel, suggesting an additional benefit of this drug combination for preventing thrombosis. rFVIIa reverses the inhibitory effect of aspirin or aspirin plus clopidogrel, and could be useful for bleeding complications or when acute surgery is needed during treatment with these antiplatelet drugs.

SummaryB~~ckground: Vascular endothelium reacts to various pathophysiologic stimuli by releasing several autocoids and cytokines that can be used along with the coagulation and fibrinolytic markers for the diagnosis of hemostatic alterations. Several newer markers for vascular distress. such as tissue plasminogen activator (TPA), tissue plasminogen activator inhibitor-I (PAI-1 ), TPMAI-1 complex, and the newly reported inhibitor of the coagulation process, namely, tissue factor pathway inhibitor (TFPI), have been implicated in the pathogenesis of pulmonary hypertension.Mrthodsls: To investigate the behavior of endothelial cells at basal and time-dependent venous stasis-induced changes, various markers were measured in patients with primnry and secondary pulmonary hypertension and compared with healthy human volunteers (controls) without any family history of thromboembolism or history of hypertensive disorders. The right atrial pressure (RAP) and pulmonary arterial pressure were measured and the hemostatic parameters were correlated to detemiine the relevance of these parameters with the alterations in the present indices.Results: A fibrinolytic deficit exists in patients with pulmonary hypertension, indicated by the prolongation of the euglobulin clot lysis time at basal conditions and after h e venous occlusion test. This defect was mainly due to increased production of PAL 1 by endothelium (patients 59.8 * 22.3 AU/mI; controls 30.3 ? 14.5 AU/ml; p = 0.005). We also report for the Accepted with revision: January S, 1996 first time that a decrease in tissue factor pathway inhibitor antigen was also observed in these patients when RAP was >9 mmHg [controls 95.6 ? 61.6 n&/ml; patients with RAP >9 mniHg 47.2 & 19.2 ng/ml (p = 0.044); patients with RAP <9 mmHg 96.6 k 32.4 ng/ml (p = 0.002 compared with patients with RAP > 9 mmHg)], indicating endothelial cell and hemostatic disturbances.Coticlu.sions: We conclude that the euglobulin clot lysis time was prolonged in patients with pulmonary hypertension compared with controls. The impairment of the fibrinolytic system was due to an elevated concentration of PAI-I . In RAP > 9 mmHg, an additional prothrombotic factor is the decrease in plasma tissue factor pathway inhibitor antigen. It appears from this study that antithrombotic treatment is indicated in these patients.

In patients with mechanical heart valve replacements, low-dose aspirin (100 mg/d) in conjunction with oral anticoagulants at an INR of 2.0 to 3.0 is as effective as the use of high-dose aspirin (650 mg/d) in the prevention of systemic embolism.

BackgroundThe systematic use of aspirin and statins in patients with diabetes and no previous cardiovascular events is controversial. We sought to assess the effects of aspirin and statins on the thrombotic risk assessed by thrombin generation (TG) among patients with type II diabetes mellitus and no previous cardiovascular events.Methodology/Principal FindingsProspective, randomized, open, blinded to events evaluation, controlled, 2×2 factorial clinical trial including 30 patients randomly allocated to aspirin 100 mg/d, atorvastatin 40 mg/d, both or none. Outcome measurements included changes in TG levels after treatment (8 to 10 weeks), assessed by a calibrated automated thrombogram. At baseline all groups had similar clinical and biochemical profiles, including TG levels. There was no interaction between aspirin and atorvastatin. Atorvastatin significantly reduced TG measured as peak TG with saline (85.09±55.34 nmol vs 153.26±75.55 nmol for atorvastatin and control groups, respectively; p = 0.018). On the other hand, aspirin had no effect on TG (121.51±81.83 nmol vs 116.85±67.66 nmol, for aspirin and control groups, respectively; p = 0.716). The effects of treatments on measurements of TG using other agonists were consistent.Conclusions/SignificanceWhile waiting for data from ongoing large clinical randomized trials to definitively outline the role of aspirin in primary prevention, our study shows that among diabetic patients without previous vascular events, statins but not aspirin reduce thrombotic risk assessed by TG.Trial RegistrationClinicalTrials.gov NCT00793754

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