Final Results from the First European Real-World Experience on Lusutrombopag Treatment in Cirrhotic Patients with Severe Thrombocytopenia: Insights from the REAl-World Lusutrombopag Treatment in ITalY Study.

Background and aims: Management of severe thrombocytopenia poses significant challenges in patients with chronic liver disease. Here, we aimed to evaluate the first real-world European post-marketing cohort of cirrhotic patients treated with lusutrombopag, a thrombopoietin receptor agonist, verifying the efficacy and safety of the drug. Methods: In the REAl-world Lusutrombopag treatment in ITalY (REALITY) study, we collected data from consecutive cirrhotic patients treated with lusutrombopag in 19 Italian hepatology centers, mostly joined to the "Club Epatologi Ospedalieri" (CLEO). Primary and secondary efficacy endpoints were the ability of lusutrombopag to avoid platelet transfusions and to raise the platelet count to ≥50,000/µL, respectively. Treatment-associated adverse events were also collected. Results: A total of 66 patients and 73 cycles of treatment were included in the study, since 5 patients received multiple doses of lusutrombopag over time for different invasive procedures. Fourteen patients (19%) had a history of portal vein thrombosis (PVT). Lusutrombopag determined a significant increase in platelet count [from 37,000 (33,000-44,000/µL) to 58,000 (49,000-82,000), p < 0.001]. The primary endpoint was met in 84% of patients and the secondary endpoint in 74% of patients. Baseline platelet count was the only independent factor associated with response in multivariate logistic regression analysis (OR for any 1000 uL of 1.13, CI95% 1.04-1.26, p 0.01), with a good discrimination power (AUROC: 0.78). Notably, a baseline platelet count ≤ 29,000/µL was identified as the threshold for identifying patients unlikely to respond to the drug (sensitivity of 91%). Finally, de novo PVT was observed in four patients (5%), none of whom had undergone repeated treatment, and no other safety or hemorrhagic events were recorded in the entire population analyzed. Conclusions: In this first European real-world series, lusutrombopag demonstrated efficacy and safety consistent with the results of registrational studies. According to our results, patients with baseline platelet counts ≤29,000/µL are unlikely to respond to the drug.

Acoustic Radiation Forced Impulse of the Liver and the Spleen, Combined with Spleen Dimension and Platelet Count in New Ratio Scores, Identifies High-Risk Esophageal Varices in Well-Compensated Cirrhotic Patients.

Acoustic radiation forced impulse (ARFI) is an integrated ultrasound method, measuring stiffness by point shear wave elastography. To evaluate the diagnostic performance of the ARFI of the liver and the spleen, combined with spleen dimension and platelet count, in predicting high-risk esophageal varices (HRVs) in cirrhotic patients, a prospective and cross-sectional study was conducted between February 2017 and February 2021. The following ratio scores were calculated based on ARFI measurements: ALSDP (ARFI Liver-Spleen Diameter-to-Platelet Ratio Score), ASSDP (ARFI Spleen-Spleen Diameter-to-Platelet Ratio Score), ASSAP (ARFI Spleen-Spleen Area-to-Platelet Ratio Score), and ALSAP (ARFI Liver-Spleen Area-to-Platelet Ratio Score). In 100 enrolled subjects, spleen ARFI, ASSDP, and ASSAP were significantly associated with HRVs in the prospective short- and long-term follow-ups and in the cross-sectional study (p < 0.05), while ALSDP and ALSAP were associated with HRVs only in the prospective long-term follow-up and cross-sectional study (p< 0.05). ASSAP was the best ARFI ratio score for HRVs at the long-term follow-up [value of area under curve (AUC) = 0.88], although all the ARFI ratio scores performed better than individual liver and spleen ARFI (AUC > 0.7). In our study, ARFI ratio scores can predict, in well-compensated cirrhotic patients, the risk of developing HVRs in short- and long-term periods.

Approaching the Sarcopenic Patient with Nonalcoholic Steatohepatitis-related Cirrhosis.

Sarcopenia is a well-known complication of chronic liver disease (CLD), and it is almost always observed in patients with cirrhosis, at least in those with decompensated disease. Since nonalcoholic fatty liver disease (NAFLD), recently renamed metabolic dysfunction-associated steatotic liver disease (MASLD), is becoming the leading cause of end-stage liver disease, a new scenario characterized by the frequent coexistence of NAFLD, obesity, and sarcopenia is emerging. Although it is not yet resolved whether the bidirectional relationship between sarcopenia and NAFLD subtends causal determinants, it is clear that the interaction of these two conditions is associated with an increased risk of poor outcomes. Notably, during the course of CLD, deregulation of the liver-muscle-adipose tissue axis has been described. Unfortunately, owing to the lack of properly designed studies, specific therapeutic guidelines for patients with sarcopenia in the context of NAFLD-related CLD have not yet been defined. Strategies aimed to induce the loss of fat mass together with the maintenance of lean body mass seem most appropriate. This can be achieved by properly designed diets integrated with specific nutritional supplementations and accompanied by adequate physical exercise. Future studies aiming to add to the knowledge of the correct assessment and approach to sarcopenia in the context of NAFLD-related CLD are eagerly awaited.

Thrombocytopenia in chronic liver disease: Physiopathology and new therapeutic strategies before invasive procedures.

Chronic liver disease is characterized by several hematological derangements resulting in a complex and barely rebalanced haemostatic environment. Thrombocytopenia is the most common abnormality observed in these patients and recent advances have led to researchers focus the attention on the multifactorial origin of thrombocytopenia and on the key role of thrombopoietin (TPO) in its physiopathology. Severe thrombocytopenia (platelet count < 50000/µL) complicates the management of patients with chronic liver disease by increasing the potential risk of bleeding for invasive procedures, which may be therefore delayed or canceled even if lifesaving. In the very last years, the development of new drugs which exceed the limits of the current standard of care (platelet transfusions, either immediately before or during the procedure) paves the way to a new scenario in the management of this population of patients. Novel agents, such as the TPO-receptor agonists avatrombopag and lusutrombopag, have been developed in order to increase platelet production as an alternative to platelet transfusions. These agents have demonstrated a good profile in terms of efficacy and safety and will hopefully allow reducing limitations and risks associated with platelet transfusion, without any delay in scheduled interventions. Altogether, it is expected that patients with chronic liver disease will be able to face invasive procedures with one more string in their bow.