preface
Thrombocytopenia is a common hematologic complication in patients with chronic liver disease. Interventions for prior chronic liver disease-associated thrombocytopenia (CLDT) include platelet transfusion, splenic artery embolization, and splenectomy. The approval of thrombopoietin receptor agonists (TPO-RA) has enriched the treatment options for CLDT. In order to help standardize the diagnosis and treatment of CLDT patients, the case sharing column of "Clear Cases Throughout" was officially launched. The primary liver cancer patient shared in this issue, due to liver cirrhosis/hypersplenism resulting in low platelet count (PLT), after hetrombopag combined with recombinant human thrombopoietin (rhTPO) treatment, the patient's plate lifting effect is still not satisfactory, and the domestic avatrombopag treatment, PLT increased significantly, and the PLT remained good after drug withdrawal, and the subsequent interventional and liver transplantation treatment was smoothly carried out. The cases in this issue were provided by Dr. Ye Sheng from Li Huili Hospital of Ningbo Medical Center, and commented by Professor Huang Jing of Ningbo Li Huili Hospital.
Case Profile
The patient is a 56-year-old male
Chief complaint: comprehensive treatment of liver cancer for more than 3 months
History of present illness: The patient went to the local hospital 3 months ago due to anorexia, and was diagnosed with liver malignancy, cT3N0M0 stage III.A, hepatitis B, liver cirrhosis, and the degree of liver cirrhosis was assessed to be severe at that time, and he was given interventional, immune, targeted and other anti-tumor treatments
Anamnesis: history of chronic hepatitis B, long-term antiviral therapy
Baseline check
Specialist examination
Liver disease. A small number of spider angiomatas may be seen on the skin of the palmar and chest. Primary liver cancer in the right lobe of the liver, cholangiocarcinoma thrombosis; Strengthened nodules in the arterial phase of the left lateral lobe of the liver, suggesting the possibility of high-grade dysplastic nodules. Cirrhosis of the liver with splenomegaly, gastric varices. Multiple small cysts in the liver.
Laboratory tests
White blood cell count 3.4×109/L; Monocyte classification 12.5%; Absolute neutrophil value 1.6×109/L; The mean hemoglobin volume was 34.2 PG; platelet count 78×109/L; Platelet hematocrit 0.08%.
MRI (November 27, 2023)
Primary liver carcinoma in the right lobe of the liver, compared with the increase in the mass and the shrinkage of the subfoci in the anterior film of MR on November 26, 2023. Cirrhosis with splenomegaly, gastric varices, and a small amount of ascites. Multiple small cysts in the liver and kidneys.
Figure 1.2023.11.27 Imaging examination
Clinical diagnosis
1.原发性肝癌（cT3N0M0 IIIA期）
2. Hyperammonemia
3. Hepatic insufficiency
4. Thrombocytopenia
5. Chronic viral hepatitis B
6. Portal hypertensive gastroenteropathy
7. Decompensated cirrhosis
8. Splenomegaly and hypersplenism
Treatment
The patient was decompensated with liver cancer in the decompensated stage of liver cirrhosis, and the risk of surgical resection was high, so hepatic artery interventional chemotherapy was first performed to control the intrahepatic tumor, and at the same time, anti-tumor therapy such as targeted and immune therapy was given. At the same time, after multidisciplinary discussion, considering that the patient's liver cancer is still within the Milan criteria, liver transplantation is recommended.
During the treatment, the patient's platelet count (PLT) was low due to liver cirrhosis/hypersplenism, which remained around 50×109/L for a long time, and was then treated with a plate rise.
- February 23-29, 2024,rhTPO 15000U QD,此前自行薬海曲泊帕2.5 mg QD。
- Feb. 26, PLT 53×109/L.
- From February 29 to March 13, 2024, oral treatment with domestic avatrombopag maleate (20 mg QD).
- March 1, Blood Normal PLT 74×109/L.
- March 2, Blood Normal PLT 92×109/L.
- On March 4, the line was intervened in TACE, idarubicin 10 mg, oxaliplatin 20 mg.
Figure 2: Trend chart of platelet indicators in March 2024
- On April 2, the second interventional treatment was performed.
- On April 8, he underwent split allogeneic liver transplantation, and the patient recovered well after surgery.
Case summary
The patient was diagnosed with primary liver cancer (cT3N0M0 stage IIIA) with cholangiocarcinoma thrombus, no extrahepatic metastases, liver cirrhosis with splenomegaly, multiple small cysts in the liver, hepatic artery interventional chemotherapy to control intrahepatic tumors, targeted and immune anti-tumor treatments, and liver transplantation. During the treatment, the patient was treated with rhTPO and hetrombopag due to low platelets due to liver cirrhosis/hypersplenism, which had a great impact on subsequent interventional and invasive treatments such as liver transplantation, but the effect was still not good. Switched to oral domestic avatrombopag maleate treatment, platelet rise was obvious.
