Thrombocytopenia In Chronic Liver Disease Research Articles

Clinical research progress of lusutrombopag for the treatment of thrombocytopenia in chronic liver disease

Thrombocytopenia is one of the common complications with the hematologic system in patients with chronic liver disease, which often causes poor quality of life and high risk of bleeding, thereby affecting their diagnosis, treatment, and prognosis. Platelet transfusion can improve the patient's declining platelet count to a certain extent, but it has problems such as high price and being easy to cause immune rejection. Thrombopoietin (TPO), as an important cytokine that affects platelet production, can bind to TPO receptors and activate megakaryocytes to produce platelets. Lusutrombopag is a newly developed small-molecule TPO receptor agonist that can induce bone marrow progenitor cells to differentiate into megakaryocytes and increase platelet production, posing characteristics of oral convenience, safety and effectiveness; thus, it has been used in many countries and regions for the treatment of patients with chronic liver diseases concurrent with thrombocytopenia. Herein, the pharmacological features and clinical research are reviewed.

Management of Thrombocytopenia with Partial Splenic Embolization in Liver Cirrhosis

Thrombocytopenia is a frequent complication in patients with cirrhosis. Thrombocytopenia is generally divided into mild, moderate, and severe thrombocytopenia. Thrombocytopenia in liver cirrhosis not only increases the risk of bleeding during surgery but can also have an impact on patient management, such as liver biopsy, administration of antiviral therapy, and postponement of elective surgery. The pathophysiology of thrombocytopenia in chronic liver disease can be caused by decreased platelet production, sequestration in the spleen, and increased platelet destruction. Partial splenic embolization (PSE) is one option for treating thrombocytopenia in chronic liver disease. PSE is an effective procedure in treating complications associated with hypersplenism and portal hypertension, such as esophageal varices, pancytopenia, portal hypertensive gastropathy and ascites.

Escitalopram induced thrombocytopenia in chronic liver disease

Escitalopram induced thrombocytopenia in chronic liver disease

A Study of Thrombocytopenia in Chronic Liver Disease and Its Correlation with Development of Esophageal Varices

Background: The aim and objective of this study was to evaluate relationship of platelet count and esophageal varices in chronic liver disease (CLD) admitted in the medicine unit and gastroenterology department of Dhaka Medical College Hospital. Methods: In this cross-sectional study, a total number of 100 randomly selected, clinically diagnosed patients of chronic liver disease were studied from June 2010 to November 2010 (6 months). All patients were assessed as per Child-Pugh class and had full blood count, HBsAg, Anti-HCV antibodies by ELISA, abdominal ultrasound and Endoscopy of upper gastrointestinal tract. Patients were divided into Group A (Platelet count <1,50,000) and Group B (platelet count>1,50,000). Result: 73 male (73%) and 27 female patients (27%) with age range of 16 to 75 years were evaluated. 24% patient were in between 45-55 years age group. 63% patient fall in child Pugh class A group, 32% fall in child Pugh class B &5% fall in child Pugh class C. Esophageal varices were present in 32 patients (32%) and absent in 68 patients (68%). Group A had 31 patients (31% of the total) with 26 patients (83.87%) having esophageal varices. Group B had 69 patients (69% of the total) with 6 patients (8.70%) having esophageal varices. Sensitivity of thrombocytopenia as a marker of esophageal varices was 81.25% and specificity 92.64%, positive predictive value 83.87% and negative predictive value 91.3% and Odds ratio was 54.6. P value is <0.001. Conclusion: In this study, It was attempted to find out the relationship between thrombocytopenia and esophageal varices in CLD. In Group A that is platelet count <1,50,000, the incidence of EV was more than Group B (platelet count >1,50,000). Hence, thrombocytopenia is a good surrogate marker for the presence of esophageal varices in CLD. Bangladesh J Medicine 2022; 33: 247-251

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.

