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Fierro-Angulo OM, González-Regueiro JA, Pereira-García A, Ruiz-Margáin A, Solis-Huerta F, Macías-Rodríguez RU. Hematological abnormalities in liver cirrhosis. World J Hepatol 2024; 16:1229-1244. [PMID: 39351511 PMCID: PMC11438588 DOI: 10.4254/wjh.v16.i9.1229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Revised: 08/09/2024] [Accepted: 08/22/2024] [Indexed: 09/23/2024] Open
Abstract
Hematological abnormalities are common in cirrhosis and are associated with various pathophysiological mechanisms. Studies have documented a prevalence of thrombocytopenia, leukopenia, and anemia in patients with compensated cirrhosis of 77.9%, 23.5%, and 21.1%, respectively. These abnormalities carry significant clinical implications, including considerations for invasive procedures, infection risk, bleeding risk, and prognosis. Previously, cirrhosis was believed to predispose patients to bleeding due to alterations observed in classical coagulation tests such as prothrombin time, partial thromboplastin time, international normalized ratio, and thrombocytopenia. However, this understanding has evolved, and cirrhosis patients are now also acknowledged as being at a high risk for thrombotic events. Hemostasis in cirrhosis patients presents a complex phenotype, with procoagulant and anticoagulant abnormalities offsetting each other. This multifactorial phenomenon is inadequately reflected by routine laboratory tests. Thrombotic complications are more prevalent in decompensated cirrhosis and may correlate with disease severity. Bleeding is primarily associated with portal hypertension, endothelial dysfunction, mechanical vessel injury, disseminated intravascular coagulation, endotoxemia, and renal injury. This review comprehensively outlines hematologic index abnormalities, mechanisms of hemostasis, coagulation, and fibrinolysis abnormalities, limitations of laboratory testing, and clinical manifestations of bleeding and thrombosis in patients with liver cirrhosis.
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Affiliation(s)
- Oscar Manuel Fierro-Angulo
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico 14080, Mexico
| | - José Alberto González-Regueiro
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico 14080, Mexico
| | - Ariana Pereira-García
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico 14080, Mexico
| | - Astrid Ruiz-Margáin
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico 14080, Mexico
| | - Fernando Solis-Huerta
- Department of Hematology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico 14080, Mexico
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2
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Maevskaya MV, Nadinskaia MY, Bessonova EN, Geyvandova NI, Zharkova MS, Kitsenko EA, Korochanskaya NV, Kurkina IA, Melikyan AL, Morozov VG, Khoronko YV, Deeva TA, Gulyaeva KA, Ivashkin VT. Correction of Thrombocytopenia before Elective Surgery / Invasive Procedures in Patients with Liver Cirrhosis (Experts’ Agreement). RUSSIAN JOURNAL OF GASTROENTEROLOGY, HEPATOLOGY, COLOPROCTOLOGY 2024; 34:115-134. [DOI: 10.22416/1382-4376-2024-1032-2784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Introduction. As a result of portal hypertension (sequestration of platelets in an enlarged spleen) and liver failure (decreased production of thrombopoietin in the liver) in liver cirrhosis, thrombocytopenia develops, which is associated with the risk of periprocedural/perioperative bleeding complications. There are still unresolved questions regarding risk stratification of bleeding complications, the prognostic role of thrombocytopenia, as well as the need for treatment of thrombocytopenia and its methods.Materials and methods. The Russian Scientific Liver Society selected a panel of experts in the field of therapeutic and surgical hepatology, hematology, transfusion medicine to make reasoned statements and recommendations on the issue of treatment of thrombocytopenia before elective surgery / invasive procedures in patients with liver cirrhosis.Results. Relevant clinical issues were determined based on the PICO principle (patient or population, intervention, comparison, outcome). The Delphi panel made five questions and gave reasoned answers, framed as ‘clinical practice recommendations and statements’ with evidence-based comments. The questions and statements were based on the results of search and critical analysis of medical literature using keywords in English- and Russian-language databases. The formulated questions could be combined into four categories: bleeding risk stratification, the prognostic value of thrombocytopenia, the necessity and methods of thrombocytopenia drug correction, and bleeding risk reduction.Conclusions. The results of experts' work are directly related to high-quality management of patients with liver cirrhosis and thrombocytopenia, who have scheduled invasive procedures/surgery. Thus, this recommendations and statements can be used in clinical practice.
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Affiliation(s)
- M. V. Maevskaya
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - M. Yu. Nadinskaia
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - E. N. Bessonova
- Ural State Medical University; Sverdlovsk Regional Clinical Hospital No. 1
| | - N. I. Geyvandova
- Stavropol State Medical University; Stavropol Regional Clinical Hospital
| | - M. S. Zharkova
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - E. A. Kitsenko
- Russian Scientific Center of Surgery named after Academician B.V. Petrovsky
| | | | - I. A. Kurkina
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | | | | | | | - T. A. Deeva
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - K. A. Gulyaeva
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - V. T. Ivashkin
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
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Rasizadeh R, Ebrahimi F, Zamani Kermanshahi A, Daei Sorkhabi A, Sarkesh A, Sadri Nahand J, Bannazadeh Baghi H. Viruses and thrombocytopenia. Heliyon 2024; 10:e27844. [PMID: 38524607 PMCID: PMC10957440 DOI: 10.1016/j.heliyon.2024.e27844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 02/03/2024] [Accepted: 03/07/2024] [Indexed: 03/26/2024] Open
Abstract
Thrombocytopenia, characterized by a decrease in platelet count, is a multifaceted clinical manifestation that can arise from various underlying causes. This review delves into the intriguing nexus between viruses and thrombocytopenia, shedding light on intricate pathophysiological mechanisms and highlighting the pivotal role of platelets in viral infections. The review further navigates the landscape of thrombocytopenia in relation to specific viruses, and sheds light on the diverse mechanisms through which hepatitis C virus (HCV), measles virus, parvovirus B19, and other viral agents contribute to platelet depletion. As we gain deeper insights into these interactions, we move closer to elucidating potential therapeutic avenues and preventive strategies for managing thrombocytopenia in the context of viral infections.
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Affiliation(s)
- Reyhaneh Rasizadeh
- Immunology Research Centre, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Virology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Fatemeh Ebrahimi
- Department of Virology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Amin Daei Sorkhabi
- Immunology Research Centre, Tabriz University of Medical Sciences, Tabriz, Iran
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Aila Sarkesh
- Immunology Research Centre, Tabriz University of Medical Sciences, Tabriz, Iran
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Javid Sadri Nahand
- Department of Virology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hossein Bannazadeh Baghi
- Immunology Research Centre, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Virology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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Calleja-Panero JL, Esteban Mur R, Jarque I, Romero-Gómez M, Group SR, García Labrador L, González Calvo J. Chronic liver disease-associated severe thrombocytopenia in Spain: Results from a retrospective study using machine learning and natural language processing. GASTROENTEROLOGIA Y HEPATOLOGIA 2024; 47:236-245. [PMID: 37236305 DOI: 10.1016/j.gastrohep.2023.05.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 05/02/2023] [Accepted: 05/19/2023] [Indexed: 05/28/2023]
Abstract
BACKGROUND Patients with chronic liver disease (CLD) often develop thrombocytopenia (TCP) as a complication. Severe TCP (platelet count<50×109/L) can increase morbidity and complicate CLD management, increasing bleeding risk during invasive procedures. OBJECTIVES To describe the real-world scenario of CLD-associated severe TCP patients' clinical characteristics. To evaluate the association between invasive procedures, prophylactic treatments, and bleeding events in this group of patients. To describe their need of medical resource use in Spain. METHODS This is a retrospective, multicenter study including patients who had confirmed diagnosis of CLD and severe TCP in four hospitals within the Spanish National Healthcare Network from January 2014 to December 2018. We analyzed the free-text information from Electronic Health Records (EHRs) of patients using Natural Language Processing (NLP), machine learning techniques, and SNOMED-CT terminology. Demographics, comorbidities, analytical parameters and characteristics of CLD were extracted at baseline and need for invasive procedures, prophylactic treatments, bleeding events and medical resources used in the follow up period. Frequency tables were generated for categorical variables, whereas continuous variables were described in summary tables as mean (SD) and median (Q1-Q3). RESULTS Out of 1,765,675 patients, 1787 had CLD and severe TCP; 65.2% were male with a mean age of 54.7 years old. Cirrhosis was detected in 46% (n=820) of patients and 9.1% (n=163) had hepatocellular carcinoma. Invasive procedures were needed in 85.6% of patients during the follow up period. Patients undergoing procedures compared to those patients without invasive procedures presented higher rates of bleeding events (33% vs 8%, p<0.0001) and higher number of bleedings. While prophylactic platelet transfusions were given to 25.6% of patients undergoing procedures, TPO receptor agonist use was only detected in 3.1% of them. Most patients (60.9%) required at least one hospital admission during the follow up and 14.4% of admissions were due to bleeding events with a hospital length of stay of 6 (3, 9) days. CONCLUSIONS NLP and machine learning are useful tools to describe real-world data in patients with CLD and severe TCP in Spain. Bleeding events are frequent in those patients who need invasive procedures, even receiving platelet transfusions as a prophylactic treatment, increasing the further use of medical resources. Because that, new prophylactic treatments that are not yet generalized, are needed.
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Affiliation(s)
| | - Rafael Esteban Mur
- Department of Hepatology, Hospital Universitario Vall d'Hebron, Barcelona, Spain
| | - Isidro Jarque
- Department of Hematology, Hospital Universitari i Politècnic La Fe, Valencia, Spain
| | - Manuel Romero-Gómez
- Department of Hepatology, Hospital Universitario Virgen del Rocío, Sevilla, Spain
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Suwała S, Białczyk A, Koperska K, Rajewska A, Krintus M, Junik R. Prevalence and Crucial Parameters in Diabesity-Related Liver Fibrosis: A Preliminary Study. J Clin Med 2023; 12:7760. [PMID: 38137829 PMCID: PMC10744287 DOI: 10.3390/jcm12247760] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 11/28/2023] [Accepted: 12/16/2023] [Indexed: 12/24/2023] Open
Abstract
Diabetes and obesity have been recognized as confirmed risk factors for the occurrence of liver fibrosis. Despite the long-standing acknowledgment of "diabesity", the simultaneous existence of diabetes and obesity, scholarly literature has shown limited attention to this topic. The aim of this pilot study was to assess the prevalence of liver fibrosis among individuals with diabetes (specifically those who are obese) in order to identify the key factors associated with hepatofibrosis and determine the most important associations and differences between patients with and without liver fibrosis. The research included a total of 164 participants (48.17% had comorbid obesity). Liver elastography (Fibroscan) was performed on these individuals in addition to laboratory tests. Liver fibrosis was found in 34.76% of type 2 diabetes patients; male gender almost doubled the risk of hepatofibrosis (RR 1.81) and diabesity nearly tripled this risk (RR 2.81; however, in degree III of obesity, the risk was elevated to 3.65 times higher). Anisocytosis, thrombocytopenia, or elevated liver enzymes raised the incidence of liver fibrosis by 1.78 to 2.47 times. In these individuals, liver stiffness was negatively correlated with MCV, platelet count, and albumin concentration; GGTP activity and HbA1c percentage were positively correlated. The regression analysis results suggest that the concentration of albumin and the activity of GGTP are likely to have a substantial influence on the future management of liver fibrosis in patients with diabesity. The findings of this study can serve as the basis for subsequent investigations and actions focused on identifying potential therapeutic and diagnostic avenues.
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Affiliation(s)
- Szymon Suwała
- Department of Endocrinology and Diabetology, Nicolaus Copernicus University, Collegium Medicum, 9 Sklodowskiej-Curie Street, 85-094 Bydgoszcz, Poland;
| | - Aleksandra Białczyk
- Evidence-Based Medicine Students Scientific Club of Department of Endocrinology and Diabetology, Nicolaus Copernicus University, Collegium Medicum, 9 Sklodowskiej-Curie Street, 85-094 Bydgoszcz, Poland; (A.B.); (K.K.); (A.R.)
| | - Kinga Koperska
- Evidence-Based Medicine Students Scientific Club of Department of Endocrinology and Diabetology, Nicolaus Copernicus University, Collegium Medicum, 9 Sklodowskiej-Curie Street, 85-094 Bydgoszcz, Poland; (A.B.); (K.K.); (A.R.)
| | - Alicja Rajewska
- Evidence-Based Medicine Students Scientific Club of Department of Endocrinology and Diabetology, Nicolaus Copernicus University, Collegium Medicum, 9 Sklodowskiej-Curie Street, 85-094 Bydgoszcz, Poland; (A.B.); (K.K.); (A.R.)
| | - Magdalena Krintus
- Department of Laboratory Medicine, Nicolaus Copernicus University, Collegium Medicum, 9 Sklodowskiej-Curie Street, 85-094 Bydgoszcz, Poland;
| | - Roman Junik
- Department of Endocrinology and Diabetology, Nicolaus Copernicus University, Collegium Medicum, 9 Sklodowskiej-Curie Street, 85-094 Bydgoszcz, Poland;
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Sohail R, Hassan IH, Rukh M, Saqib M, Iftikhar M, Mumtaz H. Assessing Thrombocytopenia and Chronic Liver Disease in Southeast Asia: A Multicentric Cross-Sectional Study. Cureus 2023; 15:e43356. [PMID: 37700968 PMCID: PMC10493634 DOI: 10.7759/cureus.43356] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/10/2023] [Indexed: 09/14/2023] Open
Abstract
Background This multicentric cross-sectional study aimed to examine the prevalence of thrombocytopenia (TCP) and investigate the various causes of chronic liver disease (CLD) across 15 Southeast Asian (India, Pakistan, and Bangladesh) tertiary care centers over a three-month period. The study focused on assessing the fibrosis index (FI) and Model for End-Stage Liver Disease (MELD)-sodium (Na) score's capacity to grade and predict the progression and outcomes of patients with already diagnosed CLD. Methods The cross-sectional study enrolled 377 CLD patients. The study utilized admission registries from 15 tertiary care hospitals in Southeast Asia, spanning from April 2023 to June 2023. Various descriptive variables were collected, including gender, tobacco use (specifically, chewed tobacco), underlying etiology, presence of anemia, leukopenia, pancytopenia, infectious state, and liver cirrhosis diagnosed via traditional ultrasonography. This study examined liver failure indicators, including alanine transaminase levels, compensation status, TCP, and liver transplant (LT) listing. The MELD-Na score was the focus of frequency and percentage analysis. MELD-Na and FI medians and standard deviations were provided. Results The study of 377 patients with CLD found that TCP was present in 4% of patients and leukopenia was present in 12% of patients. The risk of TCP was significantly higher in leukopenic patients (89.5%) than in non-leukopenic patients (52.5%) (p = 0.003). The most common CLD cause was undiagnosable (31%), followed by autoimmune (26%), hepatitis C virus (21%), hepatitis B virus (14%), and schistosomiasis (8%). The majority of patients (98%) had decompensated liver disease. Of the patients, 64% had TCP, while 36% did not. The illness severity indicators MELD score and FI had mean ± SD values of 16.89 ± 6.42 and 4.1 ± 1.06, respectively. Similarly, the prevalence of LT needs among traditional ultrasonography-diagnosed cirrhotic patients was 83.1%, compared to 59.6% among non-cirrhotic patients (p = 0.001). Conclusion Leukopenia and TCP may be linked, which may affect CLD treatment and prognosis in this population. Non-invasive indicators like the FI and MELD-Na score can detect liver fibrosis and severity without invasive procedures, enhancing patient management. These findings highlight the need to improve early diagnosis methods for CLD in Southeast Asia and raise awareness among clinicians about effective diagnostic strategies for non-infectious causes of CLD.
