Objective Lusutrombopag is recommended for severe thrombocytopenia (<5.0×104/μL) in patients with chronic liver disease who are scheduled to undergo invasive procedures. However, reports on the efficacy of repeated lusutrombopag dosing are scarce. It is also not known whether lusutrombopag causes the platelet count to exceed 5.0×104/μL. We evaluated the efficacy of repeated lusutrombopag dosing and the efficacy of the platelet prediction simulation software program. Methods We evaluated the number of platelet elevations according to the number of lusutrombopag administrations. We also evaluated the correlation between the highest software-predicted platelet count and the platelet count measured in actual clinical practice. Patients This retrospective study included 236 patients treated with lusutrombopag at 11 medical institutions in Japan. Results The platelet count increased with the number of lusutrombopag administrations (1, 2, 3, 4, >4) in all groups, and no significant difference was found among the groups (p = 0.169). In all groups, the platelet counts reached their highest levels at 8-14 days after treatment with lusutrombopag (p = 0.243). There was a correlation between the highest software-predicted platelet count and the platelet count measured in actual clinical practice in all dose frequency groups; however, the correlation was the strongest in the one-dose group (r = 0.74, p <0.0001). Conclusion Frequent lusutrombopag administration is therefore both effective and safe, and a platelet prediction simulation software program is thus considered to be useful in practice.

Oral thrombopoietin receptor agonists are used to treat thrombocytopenia in patients with chronic liver disease who are scheduled for invasive procedures. The efficacy of lusutrombopag based on the pretreatment platelet count was investigated.

Patients treated at nine hospitals from December 2015 to December 2023 were included. Efficacy was assessed by comparing the proportion of patients achieving a platelet count ≥ 50 000/μL and the change in platelet count.

Seventy patients were eligible for evaluation. Patients with a pretreatment platelet count < 40 000/μL had a significantly lower rate of achieving a platelet count of ≥ 50 000/μL than those with a pretreatment count of 40 000-50 000/μL (62.5% vs. 84.2%, p = 0.038); however, there was no significant difference in the change in platelet count (25 700 vs. 24 400/μL, p = 0.972). Patients with viral-related cirrhosis showed a significantly greater change in platelet count than the others (29 100 vs. 19 200/μL, p = 0.012). For patients receiving multiple lusutrombopag treatments, the change in platelet count was significantly lower in the second treatment than in the first treatment (26 900 vs. 20 800/μL, p = 0.041). The main adverse event observed was thrombosis (2.9%).

Lusutrombopag increases platelet count regardless of pretreatment levels, but efficacy, defined as achieving a platelet count of ≥ 50 000/μL, may be insufficient in patients with a pretreatment platelet count < 40 000/μL. Additionally, patients with non-viral liver disease responded less well to treatment compared to those with viral liver disease. Therefore, treatment strategies should be tailored based on pretreatment platelet counts and the etiology of liver disease.

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.

The management of immune thrombocytopenia (ITP) and the prediction of patient response to therapy still represent a significant and constant challenge in hematology. ITP is a heterogeneous disease with an unpredictable evolution. Although the pathogenesis of ITP is currently better known and its etiology has been extensively studied, up to 75% of adult patients with ITP may develop chronicity, which represents a significant burden on patients' quality of life. A major risk of ITP is bleeding, but knowledge on the exact relationship between the degree of thrombocytopenia and bleeding symptoms, especially at a lower platelet count, is lacking. The actual management of ITP is based on immune suppression (corticosteroids and intravenous immunoglobulins), or the use of thrombopoietin receptor agonists (TPO-RAs), rituximab, or spleen tyrosine kinase (Syk) inhibitors. A better understanding of the underlying pathology has facilitated the development of a number of new targeted therapies (Bruton's tyrosine kinase inhibitors, neonatal Fc receptors, strategies targeting B and plasma cells, strategies targeting T cells, complement inhibitors, and newer TPO-RAs for improving megakaryopoiesis), which seem to be highly effective and well tolerated and result in a significant improvement in patients' quality of life. The disadvantage is that there is a lack of knowledge of the predictive factors of response to treatments, which would help in the development of an optimized treatment algorithm for selected patients.