Thrombopoietin Level Predicts Response to Treatment with Romiplostim in Chemotherapy-Induced Thrombocytopenia

INTRODUCTION:Chemotherapy-induced thrombocytopenia (CIT) is a common complication of cancer therapy. Due to the lack of FDA-approved therapies for CIT and clear limitations of platelet transfusions, clinicians often must choose between reducing dose intensity, delaying treatment, switching to an alternative regimen less prone to thrombocytopenia, or even discontinuing therapy altogether. Lower overall survival in CIT is associated with bleeding complications in patients proceeding with chemotherapy as well as patients managed with reductions in relative dose intensity of chemotherapy due to dose reduction and/or treatment delay. Although there are no current FDA-approved therapies for CIT, evidence has emerged supporting use of romiplostim to treat CIT. However, predicting clinical response to romiplostim before initiation is not currently possible due to the lack of a known predictive biomarker. Baseline endogenous TPO levels may, however, be a predictive biomarker for response to thrombopoietin receptor agonists. Prior studies have demonstrated the utility of baseline TPO level to predict romiplostim response in ITP and avatrombopag response in thrombocytopenia of chronic liver disease. Because measurement of TPO level prior to romiplostim treatment of CIT is standard at our institution, we investigated the utility of baseline TPO level to predict romiplostim response in CIT.METHODS:We performed an observational study of patients age ≥18 years who had TPO levels measured and received romiplostim for the treatment of CIT. For each weekly on-romiplostim platelet (Plt) count assessment, clinical response was defined as Plt ≥75×10 9/L and ≥30×10 9/L above pretreatment baseline. Overall, moderate, and superior classes of treatment response were defined based on response fraction (RF) of weekly Plt assessments meeting clinical response criteria (RF >0, ≥ 0.6, and ≥ 0.8, respectively). Median TPO levels were compared in those patients with and without a moderate response or a superior response using the Mann-Whitney U test. A generalized linear model was used to model the logit transformation of RF to predict response fraction based on TPO level. Receiver operating characteristic (ROC) analysis was performed to identify TPO level thresholds for optimal discrimination of those who achieved moderate and superior responses from those who did not.RESULTS:Patients: 63 patients met inclusion criteria. Baseline patient characteristics are detailed in TABLE 1.Relation of TPO Level and Romiplostim Response: Median (IQR) TPO level was lower in patients who achieved a moderate response to romiplostim versus those who did not, 234 (135-1085) pg/mL versus 665 (244-1970) pg/mL (P=0.034) and lower still in patients who achieved a superior response versus those who did not, 212 (91-690) pg/mL versus 559 (173-1851) pg/mL (P=0.023) (FIGURE 1). A generalized linear model demonstrated a significantly higher predicted response fraction as TPO level declined (P=0.036, Figure 2). TPO level was significantly correlated with lowest effective romiplostim dose (r=0.27, P=0.049).Optimal TPO Thresholds for Predicting Response: Utilizing Youden's index, the optimally discriminant TPO level threshold for moderate response to romiplostim was ≤457 pg/mL, which predicted a 61% probability of response in those with a TPO level ≤457 pg/mL and a 65% probability of non-response in those with a TPO level >457 pg/mL (Figure 3A). The optimally discriminant TPO level threshold for superior response to romiplostim was ≤260 pg/mL, which predicted a 59% probability of response in those with a TPO level ≤260 pg/mL and a 70% probability of non-response in those with a TPO level >260 pg/mL (Figure 3B). A near trivial response rate was associated with extreme TPO elevations (e.g., 7% for TPO level >1978 pg/mL, Figure 3).CONCLUSION:Lower TPO levels predict for a higher likelihood and depth of response to romiplostim in CIT, extreme TPO elevations predict strongly for non-response, and higher doses of romiplostim may be needed in patients with moderate TPO elevations to achieve a response. Considering the significant impact of CIT on patient outcomes as a result of treatment delays and dose reductions, baseline serum TPO level in patients with CIT may be a clinically useful biomarker in predicting response to romiplostim, and therefore potentially useful in guiding patient selection and dosing. [Display omitted] DisclosuresKuter: Actelion (Syntimmune), Agios, Alnylam, Amgen, Argenx, BioCryst, Bristol Myers Squibb (BMS), Caremark, CRICO, Daiichi Sankyo, Dova, Genzyme, Immunovant, Incyte, Kyowa-Kirin, Merck Sharp Dohme, Momenta, Novartis, Pfizer, Principia, Protalex, Protalix, Rigel: Consultancy, Other: grant support and consulting fees; Up-to-Date: Patents & Royalties: Up-To-Date; Rubius: Current equity holder in publicly-traded company; Platelet Disorder Support Association: Membership on an entity's Board of Directors or advisory committees; Actelion (Syntimmune), Agios, Alnylam, Amgen, Argenx, Bristol Myers Squibb (BMS), Immunovant, Kezar, Principia, Protalex, Rigel, Takeda (Bioverativ), UCB: Research Funding. Al-Samkari: Novartis: Consultancy; Rigel: Consultancy; Moderna: Consultancy; Argenx: Consultancy; Amgen: Research Funding; Dova/Sobi: Consultancy, Research Funding; Agios: Consultancy, Research Funding. OffLabel Disclosure:Romiplostim is a thrombopoietin-receptor agonist (TPO-RA) used off-label for chemotherapy-induced thrombocytopenia. TPO-RAs are well-established in the treatment of numerous etiologies of thrombocytopenia, including immune thrombocytopenia (ITP), aplastic anemia, and thrombocytopenia of chronic liver disease.