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Affiliation(s)
- Ramsha Sohail
- Department of Medicine, Jackson Park Hospital, Chicago, USA
| | - Imran H Hassan
- Department of Medicine, Grantham and District Hospital, Grantham, GBR
| | - Mah Rukh
- Department of Medicine, Khyber Teaching Hospital, Peshawar, PAK
| | - Muhammad Saqib
- Department of Medicine, Khyber Teaching Hospital, Peshawar, PAK
| | | | - Hassan Mumtaz
- Department of Urology, Guy's and St. Thomas' Hospital, London, GBR
- General Practice, Surrey Docks Health Centre, London, GBR
- Department of Public Health, Health Services Academy, Islamabad, PAK
- Department of Clinical Research, Maroof International Hospital, Islamabad, PAK
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Chen Y, Yang C, Huang S, Liu J, Wang Y, Zhou C, Li T, Wang C, Ju S, Bai Y, Yao W, Xiong B. The impact of thrombocytopenia on variceal bleeding in cirrhotic patients with transjugular intrahepatic portosystemic shunt. Sci Rep 2023; 13:1633. [PMID: 36717590 PMCID: PMC9886967 DOI: 10.1038/s41598-023-28646-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Accepted: 01/23/2023] [Indexed: 01/31/2023] Open
Abstract
Thrombocytopenia is the most frequent haematologic disorder in patients with cirrhosis, and it is perceived as a contributory factor for bleeding events. Cirrhosis patients with portal hypertension (PHT) is often accompanied with mild to moderate thrombocytopenia when they treated with transjugular intrahepatic portosystemic shunt (TIPS). To address whether the risk of variceal hemorrhage after TIPS varies with different platelet count in patients with normal platelet count and thrombocytopenia, we conducted the retrospective controlled study to evaluate the association of platelet count with the risk of variceal bleeding after TIPS. 304 patients were selected to the study. Propensity score matching was performed to adjust for potential selection bias. 63 patients from each group could be paired. Cox proportional hazards models were used to evaluate the association between platelet and variceal bleeding after TIPS. Platelet counts of two groups are 185.0 ± 98.7 × 109/L (normal platelet count) and 70.6 ± 39.3 × 109/L (thrombocytopenia) respectively. The bleeding rates of two groups in overall cohort are 10.9% (normal platelet count) and 12.9% (thrombocytopenia). After matched, the bleeding rates of two groups are 11.1% (normal platelet count) and 14.3% (thrombocytopenia) There was no statistically significant difference in bleeding rates between the two groups, either in the whole cohort (P = 0.671) or in the matched cohort (P = 0.593). Platelet count was not associated with bleeding events after TIPS (hazard ratio (HR) 95% confidence interval: 0.986-1.005, P = 0.397 in normal platelet count and 95% confidence interval: 0.968-1.020, P = 0.648 in thrombocytopenia). Thrombocytopenia in patients with cirrhosis was not associated with the risk of variceal bleeding episodes post-TIPS. Thrombocytopenia should not be viewed as an absolute contraindication for TIPS.
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Affiliation(s)
- Yang Chen
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1277 Jiefang Avenue, Wuhan, 430022, China.,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Chongtu Yang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1277 Jiefang Avenue, Wuhan, 430022, China.,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Songjiang Huang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1277 Jiefang Avenue, Wuhan, 430022, China.,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Jiacheng Liu
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1277 Jiefang Avenue, Wuhan, 430022, China.,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Yingliang Wang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1277 Jiefang Avenue, Wuhan, 430022, China.,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Chen Zhou
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1277 Jiefang Avenue, Wuhan, 430022, China.,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Tongqiang Li
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1277 Jiefang Avenue, Wuhan, 430022, China.,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Chaoyang Wang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1277 Jiefang Avenue, Wuhan, 430022, China.,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Shuguang Ju
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1277 Jiefang Avenue, Wuhan, 430022, China.,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Yaowei Bai
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1277 Jiefang Avenue, Wuhan, 430022, China.,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Wei Yao
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1277 Jiefang Avenue, Wuhan, 430022, China.,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Bin Xiong
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1277 Jiefang Avenue, Wuhan, 430022, China. .,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China.
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8
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Al-Dholae MHH, Salah MK, Al-Ashmali OY, Al Mokdad ASM, Al-Madwami MA. Thrombocytopenia (TCP), MELD Score, and Fibrosis Index (FI) Among Hospitalized Patients with Chronic Liver Disease (CLD) in Ma'abar City, Dhamar Governorate, Yemen: A Cross-Sectional Study. Hepat Med 2023; 15:43-50. [PMID: 37143507 PMCID: PMC10153436 DOI: 10.2147/hmer.s392011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Accepted: 04/24/2023] [Indexed: 05/06/2023] Open
Abstract
Purpose This study sought to assess the prevalence of thrombocytopenia (TCP), underlying aetiologies of chronic liver disease, and the grading and prognostic systems for chronic liver disease (CLD) using non-invasive biomarkers: the Fibrosis index and the Model for End-Stage Liver Disease-Na (MELD-Na) Score, respectively. Patients and Methods This was a 15-month multi-centric cross-sectional study of 105 patients with chronic liver disease (CLD). The study was conducted using Sept 2019 to Nov 2020 admission records of CLD patients from Ma'abar City in Dhamar Governorate, Yemen. Results A total of 63 (60%) and 42 (40%) patients were identified as thrombocytopenic and non-thrombocytopenic, respectively. The means ± SD of the MELD score and FI were 19 ± 7.302 and 4.1 ± 1.06. TCP prevalence among leukopenic and non-leukopenic patients was 89.5% and 53.5%, respectively (P = 0.004). Likewise, the prevalence of traditional-ultrasonography-diagnosed cirrhotic patients needing liver transplantation (LT) was 82.3% versus 61.3% among corresponding non-cirrhotic patients (P = 0.000). Conclusion The prevalence of TCP among the participants of this study was similar to the global rate. However, the prevalence of decompensation was much higher among CLD patients than that found elsewhere, highlighting a need to improve methods for the early diagnosis of CLD in Yemen. This study also identified problems with the diagnostic work-up for non-infectious aetiologies of CLD. The findings suggest the need to improve clinician awareness about effective diagnostic strategies for these aetiologies.
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Affiliation(s)
| | - Mohammed Kassim Salah
- Department of Internal Medicine, Faculty of Medicine & Health Sciences, Thamar University, Dhamar, Yemen
| | - Omar Yahya Al-Ashmali
- Department of Pediatrics, Al-Wahda Teaching Hospital, Thamar University, Ma’abar City, Dhamar Governorate, Yemen
- Correspondence: Omar Yahya Al-Ashmali, Department of Paediatrics, Al-Wahda Teaching Hospital, Thamar University, Ma’abar City, Dhamar Governorate, Yemen, Tel +967777638063, Email
| | | | - Mohammed Ali Al-Madwami
- Department of Internal Medicine, Faculty of Medicine & Health Sciences, Thamar University, Dhamar, Yemen
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Orme ME, Bentley R, Marcella S, Peck-Radosavljevic M, Perard R, Wedemeyer H, Yoshiji H, Agarwal K, Dusheiko G. Systematic Review with Meta-Analysis: Efficacy and Safety of Lusutrombopag for Severe Thrombocytopenia in Patients with Chronic Liver Disease Undergoing Invasive Procedures. Adv Ther 2022; 39:4169-4188. [PMID: 35836089 PMCID: PMC9402754 DOI: 10.1007/s12325-022-02235-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Accepted: 06/17/2022] [Indexed: 11/25/2022]
Abstract
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.
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Affiliation(s)
- Michelle E Orme
- ICERA Consulting Ltd., 17 Redbridge Close, Swindon, Wiltshire, UK.
| | | | | | - Markus Peck-Radosavljevic
- Abteilung Innere Medizin und Gastroenterologie (IMuG), mit Zentrale Aufnahme und Erstversorgung (ZAE), Klinikum Klagenfurt am Wörthersee, Klagenfurt, Austria
| | | | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Hitoshi Yoshiji
- Department of Gastroenterology, Nara Medical University, Kashihara, Nara Prefecture, Japan
| | - Kosh Agarwal
- Institute of Liver Studies, King's College Hospital, London, UK
| | - Geoffrey Dusheiko
- University College London Medical School and King's College Hospital, London, UK
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10
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Cui Y, Ji Y, Chen X, Li J, Feng J, Zhao Q, Yao P, Wu Q, Zhu D. Efficient enzymatic synthesis of (S)-1-(3′-bromo-2′-methoxyphenyl)ethanol, the key building block of lusutrombopag. GREEN SYNTHESIS AND CATALYSIS 2022. [DOI: 10.1016/j.gresc.2022.06.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022] Open
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11
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Feng R, Liu Y, Zhu XL, Zhai WY, He Y, Fu HX, Jiang Q, Jiang H, Lu J, Liu H, Wang JW, Wang H, Xie YD, Ma H, Huang XJ, Zhang XH. Recombinant human thrombopoietin increases platelet count in severe thrombocytopenic patients with hepatitis B-related cirrhosis: Multicentre real-world observational study. J Viral Hepat 2022; 29:306-316. [PMID: 35152507 DOI: 10.1111/jvh.13655] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Revised: 11/25/2021] [Accepted: 02/03/2022] [Indexed: 12/23/2022]
Abstract
Patients with hepatitis B-related cirrhosis complicated with thrombocytopenia have a higher risk of bleeding, which may lead to higher mortality. We aimed to explore the efficacy and safety of recombinant human thrombopoietin (rhTPO) in the treatment of hepatitis B-related cirrhosis complicated with severe thrombocytopenia. Patients with hepatitis B-related compensated liver cirrhosis complicated with severe thrombocytopenia were divided into four groups according to the treatment method for thrombocytopenia. Platelet counts, the appearance of bleeding symptoms and adverse events were evaluated during the observation period. Also during the observational period, the platelet counts in the prednisone group, rhTPO group and prednisone plus rhTPO group were higher than those in the no treatment group. Patients without splenomegaly reacted better to rhTPO. Fewer bleeding events of grade 2 or worse were observed in the three treatment groups compared to the no treatment group. The platelet counts at baseline and treatment with rhTPO and/or prednisone were factors associated with bleeding events of grade 2 or worse in multivariate analysis. There could be a potential advantage for the use of rhTPO plus prednisone based on higher platelet counts and fewer bleeding events. Treatment with rhTPO was more effective in patients without splenomegaly.
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Affiliation(s)
- Ru Feng
- Department of Hematology, National Center of Gerontology, Beijing Hospital, Beijing, China.,Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Yi Liu
- Department of Hematology, the Sixth Medical Center of PLA General Hospital, Beijing, China
| | - Xiao-Lu Zhu
- Institute of Hematology, Peking University People's Hospital, Beijing, China
| | - Wan-Yi Zhai
- Institute of Hematology, Peking University People's Hospital, Beijing, China
| | - Yun He
- Institute of Hematology, Peking University People's Hospital, Beijing, China
| | - Hai-Xia Fu
- Institute of Hematology, Peking University People's Hospital, Beijing, China
| | - Qian Jiang
- Institute of Hematology, Peking University People's Hospital, Beijing, China
| | - Hao Jiang
- Institute of Hematology, Peking University People's Hospital, Beijing, China
| | - Jin Lu
- Institute of Hematology, Peking University People's Hospital, Beijing, China
| | - Hui Liu
- Department of Hematology, National Center of Gerontology, Beijing Hospital, Beijing, China
| | - Jing-Wen Wang
- Department of Hematology, Beijing Tongren Hospital, Beijing, China
| | - Hao Wang
- Institute of Hepatic Diseases, Peking University People's Hospital, Beijing, China
| | - Yan-Di Xie
- Institute of Hepatic Diseases, Peking University People's Hospital, Beijing, China
| | - Hui Ma
- Institute of Hepatic Diseases, Peking University People's Hospital, Beijing, China
| | - Xiao-Jun Huang
- Institute of Hematology, Peking University People's Hospital, Beijing, China
| | - Xiao-Hui Zhang
- Institute of Hematology, Peking University People's Hospital, Beijing, China
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12
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Eguchi Y, Takahashi H, Mappa S, Santagostino E. Phase 2 study of avatrombopag in Japanese patients with chronic liver disease and thrombocytopenia. Hepatol Res 2022; 52:371-380. [PMID: 35134259 DOI: 10.1111/hepr.13755] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 01/07/2022] [Accepted: 01/15/2022] [Indexed: 12/13/2022]
Abstract
AIM Avatrombopag, a thrombopoietin receptor agonist, can reduce the need for platelet transfusions or rescue interventions for bleeding in patients with chronic liver disease (CLD) and thrombocytopenia undergoing scheduled procedures. A model analysis indicated that the effect of avatrombopag on platelet production was reduced in East Asian versus non-East Asian patients; however, the difference was deemed not clinically significant. Furthermore, a subgroup analysis of pooled Phase 3 trials showed similar avatrombopag efficacy across racial subgroups. The aim of this Phase 2 study was to corroborate the efficacy and safety of avatrombopag in Japanese patients with thrombocytopenia due to CLD. METHODS Japanese patients with CLD and thrombocytopenia were randomized to receive placebo or avatrombopag 20, 40, or 60 mg daily for 5 days. The primary endpoint was responder rate in platelet counts at Visit 4 (10-13 days after treatment initiation), defined as the proportion of patients with platelet count ≥50 × 109 /L and ≥20 × 109 /L increase from baseline. RESULTS Thirty-nine patients were randomized and completed the study (placebo, n = 11; avatrombopag 20 mg, n = 7; 40 mg, n = 11; 60 mg, n = 10). Avatrombopag treatment was associated with significant increases in responder rate at Visit 4 in the 40 mg (63.6%; p = 0.004) and 60 mg (40%; p = 0.024) groups versus placebo (9.1%). Avatrombopag was well tolerated and no new safety signals were detected. CONCLUSIONS Efficacy and safety results from this study were consistent with previous studies in patients with CLD and thrombocytopenia undergoing elective procedures, supporting treatment with avatrombopag in the Japanese population. CLINICALTRIALS gov identifier: NCT02227693.
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Affiliation(s)
| | - Hirokazu Takahashi
- Liver Center, Saga University Hospital, Faculty of Medicine, Saga University, Saga, Japan
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13
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Yoshida M, Tateishi R, Hiroi S, Fujiwara M, Kitanishi Y, Iwasaki K, Takeshima T, Igarashi A. Changes in Platelet Counts and Thrombocytopenia Risk in Patients with Chronic Liver Disease with Different Etiologies Using Real-World Japanese Data. Adv Ther 2022; 39:992-1003. [PMID: 34928469 PMCID: PMC8866341 DOI: 10.1007/s12325-021-02008-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Accepted: 11/29/2021] [Indexed: 01/01/2023]
Abstract
INTRODUCTION Thrombocytopenia, a common complication of chronic liver disease (CLD), adversely affects the treatment in patients requiring invasive procedures. Multiple pathophysiological mechanisms contribute to the development of thrombocytopenia; thus, its incidence could differ among CLD etiologies. We investigated the risk of decline in platelet counts and developing thrombocytopenia across different CLDs in a real-world Japanese setting. METHODS A Japanese claims database including 25 million patients (April 2008-August 2018) was used. Patients with at least one CLD diagnosis were classified into nine mutually exclusive categories: hepatitis B, hepatitis C, hepatitis B and C, unspecified viral hepatitis, autoimmune hepatitis, toxin/drug-induced hepatitis, alcoholic hepatitis, nonalcoholic steatohepatitis, and others. A random effects model was used to estimate the changes in platelet counts; proportional hazard analyses were used to examine factors associated with the incidence of thrombocytopenia based on the diagnosis. Patients with laboratory test data as variables were included in each analysis. RESULTS The simulation included 68,536 patients. The mean values representing changes in the platelet count were significantly negative in the hepatitis C patients and negative, though non-significant, in the hepatitis B, toxin/drug-induced hepatitis, alcoholic hepatitis, and nonalcoholic steatohepatitis patients. In the proportional hazard analysis, 708 of 22,728 patients had thrombocytopenia. The hazard ratio (HR) was significantly high for patients with hepatitis B (HR, 2.879; p < 0.001), hepatitis C (HR, 1.876; p < 0.001), and hepatitis B and C (HR, 2.992; p < 0.001). CONCLUSION A decreasing tendency in platelet counts was observed in most CLD etiologies, with hepatitis C showing a significant decrease. The incidence of thrombocytopenia was mostly associated with hepatitis B and/or C. Further research is warranted to elucidate the discrepancy between the decline in platelet counts and thrombocytopenia diagnosis, considering the factors relevant to the diagnosis, such as the frequency of outpatient visits and CLD treatment.
