• Eltrombopag
• HPLC
• Impurity-profiling
• Related substances
• Validation

• Humans
• Chromatography, High Pressure Liquid/methods
• Drug Stability
• Liquid Chromatography-Mass Spectrometry
• Acetonitriles
• Drug Contamination
• Reproducibility of Results
• Benzoates
• Hydrazines
• Pyrazoles

• Avatrombopag
• Chronic liver disease
• Lusutrombopag
• Platelet transfusions
• Thrombocytopenia
• Thrombopoietin agonists

• Chronic Disease
• Hemostatics/therapeutic use
• Humans
• Liver Diseases/complications
• Liver Diseases/therapy
• Platelet Transfusion/adverse effects
• Thrombocytopenia/complications
• Thrombocytopenia/therapy
• Thrombopoietin/therapeutic use

Since their license in 2008, studies on thrombopoietin receptor agonists (TPO-RAs) are proceeding at a fast pace. Their favorable efficacy and safety profile makes them good candidates for the management of thrombocytopenia in different settings, even beyond their current indications. In the last 10 years, we faced patients with refractory thrombocytopenia that required treatment with off-label TPO-RA, despite the paucity of data in the literature and the possible risks, particularly that of thrombosis. We hereby report our 10-year real-life single-center experience of TPO-RA used off-label. Fourteen patients were divided into three groups according to the etiology of thrombocytopenia: myelodysplastic syndromes, post-transplantation, and lymphoproliferative diseases. Clinical features and results are reported within each group. Overall, TPO-RA proved effective in all these conditions achieving responses also in heavily pretreated patients. The overall response rate (ORR) was 100% in patients with thrombocytopenia after transplantation and in those with lymphoproliferative diseases and 75% in patients with myelodysplastic syndromes. The median duration of therapy was 285 days (range 93–1,513 days). Four patients (29%) discontinued treatment because of lack of response (n=2) or a sustained response (n=2). No grade 3–4 adverse events occurred, particularly no thrombosis. In our real-life experience, TPO-RAs were effective and safe and proved of value in the challenging management of patients with refractory thrombocytopenia associated with different conditions.

• eltrombopag
• lymphoproliferative syndromes
• myelodysplastic syndromes
• romiplostim
• thrombopoietin receptor agonist
• transplant

• Eltrombopag
• IFN-stimulated gene
• Interferon-α
• Iron chelation
• Reactive oxygen species
• Thrombocytopenia
• Viral hepatitis

Off-label drug use refers to drug use beyond the specifications authorized for marketing [J Med Case Rep. 2014 Dec;8(1):303]. Eltrombopag is a thrombopoietin receptor agonist that has been used in treating thrombocytopenia due to chronic liver disease (CLD) as an off-label medication. Treatment of thrombocytopenia in patients with CLD constitute a real dilemma as the options are limited and some of them are invasive. However, thrombopoietin receptor agonist has been increasingly used for this purpose. Here we report a 34-year-old woman who has been diagnosed with CLD due to autoimmune hepatitis 20 years ago. Her condition was complicated with portal vein thrombosis, chronic thrombocytopenia, and variceal hemorrhage, and she has been listed as a candidate for liver transplantation. Given her high risk of bleeding, we started her on low dose of eltrombopag (25 mg daily) in order to maintain a platelet level of ≥50 × 10³/µL. However, 1 year after initiation of the therapy, she developed left lower limb deep vein thrombosis.

• Chronic liver disease
• Eltrombopag
• Thrombocytopenia
• Thrombopoietin

To investigate the efficacy of eltrombopag for the treatment of thrombocytopenia in patients with chronic hepatitis C, a phase II, single-arm, open-label study with a 9-week pre-antiviral phase was conducted, followed by a 48-week antiviral phase and a 24-week follow-up phase. The proportion of patients who achieved a platelet count threshold, the proportion of patients who maintained a platelet count >50,000/µl, sustained virological response (SVR) rates and safety parameters were evaluated. Of the 45 enrolled patients (median age, 59 years; median platelet count, 63,000/µl; 98% with Child-Pugh class A), 43 (96%) achieved the platelet count threshold during the pre-antiviral phase. A total of 13 patients (29%) experienced ≥1 adverse event (AE), of which headache and vomiting were the most common, and 41 patients (mostly receiving eltrombopag 12.5 mg or 25 mg) entered the antiviral phase, of which 36 (88%) maintained the platelet count threshold; no patient platelet count decreased below 25,000/µl. Nine patients (22%) achieved an SVR at the 24-week follow-up. Grade ≥3 AEs occurred in 25 patients (61%). A total of 8 serious AEs occurred in five patients (12%). No mortality, thromboembolic events (TEEs), or cataract progression were reported. Eltrombopag increased the platelet count in chronic hepatitis C virus-infected patients with cirrhosis and thrombocytopenia and enabled them to initiate and complete interferon-based antiviral therapy (NCT01636778; first submitted: July 05, 2012).