Thrombocytopenia in Chronic Liver Disease: Challenges and Treatment Strategies.

Thrombocytopenia is a common hematologic complication seen in patients with chronic liver disease (CLD). The pathophysiology of thrombocytopenia in CLD is multifactorial, primarily stemming from platelet sequestration and decreased platelet production. This review focuses on the pathophysiology and current treatment options in the treatment of thrombocytopenia in chronic liver disease. While platelet transfusions are the gold standard of treatment, considerations ought to be given to CLD patients who can benefit from transjugular intrahepatic portosystemic shunt and splenic artery embolization. Finally, the recent approval of thrombopoietin receptor agonists for use in CLD patients paves a way for a safe and effective alternative method of improving platelet levels and reducing the need for recurrent platelet transfusions.

Thrombocytopenia in chronic liver disease: the analysis of Italian administrative healthcare data by Fondazione RES

Thrombocytopenia in chronic liver disease: the analysis of Italian administrative healthcare data by Fondazione RES

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

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. 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. 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 2days (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. 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.

The Thrombopoietin Receptor Agonist Lusutrombopag Is Effective for Patients with Chronic Liver Disease and Impaired Renal Function.

The thrombopoietin (TPO) receptor agonist lusutrombopag was developed to treat thrombocytopenia in chronic liver disease (CLD). However, its effectiveness remains unclear. The purpose of this study was to assess the efficacy of lusutrombopag and identify predictors associated with increase in platelet count. Eighty CLD patients with thrombocytopenia were enrolled. The primary endpoint was a satisfactory increase in platelets (greater than 1.0 × 104/μL from baseline) in the absence of platelet transfusion. The secondary endpoints were response rate (an increase of greater than 1.0 × 104/μL from baseline), independent predictors of increase in platelets, and the superiority of lusutrombopag over platelet transfusion. The primary endpoint was achieved in 93.8% (75 of 80) patients. The response rate was 96.2% (77 of 80). Renal function parameters (blood urea nitrogen, creatinine, eGFR) were significantly negatively associated with platelet count (p = 0.033, 0.049, and 0.0014, respectively) and were identified as independent predictors by multiple regression analysis (p = 0.049, 0.0023, and 0.0016, respectively). The median increase in platelet count was significantly higher after lusutrombopag than after platelet transfusion (41,000 vs. 12,000/μL, p = 0.015). Lusutrombopag was more effective than platelet transfusion for CLD patients, and renal function independently predicted increase in platelet count. Renal function parameters were significantly associated with platelet count.