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Affiliation(s)
- Manami Yoshida
- Medical Affairs, Shionogi & Co., Ltd., 7F, Tekko Building, 1-8-2, Marunouchi, Chiyoda-ku, Tokyo, 100-0005, Japan.
- Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
| | - Ryosuke Tateishi
- Department of Gastroenterology, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Shinzo Hiroi
- Medical Affairs, Shionogi & Co., Ltd., 7F, Tekko Building, 1-8-2, Marunouchi, Chiyoda-ku, Tokyo, 100-0005, Japan
| | - Masakazu Fujiwara
- Data Science Department, Shionogi & Co., Ltd., 3-1-8, Doshomachi, Chuo-ku, Osaka, 541-0045, Japan
| | - Yoshitake Kitanishi
- Data Science Department, Shionogi & Co., Ltd., 3-1-8, Doshomachi, Chuo-ku, Osaka, 541-0045, Japan
| | - Kosuke Iwasaki
- Milliman, Inc., 8F, Kojimachi 1-chome Building, 1-6-2 Kojimachi, Chiyoda-ku, Tokyo, 102-0083, Japan
| | - Tomomi Takeshima
- Milliman, Inc., 8F, Kojimachi 1-chome Building, 1-6-2 Kojimachi, Chiyoda-ku, Tokyo, 102-0083, Japan
| | - Ataru Igarashi
- Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
- Unit of Public Health and Preventive Medicine, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan
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The Effect of TGF-β1 Reduced Functionality on the Expression of Selected Synaptic Proteins and Electrophysiological Parameters: Implications of Changes Observed in Acute Hepatic Encephalopathy. Int J Mol Sci 2022; 23:ijms23031081. [PMID: 35163004 PMCID: PMC8835518 DOI: 10.3390/ijms23031081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 01/11/2022] [Accepted: 01/14/2022] [Indexed: 12/10/2022] Open
Abstract
Decreased platelet count represents a feature of acute liver failure (ALF) pathogenesis. Platelets are the reservoir of transforming growth factor 1 (TGF-β1), a multipotent cytokine involved in the maintenance of, i.a., central nervous system homeostasis. Here, we analyzed the effect of a decrease in TGF-β1 active form on synaptic proteins levels, and brain electrophysiology, in mice after intraperitoneal (ip) administration of TGF-β1 antibody (anti-TGF-β1; 1 mg/mL). Next, we correlated it with a thrombocytopenia-induced TGF-β1 decrease, documented in an azoxymethane-induced (AOM; 100 mM ip) model of ALF, and clarified the impact of TGF-β1 decrease on blood–brain barrier functionality. The increase of both synaptophysin and synaptotagmin in the cytosolic fraction, and its reduction in a membrane fraction, were confirmed in the AOM mice brains. Both proteins’ decrease in analyzed fractions occurred in anti-TGF-β1 mice. In turn, an increase in postsynaptic (NR1 subunit of N-methyl-D-aspartate receptor, postsynaptic density protein 95, gephyrin) proteins in the AOM brain cortex, but a selective compensatory increase of NR1 subunit in anti-TGF-β mice, was observed. The alterations of synaptic proteins levels were not translated on electrophysiological parameters in the anti-TGF-β1 model. The results suggest the impairment of synaptic vesicles docking to the postsynaptic membrane in the AOM model. Nevertheless, changes in synaptic protein level in the anti-TGF-β1 mice do not affect neurotransmission and may not contribute to neurologic deficits in AOM mice.
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15
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Nguyen G, Lejeune M, Crichi B, Frere C. Hemostasis testing in patients with liver dysfunction: Advantages and caveats. World J Gastroenterol 2021; 27:7285-7298. [PMID: 34876789 PMCID: PMC8611202 DOI: 10.3748/wjg.v27.i42.7285] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 05/08/2021] [Accepted: 10/20/2021] [Indexed: 02/06/2023] Open
Abstract
Due to concomitant changes in pro- and anti-coagulant mechanisms, patients with liver dysfunction have a “rebalanced hemostasis”, which can easily be tipped toward either a hypo- or a hypercoagulable phenotype. Clinicians are often faced with the question whether patients with chronic liver disease undergoing invasive procedures or surgery and those having active bleeding require correction of the hemostasis abnormalities. Conventional coagulation screening tests, such as the prothrombin time/international normalized ratio and the activated partial thromboplastin time have been demonstrated to have numerous limitations in these patients and do not predict the risk of bleeding prior to high-risk procedures. The introduction of global coagulation assays, such as viscoelastic testing (VET), has been an important step forward in the assessment of the overall hemostasis profile. A growing body of evidence now suggests that the use of VET might be of significant clinical utility to prevent unnecessary infusion of blood products and to improve outcomes in numerous settings. The present review discusses the advantages and caveats of both conventional and global coagulation assays to assess the risk of bleeding in patients with chronic liver disease as well as the current role of transfusion and hemostatic agents to prevent or manage bleeding.
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Affiliation(s)
- Guillaume Nguyen
- Department of Hematology, Trousseau Hospital, Assistance Publique Hôpitaux de Paris, Paris 75012, France
| | - Manon Lejeune
- Department of Hematology, Pitié-Salpêtrière Hospital, Assistance Publique Hôpitaux de Paris, Paris 75013, France
| | - Benjamin Crichi
- Department of Internal Medicine, Saint-Louis Hospital, Assistance Publique Hôpitaux de Paris, Paris 75010, France
| | - Corinne Frere
- Department of Hematology, Pitié-Salpêtrière Hospital, Assistance Publique Hôpitaux de Paris, Paris 75013, France
- Inserm UMRS_1166, Institute of Cardiometabolism and Nutrition, Sorbonne Université, Paris 75013, France
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16
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Abstract
Avatrombopag (Doptelet®) is an orally administered second generation thrombopoietin receptor agonist (TPO-RA) approved for the treatment of primary chronic immune thrombocytopenia (ITP) in adult patients who are refractory or have an unsatisfactory response to other treatments, as well as for the treatment of thrombocytopenia in adult patients with chronic liver disease (CLD) scheduled to undergo an invasive procedure. In phase III studies, avatrombopag was associated with a significantly greater platelet response than placebo in patients with chronic ITP, and was superior to placebo in reducing the requirement for platelet transfusion or rescue procedures for bleeding caused by surgery in patients with CLD with a platelet count < 50 × 109/L at baseline. Longer term data indicate that avatrombopag is associated with high durable response rates in ITP and may have corticosteroid-sparing effects. The drug was generally well tolerated in both indications. Avatrombopag thus represents a convenient and effective second-line treatment for patients with chronic ITP and can prevent bleeding events in patients with CLD scheduled to undergo a procedure, offering a useful alternative to other available treatments in both indications. Avatrombopag (Doptelet®) is an orally administered drug that mimics the natural compound (thrombopoietin) responsible for stimulating the production of platelets, an essential component of the clotting process that prevents excessive bleeding. Several conditions can cause reduced platelet levels (thrombocytopenia) to the point that intervention is needed to prevent excessive blood loss. Avatrombopag is approved for the treatment of primary chronic immune thrombocytopenia (ITP) and to prevent bleeding caused by surgery in patients with low platelet levels caused by chronic liver disease (CLD). Clinical trials in patients with ITP show that avatrombopag quickly increases platelet levels and that this increase is maintained in the longer term in many patients. Similarly, clinical trials in patients with low platelet levels because of CLD showed that giving avatrombopag prior to surgery reduced the need for platelet transfusions or rescue procedures for bleeding. Avatrombopag is thus a convenient and effective treatment for patients with chronic ITP and can prevent bleeding events in patients with CLD scheduled to undergo a procedure. In both indications avatrombopag offers a useful alternative to other available treatments.
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Affiliation(s)
- Anthony Markham
- Springer Nature, Private Bag 65901, Mairangi Bay, Auckland, 0754, New Zealand.
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17
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Sano Y, Morimoto M, Kobayashi S, Ueno M, Fukushima T, Asama H, Kawano K, Nagashima S, Tanaka S, Ohkawa S, Maeda S. Repeated Lusutrombopag Treatment for Thrombocytopenia in Patients with Chronic Liver Disease. Digestion 2021; 102:654-662. [PMID: 32841939 DOI: 10.1159/000509852] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Accepted: 06/28/2020] [Indexed: 02/04/2023]
Abstract
BACKGROUND/AIMS Lusutrombopag, a small-molecule thrombopoietin receptor agonist, is used to treat thrombocytopenia based on the results of a phase 3 trial, including data for single-use administration in patients with chronic liver disease (CLD) undergoing invasive procedures. We aimed to evaluate the efficacy and safety of repeated lusutrombopag use. METHODS Lusutrombopag was administered repeatedly in patients undergoing multi-cycle invasive procedures at intervals >1 month. RESULTS Data from 8 patients (median platelet count at baseline, 44.0 [range, 35-49] × 109/L) and 25 cycles of invasive procedures, including 2 cycles in 3 patients, 3 cycles in 4 patients, and 7 cycles in 1 patient, were retrospectively evaluated. The procedures included 18 transarterial chemoembolizations, 5 radiofrequency ablations, and 2 liver needle biopsies. Platelet counts increased significantly compared with baseline, and median changes in platelet counts were 46.0 × 109/L (p = 0.012) in cycle 1, 44.0 × 109/L (p = 0.012) in cycle 2, and 42.0 × 109/L (p = 0.008) in cycles 3-7. No severe adverse events, including portal vein thrombus or bleeding, were observed. CONCLUSIONS Repeated use of lusutrombopag might be safe and effective against thrombocytopenia in patients with CLD undergoing multi-cycle invasive procedures, although long-term data from more patients are required.
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Affiliation(s)
- Yusuke Sano
- Hepatobiliary and Pancreatic Oncology, Kanagawa Cancer Center, Yokohama, Japan
| | - Manabu Morimoto
- Hepatobiliary and Pancreatic Oncology, Kanagawa Cancer Center, Yokohama, Japan,
| | - Satoshi Kobayashi
- Hepatobiliary and Pancreatic Oncology, Kanagawa Cancer Center, Yokohama, Japan
| | - Makoto Ueno
- Hepatobiliary and Pancreatic Oncology, Kanagawa Cancer Center, Yokohama, Japan
| | - Taito Fukushima
- Hepatobiliary and Pancreatic Oncology, Kanagawa Cancer Center, Yokohama, Japan
| | - Hiroyuki Asama
- Hepatobiliary and Pancreatic Oncology, Kanagawa Cancer Center, Yokohama, Japan
| | - Kuniyuki Kawano
- Hepatobiliary and Pancreatic Oncology, Kanagawa Cancer Center, Yokohama, Japan
| | - Shuhei Nagashima
- Hepatobiliary and Pancreatic Oncology, Kanagawa Cancer Center, Yokohama, Japan
| | - Satoshi Tanaka
- Hepatobiliary and Pancreatic Oncology, Kanagawa Cancer Center, Yokohama, Japan
| | - Shinichi Ohkawa
- Hepatobiliary and Pancreatic Oncology, Kanagawa Cancer Center, Yokohama, Japan
| | - Shin Maeda
- Division of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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Multimodal Ultrasound Model Based on the Left Gastric Vein in B-Viral Cirrhosis: Noninvasive Prediction of Esophageal Varices. Clin Transl Gastroenterol 2021; 11:e00262. [PMID: 33259161 PMCID: PMC7641443 DOI: 10.14309/ctg.0000000000000262] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVES: To establish and verify a simple noninvasive model based on the left gastric vein (LGV) to predict the grade of esophageal varices (EV) and high-risk EV (HEV), to facilitate clinical follow-up and timely treatment. METHODS: We enrolled 320 patients with B-viral cirrhosis. All patients underwent endoscopy, laboratory tests, liver and spleen stiffness (SS), and ultrasonography. HEV were analyzed using the χ2 test/t test and logistic regression in the univariate and multivariate analyses, respectively. EV grades were analyzed using the variance/rank-sum test and logistic regression. A prediction model was derived from the multivariate predictors. RESULTS: In the training set, multivariate analysis showed that the independent factors of different EV grades were SS, LGV diameter, and platelet count (PLT). We developed the LGV diameter-SS to PLT ratio index (LSPI) and LGV diameter/PLT models without SS. The area under the receiver operating characteristic curve of the LSPI for diagnosis of small EV, medium EV, large EV, and HEV was 0.897, 0.899, 0.853, and 0.954, respectively, and that of the LGV/PLT was 0.882, 0.890, 0.837, and 0.942, respectively. For the diagnosis of HEV, the negative predictive value was 94.07% when LSPI < 19.8 and the positive predictive value was 91.49% when LSPI > 23.0. The negative predictive value was 95.92% when LGV/PLT < 5.15, and the positive predictive value was 86.27% when LGV/PLT > 7.40. The predicted values showed similar accuracy in the validation set. DISCUSSION: Under appropriate conditions, the LSPI was an accurate method to detect the grade of EV and HEV. Alternatively, the LGV/PLT may also be useful in diagnosing the varices when condition limited.
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Oh Y, Yoo SY, Choi GS, Kim G. Liver transplantation of a patient with extreme thrombocytopenia - A case report. Anesth Pain Med (Seoul) 2021; 16:279-283. [PMID: 34233411 PMCID: PMC8342821 DOI: 10.17085/apm.21006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Accepted: 05/17/2021] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND Patients with chronic liver disease (CLD) planned for liver transplantation (LT) often show severe thrombocytopenia, but there is a lack of evidence in deciding the threshold for prophylactic platelet transfusion. CASE A 47-year-old female with acute liver failure was referred for LT. Despite daily transfusion of platelets, platelet counts remained under 10,000/µl. During LT, 2 units of single donor platelets (SDP) were transfused. Although platelet counts remained extremely low (3,000-4,000/µl) no diffuse oozing was observed and the blood loss was 860 ml. Postoperatively, there was no sign of active bleeding or oozing, and the patient received only 1 unit SDP transfusion. CONCLUSIONS CLD patients may have severe thrombocytopenia. However, primary hemostasis may not be significantly hindered due to the existence of rebalanced hemostasis. Prophylactic platelet transfusion in these patients should not be decided based on platelet counts only, but also take other coagulation tests and clinical signs into consideration.