• chronic hepatitis C
• chronic liver disease
• eltrombopag
• ethnic difference
• pegylated interferon/ribavirin therapy
• thrombocytopenia

• T cell
• hypersplenism
• immune cell phenotype
• immune status
• liver cirrhosis
• neutrophil-to-lymphocyte ratio
• splenectomy

Four-factor prothrombin complex concentrates (4F-PCCs) have been approved for urgent vitamin K antagonist reversal in Western countries for many years. Ethnicity and genetic variations between populations may influence the pharmacokinetic profile of 4F-PCC treatments.

To report plasma levels of vitamin K-dependent coagulation factors and proteins C and S in Japanese patients following administration of a 4F-PCC approved recently in Japan.

This was a subanalysis of a prospective, open-label, Phase IIIb study in Japanese patients requiring rapid vitamin K antagonist reversal owing to major bleeding (n = 6) or need for urgent surgery (n = 5). International normalized ratio and plasma levels of factors II, VII, IX, and X, and proteins C and S were measured before PCC infusion and at specific time points for the next 24 hours. Adverse events and serious adverse events were recorded up to Day 14 and 45, respectively.

Rapid increases in plasma concentrations 30 minutes following 4F-PCC infusion were seen for all factors and proteins C and S, with median concentrations compared with baseline increasing by ≥100% and 70% in the bleeding and surgical groups, respectively. A concurrent decrease in international normalized ratio was observed. Plasma levels for each factor and protein remained within physiologic levels throughout the assessment period. No relationship between thromboembolic events and elevated plasma levels was identified.

Administration of 4F-PCC in Japanese patients receiving vitamin K antagonist anticoagulation therapy resulted in rapid and sustained increases in plasma levels and was well tolerated, indicating that this treatment is effective for the urgent reversal of vitamin K antagonist therapy in this population.

• Coagulation factor
• Hemorrhage
• Prothrombin complex concentrate
• Surgery
• Vitamin K antagonist

• chronic liver disease
• cirrhosis
• thrombocytopenia
• thrombopoietin

Although viral hepatitis treatments have evolved over the years, the resultant liver cirrhosis still does not completely heal. Platelets contain proteins required for hemostasis, as well as many growth factors required for organ development, tissue regeneration and repair. Thrombocytopenia, which is frequently observed in patients with chronic liver disease (CLD) and cirrhosis, can manifest from decreased thrombopoietin production and accelerated platelet destruction caused by hypersplenism; however, the relationship between thrombocytopenia and hepatic pathogenesis, as well as the role of platelets in CLD, is poorly understood. In this paper, experimental evidence of platelets improving liver fibrosis and accelerating liver regeneration is summarized and addressed based on studies conducted in our laboratory and current progress reports from other investigators. In addition, we describe our current perspective based on the results of these studies. Platelets improve liver fibrosis by inactivating hepatic stellate cells, which decreases collagen production. The regenerative effect of platelets in the liver involves a direct effect on hepatocytes, a cooperative effect with liver sinusoidal endothelial cells, and a collaborative effect with Kupffer cells. Based on these observations, we ascertained the direct effect of platelet transfusion on improving several indicators of liver function in patients with CLD and liver cirrhosis. However, unlike the results of our previous clinical study, the smaller incremental changes in liver function in patients with CLD who received eltrombopag for 6 mo were due to patient selection from a heterogeneous population. We highlight the current knowledge concerning the role of platelets in CLD and cancer and anticipate a novel application of platelet-based clinical therapies to treat liver disease.