Endoscopic procedures are essential in gastroenterology but pose significant risks for thrombocytopenic patients who have lower platelet counts, increasing the likelihood of bleeding complications. This systematic review and meta-analysis followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to assess bleeding risks in thrombocytopenic patients undergoing various endoscopic procedures. A comprehensive search was conducted across databases like PubMed, MEDLINE, and EBSCO, using stringent criteria for inclusion and exclusion, with study quality assessed via the Newcastle-Ottawa Scale and thrombocytopenia severity classified by Common Terminology Criteria for Adverse Events (CTCAE) criteria. Statistical analysis focused on bleeding event incidence rates at different platelet count thresholds, utilizing RevMan Web (Cochrane, London, UK) and Excel (Microsoft® Corp., Redmond, WA). The search yielded 1,675 potential articles, but only three retrospective cohort studies were selected. Results showed a significant increase in bleeding risk for patients with platelet counts below 50,000/mm3, particularly under 25,000/mm3, with a 5.5% prevalence of post-procedure bleeding in moderate to severe thrombocytopenic patients versus 4.0% in those with higher counts, and a threefold higher risk in severe thrombocytopenia. The study highlights the need for meticulous pre-procedure assessments in thrombocytopenic patients and points out disparities in guideline recommendations, suggesting personalized approaches based on patient-specific risks. It underscores balancing diagnostic yield against bleeding risks, especially in severe thrombocytopenia, and discusses the controversial role of prophylactic platelet transfusions, advocating for a nuanced approach. In conclusion, this meta-analysis provides critical insights into managing thrombocytopenia in endoscopic procedures, emphasizing the importance of individualized patient assessment and adherence to evolving guidelines, and underlining the necessity of further research to refine these guidelines and improve patient safety and outcomes in this challenging clinical scenario.

Platelet (PLT) transfusion was the most practical way to increase patients' PLT counts before invasive hepatic procedures such as radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC). A novel drug that raises the PLT count by acting on the thrombopoietin receptor has recently become available.

Lusutrombopag 3 mg was administered daily for 7 days to patients who underwent RFA for liver tumors with low PLT counts (< 50,000 PLT µL^- 1). We collected demographic data concerning the patients' liver function and PLT counts.

Lusutrombopag was administered to 91 patients, with a median age of 71 years (range 51-86). Forty-two patients had hepatitis C, 12 had hepatitis B, 21 had alcoholic liver disease, 11 had nonalcoholic steatohepatitis, and five had other diseases. The median Child-Pugh score was 7 (range 5-11). Thirty-seven patients had stage I tumors, 41 had Stage II, 12 had stage III, and one had stage IV. PLT count was elevated from 4.4 × 10⁴ ± 1.4 × 10⁴ to 8.6 × 10⁴ ± 2.5 × 10⁴ PLT µL^- 1. Lusutrombopag administration prevented PLT transfusions in 84/91 patients (92%). No patient had bleeding complications after RFA. One had portal thrombosis after lusutrombopag administration. Patients who achieved PLT counts of > 50,000 PLT µL^- 1 had higher PLT counts before lusutrombopag administration. The degree of splenomegaly did not affect the rate of PLT count elevation. There was no specific adverse effect by administrating lusutrombopag for patients with PLT counts of around 50,000 µL^- 1 but > 50,000 µL^- 1.

Lusutrombopag administration before RFA was effective and seemed to be relatively safe for hepatocellular carcinoma patients with low PLT counts.

This study was approved by Japanese Red Cross Medical Center Institutional Reseach Comittie (#862, 07/03/2016), and was registered in a publically accessible primary register (#UMIN000046629, registered date: 14/01/2022).

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.

Thrombocytopenia is highly prevalent in patients with chronic liver disease (CLD) and these patients often require invasive procedures that carry a risk of bleeding. To prevent bleeding, guidelines recommend increasing platelet counts in patients with CLD who have thrombocytopenia and are planned to undergo invasive procedures. There are currently two options to increase platelet counts in patients in this setting: platelet transfusion or thrombopoietin receptor agonists (TPORAs). Several treatment algorithms have been developed in the US to help physicians choose the best course of treatment for each patient; however, to date, no such algorithm has been proposed in other countries, where the choice of treatment has been based on each physician's judgment and experience. Here, we discuss the pathogenesis and treatment of thrombocytopenia in patients with CLD, we review and present current evidence of the efficacy of TPORAs for the treatment of thrombocytopenia in patients with CLD, and we present our expert opinion on a Japanese treatment algorithm for thrombocytopenia in patients with CLD who are planned to undergo invasive procedures. This algorithm aims to provide guidance for optimal decision making in the selection of TPORA therapy or platelet transfusion based on the latest evidence and according to actual clinical practice.