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Affiliation(s)
- Yena Oh
- Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Seung Yeon Yoo
- Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Gyu-Seong Choi
- Department of Transplantation Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Gaabsoo Kim
- Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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Giannini EG, Kano T, Ochiai T, Bentley R, Shrestha P, Afdhal N. Bleeding events in lusutrombopag-treated thrombocytopenic patients. Eur J Clin Invest 2021; 51:e13503. [PMID: 33523482 PMCID: PMC8243945 DOI: 10.1111/eci.13503] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 01/22/2021] [Accepted: 01/26/2021] [Indexed: 12/12/2022]
Affiliation(s)
- Edoardo Giovanni Giannini
- Gastroenterology Unit, Department of Internal Medicine, University of Genoa, IRCCS-Ospedale Policlinico San Martino, Genoa, Italy
| | - Takeshi Kano
- Global Project Management Department, Shionogi & Co., Ltd., Osaka, Japan
| | | | - Roy Bentley
- US Global Market Access, Shionogi Inc., Florham Park, NJ, USA
| | - Pomy Shrestha
- Product Safety and Pharmacovigilance, Shionogi Inc., Florham Park, NJ, USA
| | - Nezam Afdhal
- Liver Center, Beth Israel Deaconess Medical Center, Boston, MA, USA
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21
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Alvaro D, Caporaso N, Giannini EG, Iacobellis A, Morelli M, Toniutto P, Violi F. Procedure-related bleeding risk in patients with cirrhosis and severe thrombocytopenia. Eur J Clin Invest 2021; 51:e13508. [PMID: 33539542 PMCID: PMC8244048 DOI: 10.1111/eci.13508] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 12/16/2020] [Accepted: 01/29/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND Gaps of knowledge still exist about the potential association between severe thrombocytopenia and increased risk of procedure-associated bleeding in patients with liver disease. METHODS In this narrative review, we aimed at examining the association between procedure-related bleeding risk and platelet count in patients with cirrhosis and severe thrombocytopenia in various settings. We updated to 2020 a previously conducted literature search using MEDLINE/PubMed and EMBASE. The search string included clinical studies, adult patients with chronic liver disease and thrombocytopenia undergoing invasive procedures, any interventions and comparators, and haemorrhagic events of any severity as outcome. RESULTS The literature search identified 1276 unique publications, and 15 studies met the inclusion criteria and were analysed together with those identified by the previous search. Most of the new studies included in our analysis did not assess the association between post-procedural bleeding risk and platelet count alone in patients with chronic liver disease. Furthermore, some results could have been biased by prophylactic platelet transfusions. A few studies found that severe thrombocytopenia may be predictive of bleeding following percutaneous liver biopsy, dental extractions, percutaneous ablation of liver tumours and endoscopic polypectomy. CONCLUSIONS Currently available literature cannot support definitive conclusions about the appropriate target platelet counts to improve the risk of bleeding in cirrhotic patients who underwent invasive procedures; moreover, it showed enormous variability in the use of prophylactic platelet transfusions.
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Affiliation(s)
- Domenico Alvaro
- Department of Translational and Precision MedicineSapienza University of RomeRomeItaly
| | - Nicola Caporaso
- Department of Clinical Medicine and SurgeryUniversity of Naples 'Federico II'NaplesItaly
| | - Edoardo Giovanni Giannini
- Gastroenterology UnitDepartment of Internal MedicineUniversity of Genoa, IRCCS‐Ospedale Policlinico San MartinoGenoaItaly
| | - Angelo Iacobellis
- Division of GastroenterologyFondazione IRCCS Casa Sollievo della SofferenzaFoggiaItaly
| | | | - Pierluigi Toniutto
- Hepatology and Liver Transplantation UnitAzienda Sanitaria Universitaria IntegrataAcademic HospitalUdineItaly
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22
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Surana P, Hercun J, Takyar V, Kleiner DE, Heller T, Koh C. Platelet count as a screening tool for compensated cirrhosis in chronic viral hepatitis. World J Gastrointest Pathophysiol 2021; 12:40-50. [PMID: 34084591 PMCID: PMC8160599 DOI: 10.4291/wjgp.v12.i3.40] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 02/25/2021] [Accepted: 03/31/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Simple tools for clinicians to identify cirrhosis in patients with chronic viral hepatitis are medically necessary for treatment initiation, hepatocellular cancer screening and additional medical management.
AIM To determine whether platelets or other laboratory markers can be used as a simple method to identify the development of cirrhosis.
METHODS Clinical, biochemical and histologic laboratory data from treatment naive chronic viral hepatitis B (HBV), C (HCV), and D (HDV) patients at the NIH Clinical Center from 1985-2019 were collected and subjects were randomly divided into training and validation cohorts. Laboratory markers were tested for their ability to identify cirrhosis (Ishak ≥ 5) using receiver operating characteristic curves and an optimal cut-off was calculated within the training cohort. The final cut-off was tested within the validation cohort.
RESULTS Overall, 1027 subjects (HCV = 701, HBV = 240 and HDV = 86), 66% male, with mean (standard deviation) age of 45 (11) years were evaluated. Within the training cohort (n = 715), platelets performed the best at identifying cirrhosis compared to other laboratory markers [Area Under the Receiver Operating Characteristics curve (AUROC) = 0.86 (0.82-0.90)] and sensitivity 77%, specificity 83%, positive predictive value 44%, and negative predictive value 95%. All other tested markers had AUROCs ≤ 0.77. The optimal platelet cut-off for detecting cirrhosis in the training cohort was 143 × 109/L and it performed equally well in the validation cohort (n = 312) [AUROC = 0.85 (0.76-0.94)].
CONCLUSION The use of platelet counts should be considered to identify cirrhosis and ensure optimal care and management of patients with chronic viral hepatitis.
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Affiliation(s)
- Pallavi Surana
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, United States
| | - Julian Hercun
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, United States
| | - Varun Takyar
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, United States
| | - David E Kleiner
- Laboratory of Pathology, National Cancer Institute, Bethesda, MD 20892, United States
| | - Theo Heller
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, United States
| | - Christopher Koh
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, United States
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23
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Brown RS, Imawari M, Izumi N, Osaki Y, Bentley R, Ochiai T, Kano T, Peck-Radosavljevic M. Assessing the periprocedural magnitude of platelet count change in response to lusutrombopag. JHEP Rep 2021; 3:100228. [PMID: 33644726 PMCID: PMC7887643 DOI: 10.1016/j.jhepr.2021.100228] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 11/20/2020] [Accepted: 12/08/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND & AIMS Despite limitations, platelet transfusion has been used to minimise bleeding risk in patients with thrombocytopaenia. Lusutrombopag is an oral, thrombopoietin receptor agonist approved for treatment of thrombocytopaenia associated with chronic liver disease in patients undergoing planned invasive procedures. This post-hoc analysis assessed the magnitude of platelet count change based on the integrated per-protocol population from 2 similar phase III multicentre, randomised, double-blind, placebo-controlled trials. METHODS Adults with chronic liver disease-induced thrombocytopaenia and platelet count <50 (× 109/L) received lusutrombopag 3 mg or placebo ≤7 days before invasive procedure scheduled 9-14 days after randomisation. Platelet transfusion was required per protocol if the platelet count remained <50 no more than 2 days before the planned invasive procedure. Post-hoc analysis included: proportion of patients with platelet count ≥50, ≥1.5-fold increase, and a doubling of platelet count; maximum and maximum change in platelet count; and platelet count time course. RESULTS Platelet count ≥50, a platelet count increase ≥1.5-fold, and at least a doubling in platelet count were achieved in 88.3%, 86.9%, and 52.6% of patients in the lusutrombopag group (n = 137) vs. 58.6%, 32.3%, and 6.0% of patients in the placebo group (n = 133), respectively. In the lusutrombopag group, median maximum platelet count across baseline platelet counts of <30, ≥30 to <40, and ≥40 was 46, 76, and 87, respectively. Median maximum change in platelet count by baseline platelet count was +24, +42, and +40, respectively. Patients who received lusutrombopag without platelet transfusion achieved a median platelet count ≥50 for 3 weeks. CONCLUSIONS Patients treated with lusutrombopag experienced a clinically relevant response in platelet count for a substantial duration of time. LAY SUMMARY Patients with low platelet counts caused by chronic liver disease may not receive planned invasive procedures or surgeries because of an increased risk of bleeding. Lusutrombopag has previously demonstrated efficacy in raising platelet counts and is approved to treat chronic liver disease patients with low platelet counts in advance of a planned surgery. Physicians need to understand more clearly what to expect in terms of platelet count change when using lusutrombopag; this integrated analysis provides data to help guide its clinical application.
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Key Words
- AE, adverse event
- CLD, chronic liver disease
- CT, computerised tomography
- GCP, Good Clinical Practice
- HR, hazard ratio
- ICF, informed consent form
- ICH, International Conference on Harmonisation
- ITT, intention-to-treat
- LUSU, lusutrombopag
- Lusutrombopag
- MRI, magnetic resonance imaging
- Magnitude
- PBO, placebo
- PP, per protocol
- PT, platelet transfusion
- Platelet
- Procedural
- TCP, thrombocytopaenia
- TEAE, treatment-emergent adverse event
- Thrombocytopaenia
- US, ultrasonography
- WHO, World Health Organization
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Affiliation(s)
- Robert S. Brown
- Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, NY, USA
| | - Michio Imawari
- Institute for Gastrointestinal and Liver Disease, Shin-Yurigaoka General Hospital, Kawasaki, Japan
| | - Namiki Izumi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | | | - Roy Bentley
- Global Market Access, Shionogi Inc., Florham Park, NJ, USA
| | | | - Takeshi Kano
- Global Project Management Department, Shionogi & Co., Ltd., Osaka, Japan
| | - Markus Peck-Radosavljevic
- Abteilung Innere Medizin & Gastroenterologie (IMuG), mit Zentrale Aufnahme & Erstversorgung (ZAE), Klinikum Klagenfurt am Wörthersee, Klagenfurt, Austria
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24
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Nishida Y, Kawaoka T, Imamura M, Namba M, Fujii Y, Uchikawa S, Ohya K, Daijo K, Teraoka Y, Morio K, Fujino H, Nakahara T, Yamauchi M, Hiramatsu A, Tsuge M, Aikata H, Takahashi S, Hayes CN, Fukuhara T, Tsuji K, Arataki K, Nagaoki Y, Aisaka Y, Kamada K, Kodama H, Chayama K. Efficacy of Lusutrombopag for Thrombocytopenia in Patients with Chronic Liver Disease Scheduled to Undergo Invasive Procedures. Intern Med 2021; 60:829-837. [PMID: 33087674 PMCID: PMC8024946 DOI: 10.2169/internalmedicine.5930-20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Objective Lusutrombopag is a thrombopoietin receptor agonist that improves thrombocytopenia in patients with chronic liver disease scheduled to undergo invasive procedures. However, information on the efficacy of repeated lusutrombopag treatment and factors associated with the treatment is scarce. We analyzed the efficacy of repeated lusutrombopag treatment and the factors associated with a response to lusutrombopag. Methods Thirty-nine patients with chronic liver disease who received lusutrombopag treatment before undergoing invasive procedures were enrolled in this retrospective study. Of the 39 patients, 10 received lusutrombopag treatment multiple times for a total of 53 regimens of lusutrombopag treatment. Changes in platelet counts, the effects of repeated lusutrombopag treatment, and factors associated with response to lusutrombopag were analyzed. Results The median platelet count increased significantly from 4.5×104/μL before lusutrombopag treatment to 7.2×104/μL before the invasive procedure (p<0.01), and patients undergoing 49 of the 53 (92%) treatment regimens succeeded in undergoing invasive procedures without needing platelet transfusions. In patients who received lusutrombopag treatment repeatedly, the median platelet count significantly increased following the second administration of lusutrombopag, and the effects of lusutrombopag were similar between the first and second administration. A multivariate analysis identified the absence of diabetes mellitus (odds ratio, 5.56 for presence; p=0.04) as a significant and independent predictor of a response to lusutrombopag. Conclusion Lusutrombopag treatment significantly increased platelet counts in patients with chronic liver disease, making it possible to receive invasive procedures. The treatment produced identical effects when it was repeated. The efficacy of lusutrombopag might be decreased in patients with diabetes mellitus.
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Affiliation(s)
- Yuno Nishida
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Japan
| | - Tomokazu Kawaoka
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Japan
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Japan
| | - Maiko Namba
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Japan
| | - Yasutoshi Fujii
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Japan
| | - Shinsuke Uchikawa
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Japan
| | - Kazuki Ohya
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Japan
| | - Kana Daijo
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Japan
| | - Yuji Teraoka
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Japan
| | - Kei Morio
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Japan
| | - Hatsue Fujino
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Japan
| | - Takashi Nakahara
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Japan
| | - Masami Yamauchi
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Japan
| | - Akira Hiramatsu
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Japan
| | - Masataka Tsuge
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Japan
| | - Shoichi Takahashi
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Japan
| | - C Nelson Hayes
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Japan
| | - Takayuki Fukuhara
- Department of Gastroenterology/Liver Center, Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, Japan
| | - Keiji Tsuji
- Department of Gastroenterology/Liver Center, Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, Japan
| | - Keiko Arataki
- Department of Gastroenterology, Tsuchiya General Hospital, Japan
| | - Yuko Nagaoki
- Department of Gastroenterology, Mazda Hospital, Japan
| | - Yasuyuki Aisaka
- Department of Gastroenterology, JA Hiroshima General Hospital, Japan
| | - Koji Kamada
- Department of Internal Medicine, Shobara Red Cross Hospital, Japan
| | - Hideaki Kodama
- Department of Hepatology, Hiroshima-Nishi Medical Center, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Japan
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25
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Yoshikawa Y, Kawaoka T, Andou Y, Kosaka Y, Suehiro Y, Uchikawa S, Nishida Y, Morio K, Nakahara T, Murakami E, Yamauchi M, Hiramatsu A, Imamura M, Aikata H, Chayama K. A case of successful repeated lusutrombopag administration for thrombocytopenia in a patient with cirrhosis requiring multiple invasive procedures. KANZO 2021; 62:136-143. [DOI: 10.2957/kanzo.62.136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Affiliation(s)
- Yuki Yoshikawa
- Department of Gastroenterology and Metabolism, Hiroshima University
| | - Tomokazu Kawaoka
- Department of Gastroenterology and Metabolism, Hiroshima University
| | - Yuuwa Andou
- Department of Gastroenterology and Metabolism, Hiroshima University
| | - Yumi Kosaka
- Department of Gastroenterology and Metabolism, Hiroshima University
| | - Yousuke Suehiro
- Department of Gastroenterology and Metabolism, Hiroshima University
| | | | - Yuno Nishida
- Department of Gastroenterology and Metabolism, Hiroshima University
| | - Kei Morio
- Department of Gastroenterology and Metabolism, Hiroshima University
| | - Takashi Nakahara
- Department of Gastroenterology and Metabolism, Hiroshima University
| | - Eisuke Murakami
- Department of Gastroenterology and Metabolism, Hiroshima University
| | - Masami Yamauchi
- Department of Gastroenterology and Metabolism, Hiroshima University
| | - Akira Hiramatsu
- Department of Gastroenterology and Metabolism, Hiroshima University
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Hiroshima University
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Hiroshima University
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Hiroshima University
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Gotlieb N, Schwartz N, Zelber-Sagi S, Chodick G, Shalev V, Shibolet O. Longitudinal decrease in platelet counts as a surrogate marker of liver fibrosis. World J Gastroenterol 2020; 26:5849-5862. [PMID: 33132639 PMCID: PMC7579756 DOI: 10.3748/wjg.v26.i38.5849] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 06/10/2020] [Accepted: 08/25/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Liver cirrhosis is a significant source of morbidity and mortality worldwide. The disease is usually indolent and asymptomatic early in its course while many cirrhotic patients are diagnosed late when severe complications occur. A major challenge is to diagnose advanced fibrosis as early as possible, using simple and non-invasive diagnostics tools. Thrombocytopenia represents advanced fibrosis and portal hypertension (HTN) and most non-invasive scores that predict liver fibrosis incorporate platelets as a strong risk factor. However, little is known about the association between longitudinal changes in platelet counts (PTC), when still within the normal range, and the risk of cirrhosis.
AIM To explore whether platelet counts trajectories over time, can predict advanced liver fibrosis across the different etiologies of liver diseases.
