Oral Xa Inhibitors

El rivaroxabán es un inhibidor directo de factor X activado y el dabigatrán un inhibidor directo de la trombina. Estos nuevos anticoagulantes orales han demostrado en ensayos clínicos su eficacia y seguridad en el tratamiento de la enfermedad tromboembólica venosa (trombosis venosa profunda y tromboembolia pulmonar).

Rivaroxaban is a direct inhibitor of activated factor X, and dabigatran is a direct inhibitor of thrombin. These new oral anticoagulants have demonstrated to be effective and safe in clinical trials on the treatment of venous thromboembolic disease (deep vein thrombosis and pulmonary thromboembolism).

Bleeding complications, particularly in the gastro-intestinal tract, may complicate the clinical course of liver cirrhosis. Coexistence of abnormal global tests exploring the platelet and clotting systems generated the hypothesis that cirrhotic patients have “coagulopathy” predisposing to bleeding complications. Using more sophisticated laboratory methods this hypothesis has been partly confuted as cirrhotic patients actually disclose an ongoing prothrombotic state in the portal and systemic circulation that could predispose to thrombosis. Recent data of the literature support this hypothesis as portal vein thrombosis and peripheral thrombosis are frequent features of cirrhosis. We reviewed the literature data to assess the prevalence of bleeding and thrombotic complication in cirrhosis and the role of clotting activation in precipitating them. Whilst it appears scarcely relevant the interplay between the so called “coagulopathy” and bleeding, the interplay between clotting activation and thrombosis seems to be relevant but needs more accurate investigation in larger study populations.

Because of its high recurrence rate, active secondary prevention is mandatory once an episode of stroke has occurred. In non-cardioembolic stroke, in addition to lifestyle changes and to targeted treatments, current guidelines recommend Aspirin, Clopidogrel or Aspirin+extended-release dipyridamole. In cardioembolic stroke (due to atrial fibrillation or flutter [AF]), Vitamin K antagonists (VKAs) are recommended in most of patients. A favorable risk/benefit ratio of these treatments has been demonstrated also in elderly patients. However, registry data emphasize that such interventions are often under-used, especially in AF patients. A poor knowledge of current guidelines may play a role in hampering their application in clinical practice. The risk of major bleeding associated with antithrombotic drugs, their inherent limitations, such as socio-demographic (age > 80 years, living alone) and clinical (previous or recent bleeding, trauma, cancer, dementia) features, may account for the gap between current guidelines for stroke/TIA prevention and clinical practice.

The objective of the present report is to evaluate the gap between current recommendations/guidelines for stroke/TIA prevention and clinical practice (registry findings). In our opinion new antithrombotic drugs and detailed educational programs (especially devoted to general practitioners and to some medical specialists), concerning efficacy, safety and limitations of these strategies, are needed to better manage stroke epidemics in the third millennium.

This study evaluated shedding of the platelet collagen receptor, glycoprotein VI (GPVI) in human plasma. Collagen or other ligands induce metalloproteinase-mediated GPVI ectodomain shedding, generating approximately 55-kDa soluble GPVI (sGPVI) and approximately 10-kDa platelet-associated fragments. In the absence of GPVI ligands, coagulation of platelet-rich plasma from healthy persons induced GPVI shedding, independent of added tissue factor, but inhibitable by metalloproteinase inhibitor, GM6001. Factor Xa (FXa) common to intrinsic and tissue factor-mediated coagulation pathways was critical for sGPVI release because (1) shedding was strongly blocked by the FXa-selective inhibitor rivaroxaban but not FIIa (thrombin) inhibitors dabigatran or hirudin; (2) Russell viper venom that directly activates FX generated sGPVI, with complete inhibition by enoxaparin (inhibits FXa and FIIa) but not hirudin; (3) impaired GPVI shedding during coagulation of washed platelets resuspended in FX-depleted plasma was restored by adding purified FX; and (4) purified FXa induced GM6001-inhibitable GPVI shedding from washed platelets. In 29 patients with disseminated intravascular coagulation, mean plasma sGPVI was 53.9 ng/mL (95% confidence interval, 39.9-72.8 ng/mL) compared with 12.5 ng/mL (95% confidence interval, 9.0-17.3 ng/mL) in thrombocytopenic controls (n = 36, P < .0001), and 14.6 ng/mL (95% confidence interval, 7.9-27.1 ng/mL) in healthy subjects (n = 25, P = .002). In conclusion, coagulation-induced GPVI shedding via FXa down-regulates GPVI under procoagulant conditions. FXa inhibitors have an unexpected role in preventing GPVI down-regulation.