A study on prevention of bleeding complications using lusutrombopag for safe RFA in patients with hepatocellular carcinoma with low platelet counts: prospective observational study.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Lusutrombopag administration before RFA was effective and seemed to be relatively safe for hepatocellular carcinoma patients with low PLT counts. TRIAL REGISTRATION: 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).

Safety and effectiveness of lusutrombopag in patients who have chronic liver disease with thrombocytopenia and undergoing invasive procedures: Real-world post-marketing surveillance in Japan.

AIM: Lustrombopag has been approved for the treatment of thrombocytopenia in patients with chronic liver diseases who are scheduled to undergo an invasive procedure. Here, we report the final results of a post-marketing surveillance assessing the safety and effectiveness of lusutrombopag in Japan. METHODS: This multicenter, prospective, real-world surveillance collected data from case report forms between October 2016 and May 2021. The observation period was 2 months after the first day of lusutrombopag treatment. Safety and effectiveness (proportion of patients avoiding preoperative platelet transfusion and responders who achieved platelet count increase from baseline) were assessed. RESULTS: The safety analysis set included 1033 (100.0%), 130 (12.6%), and 14 (1.4%) patients who received one or more, two or more, and three or more treatment cycle(s), and 482 (48.9%), 457 (46.3%), and 43 (4.4%) patients who were Child-Pugh class A, B, and C, respectively. The most common serious adverse drug reactions were portal vein thrombosis, pancytopenia, and white blood cell count decrease, reported in 14 (1.36%), three (0.29%), and two (0.19%) patients, respectively. The incidence of adverse drug reactions was not higher in patients with Child-Pugh class C or those undergoing retreatment cycles compared with other Child-Pugh classes or the first treatment cycle, respectively. During the observation period of the first treatment cycle, 94.7% (889/939) of patients avoided preoperative platelet transfusion and 82.8% (741/895) of the patients met the responder criteria. CONCLUSIONS: This surveillance study further supports the safety and effectiveness of lusutrombopag in a broad range of patients with chronic liver diseases undergoing planned invasive procedures. CLINICAL TRIAL REGISTRATION: JapicCTI-163432.

Impact of Anti-GPIIb/IIIa Antibody-Producing B Cells as a Predictor of the Response to Lusutrombopag in Thrombocytopenic Patients with Liver Disease.

BACKGROUND: To make an accurate estimate of the response to thrombopoietin (TPO) receptor agonists for thrombocytopenia associated with chronic liver disease, we evaluated the influence of antiplatelet autoantibodies on the response to lusutrombopag in thrombocytopenic patients with liver disease. METHODS: A prospective study was conducted at 2 hospitals. Thrombocytopenic patients with liver disease received oral lusutrombopag 3.0 mg once daily for up to 7 days. We analyzed changes in platelet counts from baseline to the maximum platelet count on days 9-14. The definition of clinical response was a platelet count of ≥5 × 104/µL with an increased platelet count of ≥2 × 104/µL from baseline. We assessed the correlation between the response to treatment drug and antiplatelet autoantibodies measured by anti-GPIIb/IIIa antibody-producing B cells. RESULTS: Thirty patients received the trial drug. There were 25 responders and 5 nonresponders. The median change in platelet counts was 3.9 × 104/µL (95% CI 2.8-4.6, p < 0.0001). The correlation between change in platelet counts and the frequency of the anti-glycoprotein IIb/IIIa antibody-producing B cells was moderate (r = 0.414, 95% CI 0.064-0.674, p = 0.023). In multivariate analysis of factors affecting the change in platelet counts, the anti-GPIIb/IIIa antibody-producing B cells were identified as an independent factor (regression coefficient [B] = 0.089; CI 0.021-0.157, p = 0.013). CONCLUSION: Anti-GPIIb/IIIa antibody-producing B cells may be a predictor for TPO receptor agonists in patients with chronic liver disease.

Human mass balance, metabolism, and cytochrome P450 phenotyping of lusutrombopag.