METHODS A nested case-control study utilizing a large computerized database. Cirrhosis cases (n = 5258) were compared to controls (n = 15744) matched for age and sex at a ratio of 1:3. All participants had multiple laboratory measurements prior to enrollment. We calculated the trends of PTC, liver enzymes, bilirubin, international normalized ratio, albumin and fibrosis scores (fibrosis-4 and aspartate transaminase-to-platelet ratio index) throughout the preceding 20 years prior to cirrhosis diagnosis compared to healthy controls. The association between PTC, cirrhosis complications and fibrosis scores prior to cirrhosis diagnosis was investigated.
RESULTS The mean age in both groups was 56 (SD 15.8). Cirrhotic patients were more likely to be smokers, diabetic with chronic kidney disease and had a higher prevalence of HTN. The leading cirrhosis etiologies were viral, alcoholic and fatty liver disease. The mean PTC decreased from 240000/μL to 190000/μL up to 15 years prior to cirrhosis diagnosis compared to controls who’s PTC remained stable around the values of 240000/μL. This trend was consistent regardless of sex, cirrhosis etiology and was more pronounced in patients who developed varices and ascites. Compared to controls whose values remained in the normal range, in the cirrhosis group aspartate aminotransferase and alanine aminotransferase, increased from 40 U/L to 75 U/L and FIB-4 increased gradually from 1.3 to 3 prior to cirrhosis diagnosis. In multivariable regression analysis, a decrease of 50 units in PTC was associated with 1.3 times odds of cirrhosis (95%CI 1.25-1.35).
CONCLUSION In the preceding years before the diagnosis of cirrhosis, there is a progressive decline in PTC, within the normal range, matched to a gradual increase in fibrosis scores.
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Affiliation(s)
- Neta Gotlieb
- Department of Gastroenterology and Hepatology, Tel-Aviv Sourasky Medical Center, Tel Aviv 6423906, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Naama Schwartz
- School of Public Health, University of Haifa, Haifa 3498838, Israel
| | - Shira Zelber-Sagi
- Department of Gastroenterology and Hepatology, Tel-Aviv Sourasky Medical Center, Tel Aviv 6423906, Israel
- School of Public Health, University of Haifa, Haifa 3498838, Israel
| | - Gabriel Chodick
- Institute for Research and Innovation, Maccabi Health Services, Tel Aviv 6812509, Israel
| | - Varda Shalev
- Institute for Research and Innovation, Maccabi Health Services, Tel Aviv 6812509, Israel
| | - Oren Shibolet
- Department of Gastroenterology and Hepatology, Tel-Aviv Sourasky Medical Center, Tel Aviv 6423906, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
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27
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Calleja-Panero JL, Andrade RJ, Bañares R, Crespo J, Esteban R, Jarque I, Mingot-Castellano ME, Romero-Gómez M, Muñoz-Peñín R, Bentley R, Shepherd J, Gil Aguirre A. Management of chronic liver disease-associated severe thrombocytopenia in Spain: a view from the experts. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2020; 112:778-783. [PMID: 32954777 DOI: 10.17235/reed.2020.6895/2020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
BACKGROUND chronic liver disease (CLD) patients often present thrombocytopenia (TCP) and when severe, it may prevent them from undergoing necessary invasive procedures due to an increased bleeding risk. The lack of scientific evidence makes it impossible to determine key aspects of the current management and associated healthcare burden of these patients in Spain. PURPOSE to gain insight into the current situation of patients with CLD-associated severe TCP undergoing invasive procedures in Spain, based on the experience of clinical experts. METHODS national Delphi study involving 32 medical experts. RESULTS the estimated prevalence of CLD-associated severe TCP is approximately 5,967, with an annual incidence of 1,148 new patients. Patients undergo a median of 1 (0-3) invasive procedures/year. Platelet transfusions (PTs) are the standard option to raise platelet counts and are associated with significant burden. The achievement of target platelet levels (≥ 50 x 109/l) after a transfusion is not routinely measured. The lack of effectiveness and short life span of transfused platelets can lead to procedure cancellations and bleeding events, which potentially affect patient outcomes. Adverse events occur in 1-25 % of patients, including mild (febrile and allergic reactions) and severe events (e.g., transfusion-related acute lung injury). Between 5-15 % of patients are unfit to receive PTs and approximately 3 % are treated off-label with thrombopoietin receptor agonists. CONCLUSIONS this study provides a snapshot of the current situation in Spain, highlighting that the current management is poorly standardized and suboptimal in some cases. The results suggest the benefit of developing a consensus document to address some of these shortcomings and to advance in the search for alternatives to PTs.
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Affiliation(s)
| | - Raúl J Andrade
- Unidad de Gestión Clínica de Aparato Digestivo, Hospital Universitario Virgen de la Victoria. Instituto de Investigación Biomédica de Málaga-IBIMA, España
| | - Rafael Bañares
- Hepatología, Hospital General Universitario Gregorio Marañón, España
| | - Javier Crespo
- Hepatología, Hospital Universitario Marqués de Valdecilla, España
| | - Rafael Esteban
- Hepatología, Hospital Universitario Vall d'Hebron, España
| | - Isidro Jarque
- Hematología, Hospital Universitari i Politècnic La Fe, España
| | | | | | | | - Roy Bentley
- Global Market Access, Shionogi Inc., Estados Unidos
| | - John Shepherd
- Pricing and Market Access, Omakase Consulting, España
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28
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Mladsi D, Barnett C, Aggarwal K, Vredenburg M, Dieterich D, Kim R. Cost- Effectiveness of Avatrombopag for the Treatment of Thrombocytopenia in Patients with Chronic Liver Disease. CLINICOECONOMICS AND OUTCOMES RESEARCH 2020; 12:515-526. [PMID: 32982341 PMCID: PMC7500829 DOI: 10.2147/ceor.s262772] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Accepted: 08/13/2020] [Indexed: 12/12/2022] Open
Abstract
Background and Aim Thrombocytopenia is common in people with chronic liver disease, who frequently undergo invasive procedures. To minimize the risk of bleeding, prophylactic platelet transfusions have traditionally been used but carry many risks. The aim of this study was to evaluate the cost-effectiveness of avatrombopag compared with platelet transfusion and lusutrombopag as a treatment for thrombocytopenia in adult patients with chronic liver disease scheduled to undergo a medical procedure. Methods A decision-tree model was developed from a US payer perspective to capture acute events observed in phase 3 global randomized controlled clinical trials and, to support exploratory analyses, potential longer-term complications resulting from a major bleed or thromboembolic event. Treatment costs were taken from publicly available data sources. The interventions were evaluated in the overall trial populations and in subpopulations with higher and lower baseline platelet counts. Results were presented as incremental cost per platelet transfusion avoided. One-way and probabilistic sensitivity analyses were conducted. Results In the overall population, avatrombopag reduced the need for platelet transfusions and produced cost-savings compared with platelet transfusion (80% fewer prophylactic platelet transfusions, $4250 lower costs) and lusutrombopag (42% fewer prophylactic platelet transfusions, $5819 lower costs). Similar results were seen in both the higher and lower platelet count subpopulations. The one-way and probabilistic sensitivity analyses found that the use of avatrombopag is cost-saving with the incremental cost-effectiveness ratio in quadrant IV (decreased costs, prophylactic platelet transfusions avoided). Conclusion The use of avatrombopag is expected to be cost-saving while reducing the need for prophylactic platelet transfusions compared with platelet transfusion and lusutrombopag.
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Affiliation(s)
| | | | | | | | | | - Ray Kim
- School of Medicine, Stanford University, Stanford, CA, USA
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29
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Labidi A, Baccouche H, Fekih M, Mahjoub S, BenMustapha N, Serghini M, BenRomdhane N, Boubaker J. The relationship between coagulation disorders and the risk of bleeding in cirrhotic patients. Ann Hepatol 2020; 18:627-632. [PMID: 31097395 DOI: 10.1016/j.aohep.2018.12.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Revised: 12/06/2018] [Accepted: 10/04/2018] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND OBJECTIVES For long, bleeding in cirrhotic patients has been associated with acquired coagulation disorders. The aim of our study was to investigate the impact of acquired coagulation disorders on bleeding risk in cirrhotic patients. MATERIALS AND METHODS Blood samples were collected from 51 cirrhotic patients with (H+) or without (H-) bleeding events and 50 controls matched by age and sex. Thrombin generation was assessed as endogenous thrombin potential (ETP). Hemostatic balance was assessed by means of ratios of pro- to anticoagulant factors and by ETP ratio with/without protein C (PC) activator (ETP ratio). RESULTS Bleeding events occurred in 9 patients (17.6%). Compared with controls, VIII/anticoagulant factors, VII/PC and XII/PC were significantly higher in (H+) patients. No significant difference as regards all ratios across patient groups was detected. ETP ratio was significantly higher in (H+) patients than in controls (p=0.017). However, there was no significant difference between patient groups as regards ETP ratio. CONCLUSION Hemostatic balance is shifted toward a hypercoagulability state even in cirrhotic patients who experienced bleeding. These findings provide evidence against traditional concept of hemostasis-related bleeding tendency in cirrhotic patients.
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Affiliation(s)
- Asma Labidi
- Department of Gastroenterology and Hepatology, Rabta Hospital, Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia.
| | - Héla Baccouche
- Department of Hematology, Rabta Hospital, Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia
| | - Monia Fekih
- Department of Gastroenterology and Hepatology, Rabta Hospital, Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia
| | - Sonia Mahjoub
- Department of Hematology, Rabta Hospital, Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia
| | - Nadia BenMustapha
- Department of Gastroenterology and Hepatology, Rabta Hospital, Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia
| | - Meriem Serghini
- Department of Gastroenterology and Hepatology, Rabta Hospital, Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia
| | - Neila BenRomdhane
- Department of Hematology, Rabta Hospital, Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia
| | - Jalel Boubaker
- Department of Gastroenterology and Hepatology, Rabta Hospital, Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia
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Nilles KM, Flamm SL. Thrombocytopenia in Chronic Liver Disease: New Management Strategies. Clin Liver Dis 2020; 24:437-451. [PMID: 32620282 DOI: 10.1016/j.cld.2020.04.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Thrombocytopenia is common in advanced liver disease, and such patients frequently need invasive procedures. Numerous mechanisms for thrombocytopenia exist, including splenic sequestration and reduction of levels of the platelet growth factor thrombopoietin. Traditionally, platelet transfusions have been used to increase platelet counts before elective procedures, usually to a threshold of greater than or equal to 50,000/μL, but levels vary by provider, procedure, and specific patient. Recently, the thrombopoietin receptor agonists avatrombopag and lusutrombopag were studied and found efficacious for increasing platelet count in the outpatient setting for select patients with advanced liver disease who need a procedure.
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Affiliation(s)
- Kathy M Nilles
- Division of Gastroenterology and Hepatology, MedStar Georgetown Transplant Institute, Georgetown University School of Medicine, 3800 Reservoir Road NW, 2-PHC, Washington, DC 20007, USA
| | - Steven L Flamm
- Division of Gastroenterology and Hepatology, Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, 676 North St Clair Street, Arkes Suite 1900, Chicago, IL 60611, USA.
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A pre-operative platelet transfusion algorithm for patients with cirrhosis and hepatocellular carcinoma undergoing laparoscopic microwave ablation. Surg Endosc 2020; 35:3811-3817. [PMID: 32632482 DOI: 10.1007/s00464-020-07760-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Accepted: 06/23/2020] [Indexed: 10/23/2022]
Abstract
BACKGROUND Thrombocytopenia is a common finding in patients with chronic liver disease. It is associated with poor clinical outcomes due to increased risk of bleeding after even minor procedures. We sought to determine an algorithm for pre-operative platelet transfusion in patients with cirrhosis and hepatocellular carcinoma (HCC) undergoing laparoscopic microwave ablation (MIS-MWA). METHODS A retrospective review identified all patients with cirrhosis and HCC who underwent MIS-MWA at a single tertiary institution between 2007 and 2019. Demographics, pre-operative and post-operative laboratory values, transfusion requirements, and bleeding events were collected. The analyzed outcome of bleeding risk included any transfusion received intra-operatively or a transfusion or surgical intervention post-operatively. Logistic regression models were created to predict bleeding risk and identify patients who would benefit from pre-operative transfusion. RESULTS There were 433 patients with cirrhosis and HCC who underwent MIS-MWA identified; of these, 353 patients had complete laboratory values and were included. Bleeding risk was evaluated through bivariate analysis of statistically and clinically significant variables. The accuracy of both models was substantiated through bootstrap validation for 500 iterations (model 1: ROC 0.8684, Brier score 0.0238; model 2: ROC 0.8363, Brier score 0.0252). The first model captured patients with both thrombocytopenia and anemia: platelet count < 60 × 109 / L (OR 7.75, p 0.012, CI 1.58-38.06) and hemoglobin < 10 gm/dL (OR 5.76, p 0.032, CI 1.16-28.63). The second model captured patients with thrombocytopenia without anemia: platelet count < 30 × 109/L (OR 8.41, p 0.05, CI 0.96-73.50) and hemoglobin > 10 gm/dL (OR 0.16, p 0.026, CI 0.031-0.80). CONCLUSION The prediction of patients with cirrhosis and HCC requiring pre-operative platelet transfusions may help to avoid bleeding complications after invasive procedures. This study needs to be prospectively validated and ultimately may be beneficial in assessment of novel therapies for platelet-based clinical treatment in liver disease.
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Rawi S, Wu GY. Pathogenesis of Thrombocytopenia in Chronic HCV Infection: A Review. J Clin Transl Hepatol 2020; 8:184-191. [PMID: 32832399 PMCID: PMC7438357 DOI: 10.14218/jcth.2020.00007] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 03/25/2020] [Accepted: 03/31/2020] [Indexed: 12/12/2022] Open
Abstract
A large proportion of patients with chronic hepatitis C have associated thrombocytopenia (TCP). Due to bleeding risks, TCP, when severe, can limit diagnostic and therapeutic procedures, treatments, and increases risk of complications, especially excessive bleeding. It is important to understand the mechanisms that cause TCP in order to manage it. In general, TCP can be due to increased destruction or decreased production. Proposed mechanisms of increased destruction include autoantibodies to platelets and hypersplenism with sequestration. Proposed mechanisms of decreased production include virus-induced bone marrow suppression and decreased TPO production. Autoantibodies directed against platelet surface antigens have demonstrated an inverse correlation with platelet counts. Hypersplenism with sequestration involves the interaction of portal hypertension, splenomegaly, and platelet destruction. Decreased production mechanisms involve appropriate and inappropriate levels of TPO secretion. There is limited evidence to support viral-induced bone marrow suppression. In contrast, there is strong evidence to support low levels of TPO in liver failure as a major cause of TCP. TPO-agonists, specifically eltrombopag, have been shown in hepatitis C patients to increase platelet counts without reducing portal hypertension or splenomegaly. We conclude that TCP in hepatitis C virus-induced liver disease is often multifactorial, but an understanding of the mechanisms can lead to judicious use of new drugs for treatment.