• Platelet
• Liver cirrhosis
• Liver regeneration
• Cancer
• Thrombopoietin
• Thrombopoietin agonist
• Eltrombopag

• Animals
• Benzoates/pharmacology
• Blood Platelets/cytology
• Cell Movement
• Clinical Trials as Topic
• End Stage Liver Disease/blood
• End Stage Liver Disease/complications
• Fibrosis
• Hepatic Stellate Cells/cytology
• Humans
• Hydrazines/pharmacology
• Killer Cells, Natural/cytology
• Liver/pathology
• Liver Diseases/blood
• Liver Diseases/complications
• Liver Regeneration
• Neoplasm Metastasis
• Neoplasms/blood
• Neoplasms/complications
• Pyrazoles/pharmacology
• Regeneration
• Shear Strength
• Thrombocytopenia/blood
• Thrombocytopenia/complications
• Thrombopoietin/agonists
• Thrombopoietin/blood

• hepatocellular carcinoma
• eltrombopag
• deferoxamine cell cycle
• iron chelate
• thrombopoietin
• huh7
• thrombocytopenia
• cirrhosis
• liver cirrhosis
• liver cancer
• sorafenib

• Apoptosis/drug effects
• Benzoates/administration & dosage
• Carcinoma, Hepatocellular/drug therapy
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/pathology
• Cell Cycle Checkpoints/drug effects
• Cell Line, Tumor
• Cell Proliferation/drug effects
• Cyclin D1/biosynthesis
• Drug Synergism
• Gene Expression Regulation, Neoplastic/drug effects
• Hep G2 Cells
• Humans
• Hydrazines/administration & dosage
• Liver Neoplasms/drug therapy
• Liver Neoplasms/genetics
• Liver Neoplasms/pathology
• Niacinamide/administration & dosage
• Niacinamide/analogs & derivatives
• Phenylurea Compounds/administration & dosage
• Pyrazoles/administration & dosage
• Receptors, Thrombopoietin/agonists
• Receptors, Thrombopoietin/biosynthesis
• Sorafenib

Second generation thrombopoietin agonists including eltrombopag and romiplostim act on the thrombopoietin receptor to increase the megakaryocyte production. These agents were needed as use of first generation recombinant products was associated with formation of autoantibodies. Eltrombopag is an oral thrombopoietin agonist found effective in raising platelet counts in patients with immune thrombocytopenia. The drug has now been found to be useful in raising platelet counts in thrombocytopenia related to liver disease including cirrhosis and chronic viral hepatitis. Although the drug may help enable adequate interferon therapy in patients with HCV infection and help carry out invasive procedures in patients with cirrhosis, concerns have been raised of possible thrombotic complications including portal vein thrombosis. Randomized trials have shown that use of eltrombopag concomitant with pegylated interferon and ribavirin increased the chances of sustained virologic response while decreasing the dose reductions of interferon. The data on use of romiplostim in these clinical indications is also emerging. However, in the future, availability of interferon free regimens is likely to decrease the use of eltrombopag for enabling antiviral therapy. The review discusses the role of eltrombopag in management of liver disease related thrombocytopenia in wake of recent data as also the dosage, precautions and adverse effects associated with its use.

• Cirrhosis
• Thrombopoietin
• Eltrombopag
• Romiplostim
• Hepatitis
• Hepatitis C virus
• Splenectomy
• Thrombocytopenia

• chronic liver disease
• eltrombopag
• platelet count
• population pharmacokinetics/pharmacodynamics