Case reviews
The prevalence of thrombocytopenia is high in patients with chronic liver disease, ranging from 6% to 16% in patients with chronic hepatitis and up to 78% in patients with cirrhosis. The common hepatitis virus-associated thrombocytopenia is a decrease in platelet production and increased destruction due to factors such as liver lesions, spleen lesions, immune destruction, and bone marrow suppression, which ultimately leads to thrombocytopenia. For patients with liver tumors, thrombocytopenia can be further exacerbated by tumor treatments (such as interventional, radiotherapy, chemotherapy, and targeted and immunotherapy) in addition to liver disease itself1. Clinically, a platelet count < 100×109/L is generally defined as thrombocytopenia and a platelet count < 50×109/L is defined as severe thrombocytopenia2. Patients with PLT < 50×109/L and liver cirrhosis are usually not suitable for liver biopsy, intervention, surgery and other liver disease operations, which seriously limits the diagnosis and treatment process of such patients3. Therefore, for patients with liver cancer with thrombocytopenia, platelet-elevating therapy is required before invasive procedures or anti-tumor therapy to ensure a more comprehensive benefit.
Proplateletizing drugs include rhTPO and TPO-RA, which regulate megakaryocyte proliferation, differentiation and maturation by specifically binding to TPO receptors and promote platelet production. At present, a variety of thrombocytopoietic drugs have been approved for clinical application worldwide. Among them, avatrombopag maleate, as the first therapeutic drug for CLDT in China, fills the gap in the clinical needs of CLDT in China, and the drug has demonstrated therapeutic value in various CLDT patients in clinical studies4. Results from the global multicenter, randomized, double-blind, placebo-controlled, phase III clinical study (ADAPT-1, ADAPT-2) showed that avatrombopag significantly reduced the proportion of adult patients with CLDT who received perioperative platelet transfusions or were rescued due to bleeding5. A retrospective study of liver cancer showed that 81.7% of patients with platelet < 50×109/L were treated with avatrombopag for 5 days, and the peak platelet count was ≥ 50×109/L and an ≥increase of 20×109/L compared with baseline, indicating a higher disease control rate for patients with avatrombopag response. In addition, avatrombopag has been reported to improve hematopoietic function in patients with severe hepatitis-related aplastic anemia and lenvatinib-associated severe aplastic anemia1. In terms of safety, avatrombopag was well tolerated overall3.
Based on the good efficacy and tolerability of avatrombopag, it has been written into clinical guidelines and expert consensus at home and abroad, including the Guidelines for the Diagnosis and Treatment of Primary Liver Cancer (2024 Edition), the Chinese Expert Consensus on the Clinical Management of Liver Disease-Associated Thrombocytopenia, the Chinese Expert Consensus on the Management of Thrombocytopenia in Patients with Tumor Complicated with Liver Injury, and the 2023 ISTH Guidelines: Management of Chemotherapy-Associated Thrombocytopenia1,6,7,8. At the same time, avatrombopag has been included in the mainland medical insurance list, which greatly increases the accessibility of the drug and is expected to benefit more CLDT patients.
In this case, the primary liver cancer patient had low platelets due to liver cirrhosis/hypersplenism, which remained around 50×109/L for a long time, which had a great impact on subsequent interventional and invasive treatments such as liver transplantation. After evaluation, oral avatrombopag maleate was treated, and the platelet count increased significantly, and the platelet count remained good after discontinuation of the drug, which escorted many subsequent invasive diagnosis and treatment.
Overall, the use of avatrombopag maleate can bring significant clinical benefit to patients with CLDT. With the accumulation of clinical experience and the deepening of research, it is expected that it can play a greater role in clinical practice in the future and benefit more patients.
Bibliography:
1. National Clinical Research Center for Infectious Diseases, Hepatology Branch of Beijing Medical Association, Translational Medicine Branch of Chinese Society of Gerontology and Geriatrics. Chinese expert consensus on the clinical management of liver disease-associated thrombocytopenia. Journal of Clinical Hepatobiliary Diseases. 2023, 39(10): 2307-2320.
2. Critical Care Medicine Professional Committee of the Army, Laboratory Medicine Branch of Chinese Medical Association. Expert consensus on the diagnosis and treatment of thrombocytopenia in Chinese adult patients with severe disease. PLA Medical Journal.2020,45(2):95-112.
3. Wu Yongle, Yi Yin, Zhang Jinhe, et al. Clinical efficacy of avatrombopag maleate in the treatment of liver cirrhosis complicated with thrombocytopenia. Beijing Medical Journal,2024,46(01):1-4.
4. Thrombosis and Haemostasis Group, Hematology Branch, Chinese Medical Association. Chinese Expert Consensus on the Clinical Application and Management of Thrombocytopoietic Drugs (2023 Edition).Chinese Journal of Hematology, 2023,44(7) : 535-542.
5. Terrault N, Chen YC, Izumi N, et al. Avatrombopag Before Procedures Reduces Need for Platelet Transfusion in Patients With Chronic Liver Disease and Thrombocytopenia. Gastroenterology. 2018 Sep; 155(3):705-718.
6. Department of Medical Administration, National Health Commission, People's Republic of China. Guidelines for the diagnosis and treatment of primary liver cancer (2024 edition). Chin J Practical Surg,2024,44(4):361-386.
7. Tumor Supportive Care Committee of Chinese Anti-Cancer Association. Chinese Expert Consensus on the Management of Thrombocytopenia in Patients with Tumor and Liver Injury (2022 Edition). Journal of Cancer Prevention and Treatment Research, 2023, 50(3): 211-223.
8. Terrault N, Chen YC, Izumi N, et al. Management of chemotherapy-induced thrombocytopenia: guidance from the ISTH Subcommittee on Hemostasis and Malignancy. J Thromb Haemost. 2024 Jan; 22(1):53-60.
Review experts