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Affiliation(s)
- Sarah Rawi
- Department of Medicine, Division of Gastroenterology-Hepatology, University of Connecticut Health Center, Farmington, CT, USA
- Correspondence to: Sarah Rawi, Department of Medicine, University of Connecticut Health Center, 263 Farmington Ave, Farmington, CT 06032, USA. Tel: +1-858-692-2372, E-mail:
| | - George Y Wu
- Department of Medicine, Division of Gastroenterology-Hepatology, University of Connecticut Health Center, Farmington, CT, USA
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Catanzaro R, Sciuto M, Lanzafame C, Balakrishnan B, Marotta F. Platelet to lymphocyte ratio as a predictive biomarker of liver fibrosis (on elastography) in patients with hepatitis C virus (HCV)-related liver disease. Indian J Gastroenterol 2020; 39:253-260. [PMID: 32833144 DOI: 10.1007/s12664-020-01038-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2019] [Accepted: 04/13/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Liver fibrosis is a frequent complication of chronic hepatitis C virus (HCV) infection. Its evaluation is very important for the prognosis of these patients. The aim of this study was to evaluate the possibility of exploiting the platelet to lymphocyte ratio and the neutrophil to lymphocyte ratio as non-invasive predictive markers of liver fibrosis. METHODS We recruited 120 patients with chronic HCV infection. They were subjected to various clinical investigations to assess the severity of fibrosis. Transient elastography and some serological tests were performed, and the platelet to lymphocyte ratio and the neutrophil to lymphocyte ratio were estimated. RESULTS Sixty-four patients had F4 fibrosis (defined by elastography) and their platelet to lymphocyte ratio (69.92 ± 26.47) was lower than in patients with non-F4 fibrosis (95.19 ± 48.15) (p = 0.001). The neutrophil to lymphocyte ratio was also estimated, but the difference between the 2 groups of patients was not significant statistically (p = 0.07). CONCLUSION The platelet to lymphocyte ratio can be used as a predictive biomarker of liver fibrosis, unlike the neutrophil to lymphocyte ratio which is not predictive of this HCV-related chronic hepatitis complication. More studies are needed to validate this hypothesis.
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Affiliation(s)
- Roberto Catanzaro
- Department of Clinical and Experimental Medicine, Gastroenterology Section, "Gaspare Rodolico" Policlinico Hospital, University of Catania, Via Santa Sofia, 78, 95123, Catania, Italy.
| | - Morena Sciuto
- Department of Clinical and Experimental Medicine, Gastroenterology Section, "Gaspare Rodolico" Policlinico Hospital, University of Catania, Via Santa Sofia, 78, 95123, Catania, Italy
| | - Cristina Lanzafame
- Department of Clinical and Experimental Medicine, Gastroenterology Section, "Gaspare Rodolico" Policlinico Hospital, University of Catania, Via Santa Sofia, 78, 95123, Catania, Italy
| | | | - Francesco Marotta
- ReGenera R&D International for Aging Intervention & San Babila Clinic, Milan, Italy
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Sirolimus-Induced Delayed Severe Thrombocytopenia After Liver Transplantation: A Case Report. Transplant Proc 2020; 52:1950-1952. [PMID: 32444121 DOI: 10.1016/j.transproceed.2020.02.125] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 01/31/2020] [Accepted: 02/09/2020] [Indexed: 11/22/2022]
Abstract
OBJECTIVE Thrombocytopenia is a common condition in patients undergoing liver transplantation (LT). Thrombocytopenia is prevalent in early postoperative phase, and it gradually improves after several weeks. Delayed severe thrombocytopenia occurring after the initial recovery of platelets is rare. We report a case of a patient with delayed severe thrombocytopenia 59 weeks after LT. CASE PRESENTATION Our patient was a 61-year-old man who presented to our institution 59 weeks after undergoing LT. He presented for removal of a bile duct stent that was inserted 3 months prior. Tacrolimus replaced sirolimus for immunosuppression during the seventh week after transplantation due to sirolimus-induced nephrotoxicity. On admission, the patient's vital signs were normal and his physical examination was unremarkable. Laboratory parameters demonstrated that the platelet (PLT) level was significantly decreased to 18 × 109/L. PLTs reached a nadir of 3 × 109/L even after utilization of interleukin-11, thrombopoietin, and low-dose prednisone. Although rare, sirolimus toxicity was suspected. Therefore, sirolimus was gradually replaced by cyclosporin A in combination with low-dose prednisone. Subsequently, a normal PLT level was gradually recovered. This study was approved by the ethical committee of the First Hospital of Jilin University and was performed in accordance with the ethical standards of the Helsinki Congress and Istanbul Declaration. CONCLUSIONS Recurrent delayed severe thrombocytopenia is rare after LT. Sirolimus toxicity might be a reason for its occurrence if other possible factors are excluded. After diagnosis, sirolimus therapy should be discontinued and patients should be treated with an alternative immunosuppressive regimen.
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Park J, Jeong J, Choi HJ, Shim JW, Lee HM, Hong SH, Park CS, Choi JH, Chae MS. Role of thrombocytopenia in risk stratification for acute kidney injury after living donor liver transplantation. Platelets 2020; 32:453-462. [PMID: 32299264 DOI: 10.1080/09537104.2020.1754377] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
The aim of our study was to investigate pre and intraoperative clinical factors, including platelet count, which could inform risk stratification of early acute kidney injury (AKI) after living donor liver transplantation (LDLT). Additionally, the impact of severe thrombocytopenia on AKI risk was assessed using a propensity score (PS)-matched analysis. In total, 591 adult patients who underwent LDLT between January 2009 and December 2018 at our hospital were retrospectively analyzed. Early postoperative AKI was determined based on the KDIGO criteria, and 149 patients (25.2%) developed AKI immediately after surgery. In a multivariate analysis, a lower preoperative platelet count was significantly associated with early postoperative AKI, together with diabetes mellitus, lower hourly urine output, and longer graft ischemic time; furthermore, a decrease in platelet count was correlated with AKI severity. After adjusting for the PS, the probability of AKI was significantly (1.9-fold) higher in patients with severe thrombocytopenia than in those without severe thrombocytopenia. Patients with thrombocytopenia showed a higher postoperative incidence of AKI and a higher requirement for dialysis than those without thrombocytopenia. The platelet count can easily be obtained via regular blood analysis of patients scheduled for LDLT and can be used to identify patients at risk for AKI.
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Affiliation(s)
- Jaesik Park
- Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Anesthesiology and Pain Medicine, Seocho-gu, Seoul, Korea (The Republic Of)
| | - Jangsu Jeong
- Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Anesthesiology and Pain Medicine, Seocho-gu, Seoul, Korea (The Republic Of)
| | - Ho Joong Choi
- Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Surgery, Seocho-gu, Seoul, Korea (The Republic Of)
| | - Jung-Woo Shim
- Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Anesthesiology and Pain Medicine, Seocho-gu, Seoul, Korea (The Republic Of)
| | - Hyung Mook Lee
- Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Anesthesiology and Pain Medicine, Seocho-gu, Seoul, Korea (The Republic Of)
| | - Sang Hyun Hong
- Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Anesthesiology and Pain Medicine, Seocho-gu, Seoul, Korea (The Republic Of)
| | - Chul Soo Park
- Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Anesthesiology and Pain Medicine, Seocho-gu, Seoul, Korea (The Republic Of)
| | - Jong Ho Choi
- Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Anesthesiology and Pain Medicine, Seocho-gu, Seoul, Korea (The Republic Of)
| | - Min Suk Chae
- Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Anesthesiology and Pain Medicine, Seocho-gu, Seoul, Korea (The Republic Of)
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Ali RO, Moon MS, Townsend EC, Hill K, Zhang GY, Bradshaw A, Guan H, Hamilton D, Kleiner DE, Auh S, Koh C, Heller T. Exploring the Link Between Platelet Numbers and Vascular Homeostasis Across Early and Late Stages of Fibrosis in Hepatitis C. Dig Dis Sci 2020; 65:524-533. [PMID: 31407130 PMCID: PMC7988415 DOI: 10.1007/s10620-019-05760-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Accepted: 07/23/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND Thrombocytopenia is a hallmark of advanced liver disease. Platelets, growth factors (GFs), and vascular integrity are closely linked factors in disease pathogenesis, and their relationship, particularly in early disease stages, is not entirely understood. The aim was to compare circulating platelets, growth factors, and vascular injury markers (VIMs) in hepatitis C-infected (HCV) patients with early fibrosis and cirrhosis. METHODS Retrospective evaluation of serum GFs and VIMs by ELISA were evaluated from twenty-six HCV patients. Analytes from an earlier time-point were correlated with MELD at a later time-point. RESULTS Platelets and GFs decreased, and VIMs increased with fibrosis. Platelets correlated positively with PDGF-AA, PDGF-BB, TGFB1, EGF, and P-selectin, and negatively with ICAM-3 and VCAM-1. P-selectin showed no correlations with VIMs but positively correlated with PDGF-AA, PDGF-BB, TGFB1, and EGF. Soluble VCAM-1 and ICAM-3 were linked to increasing fibrosis, liver enzymes, and synthetic dysfunction. Higher VCAM-1 and ICAM-3 and lower P-selectin at an earlier time-point were linked to higher MELD score at a later time-point. CONCLUSION In chronic HCV, progressive decline in platelets and growth factors with fibrosis and their associations suggest that platelets are an important source of circulating GFs and influence GF decline with fibrosis. Enhanced markers of vascular injury in patients with early fibrosis suggest an earlier onset of endothelial dysfunction preceding cirrhosis. Associations of VIMs with platelets suggest a critical link between platelets and vascular homeostasis. Circulating markers of vascular injury may not only have prognostic importance but emphasize the role of vascular dysfunction in liver disease pathogenesis (NCT00001971).
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Affiliation(s)
- Rabab O Ali
- Translational Hepatology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 10, Room 9B16, 10 Center Dr. MSC 1800, Bethesda, MD, 20892-1800, USA.
| | - Mi Sun Moon
- Translational Hepatology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 10, Room 9B16, 10 Center Dr. MSC 1800, Bethesda, MD, 20892-1800, USA
| | - Elizabeth C Townsend
- Translational Hepatology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 10, Room 9B16, 10 Center Dr. MSC 1800, Bethesda, MD, 20892-1800, USA
| | - Kareen Hill
- Translational Hepatology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 10, Room 9B16, 10 Center Dr. MSC 1800, Bethesda, MD, 20892-1800, USA
| | - Grace Y Zhang
- Translational Hepatology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 10, Room 9B16, 10 Center Dr. MSC 1800, Bethesda, MD, 20892-1800, USA
| | - Alyson Bradshaw
- Translational Hepatology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 10, Room 9B16, 10 Center Dr. MSC 1800, Bethesda, MD, 20892-1800, USA
| | - Hannah Guan
- Translational Hepatology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 10, Room 9B16, 10 Center Dr. MSC 1800, Bethesda, MD, 20892-1800, USA
| | - Destanee Hamilton
- Translational Hepatology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 10, Room 9B16, 10 Center Dr. MSC 1800, Bethesda, MD, 20892-1800, USA
| | - David E Kleiner
- Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Sungyoung Auh
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Christopher Koh
- Translational Hepatology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 10, Room 9B16, 10 Center Dr. MSC 1800, Bethesda, MD, 20892-1800, USA
| | - Theo Heller
- Translational Hepatology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 10, Room 9B16, 10 Center Dr. MSC 1800, Bethesda, MD, 20892-1800, USA.
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Hirooka M, Ochi H, Hiraoka A, Koizumi Y, Tanaka T, Sunago K, Yukimoto A, Imai Y, Watanabe T, Yoshida O, Abe M, Joko K, Michitaka K, Hiasa Y. Role of severe thrombocytopenia in preventing platelet count recovery in thrombocytopenic patients with chronic liver disease. J Gastroenterol Hepatol 2020; 35:299-304. [PMID: 31318996 DOI: 10.1111/jgh.14786] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Revised: 05/31/2019] [Accepted: 07/10/2019] [Indexed: 12/13/2022]
Abstract
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.
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Affiliation(s)
- Masashi Hirooka
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Japan
| | - Hironori Ochi
- Center for Liver-Biliary-Pancreatic Diseases, Matsuyama Red Cross Hospital, Matsuyama, Japan
| | - Atsushi Hiraoka
- Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, Japan
| | - Yohei Koizumi
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Japan
| | - Takaaki Tanaka
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Japan
| | - Kotaro Sunago
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Japan
| | - Atsushi Yukimoto
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Japan
| | - Yusuke Imai
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Japan
| | - Takao Watanabe
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Japan
| | - Osamu Yoshida
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Japan
| | - Masanori Abe
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Japan
| | - Kouji Joko
- Center for Liver-Biliary-Pancreatic Diseases, Matsuyama Red Cross Hospital, Matsuyama, Japan
| | - Kojiro Michitaka
- Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, Japan
| | - Yoichi Hiasa
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Japan
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Sayyar M, Saidi M, Zapatka S, Deng Y, Ciarleglio M, Garcia-Tsao G. Platelet count increases after viral elimination in chronic HCV, independent of the presence or absence of cirrhosis. Liver Int 2019; 39:2061-2065. [PMID: 31365178 PMCID: PMC11340272 DOI: 10.1111/liv.14203] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Revised: 07/02/2019] [Accepted: 07/28/2019] [Indexed: 12/29/2022]
Abstract
Platelet (PLT) count is included in non-invasive scores assessing liver fibrosis in patients with chronic liver disease. Improvement in fibrosis scores after antiviral treatment for hepatitis C virus (HCV) has been interpreted as indicative of an improvement in fibrosis. HCV itself can lower PLT and, therefore, an increase in PLT would be expected after viral elimination irrespective of pretreatment fibrosis stage. The aim of this study was to investigate this hypothesis by assessing changes in PLT after viral elimination in patients with chronic HCV stratified by the absence or presence of cirrhosis. METHODS Retrospective analysis of patients with chronic HCV infection treated with direct-acting antivirals (DAAs) who achieved viral elimination and in whom PLT were obtained prior to treatment, at first negative HCV-RNA, at treatment completion and at 6 months, and 1 year after treatment completion. Comparisons were made between patients with and without cirrhosis. RESULTS A total of 420 patients with chronic HCV were treated, of which 208 were excluded, leaving 212 patients eligible for analysis (142 without cirrhosis, 70 with cirrhosis). Overall, a significant increase in PLT was observed up to 1 year after antiviral treatment completion (P < .001). Changes in PLT between patients with and without cirrhosis were not significantly different at any of the time points. CONCLUSION Platelet count increased significantly in patients with HCV who achieved viral elimination irrespective of the absence or presence of cirrhosis. This suggests that changes in PLT post-viral elimination should not be interpreted as being reflective of changes in liver fibrosis or portal hypertension.