The human mass balance of lusutrombopag, an orally bioavailable thrombopoietin (TPO) receptor agonist, was characterised in seven healthy male subjects after a single oral dose of [14C]-lusutrombopag (2 mg, 100 µCi) in solution. Lusutrombopag was the main component in plasma, accounting for 56% of plasma radioactivity AUC0-∞. In plasma, the half-life of radioactivity (70.7 h) was longer than that of lusutrombopag (25.7 h), suggesting the presence of long circulating metabolites. The main excretion pathway of lusutorombopag was feces, with a radioactivity recovery of approximately 83% within 336 h post-dose. M6 (lusutrombopag-O-propanol or lusutrombopag-O-acetic acid) and M7 (lusutrombopag-O-ethane-1,2-diol) were also identified as main components in feces, accounting for at most 17.9%, and 16.9% of the dose, respectively, and were ß-oxidation related metabolites. Our in vitro metabolism study of lusutrombopag indicated that ß-oxidation was a subsequent metabolism of ω-oxidation and CYP4 enzymes, including CYP4A11, were the major isozymes contributing to ω-oxidation. In conclusion, lusutrombopag is primarily eliminated via ω-oxidation and excreted in the feces, where CYP4 enzymes play an important role.

Effectiveness of Lusutrombopag in Patients with Mild to Moderate Thrombocytopenia.

AIMS: Thrombocytopenia is a common complication among patients with chronic liver disease (CLD). To increase platelet counts, lusutrombopag, a small-molecule, second-generation thrombopoietin receptor agonist, was developed in September 2015. Lusutrombopag is mainly used in patients with platelet counts <50,000/µL. However, its usefulness in patients with platelet counts ≥50,000/µL remains unknown. We studied the effectiveness of lusutrombopag administration in patients with platelet counts of ≥50,000/µL. METHODS: We evaluated 36 patients who received lusutrombopag for CLD. Changes in platelet counts were evaluated. A treatment response was defined as an increasing platelet count ≥20,000/µL from baseline after drug administration. The differences related to these changes between platelet counts ≥50,000 and <50,000/µL were evaluated. RESULTS: Of the patients, 25 had platelet counts ≥50,000/µL. The increase in platelet count and the date in which it reached a maximum did not significantly differ between the groups. The effectiveness of lusutrombopag did not significantly differ between the groups. In both groups, no adverse reaction was observed during lusutrombopag administration. CONCLUSION: In this study, we showed the effectiveness of lusutrombopag, which had no complications. This study is the first to report that the effectiveness of lusutrombopag was the same for patients with platelet counts ≥50,000/µL and <50,000/µL.

Effect of three or more treatments with lusutrombopag in patients with cirrhotic thrombocytopenia: A retrospective single-center study.

AIMS: Thrombocytopenia is a common complication among patients with chronic liver disease (CLD). Lusutrombopag, an oral thrombopoietin receptor agonist, is used to reduce the risk of hemorrhage in patients with thrombocytopenia who are undergoing invasive procedures. Platelet transfusion was the standard treatment for thrombocytopenia; however, multiple platelet transfusions lead to the production of antiplatelet antibody. The effect of giving lusutrombopag three times or more has not been previously reported. In this study, we investigated the effect of lusutrombopag readministration in patients with thrombocytopenia. METHODS: This study included 14 patients (total, 24 readministrations) who received lusutrombopag two times or more. Changes in platelet counts were evaluated. Treatment response was defined as an increased platelet count of ≥20 000/µL after lusutrombopag treatment. RESULTS: Lusutrombopag was given twice in nine patients, three times in three patients, five times in one patient, and six times in one patient. An elevated platelet count of <20 000/µL was noted in only one of the 24 readministrations. There were no postoperative hemorrhagic complications, and no patient had an increased platelet count of >200 000/µL. One patient had a portal venous mural thrombus; however, he was asymptomatic, and the thrombus resolved after anticoagulant treatment, without recurrence. The comparison between the first, second, and third or more treatments showed there was no significant difference in platelet increase. CONCLUSION: Repeated treatment of lusutrombopag is effective for CLD patients with thrombocytopenia. Moreover, three or more treatments with lusutrombopag showed equal effect compared with one and two treatments with the medication.

Thrombopoietin receptor agonist is more effective than platelet transfusion for chronic liver disease with thrombocytopenia, shown by propensity score matching.