Treatment Options for Thrombocytopenia in Patients With Chronic Liver Disease Undergoing a Scheduled Procedure.

Thrombocytopenia is a consequence of portal hypertension and is the most common hematological manifestation of chronic liver disease (CLD) (ie, cirrhosis). Data indicates the rates of CLD are increasing and, as a result, so will the incidence of this complication. Although bleeding risks are only relevant when elective procedures are performed, this is a frequent concern as these procedures are commonly part of the spectrum of care for patients with cirrhosis. As such, thrombocytopenia remains a pertinent issue. Fortunately, we now have effective and accurate treatment modalities to raise platelet counts before scheduled procedures, known as thrombopoietin receptor agonists. Two drugs in this therapeutic class (avatrombopag and lusutrombopag) are now approved for the treatment of thrombocytopenia in adults with CLD undergoing a procedure and have revolutionized how this is managed. Although there is progress in the field, peer-reviewed literature and expert guidance are lacking. Recognizing these unmet needs, a group of expert hepatologists comprised this review, which summarizes the most current and relevant peer-reviewed literature on thrombocytopenia in CLD and provides clinical expertise on this timely topic.

Avatrombopag for the treatment of immune thrombocytopenia and thrombocytopenia of chronic liver disease.

Avatrombopag is an orally-administered small molecule thrombopoietin receptor agonist. It was the third thrombopoietin receptor agonist approved for the treatment of immune thrombocytopenia and the first approved to treat periprocedural thrombocytopenia in patients with chronic liver disease (thereby providing an alternative to blood transfusions for these patients). Unlike eltrombopag, avatrombopag does not require a 4 hr food-restricted window around its use and it has not been associated with hepatotoxicity in ITP patients or portal vein thrombosis in patients with chronic liver disease. In ITP patients it can often be dosed less frequently than once daily. It is overall well-tolerated with a side-effect profile similar to placebo in randomized clinical trials. This article will review the clinical development, efficacy, safety, and pharmacology of avatrombopag for use in patients with ITP and thrombocytopenia of chronic liver disease.

Procedural Risk of Bleeding: Does the Management of Thrombocytopenia in Chronic Liver Disease Patients Make a Difference? A Debate

Prof Nezam Afdhal provided a background to thrombocytopenia (TCP) in chronic liver disease (CLD). He explored the causes of TCP and discussed what are considered acceptable platelet levels. He described the delicate balance between thrombosis risk and bleeding risk that puts CLD patients with TCP at risk of complications, particularly when they require invasive procedures. Through a series of case studies, the faculty highlighted current management dilemmas and novel approaches to TCP management. Prof Edoardo Giannini presented the case of a patient with hepatocellular carcinoma (HCC) (platelet count of &lt;50×109/L) who was given a platelet transfusion prior to radiofrequency thermal ablation (RFTA). The patient’s increase in platelet count was not clinically significant; therefore, the procedure was cancelled. Prof Giannini noted that radiology guidelines state that for procedures with a moderate risk of bleeding (such as RFTA), platelet transfusion is recommended for counts &lt;50×109/L. Prof Mark Thursz presented a case of a nonalcoholic steatohepatitis and refractory ascites, in which the patient had a number of large-volume paracentesis procedures. He then presented paracentesis studies highlighting that bleeding events are often unrelated to patients’ platelet levels. Prof Giannini described a study in patients with acute-on-chronic liver failure (AoCLF) who underwent paracentesis and in whom the bleeding rate was 3%. Following these case presentations, Prof Markus Peck-Radosavljevic discussed the role of thrombopoietin (TPO) in TCP in CLD. He then examined the pivotal trials of various TPO-receptor (TPO-R) agonists which have been studied in CLD patients with TCP undergoing invasive procedures. Clinical studies of the TPO-R agonist lusutrombopag included a large proportion of high-risk bleeding patients and therapy with this agent has been shown to elevate platelet count levels for up to 2 weeks, allowing a window in which to schedule invasive procedures.

