First, thrombosis as shown by the post-hoc analysis reported by Afdhal et al.[10] occurred more frequently in patients with platelet counts higher than 200 × 109/L. One may argue that such a relatively high platelet count is not needed in these patients to prevent bleeding. Therefore, the study could have aimed at reaching a lower platelet count. Perhaps a lower than 75 mg dose of eltrombopag able to achieve only a moderate increase click here of the platelet count could be associated with fewer thrombotic events. According to a previous phase I study on eltrombopag in healthy subjects, a ratio of the platelet count corresponding to approximately

1.3 and 1.5 times the baseline value was achieved at an eltrombopag dose of 30 or 50 mg, respectively, with little gain at 75 mg.[11] Whether this is valid also for patients with chronic liver disease is not MLN0128 mw known, but would deserve attention. Second, although this was only a secondary

endpoint of the study, the occurrence of bleeding during/after invasive procedures was not different in the eltrombopag as opposed to the placebo group.[10] This consideration points to the real need of correcting thrombocytopenia in patients who are moderately thrombocytopenic. If one considers that (albeit in vitro) primary hemostasis (i.e., platelet-vessel wall interaction) in chronic liver disease is apparently rebalanced, owing to the relatively high increase of von Willebrand factor[6] and that thrombin generation (albeit in vitro) is near normal

when platelet counts are around 50 × 109/L,[7] the logical consequence should be that correcting thrombocytopenia before invasive procedures would be required only in severe thrombocytopenia. However, how severe Tideglusib should the thrombocytopenia be before being worried about clinical bleeding should be determined with appropriate clinical trials, which (we are afraid) will never be carried out because of their complexity. The same considerations apply to the question of whether or not one has to correct hypocoagulability (based on abnormal prothrombin time, international normalized ratio [PT-INR]) in cirrhosis before invasive procedures. The rebalanced coagulation[12, 13] due to the concomitant reduction of procoagulant and anticoagulant factors, which is a typical feature of patients with stable cirrhosis, would support the concept that infusion of plasma or coagulation factor concentrates are not useful and should not be used indiscriminately or based solely on the prolongation of the PT-INR. In this respect, the current literature provides strong evidence that, at variance with platelets, there are many randomized/controlled clinical trials that failed to show significant benefit of recombinant activated factor VII (one of the most potent procoagulant agents) to stop esophageal variceal bleeding[14] or to affect intraoperative blood loss in patients undergoing liver transplantation.