AIM: The thrombopoietin receptor agonist, lusutrombopag, was recently adapted for treatment of thrombocytopenia in chronic liver disease. However, no studies have compared the effects of lusutorombopag and platelet transfusion. Therefore, we aimed to clarify the efficacy and proportion of responders of lusutrombopag compared with platelet transfusion, by propensity score matching. METHODS: A total of 200 patients (90 lusutrombopag, 110 platelet transfusion) with thrombocytopenia were enrolled, and matched for age, liver function, renal function, platelet count, peripheral blood count, and spleen size, using the propensity score-matching method. Finally, 52 patients (26 lusutrombopag, 26 platelet transfusion) were included. The primary end-point was an increase in platelet count. Secondary end-points were the proportion of responders, duration of the sustained effect, incidence of adverse events, and predictors associated with an increase in platelet count. RESULTS: The median increase in platelets from baseline was 48 × 103 /µL versus 9.5 × 103 /µL (lusutrombopag vs. transfusion, P < 0.0001). The proportion of responders (increase of >10 × 103 /µL) was 100% versus 50.0% (P < 0.0001). Median duration of the sustained effect (increase of >50 × 103 /µL) was 10 versus 2 days (P < 0.0001). The incidence of adverse events was 7.7% versus 50.0% (P = 0.036). Predictors associated with an increase in platelets were hemoglobin and spleen size by multiple regression analysis. CONCLUSION: Lusutrombopag was more effective in chronic liver disease patients than platelet transfusion. The proportion of responders, effect duration, and non-incidence rate of adverse events were higher in the lusutrombopag group.

Is platelet monitoring during 7-day lusutrombopag treatment necessary in chronic liver disease patients with thrombocytopenia undergoing planned invasive procedures? A phase IIIb open-label study.

AIM: Lusutrombopag is approved for thrombocytopenia in chronic liver disease patients planned to undergo invasive procedures. In previous clinical studies, lusutrombopag treatment was stopped in patients with an increase in platelet count (PC) of ≥20 × 109 /L from baseline and whose PC was ≥50 × 109 /L (discontinuation criteria). We assessed the influence of platelet monitoring during lusutrombopag treatment in lusutrombopag-naïve patients. METHODS: In this open-label study, Child-Pugh class A and B (A/B) patients were enrolled and treated with lusutrombopag (3 mg/day) for 7 days. In the treatment-naïve A/B-1 group, the discontinuation criteria were applied on day 6. In the treatment-naïve A/B-2 group, the criteria were not applied. In a non-naïve A/B group, the criteria were applied on days 3 and 5-7. The main efficacy end-point was the proportion of patients without platelet transfusion (PT) before the primary invasive procedure. RESULTS: In the A/B-1, A/B-2, and non-naïve A/B groups, the proportions of patients without PT were 80.9% (38/47), 83.0% (39/47), and 75.0% (6/8), respectively. The mean durations of PC ≥ 50 × 109 /L without PT were 20.7, 20.3, and 22.8 days, respectively. Excessive PC increases (≥200 × 109 /L) were not detected in any group. Treatment-related adverse events occurred in 4.3%, 6.4%, and 0% of A/B-1, A/B-2, and non-naïve A/B patients, respectively. Severe portal vein thrombosis occurred in one A/B-2 patient (PC 75 × 109 /L at onset). CONCLUSIONS: No meaningful efficacy and safety differences were observed among the groups with or without discontinuation criteria and the non-naïve group. These findings support lusutrombopag treatment without platelet monitoring and retreatment with lusutrombopag.

Role of severe thrombocytopenia in preventing platelet count recovery in thrombocytopenic patients with chronic liver disease.

BACKGROUND AND AIM: Certain thrombocytopenic patients with chronic liver disease have inadequate platelet count recovery after platelet transfusion or lusutrombopag administration. We aimed to identify the reasons for this phenomenon. METHODS: We investigated 58 and 86 thrombocytopenic patients with chronic liver disease who received lusutrombopag (3 mg orally for up to 7 days) or underwent blood transfusions, respectively. Thirty patients underwent simultaneous hepatic surgery and splenectomy. Factors preventing platelet count recovery above 50 × 103 /µL were identified. RESULTS: The median patient age was 64 years. Eleven, 78, and 55 patients had hepatitis B, hepatitis C, or another etiology, respectively; 59, 69, and 16 had Child-Pugh classes A, B, and C, respectively. The median spleen volume was 432 mL, and a median of 10 blood units were transfused per patient. The median platelet count rose significantly (from 41.5 × 103 /µL to 81.0 × 103 /µL) after lusutrombopag administration but not after blood transfusion before invasive procedures. However, maximum platelet counts in patients who underwent splenectomy before platelet transfusion were markedly improved over those who did not. Increasing platelet counts above 50 × 103 /µL required baseline platelets > 30 × 103 /µL and lusutrombopag administration for all patients. Platelet count recovery was dependent on a spleen volume of < 300 mL and baseline platelets of > 40 × 103 /µL in patients who underwent platelet transfusions, while a baseline platelet count of > 30 × 103 /µL was required for patients administered with lusutrombopag. CONCLUSION: Neither blood transfusion nor lusutrombopag improves thrombocytopenia in patients with severe conditions; however, the degree of platelet count elevation following lusutrombopag administration is higher than that following blood transfusion.