Platelets Accumulation In The Liver : A novel Mechanism Of Thrombocytopenia In Chronic Hepatic C Patients

Background and aim: Thrombocytopenia is a common complication of chronicliver diseases and is due to various causes.The effect of thrombocytopenia on liver damage and the exact mechanisms that lead to thrombocytopenia in chronic liver disease and cirrhosis are still unclear. As Platelets Derived Growth Factor s (PDGF-s) is released from platelets (PLTs) upon activation. We tried to identify PLTs and PDGFR- s in the liver to shed some light on the pathophysiology of thrombocytopenia and liver fibrosis in chronic hepatic C patients. Patients and Methods: Analytical cross-sectional study was conducted on fiftypatients with proven chronic hepatitis C. All patients were referred to Tropical Medicine and Gastroenterology Department, Sohag University Hospital. Patients were categorized into two groups. Group 1 includes patients with PLT count less than 150000/µL (thrombocytopenia). Group 2 includes patients with normal PLT count (150000-450000/µL). All patients were subjected to full history taking, complete clinical examination, complete blood count, liver function tests. Liver biopsy was obtained for histological staging and grading. Immunohistochemical study of PLTs and PDGFR- s were done using monoclonal antibodies against PLT's surface marker CD41 and PDGFR- s. Results: The included patients were 80 % males and 20 % females. Their mean agewas 44.42± 11.17 years. The mean average weighted score (AWS) of Imunohisto-chemical expression of CD41was significantly higher in thrombocytopenic group compared to normal PLTs group (5.8±2.86 vs 3.43±3.03; P<0.001). There was a significant negative correlation between CD41 expression and peripheral PLT count (r=-0.4; P=0.007). PDGFR- s expression was significantly stronger in thrombocytopenic patients than patients with normal PLT count (6.9±3.6 vs 5.27±3.92; P=0.001). It showed also a significant negative correlation with peripheral PLT count (r=-0.34, P=0.045). Both CD41 and PDGFR- s expression were significantly elevated in patients with advanced stage of fibrosis than in those with earlier stages (7.26±5.23 vs 5.88±3.24; P=0.04 &9.2±2.7 vs 6.7±3.6; P Conclusion: The accumulation of PLTs in the liver in patients with chronic hepatitisC may be involved in thrombocytopenia and liver fibrosis.

Development of a new knock-in mouse model and evaluation of pharmacological activities of lusutrombopag, a novel, nonpeptidyl small-molecule agonist of the human thrombopoietin receptor c-Mpl

Lusutrombopag (S-888711), an oral small-molecule thrombopoietin receptor (TPOR) agonist, has gained first approval as a drug to treat thrombocytopenia of chronic liver disease in patients undergoing elective invasive procedures in Japan. Preclinical studies were performed to evaluate its efficacy against megakaryopoiesis and thrombopoiesis. To investigate the proliferative activity and efficacy of megakaryocytic colony formation via human TPOR, lusutrombopag was applied to cultured human c-Mpl-expressing Ba/F3 (Ba/F3-hMpl) cells and human bone marrow-derived CD34-positive cells, respectively. Lusutrombopag caused a robust increase in Ba/F3-hMpl cells by activating pathways in a manner similar to that of thrombopoietin and induced colony-forming units-megakaryocyte and polyploid megakaryocytes in human CD34-positive cells. Because lusutrombopag has high species specificity for human TPOR, there was no suitable experimental animal model for drug evaluation, except for immunodeficient mouse-based xenograft models. Therefore, a novel genetically modified knock-in mouse, TPOR-Ki/Shi, was developed by replacing mouse Mpl with human-mouse chimera Mpl. In TPOR-Ki/Shi mice, lusutrombopag significantly increased circulating platelets in a dose-dependent manner during 21-day repeated oral administration. Histopathological study of the TPOR-Ki/Shi mice on day 22 also revealed a significant increase in megakaryocytes in the bone marrow. These results indicate that lusutrombopag acts on human TPOR to upregulate differentiation and proliferation of megakaryocytic cells, leading to platelet production.