Chronic hepatitis C is a public health problem worldwide. Unfortunately, not all patients may benefit from antiviral therapy due to thrombocytopenia. Its causes are represented by portal hypertension and platelet sequestration in the spleen, decreased serum levels or activity of thrombopoietin, the bone marrow suppression induced by hepatitis C virus and a possible adverse effect of interferon. Thrombopoietin receptor analogs may contribute to increase platelet counts in these patients. Eltrombopag binds to another region of the thrombopoietin receptor compared to endogenous thrombopoietin and stimulates the proliferation and maturation of megakaryocytes and the platelet production in a dose-dependent manner. Eltrombopag has proven its effectiveness for the treatment of patients with primary immune thrombocytopenia. Its indication for other hemopathies or situations (like thrombocytopenia secondary to chemo- or radiotherapy, acute leukemia, myelodysplastic syndroms, acquired and hereditary bone marrow failure, and platelet donors) is under study. Eltrombopag may be particularly useful in patients with advanced chronic hepatitis or liver cirrhosis who require antiviral treatment. We present a minireview on the results of treatment with eltrombopag in patients chronically infected with hepatitis C virus, highlighting the benefits and mentioning possible adverse effects. In some studies eltrombopag increased the number of virological responses after clasical antiviral treatment of patients with chronic hepatitis C and reduced the transfusional requirements of those who had to be subjected to invasive surgery. Eltrombopag is a solution for many of these patients, which allows them receiving antiviral therapy and sometimes getting a sustained virological response, but they must be well monitored to prevent possible thromboembolic or bone marrow complications or liver failure occurrence.

• Eltrombopag
• Chronic hepatitis C
• Hepatitis C virus
• Platelets
• Thrombocytopenia

• Antiviral Agents/adverse effects
• Benzoates/adverse effects
• Benzoates/therapeutic use
• Blood Platelets/drug effects
• Blood Platelets/metabolism
• Hematologic Agents/adverse effects
• Hematologic Agents/therapeutic use
• Hepatitis C, Chronic/blood
• Hepatitis C, Chronic/complications
• Hepatitis C, Chronic/diagnosis
• Hepatitis C, Chronic/drug therapy
• Humans
• Hydrazines/adverse effects
• Hydrazines/therapeutic use
• Pyrazoles/adverse effects
• Pyrazoles/therapeutic use
• Receptors, Thrombopoietin/agonists
• Receptors, Thrombopoietin/metabolism
• Risk Factors
• Signal Transduction/drug effects
• Thrombocytopenia/blood
• Thrombocytopenia/chemically induced
• Thrombocytopenia/diagnosis
• Thrombocytopenia/drug therapy
• Thrombopoiesis/drug effects
• Treatment Outcome

• platelet
• stat3
• akt
• erk1/2
• s1p
• adenosine
• cyclic amp

• Adenosine/biosynthesis
• Animals
• Blood Platelets/metabolism
• Cyclic AMP/biosynthesis
• Endothelial Cells/metabolism
• Enzyme Activation
• Extracellular Signal-Regulated MAP Kinases/biosynthesis
• Hepatic Stellate Cells/metabolism
• Hepatocytes/metabolism
• Humans
• Interleukin-6/metabolism
• Liver Cirrhosis/pathology
• Liver Regeneration/physiology
• Mice
• Proto-Oncogene Proteins c-akt/biosynthesis
• STAT3 Transcription Factor/biosynthesis
• Signal Transduction
• Thrombopoietin/metabolism

• chronic liver disease
• growth
• hepatoma
• megakaryocyte growth and development factor
• thrombopoietin receptor

• hepatic stellate cells
• hepatocytes
• liver cirrhosis
• platelets
• thrombocytopenia

Eltrombopag is a 2nd generation thrombopoietin-receptor agonist. It binds with the thrombopoietin-receptors found on the surfaces of the megakaryocytes & increases platelet production. Many recent studies have suggested a potential role for this novel agent in the treatment of thrombocytopenia associated with hepatitis-C infection. Studies have shown that adjunct treatment with Eltrombopag can help avoid dose reductions/withdrawals of pegylated interferon secondary to thrombocytopenia. It may also have a role in priming up platelet levels to help initiate antiviral therapy. Similarly, chronic liver disease patients with thrombocytopenia who need to undergo an invasive procedure may be potential candidates for short two-week courses of eltrombopag in the periprocedural period to help reduce the risk of bleeding. Besides the price (deemed very expensive and probably not cost-effective), there are some legitimate concerns about the safety profile of this novel agent (most importantly, portal vein thrombosis, bone marrow fibrosis and hepatotoxicity). In this article, the potential role of eltrombopag in the context of hepatitis C virus (HCV)-related thrombocytopenia is reviewed. To write this article, a MEDLINE search was conducted (1990 to November 2012) using the search terms “eltrombopag,” “HCV,” and “thrombocytopenia.”

• chronic immune thrombocytopenic purpura
• liver disease
• romiplostim
• thrombopoietin-receptor agonist