Evaluation of drug-drug interaction of lusutrombopag, a thrombopoietin receptor agonist, via metabolic enzymes and transporters.

PURPOSE: Drug-drug interaction (DDI) potentials of lusutrombopag, a thrombopoietin receptor agonist, on the activity of cytochrome P450 (CYP) 3A and of cyclosporine, which inhibits P-glycoprotein and breast cancer resistance protein, on lusutrombopag pharmacokinetics were assessed via clinical studies and physiologically based pharmacokinetic (PBPK) modeling. METHODS: The effect of lusutrombopag on midazolam (a CYP3A probe substrate) pharmacokinetics was assessed in 15 healthy subjects receiving a single midazolam 5-mg dose with or without coadministration of lusutrombopag 0.75 mg for 6 days (first dose: 1.5-mg dose). The effect of cyclosporine on lusutrombopag pharmacokinetics was assessed in 16 healthy subjects receiving a single lusutrombopag 3-mg dose with or without a single cyclosporine 400- to 600-mg dose. PBPK modeling was employed to extrapolate the effect of lusutrombopag at the clinical dose (3 mg once daily) on midazolam pharmacokinetics. RESULTS: In the clinical study, mean ratios (90% confidence intervals [CIs]) of with/without lusutrombopag for maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of midazolam were 1.01 (0.908-1.13) and 1.04 (0.967-1.11), respectively, indicating no effect of lusutrombopag on midazolam pharmacokinetics. PBPK modeling suggested no effect of lusutrombopag at the clinical dose on midazolam pharmacokinetics. Mean ratios (90% CIs) of with/without cyclosporine for lusutrombopag Cmax and AUC were 1.18 (1.11-1.24) and 1.19 (1.13-1.25), respectively, indicating a slight increase in lusutrombopag exposure. CONCLUSIONS: In consideration with in vitro data, the in vivo and in silico results suggested no clinically significant DDI potential of lusutrombopag with other medical products via metabolic enzymes and transporters.

Safety and effectiveness of lusutrombopag in Japanese chronic liver disease patients with thrombocytopenia undergoing invasive procedures: Interim results of a postmarketing surveillance.

AIM: Lusutrombopag is approved for the treatment of thrombocytopenia in chronic liver disease patients undergoing invasive procedures. This real-world surveillance assesses the safety and effectiveness of lusutrombopag in Japan. METHODS: This ongoing, multicenter, prospective, real-world surveillance is collecting data from case report forms between October 2016 and May 2021. Interim data up to September 2018 were used to evaluate safety (adverse events and adverse drug reactions [ADRs]) and effectiveness (proportion of patients avoiding preoperative platelet transfusion and change in platelet count from baseline). RESULTS: The safety analysis set included 331 patients. The mean baseline platelet count was 46.2 ± 13.7 × 109 /L. Of 377 invasive procedures, radiofrequency ablation (110 procedures, 29.2%) was the most frequent. The mean time from starting lusutrombopag treatment to invasive procedure was 12.3 days. Incidences of serious adverse events and ADRs were 8.76% and 3.32%, respectively. Six cases (1.81%) of portal vein thrombosis were considered serious adverse events; of these, four cases (1.21%) were classified as serious ADRs. Of 300 patients who underwent an invasive procedure (excluding those with platelet transfusion refractoriness), 282 (94.0%) avoided preoperative platelet transfusion. In patients with platelet measurements before and after lusutrombopag administration who did not undergo platelet transfusion, the mean maximum change in platelet count from baseline was 41.7 ± 31.4 × 109 /L (range, -6 to 276; n = 286). All patients receiving second (n = 20) and third (n = 1) treatments avoided preoperative platelet transfusion without developing any ADRs. CONCLUSIONS: This real-world surveillance further supports the safety and effectiveness of lusutrombopag in patients with chronic liver disease undergoing invasive procedures.