The pathophysiology of thrombocytopenia in chronic liver disease.

Thrombocytopenia is the most common hematological abnormality encountered in patients with chronic liver disease (CLD). In addition to being an indicator of advanced disease and poor prognosis, it frequently prevents crucial interventions. Historically, thrombocytopenia has been attributed to hypersplenism, which is the increased pooling of platelets in a spleen enlarged by congestive splenomegaly secondary to portal hypertension. Over the past decade, however, there have been significant advances in the understanding of thrombopoiesis, which, in turn, has led to an improved understanding of thrombocytopenia in cirrhosis. Multiple factors contribute to the development of thrombocytopenia and these can broadly be divided into those that cause decreased production, splenic sequestration, and increased destruction. Depressed thrombopoietin levels in CLD, together with direct bone marrow suppression, result in a reduced rate of platelet production. Thrombopoietin regulates both platelet production and maturation and is impaired in CLD. Bone marrow suppression can be caused by viruses, alcohol, iron overload, and medications. Splenic sequestration results from hypersplenism. The increased rate of platelet destruction in cirrhosis also occurs through a number of pathways: increased shear stress, increased fibrinolysis, bacterial translocation, and infection result in an increased rate of platelet aggregation, while autoimmune disease and raised titers of antiplatelet immunoglobulin result in the immunologic destruction of platelets. An in-depth understanding of the complex pathophysiology of the thrombocytopenia of CLD is crucial when considering treatment strategies. This review outlines the recent advances in our understanding of thrombocytopenia in cirrhosis and CLD.

Platelet satellitism: a spurious cause of thrombocytopenia in chronic liver disease

Platelet satellitism: a spurious cause of thrombocytopenia in chronic liver disease

Thrombocytopenia and Bleeding in Veterans with Non-hepatitis C-related Chronic Liver Disease

Thrombocytopenia in chronic liver disease (CLD) typically reflects disease severity and may indicate an increased risk for bleeding. To describe the longitudinal course of thrombocytopenia and risks for bleeding in veteran patients with non-hepatitis C-related CLD. We identified 2,349 patients with non-hepatitis C-related CLD from databases of the New England Veterans Healthcare System between 1999 and 2008. The cohort was stratified by baseline platelet counts of <50,000, 50-100,000, > 100,000-150,000, and >150,000/μl. Primary outcomes were the incidence and hazard rates for bleeding episodes requiring hospitalization and incident severe thrombocytopenia (<50,000/μl). Over a median follow-up of 3.3 years (IQR 1.2, 6.3), incident major bleeds, predominantly gastrointestinal, occurred in 254 patients (10.8 % of the cohort) and in 19.9 % of those with baseline platelets <50,000/μl. Incident severe thrombocytopenia occurred in 315 patients (13.4 % of cohort) and in 40.7 % of those with baseline platelet counts between 50,000 and 100,000/μl. Baseline platelet counts between 50,000 and 100,000/μl independently predicted bleeding [adjusted HR 2.89 (1.76, 4.73) p < 0.001] as did esophageal varices, hemoglobin ≤ 9.9 g %, and INR 1.4-2.0. Incident severe thrombocytopenia and minimum platelet counts <25,000/μl each associated with bleeding episodes, but the average of minimum platelet counts recorded for those who bled was 76,000/μl. Among veteran patients with non-hepatitis C-related CLD, baseline platelet counts of 50,000 to 100,000/μl increased subsequent risks for both incident severe thrombocytopenia and major bleeding events. Whereas associations between severe thrombocytopenia and bleeding most likely reflect CLD severity, liver-related coagulopathies, and co-morbid bleeding risks, interventions to enhance platelet production may be beneficial for such patients.