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Affiliation(s)
- Mubarak Sayyar
- Section of Digestive Diseases, VA-Connecticut Healthcare System, West Haven, CT, USA
- Section of Digestive Diseases, Yale School of Medicine, New Haven, CT, USA
| | - Marie Saidi
- Section of Digestive Diseases, VA-Connecticut Healthcare System, West Haven, CT, USA
- Section of Digestive Diseases, Yale School of Medicine, New Haven, CT, USA
| | - Susan Zapatka
- Section of Digestive Diseases, Yale School of Medicine, New Haven, CT, USA
| | - Yanhong Deng
- Yale Center for Analytical Sciences, Yale School of Public Health, New Haven, CT, USA
| | - Maria Ciarleglio
- Yale Center for Analytical Sciences, Yale School of Public Health, New Haven, CT, USA
| | - Guadalupe Garcia-Tsao
- Section of Digestive Diseases, VA-Connecticut Healthcare System, West Haven, CT, USA
- Section of Digestive Diseases, Yale School of Medicine, New Haven, CT, USA
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Abdela J. Current Advance in Thrombopoietin Receptor Agonists in the Management of Thrombocytopenia Associated With Chronic Liver Disease: Focus on Avatrombopag. PLASMATOLOGY 2019; 12:1179545X19875105. [PMID: 31673229 PMCID: PMC6804364 DOI: 10.1177/1179545x19875105] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Accepted: 08/20/2019] [Indexed: 12/22/2022]
Abstract
Chronic liver disease (CLD) is a condition that progresses over time toward advanced disease state which is known as liver cirrhosis. Liver cirrhosis leads to dangerous health problems among people living across the world. One such problem that observed in about 75% of cirrhotic patients is thrombocytopenia; which in turn associated with poor prognosis and recovery from CLD. Beyond these, thrombocytopenia in cirrhotic patients led to impairment of coagulation cascade and significantly influenced the utilization of effective mechanism in the management of CLD. By nature, treatment of CLD involves invasive diagnostic and treatment procedures; therefore, in the presence of thrombocytopenia implementing these methods put the lives of patients in a critical health problem due to increased risk of bleeding and mortality. Because of these reasons, prophylactic transfusion of platelets is considered to be one of the most effective options that reduce the risk of bleeding in patients with CLD that required to undergo an invasive procedure. Although platelet transfusion presented with significant advantages in facilitating the invasive procedure in patients with CLD, refractoriness with repeated use and various problems associated with its transfusion limit the continuous utilization of this important option. With these challenges and current advance in the knowledge of thrombopoiesis, the development of relatively safe and alternative drugs that enhance the production of platelets by interacting with thrombopoietin receptor agonists provides a promising option to platelet transfusion. The discovery and approval of romiplostim and eltrombopag in August 2008 and November 2008, respectively, for the treatment of chronic immune thrombocytopenia paved a way and followed by the Food and Drug Administration (FDA) approval of 2 potentially advantageous drugs, lusutrombopag, and avatrombopag, in 2018 for the treatment of thrombocytopenia in patients with CLD that required to undergo elective surgery. Therefore, this review aims to assess pathogenesis of thrombocytopenia and its challenges in the management of liver-related issues and, more importantly, gives emphasis to address the potential use of avatrombopag in the treatment of thrombocytopenia underlying CLD, its pharmacokinetics and pharmacodynamics, as well as its toxicological profiles by presenting the most commonly reported adverse events in various trials.
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Affiliation(s)
- Jemal Abdela
- Department of Pharmacology and Toxicology, School of Pharmacy, College of Health and Medical Sciences, Haramaya University, Harar, Ethiopia
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40
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Ghasemi A, Zadsar M, Shaiegan M, Samiei S, Namvar A, Rasouli M, Moosanejad M. Human platelet antigens polymorphisms; association to the development of liver fibrosis in patients with chronic hepatitis C. J Med Virol 2019; 92:45-52. [PMID: 30729550 DOI: 10.1002/jmv.25423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2018] [Revised: 01/20/2019] [Accepted: 02/02/2019] [Indexed: 11/09/2022]
Abstract
Recently, human platelet antigens (HPAs) polymorphisms are found to play a role in susceptibility to hepatitis C virus (HCV) infection and fibrosis progression. The aim of the current study was to evaluate the possible association between the HPAs polymorphisms with liver fibrosis progression in HCV patients. HPAs polymorphisms genotyping was performed in HCV patients (n = 71) by Sequence-specific primers-polymerase chain reaction. Fibrosis progression was evaluated using the Metavir scoring system and liver biopsy, and the patients were assigned to two groups, namely, G1 (n = 35) that included patients with F1 (portal fibrosis without septa) or F2 (few septa) and G2 (n = 36) that comprised patients with F3 (numerous septa) or F4 (cirrhosis). The data analyses were performed using Pearson's χ2 test. The genotype frequency of HPA-3ab was significantly higher in G1 patients than in G2 patients (P = 0.015). No statistically significant differences were found between the patient groups (G1 and G2) regarding the distributions of the allelic and genotypic frequencies of the HPA-1, -2, -4, -5, and -15 systems. Multivariate logistic regression showed an independent association between the genotype HPA-3aa/BB and severe fibrosis (F3-F4), when compared with genotype HPA-3ab, independent of the viral genotype, high alanine transaminase, sex, age, time of infection, diabetes, and high cholesterol as risk factors. The present study suggested that the HPA-3ab genotype could be noticed as a potential protecting factor against hepatic fibrosis. Therefore, the antigenic variation of integrins might be considered as a part of the coordinated inflammatory process involved in the progression of liver fibrosis.
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Affiliation(s)
- Ali Ghasemi
- Department of Hematology, Blood Transfusion Research Center, High Institute for Research & Education in Transfusion Medicine, Tehran, Iran
| | - Maryam Zadsar
- Department of Microbiology, Blood Transfusion Research Center, High Institute for Research & Education in Transfusion Medicine, Tehran, Iran
| | - Mojgan Shaiegan
- Department of Immunohematology, Blood Transfusion Research Center, High Institute for Research & Education in Transfusion Medicine, Tehran, Iran
| | - Shahram Samiei
- Department of Biochemistry, Blood Transfusion Research Center, High Institute for Research & Education in Transfusion Medicine, Tehran, Iran
| | - Ali Namvar
- Department of Genetics, Iranian Comprehensive Hemophilia Care Center, Tehran, Iran
| | - Mahboobeh Rasouli
- Department of Biostatics, School of Public Health, Iran University of Medical Science, Tehran, Iran
| | - Molood Moosanejad
- Department of Clinical Consult, Blood Transfusion Research Center, High Institute for Research & Education in Transfusion Medicine, Tehran, Iran
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Peck‐Radosavljevic M, Simon K, Iacobellis A, Hassanein T, Kayali Z, Tran A, Makara M, Ben Ari Z, Braun M, Mitrut P, Yang S, Akdogan M, Pirisi M, Duggal A, Ochiai T, Motomiya T, Kano T, Nagata T, Afdhal N. Lusutrombopag for the Treatment of Thrombocytopenia in Patients With Chronic Liver Disease Undergoing Invasive Procedures (L-PLUS 2). Hepatology 2019; 70:1336-1348. [PMID: 30762895 PMCID: PMC6849531 DOI: 10.1002/hep.30561] [Citation(s) in RCA: 106] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Accepted: 02/10/2019] [Indexed: 12/21/2022]
Abstract
Thrombocytopenia may be associated with increased bleeding risk impacting timing and outcome of invasive procedures in patients with chronic liver disease (CLD). Lusutrombopag, a small-molecule, thrombopoietin (TPO) receptor agonist, was evaluated as a treatment to raise platelet counts (PCs) in patients with thrombocytopenia and CLD undergoing invasive procedures. L-PLUS 2 was a global, phase 3, randomized, double-blind, placebo-controlled study. Adults with CLD and baseline PCs < 50 × 109 /L were randomized to receive once-daily lusutrombopag 3 mg or placebo ≤ 7 days before an invasive procedure scheduled 2-7 days after the last dose. The primary endpoint was avoidance of preprocedure platelet transfusion and avoidance of rescue therapy for bleeding. A key secondary endpoint was number of days PCs were ≥ 50 × 109 /L throughout the study. Safety analysis was performed on patients who received at least one dose of study drug. This study occurred between June 15, 2015, and April 19, 2017, with a total of 215 randomized patients (lusutrombopag, 108; placebo, 107); 64.8% (70/108) of patients in the lusutrombopag group versus 29.0% (31/107) in the placebo group met the primary endpoint (P < 0.0001; difference of proportion 95% confidence interval [CI], 36.7 [24.9, 48.5]). The median duration of PCs ≥ 50 × 109 /L was 19.2 days with lusutrombopag (without platelet transfusion) compared with 0.0 in the placebo group (with platelet transfusion) (P = 0.0001). Most adverse events were mild or moderate in severity, and rates were similar in the lusutrombopag and placebo groups (47.7% and 48.6%, respectively). Conclusion: Lusutrombopag was superior to placebo for reducing the need for platelet transfusions and achieved durable PC response in patients with thrombocytopenia and CLD undergoing invasive procedures, with a safety profile similar to placebo.
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Affiliation(s)
- Markus Peck‐Radosavljevic
- Abteilung Innere Medizin & Gastroenterologiemit Zentraler Aufnahme & Erstversorgung, Klinikum Klagenfurt am WörtherseeKlagenfurtAustria
| | - Krzysztof Simon
- Department of Infectious Diseases and HepatologyWroclaw Medical UniversityWroclawPoland
| | - Angelo Iacobellis
- Division of GastroenterologyIstituti di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale Casa Sollievo della SofferenzaSan Giovanni RotondoItaly
| | | | - Zeid Kayali
- Inland Empire Liver Foundation, University of CaliforniaRiverside, RialtoCA
| | - Albert Tran
- Institut national de la santé et la recherche médicale (INSERM), Unit 1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Team 8: “Chronic liver diseases associated with obesity and alcohol”NiceFrance,Centre Hospitalier Universitaire de NiceDigestive CenterNiceFrance
| | - Mihaly Makara
- Dél‐pesti Centrumkórház–Országos Hematológiai és Infektológiai IntézetBudapestHungary
| | - Ziv Ben Ari
- Liver Disease Center, Chaim Sheba Medical CenterRamat GanIsrael
| | - Marius Braun
- Department of GastroenterologyRabin Medical Center Belinson CampusPetah‐TikvaIsrael
| | - Paul Mitrut
- Spitalul Clinic Judetean de Urgenta CraiovaCraiovaRomania
| | - Sheng‐Shun Yang
- Division of Gastroenterology & Hepatology, Department of Internal MedicineTaichung Veterans General HospitalTaichungTaiwan
| | - Meral Akdogan
- Department of GastroenterologyTürkiye Yüksek Ihtisas HospitalAnkaraTurkey
| | - Mario Pirisi
- Department of Translational MedicineUniversità del Piemonte OrientaleNovaraItaly
| | | | | | | | | | | | - Nezam Afdhal
- Beth Israel Deaconess Medical CenterHarvard Medical SchoolBostonMA
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Nilles KM, Caldwell SH, Flamm SL. Thrombocytopenia and Procedural Prophylaxis in the Era of Thrombopoietin Receptor Agonists. Hepatol Commun 2019; 3:1423-1434. [PMID: 31701067 PMCID: PMC6824078 DOI: 10.1002/hep4.1423] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Accepted: 08/10/2019] [Indexed: 02/06/2023] Open
Abstract
Thrombocytopenia is common in patients with advanced liver disease. These patients frequently require invasive diagnostic or therapeutic procedures in the setting of thrombocytopenia. A common platelet goal before such procedures is ≥50,000/μL, but target levels vary by provider and the procedure. Platelet transfusion has disadvantages, including safety and cost. No other short‐term options for ameliorating thrombocytopenia before procedures were available until the thrombopoietin receptor agonists were recently approved. Avatrombopag and lusutrombopag can be used in certain patients with thrombocytopenia due to advanced liver disease undergoing elective invasive procedures; these new agents are highly effective in carefully selected patients, and real world data of safety and efficacy are awaited. TPO receptor agonists are an exciting new development that can raise platelet counts in liver patients with thrombocytopenia before elective procedures. We review the strategies to address peri‐procedure thrombocytopenia including data on the most recent trials involving TPO receptor agonists.
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Affiliation(s)
- Kathy M Nilles
- Division of Gastroenterology and Hepatology Comprehensive Transplant Center Department of Medicine Northwestern University Feinberg School of Medicine Chicago IL
| | - Stephen H Caldwell
- Division of Gastroenterology and Hepatology Department of Medicine Center for Coagulation in Liver Disease University of Virginia School of Medicine Charlottesville VA
| | - Steven L Flamm
- Division of Gastroenterology and Hepatology Comprehensive Transplant Center Department of Medicine Northwestern University Feinberg School of Medicine Chicago IL
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Ayadi A, Nafari AH, Sakhaee F, Rajabi K, Ghaderi Y, Rahimi Jamnani F, Vaziri F, Siadat SD, Fateh A. Host genetic factors and clinical parameters influencing the occult hepatitis C virus infection in patients on chronic hemodialysis: Is it still a controversial infection? Hepatol Res 2019; 49:605-616. [PMID: 30821879 DOI: 10.1111/hepr.13325] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Revised: 02/04/2019] [Accepted: 02/21/2019] [Indexed: 12/11/2022]
Abstract
AIM The presence of occult hepatitis C virus (HCV) infection (OCI) is still controversial, however, this infection cannot be ignored. Therefore, the current study aimed at assessing the OCI frequency in patients on chronic hemodialysis (CHD) and also evaluating the association between OCI incidence with clinical parameters and interferon lambda 3/4 (IFNL3/4) gene polymorphisms. METHODS A total of 515 patients on CHD and HCV negative markers were selected. Plus- and minus-stranded HCV-RNA was tested in peripheral blood mononuclear cell samples by reverse transcription-polymerase chain reaction and then genotyped using the restriction fragment length polymorphism method. RESULTS The frequency of OCI was 11.3% in patients on CHD. Among 58 patients with OCI, 25.8%, 62.1%, and 12.1% were infected with HCV-1a, HCV-1b, and HCV-3a, respectively. The mean alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase levels were 31.9 ± 24.8, 32.3 ± 19.1, and 171.6 ± 88.9, respectively. None of the patients with OCI had a history of liver disease. Multivariate logistic regression analysis indicated that cholesterol, triglyceride, low-density lipoprotein, 25-hydroxyvitamin D, platelets, duration of hemodialysis, HCV subtypes, IFNL3 rs12979860 TT, IFNL3 rs8099917 GG, IFNL3 rs12980275 GG, and IFNL4 ss469415590 ΔG/ΔG genotypes were associated with OCI. CONCLUSION There was a moderate prevalence of OCI in Iranian patients on CHD. The current study findings indicated that this infection was associated with clinical parameters and unfavorable genotypes of IFNL3 single nucleotide polymorphisms and IFNL4 ss469415590. Further studies are required to determine the correlation between OCI incidence with clinical parameters and host genetic factors.
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Affiliation(s)
- Ahmad Ayadi
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Amir Hossein Nafari
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Fatemeh Sakhaee
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran, Iran.,Microbiology Research Center (MRC), Pasteur Institute of Iran, Tehran, Iran
| | - Kimia Rajabi
- Department of Microbiology, Islamic Azad University, Pharmaceutical, Sciences Branch, Tehran, Iran
| | - Yaser Ghaderi
- Islamic Azad University Central Tehran Branch, Faculty of Basic Science, Tehran, Iran
| | - Fatemeh Rahimi Jamnani
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran, Iran.,Microbiology Research Center (MRC), Pasteur Institute of Iran, Tehran, Iran
| | - Farzam Vaziri
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran, Iran.,Microbiology Research Center (MRC), Pasteur Institute of Iran, Tehran, Iran
| | - Seyed Davar Siadat
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran, Iran.,Microbiology Research Center (MRC), Pasteur Institute of Iran, Tehran, Iran
| | - Abolfazl Fateh
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran, Iran.,Microbiology Research Center (MRC), Pasteur Institute of Iran, Tehran, Iran
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44
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Saleh MI, Melhim SB, Al-Ramadhani HM, Alzubiedi S. Bayesian Population Pharmacokinetic Modeling of Eltrombopag in Chronic Hepatitis C Patients. Eur J Drug Metab Pharmacokinet 2019; 44:31-42. [PMID: 29948848 DOI: 10.1007/s13318-018-0490-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
BACKGROUND AND OBJECTIVES Eltrombopag is a thrombopoietic growth factor that is approved for the treatment of thrombocytopenia in chronic hepatitis C virus (HCV) patients. We aimed to describe eltrombopag population pharmacokinetics in hepatitis C patients. Bayesian statistical approach will be applied to screen for patients' characteristics associated with eltrombopag pharmacokinetic parameters. METHODS A population pharmacokinetic analysis was conducted using WinBUGS version 1.4.3. Data from 483 individuals with chronic HCV infection were analyzed. This analysis is a secondary analysis of two clinical studies (ENABLE1 and ENABLE2) sponsored by GlaxoSmithKline. Several patients' characteristics were examined as possible covariates of the population pharmacokinetic model. Prior information from previous studies was incorporated in the bayesian model as prior distribution to estimate pharmacokinetic parameters. RESULTS A two-compartment pharmacokinetic model with first-order absorption with exponential error model best fit the data. We identified East Asian race and total bilirubin level as predictors of eltrombopag clearance. Typical value for distributional clearance was 0.762 L/h (95% Bayesian credible set, 0.703-0.826), for volume of distribution of the central and peripheral compartments were 12 L (10.9-13.4) and 10.9 L (10.4-11.5), and for absorption lag time was 0.947 h (0.918-0.977). Assuming an average total bilirubin of 21.7 µmol/L, the typical elimination clearance value for an East Asian patient was 0.14 L/h and for other races was 0.20 L/h. CONCLUSIONS Eltrombopag pharmacokinetic behavior was described using population bayesian approach. This model can be applied to optimize eltrombopag dosing in order to reduce the incidence of thrombocytopenia in HCV-infected patient receiving interferon-based therapy.