Efficacy and safety of repeated use of lusutrombopag prior to radiofrequency ablation in patients with recurrent hepatocellular carcinoma and thrombocytopenia.

AIMS: Thrombocytopenia is often associated with chronic liver disease. Lusutrombopag is a small molecule thrombopoietin receptor agonist designed to temporarily increase the platelet count in patients with chronic liver disease for whom elective invasive procedures are planned. In the present study, the efficacy and safety of repeated use of lusutrombopag prior to radiofrequency ablation (RFA) for recurrent hepatocellular carcinoma were examined. METHODS: Eight patients with hepatocellular carcinoma who had a platelet count <50 000/µL prior to both initial and repeat RFA at the time of recurrence received lusutrombopag (3 mg/day) orally for 7 days between March 2016 and August 2018. The following were compared: the effect of lusutrombopag to increase the platelet count as determined by the platelet count after the initial and repeated use of lusutrombopag, the rate of avoiding platelet transfusion, and the presence of any complications. RESULTS: The platelet count increased to 103 100 ± 22 800/µL 14 days after the first treatment and to 110 700 ± 17 800/µL 14 days after the repeated use. None of the patients required platelet transfusion. None of the patients developed clinical symptoms such as thrombosis, fever, rash, portal vein thrombosis, bleeding, or any other serious adverse events. CONCLUSIONS: Repeated use of lusutrombopag increased the platelet count. It did not cause any serious adverse events and led to avoidance of platelet transfusion. Radiofrequency ablation was carried out safely in all patients. Future studies with more cases of repeated use are needed to examine the long-term efficacy and safety of lusutrombopag.

New Small Molecule Drugs for Thrombocytopenia: Chemical, Pharmacological, and Therapeutic Use Considerations.

This review provides details about three small molecules that were recently approved by the FDA for the treatment of thrombocytopenia. The new treatments include lusutrombopag, avatrombopag, and fostamatinib. The first two drugs are orally active thrombopoietin receptor (TPO-R) agonists which are FDA-approved for the treatment of thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a procedure. Fostamatinib is orally active prodrug that, after activation, becomes spleen tyrosine kinase (SYK) inhibitor. Fostamatinib is currently used to treat chronic and refractory immune thrombocytopenia in patients who have had insufficient response to previous treatment. Chemical structures, available dosage forms, recommended dosing, pharmacokinetics, results of toxicity studies in animals, most frequent adverse effects, significant outcomes of the corresponding clinical trials, and their use in specific patient populations are thoroughly described. Described also is a comparative summary of the different aspects of five currently available therapies targeting TPO-R or SYK for the treatment of thrombocytopenia.

Lusutrombopag as a Repurposing Drug in Combination with Aminoglycosides against Vancomycin-Resistant Enterococcus.

Due to the widespread abuse of antibiotics, drug resistance in Enterococcus has been increasing. However, the speed of antibiotic discovery cannot keep pace with the acquisition of bacterial resistance. Thus, drug repurposing is a proposed strategy to solve the crises. Lusutrombopag (LP) has been approved as a thrombopoietin receptor agonist by the Food and Drug Administration. This study demonstrated that LP exhibited significant antimicrobial activities against vancomycin-resistant Enterococcus in vitro with rare resistance occurrence. Further, LP combined with tobramycin exhibited synergistic antimicrobial effects in vitro and in vivo against Enterococcus. No in vitro or in vivo detectable toxicity was observed when using LP. Mechanism studies indicated that the disrupted proton motive force may account for LP's antimicrobial activity. In summary, these results demonstrate that LP has the previously undocumented potential to serve as an antibacterial agent against refractory infections caused by Enterococcus.

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.

Minimum platelet count threshold before invasive procedures in cirrhosis: Evolution of the guidelines.

Cirrhotic patients with severe thrombocytopenia are at increased risk of bleeding during invasive procedures. The need for preprocedural prophylaxis aimed at reducing the risk of bleeding in cirrhotic patients with thrombocytopenia who undergo scheduled procedures is assessed via the platelet count; however, establishing a minimum threshold considered safe is challenging. A platelet count ≥ 50000/µL is a frequent target, but levels vary by provider, procedure, and specific patient. Over the years, this value has changed several times according to the different guidelines proposed in the literature. According to the latest guidelines, many procedures can be performed at any level of platelet count, which should not necessarily be checked before the procedure. In this review, we aim to investigate and describe how the guidelines have evolved in recent years in the evaluation of the minimum platelet count threshold required to perform different invasive procedures, according to their bleeding risk.