Reply to the letter by H. Mawatari et al. regarding “Thrombocytopenia is more severe in patients with advanced chronic hepatitis C than B with the same grade of liver stiffness and splenomegaly”

We thank Mawatari et al. for their interest in our article [1] and their presenting data regarding the platelet count in patients with hepatitis C virus-related chronic liver disease (CLD-C) and in those with nonalcoholic fatty liver disease (NAFLD) (please see Letter to the editor). The usefulness of transient elastography for the detection of liver fibrosis in NAFLD has been well established [2, 3], although the controversy still exits [4]. We had an impression in the clinical setting that thrombocytopenia might be less severe in patients with NAFLD than in those with CLD-C, and this point has been clearly determined in their study with adjustment for the degree of liver stiffness. Considering the mechanism of the decrease in the platelet count, we are interested in the splenomegaly in their patients with CLD-C and NAFLD. If the spleen size is not different in patients with the same degree of liver stiffness, the impaired platelet production rather than the enhanced platelet destruction may explain the distinct thrombocytopenia between CLD-C and NAFLD as well as hepatitis B virus-related chronic liver disease and CLD-C [1]. Nonetheless, it has become more likely that thrombocytopenia in chronic liver disease may vary according to its etiology. Thrombocytopenia is still a big problem in chronic liver disease, considering the interferon therapy for CLD-C or the treatment for hepatocellular carcinoma frequently arisen from chronic liver disease. Its mechanism should be further investigated.

In-Vitro Effect of the Small Molecule Thrombopoietin (TPO) Receptor Agonist Eltrombopag in Chronic Lymphocytic Leukemia (CLL).

Abstract 4408 BackgroundSevere thrombocytopenia resulting from packed marrow, splenomegaly, toxicity of therapy, or autoimmunity/idiopathic thrombocytopenic purpura (ITP) is frequent in CLL. Eltrombopag is a small molecule TPO receptor (TPO-R) agonist being developed as a treatment for thrombocytopenia. Eltrombopag is used and approved for the treatment of chronic ITP and is under investigation for thrombocytopenia of chronic liver disease. In order to provide the basis for the investigational clinical use of eltrombopag (with and without chemotherapy) in CLL, we have studied eltrombopag effects in vitro on primary CLL cells in order to provide evidence that eltrombopag does not stimulate CLL cells by untoward or off-target effects. MethodsWe analyzed cell number and apoptosis induction in a set of CLL patient samples (n=15) after 48h incubation with eltrombopag, thrombopoietin or fludarabine. CLL cases were characterized with respect to genetics (genomic aberrations, TP53 mutation, IGHV mutation status), as well as clinical course and immunophenotype. To study the effect on CLL cells, we used in vitro treatment with eltrombopag (0.1nM-30μM), thrombopoietin (0.3ng-30ng/ml) and Fludarabine (1-10μM). We assessed the effect using FACS (7-AAD) and CellTiterGlo for viability. We studied 8 CLL patients' cells with low risk disease and 7 with high risk disease (17p-, TP53 mutation or F-refractory CLL). ResultsIn spite of increasing concentrations up to 30μM we did not observe significant changes in cell number suggesting that there is no growth stimulation or apoptosis induction in primary CLL cells by eltrombopag in vitro. In contrast, Fludarabine caused a dose dependent decrease in cell viability (mean 60-80% (1, 10μM) viable cells at 48 hours). As shown in Fig. 1 the response to fludarabine but not to eltrombopag was dependent on the risk profile. Cases with F-refractory disease or 17p deletion did not respond to Fludarabine. The effect of eltrombopag on the CLL marker profile (CD5, 19, 20, 23, 38) and CD41/CD61 expression was also investigated, but no differences were observed. In order to more broadly explore the possibility of (untoward) effects of eltrombopag in CLL we are currently generating gene expression profiles on eltrombopag treated CLL cells to assess potential cellular responses and pathway activation. ConclusionOur results suggest that eltrombopag is unlikely to stimulate the growth of CLL cells. Our data therefore suggest that clinical trials investigating its effect on platelet counts in CLL are warranted. [Display omitted] Disclosures:Zenz:GSK: Membership on an entity's Board of Directors or advisory committees. Erickson-Miller:GSK: Employment. Mostafa Kamel:GSK: Employment. Stilgenbauer:GSK: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.