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Affiliation(s)
- Mohammad I Saleh
- School of Pharmacy, The University of Jordan, Amman, 11942, Jordan.
| | | | | | - Sameh Alzubiedi
- School of Pharmacy, The University of Jordan, Amman, 11942, Jordan
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Ishikawa T, Okoshi M, Tomiyoshi K, Kojima Y, Horigome R, Imai M, Nozawa Y, Iwanaga A, Sano T, Honma T, Yoshida T. Efficacy and safety of repeated use of lusutrombopag prior to radiofrequency ablation in patients with recurrent hepatocellular carcinoma and thrombocytopenia. Hepatol Res 2019; 49:590-593. [PMID: 30602063 PMCID: PMC6849762 DOI: 10.1111/hepr.13305] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2018] [Revised: 12/20/2018] [Accepted: 12/22/2018] [Indexed: 12/11/2022]
Abstract
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.
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Affiliation(s)
- Toru Ishikawa
- Department of Gastroenterology and HepatologySaiseikai Niigata Daini HospitalNiigataJapan
| | - Marina Okoshi
- Department of Gastroenterology and HepatologySaiseikai Niigata Daini HospitalNiigataJapan
| | - Kei Tomiyoshi
- Department of Gastroenterology and HepatologySaiseikai Niigata Daini HospitalNiigataJapan
| | - Yuichi Kojima
- Department of Gastroenterology and HepatologySaiseikai Niigata Daini HospitalNiigataJapan
| | - Ryoko Horigome
- Department of Gastroenterology and HepatologySaiseikai Niigata Daini HospitalNiigataJapan
| | - Michitaka Imai
- Department of Gastroenterology and HepatologySaiseikai Niigata Daini HospitalNiigataJapan
| | - Yujiro Nozawa
- Department of Gastroenterology and HepatologySaiseikai Niigata Daini HospitalNiigataJapan
| | - Akito Iwanaga
- Department of Gastroenterology and HepatologySaiseikai Niigata Daini HospitalNiigataJapan
| | - Tomoe Sano
- Department of Gastroenterology and HepatologySaiseikai Niigata Daini HospitalNiigataJapan
| | - Terasu Honma
- Department of Gastroenterology and HepatologySaiseikai Niigata Daini HospitalNiigataJapan
| | - Toshiaki Yoshida
- Department of Gastroenterology and HepatologySaiseikai Niigata Daini HospitalNiigataJapan
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Takada H, Kurosaki M, Nakanishi H, Takahashi Y, Itakura J, Tsuchiya K, Yasui Y, Tamaki N, Takaura K, Komiyama Y, Higuchi M, Kubota Y, Wang W, Okada M, Shimizu T, Watakabe K, Enomoto N, Izumi N. Real-life experience of lusutrombopag for cirrhotic patients with low platelet counts being prepared for invasive procedures. PLoS One 2019; 14:e0211122. [PMID: 30768601 PMCID: PMC6377090 DOI: 10.1371/journal.pone.0211122] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Accepted: 01/08/2019] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND AND AIMS The present study aimed to report our real-life experience of the TPO receptor agonist lusutrombopag for cirrhotic patients with low platelet counts. METHODS We studied platelet counts in 1,760 cirrhotic patients undergoing invasive procedures at our hospital between January 2014 and December 2017. In addition, we studied 25 patients who were administered lusutrombopag before invasive procedures between June 2017 and January 2018. Effectiveness of lusutrombopag to raise platelet counts and to avoid transfusion and treatment-related adverse events were analyzed. RESULTS In 1,760 cirrhotic patients without lusutrombopag prior to invasive procedures, proportion of patients whose platelet counts <50,000/μL and needed platelet transfusions were 66% (n = 27/41) for radiofrequency ablation, 43% (n = 21/49) for transarterial chemoembolization, and 55% (n = 21/38) for endoscopic injection sclerotherapy / endoscopic variceal ligation, respectively. In 25 cirrhotic patients treated by lusutrombopag prior to the invasive procedures, platelet counts significantly increased compared with baseline (82,000 ± 26,000 vs. 41,000 ± 11,000/μL) (p < 0.01). Out of 25 patients, only 4 patients (16%) needed platelet transfusion before the invasive procedures. The proportion of patients with low platelet count and who needed platelet transfusions was significantly low in patients treated with lusutrombopag compared to those not treated with lusutrombopag (16% (4/25) vs. 54% (69/128), p = 0.001). Platelet counts after lusutrombopag treatment and prior to invasive procedures were lower in patients with a baseline platelet count ≤30,000/μL (n = 8) compared with those with a baseline platelet count >30,000/μL (n = 17) (50,000 ± 20,000 vs 86,000 ± 26,000/μL, p = 0.002). Patients with a baseline platelet count ≤30,000/μL with spleen index (calculated by multiplying the transverse diameter by the vertical diameter measured by ultrasonography) ≥40 cm2 (n = 3) had a lower response rate to lusutrombopag compared to those with spleen index <40 cm2 (n = 5) (0% vs. 100%, p = 0.02). Hemorrhagic complication was not observed. Recurrence of portal thrombosis was observed and thrombolysis therapy was required in one patient who had prior history of thrombosis. CONCLUSIONS Lusutrombopag is an effective and safe drug for thrombocytopenia in cirrhotic patients, and can reduce the frequency of platelet transfusions.
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Affiliation(s)
- Hitomi Takada
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Hiroyuki Nakanishi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Yuka Takahashi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Jun Itakura
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Kaoru Tsuchiya
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Yutaka Yasui
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Nobuharu Tamaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Kenta Takaura
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Yasuyuki Komiyama
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Mayu Higuchi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Youhei Kubota
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Wann Wang
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Mao Okada
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Takao Shimizu
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Keiya Watakabe
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Nobuyuki Enomoto
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Namiki Izumi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
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Elbedewy TA, Elsebaey MA, Elshweikh SA, Elashry H, Abd-Elsalam S. Predictors for eltrombopag response in patients with hepatitis C virus-associated thrombocytopenia. Ther Clin Risk Manag 2019; 15:269-274. [PMID: 30804674 PMCID: PMC6375108 DOI: 10.2147/tcrm.s186106] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background and aims Thrombocytopenia is a common hematological abnormality observed in patients infected with hepatitis C virus (HCV). The use of eltrombopag has been approved for HCV-associated thrombocytopenia. This is the first study aiming to determine the predictive factors of response to eltrombopag therapy in patients with HCV-associated thrombocytopenia. Patients and methods This prospective study was carried out on 130 patients with chronic HCV-associated thrombocytopenia (<50,000×109/L) that precludes the initiation of HCV therapy. Eltrombopag was initiated at a dose of 25 mg once daily; the dose was adjusted with 25 mg increments every 2 weeks to achieve the target platelet count. The primary end point was to achieve stable target platelet count (50,000-100,000×109/L) required to initiate antiviral therapy. Results Treatment response was achieved in 111 (85.38%) patients. This prospective study showed that megakaryocyte hypoplasia or aplasia and splenectomy were independent risk factors for eltrombopag nonresponse in chronic HCV-associated thrombocytopenic patients. Conclusion Eltrombopag is safe and effective for patients with HCV-associated thrombocytopenia. Bone marrow examination should be considered before initiating treatment with eltrombopag in chronic HCV-associated thrombocytopenic patients, especially in patients with splenectomy.
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Affiliation(s)
- Tamer A Elbedewy
- Internal Medicine Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Mohamed A Elsebaey
- Internal Medicine Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Samah A Elshweikh
- Internal Medicine Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Heba Elashry
- Tropical Medicine Department, Faculty of Medicine, Tanta University, Tanta, Egypt,
| | - Sherief Abd-Elsalam
- Tropical Medicine Department, Faculty of Medicine, Tanta University, Tanta, Egypt,
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A randomized controlled trial of lusutrombopag in Japanese patients with chronic liver disease undergoing radiofrequency ablation. J Gastroenterol 2019; 54:171-181. [PMID: 30105510 PMCID: PMC6349796 DOI: 10.1007/s00535-018-1499-2] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2017] [Accepted: 07/31/2018] [Indexed: 02/04/2023]
Abstract
BACKGROUND Thrombocytopenia represents an obstacle for invasive procedures in chronic liver disease (CLD) patients. We aimed to estimate the appropriate dose and evaluate the efficacy and safety of lusutrombopag for the treatment of thrombocytopenia before percutaneous liver radiofrequency ablation (RFA) for primary hepatic cancer in patients with CLD. METHODS In this multicenter, randomized, double-blind, placebo-controlled study conducted in Japan, 61 CLD patients with platelet count < 50 × 103/µL at screening were randomized to placebo or lusutrombopag 2, 3, or 4 mg once daily for 7 days, followed by a 28-day post-treatment assessment period. The primary efficacy endpoint was the proportion of patients who did not require platelet transfusion before RFA. The pre-specified key secondary efficacy endpoint was the proportion of responders. Adverse events (AEs) and thrombosis-related AEs were evaluated. RESULTS The proportion of patients who did not require platelet transfusion before RFA and that of responders were significantly higher (p < 0.01) in the 2-mg (80.0, 66.7%), 3-mg (81.3, 68.8%), and 4-mg groups (93.3, 80.0%) compared with the placebo group (20.0, 6.7%) and showed a dose-dependent effect. The incidence of AEs was 97.8 and 100% in the lusutrombopag (all groups) and placebo groups, respectively; no dose-related increase was observed. Four patients experienced thrombosis-related events (one each in the placebo and 2-mg groups, and two in the 4-mg group). A total of 16 (18%) adverse drug reactions occurred in the safety analysis set. CONCLUSIONS Lusutrombopag 3 mg once daily for 7 days was effective without raising concerns about excessive increases in platelet count. CLINICAL TRIAL REGISTRATION The study is registered at JapicCTI-121944.
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Terrault N, Chen YC, Izumi N, Kayali Z, Mitrut P, Tak WY, Allen LF, Hassanein T. Avatrombopag Before Procedures Reduces Need for Platelet Transfusion in Patients With Chronic Liver Disease and Thrombocytopenia. Gastroenterology 2018; 155:705-718. [PMID: 29778606 DOI: 10.1053/j.gastro.2018.05.025] [Citation(s) in RCA: 165] [Impact Index Per Article: 23.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Revised: 04/30/2018] [Accepted: 05/11/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Patients with thrombocytopenia and chronic liver disease (CLD) may require platelet transfusions before scheduled procedures to decrease risk of bleeding. We performed 2 randomized, placebo-controlled, phase 3 trials in patients with thrombocytopenia and CLD undergoing scheduled procedures to evaluate the safety and efficacy of avatrombopag in increasing platelet counts in this patient population. METHODS In the ADAPT-1 and ADAPT-2 studies, adults with thrombocytopenia and CLD (n = 231 and n = 204, respectively) were in 1 of 2 cohorts according to their baseline platelet count (below 40 × 109/L or 40 to below 50 × 109/L) and within each cohort were randomized (2:1) to receive 5 daily doses of avatrombopag (60 mg if baseline platelet count below 40 × 109/L or 40 mg if 40 to below 50 × 109/L) or placebo. ADAPT-1 was conducted at 75 study sites in 20 countries, from February 2014 through January 2017, and ADAPT-2 was conducted at 74 sites in 16 countries, from December 2013 through January 2017. The primary endpoint was the proportion of patients not requiring platelet transfusions or rescue procedures for bleeding up to 7 days after a scheduled procedure. RESULTS In the ADAPT-1 study, 65.6% of patients who received 60 mg avatrombopag and 88.1% of patients who received 40 mg avatrombopag met the primary endpoint compared with 22.9% and 38.2% of patients receiving placebo, respectively (P < .0001 for both). In the ADAPT-2 study, 68.6% of patients who received 60 mg avatrombopag and 87.9% of patients who received 40 mg avatrombopag met the primary endpoint compared with 34.9% and 33.3% of patients who received placebo, respectively (P < .001 for both). Avatrombopag led to a measured increase in platelet counts and increased the proportion of patients who achieved the target platelet count ≥ 50 × 109/L on procedure day vs placebo. The incidence and severity of adverse events were similar for the avatrombopag and placebo groups and were consistent with those expected in the CLD population. CONCLUSIONS In 2 phase 3 randomized trials, avatrombopag was superior to placebo in reducing the need for platelet transfusions or rescue procedures for bleeding in patients with thrombocytopenia and CLD undergoing a scheduled procedure. ClinicalTrials.gov nos.: NCT01972529 and NCT01976104.
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Affiliation(s)
- Norah Terrault
- University of California San Francisco, San Francisco, California.
| | - Yi-Cheng Chen
- Chang Gung Memorial Hospital and University, Taoyuan, Taiwan
| | | | - Zeid Kayali
- Inland Empire Liver Foundation, Rialto, California
| | - Paul Mitrut
- University of Medicine and Pharmacy of Craiova, Craiova, Romania
| | | | - Lee F Allen
- Dova Pharmaceuticals, Durham, North Carolina
| | - Tarek Hassanein
- Southern California GI and Liver Centers, Coronado, California
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Sofosbuvir Based Regimens in the Treatment of Chronic Hepatitis C with Compensated Liver Cirrhosis in Community Care Setting. Int J Hepatol 2018; 2018:4136253. [PMID: 30155312 PMCID: PMC6093047 DOI: 10.1155/2018/4136253] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Accepted: 07/19/2018] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Direct-acting antiviral (DAA) drugs have been highly effective in the treatment of chronic hepatitis C (CHC) infection. We aim to evaluate the treatment response of Sofosbuvir based DAA in CHC patients with compensated liver cirrhosis as limited data exists in the real-world community setting. METHODS All the CHC patients with compensated liver cirrhosis treated with Sofosbuvir based DAAs between January 2014 and December 2017 in a community clinic setting were retrospectively analyzed. Pretreatment baseline patient characteristics, treatment efficacy with the sustained virologic response at 12 weeks posttreatment (SVR12), and adverse reactions were assessed. RESULTS One hundred and twelve patients with CHC infection and concurrent compensated cirrhosis were included in the study. Black patients represented the majority of the study population (64%). Eighty-seven patients were treated with Ledipasvir/Sofosbuvir (LDV/SOF) ±Ribavirin and 25 patients were treated with Sofosbuvir/Velpatasvir (SOF/VEL). Overall, SVR 12 after treatment was achieved in 90% in patients who received one of the two DAA regimens (89.7% in LDV/SOF group and 92% in SOF/VEL group). SVR 12 did not vary based on age, sex, body mass index, baseline HCV viral load, HCV/HIV coinfection, type of genotype, and prior treatment status. Apart from a low platelet count, there were no other factors associated with a statistical difference in SVR 12(p=0.002) between the two regimens. Fatigue (35%) was the most common adverse effect and no patients discontinued treatment due to adverse effects. CONCLUSION In the community care setting, Sofosbuvir based DAAs are safe, effective with high overall SVR, and well tolerated in patients with CHC patients with compensated liver cirrhosis.
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