Lusutrombopag has slightly stronger effects on patients with mild thrombocytopenia compared with those with severe thrombocytopenia: A multicenter propensity score matching study.

BACKGROUND: Lusutrombopag effectively increases platelet count in patients with severe thrombocytopenia. However, no multicenter studies analyzing the effects of Lusutrombopag on patients with mild thrombocytopenia (platelet count > 50 000/µL) have been performed. In this study, we aimed to clarify the efficacy of Lusutrombopag on these patients by unifying background factors by propensity score matching. METHODS: A total of 139 patients with thrombocytopenia were enrolled, and matched for age, sex, etiology, disease, treatment, liver function, renal function, peripheral blood count, and spleen index. The primary endpoint was to compare the increase in platelet count from baseline between the high-platelet group (>50 000/µL) and the low-platelet group (<50 000/µL) after Lusutrombopag treatment, using propensity score matching. The secondary endpoint was to clarify platelet transfusion avoidance rate and adverse events, moreover, to identify independent predictors associated with the increase in platelet count. RESULTS: The mean increase in platelet count was 67 000/µL vs 48 000/µL in all patients (high- vs low-platelet group, P = .024), and 64 000/µL vs 48 000/µL (P = .12) after propensity score matching. The increase in platelet count and the platelet transfusion avoidance rate tended to be higher in the high-platelet group. There was no significant difference between adverse events. Predictors associated with an increase in platelet count were sex, estimated glomerular filtration rate, and spleen index by multivariate analysis. CONCLUSION: Lusutrombopag has a little stronger effect in patients with mild thrombocytopenia than those with severe thrombocytopenia and showed a more substantial effect in patients with impaired renal function and small spleen.

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.

Systematic Review with Meta-Analysis: Efficacy and Safety of Lusutrombopag for Severe Thrombocytopenia in Patients with Chronic Liver Disease Undergoing Invasive Procedures.

INTRODUCTION: Lusutrombopag is an oral thrombopoietin receptor agonist (TPO-RA). Clinical trials have shown lusutrombopag's efficacy in reducing need for preoperative platelet transfusion in patients with chronic liver disease (CLD) and severe thrombocytopenia. This analysis assessed efficacy and safety of lusutrombopag in patients with severe thrombocytopenia and CLD undergoing planned invasive procedures. METHODS: An electronic database search (through 1 December 2020) identified three randomised, placebo-controlled, double-blind clinical trials comparing lusutrombopag with placebo in patients with CLD and platelet count below 50 × 109/L scheduled to undergo a procedure with a perioperative bleeding risk. A random-effects meta-analysis examined treatment effect, with Cochrane Collaboration's tool assessing risk of bias. RESULTS: The meta-analysis included 343 (lusutrombopag 3 mg, n = 173; placebo, n = 170) patients. More patients met the criteria for treatment response (platelet count at least 50 × 109/L and increase of at least 20 × 109/L from baseline anytime during the study) with lusutrombopag versus placebo (risk ratio [RR] 6.39; 95% confidence interval [CI] 3.69, 11.07; p < 0.0001). The primary efficacy outcome, proportion of patients requiring no platelet transfusion and no rescue therapy for bleeding for at least 7 days post procedure, was achieved by more patients treated with lusutrombopag versus placebo (RR 3.42; 95% CI 1.86, 6.26; p = 0.0001). The risk of any bleeding event was significantly lower with lusutrombopag compared to placebo (RR 0.55; 95% CI 0.32, 0.95; p = 0.03); conversely, thrombosis event rates were similar between lusutrombopag and placebo (RR 0.79; 95% CI 0.19, 3.24; p = 0.74). CONCLUSION: This meta-analysis showed that treatment of severe thrombocytopenia with lusutrombopag in patients with CLD prior to a planned invasive procedure was efficacious and safe in increasing platelet counts, avoiding the need for platelet transfusions, and reducing risk of bleeding, thereby enhancing the certainty of evidence supporting the efficacy and safety of lusutrombopag.