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Zhang Y, Wang Z, Zhou P, Zhang H. From reticulated platelets to immature platelet fraction: structure, function, and clinical applications. Platelets 2025; 36:2467383. [PMID: 40035091 DOI: 10.1080/09537104.2025.2467383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2024] [Revised: 01/12/2025] [Accepted: 01/12/2025] [Indexed: 03/05/2025]
Abstract
In comparison to mature platelets, reticulated platelets (RPs) are newly released from the bone marrow and exhibit a larger size, higher reactivity, and a greater quantity of RNA, and can be an agile indicator of platelet turnover. The transcriptome associated with platelet function is significantly upregulated in RPs, which is a possible explanation for RPs intrinsic hyper-reactivity. We presented a comprehensive overview of the detection techniques for RPs. Current methods to quantify RPs in clinical routine are flow cytometry and fully automated hematology analyzers (Sysmex-XE/XN, Abbott, ADVIA, Mindray), which make the detection of RPs simpler, faster and more affordable. The proportion of RPs increased in the circulation has potential diagnostic and prognostic values in multiple clinical settings (risk stratification in cardiovascular diseases, the effect on antiplatelet drugs, differential diagnosis of thrombocytopenia, monitor platelet recovery after bone marrow or stem cell transplantation, and other diseases). There have been several studies focusing on RPs in recent years, particularly in cardiovascular disease and thrombocytopenia. In this review we summarizes the current study with regard to RPs and discuss their likely contribution in clinical routine.
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Affiliation(s)
- Yuxin Zhang
- Class 2020 Clinical Medicine, Southwest Medical University, Luzhou, Sichuan, Peoples Republic of China
| | - Ziyun Wang
- Class 2021 Clinical Medicine, Southwest Medical University, Luzhou, Sichuan, Peoples Republic of China
| | - Pan Zhou
- Department of Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, Peoples Republic of China
| | - Hongwei Zhang
- Department of Blood Transfusion, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, Peoples Republic of China
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Tu J, Wang B, Wang X, Huo K, Hu W, Zhang R, Li J, Zhu S, Liang Q, Han S. Current status and new directions for hepatocellular carcinoma diagnosis. LIVER RESEARCH 2024; 8:218-236. [PMID: 39958920 PMCID: PMC11771281 DOI: 10.1016/j.livres.2024.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 10/17/2024] [Accepted: 12/01/2024] [Indexed: 02/18/2025]
Abstract
Liver cancer ranks as the sixth most common cancer globally, with hepatocellular carcinoma (HCC) accounting for approximately 75%-85% of cases. Most patients present with moderately advanced disease, while those with advanced HCC face limited and ineffective treatment options. Despite diagnostic efforts, no ideal tumor marker exists to date, highlighting the urgent clinical need for improved early detection of HCC. A key research objective is the development of assays that target specific pathways involved in HCC progression. This review explores the pathological origin and development of HCC, providing insights into the mechanistic rationale, clinical statistics, and the advantages and limitations of commonly used diagnostic tumor markers. Additionally, it discusses the potential of emerging biomarkers for early diagnosis and offers a brief overview of relevant assay methodologies. This review aims to summarize existing markers and investigate new ones, providing a basis for subsequent research.
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Affiliation(s)
- Jinqi Tu
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi, Xinjiang, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui, China
| | - Bo Wang
- Animal Experimental Center, Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Xiaoming Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui, China
| | - Kugeng Huo
- Cyagen Biosciences (Guangzhou) Inc., Guangzhou, Guangdong, China
| | - Wanting Hu
- MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Beijing Key Lab of Microanalytical Methods & Instrumentation, Center for Synthetic and Systems Biology, Department of Chemistry, Tsinghua University, Beijing, China
| | - Rongli Zhang
- Department of Medicine, Institute for Transformative Molecular Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA
- Cardiovascular Research Institute, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Jinyao Li
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi, Xinjiang, China
| | - Shijie Zhu
- Department of Oncology, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Qionglin Liang
- MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Beijing Key Lab of Microanalytical Methods & Instrumentation, Center for Synthetic and Systems Biology, Department of Chemistry, Tsinghua University, Beijing, China
| | - Shuxin Han
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi, Xinjiang, China
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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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Zanetto A, Toffanin S, Campello E, Radu CM, Gavasso S, Burra P, Russo FP, Senzolo M, Simioni P. Reticulated platelets are increased and hyper-activated in patients with cirrhosis, especially those with poor outcome. Dig Liver Dis 2024; 56:1327-1334. [PMID: 38553338 DOI: 10.1016/j.dld.2024.03.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 02/26/2024] [Accepted: 03/11/2024] [Indexed: 07/29/2024]
Abstract
BACKGROUND Reticulated platelets (RePLT) are emergency circulating platelets released to contrast peripheral platelet destruction. AIM We conducted a prospective study to [a] characterize RePLT in cirrhosis; [b] evaluate the association between RePLT and hepatic decompensation/death. METHODS Cirrhosis patients without hepatocellular carcinoma were prospectively recruited and underwent assessment of RePLT and thrombopoietin (TPO). RePLT were evaluated by cytofluorimetry and immuno-fluorescence microscopy. Twenty healthy subjects were included as controls. Patients were followed for 6 months for hepatic decompensation and further decompensation/ACLF. RESULTS Forty-five patients were included (Child-Pugh [CP] A/B/C 18/11/16). Compared to controls, RePLT in cirrhosis were significantly increased (0.82% vs. 0.05%; p < 0.001) and hyperactivated (4.35% vs. 0.17%; p = 0.004). No correlation was observed between RePLT and CP, platelet count, TPO, MELD score, and C-reactive protein. TPO was lower in cirrhosis than controls (28 pg/mL vs. 52 pg/mL; p = 0.005), decreasing significantly with CP stage. In CP B/C patients (n = 27), RePLT were significantly higher in those who progressed towards further decompensation/ACLF (2.11 [0.56-2.95] vs. 0.69 [0.02-1.22]; p < 0.01). A proportion of RePLT >2% accurately identified high-risk patients (AUROC 0.818; 95%CI: 0.639-0.997; sensitivity 94%, specificity 73%). CONCLUSION RePLT in cirrhosis are increased and hyper-activated. In decompensated patients, higher RePLT appear to be associated with worse outcomes.
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Affiliation(s)
- Alberto Zanetto
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padova University Hospital, Padova, Italy
| | - Serena Toffanin
- Thrombotic and Haemorrhagic Disease Unit and Haemophilia Center, Department of Medicine (DIMED), University of Padova, Italy
| | - Elena Campello
- Thrombotic and Haemorrhagic Disease Unit and Haemophilia Center, Department of Medicine (DIMED), University of Padova, Italy; General Internal Medicine Unit, Azienda Ospedale - Università Padova, Padova, Italy
| | - Claudia Maria Radu
- Thrombotic and Haemorrhagic Disease Unit and Haemophilia Center, Department of Medicine (DIMED), University of Padova, Italy
| | - Sabrina Gavasso
- Thrombotic and Haemorrhagic Disease Unit and Haemophilia Center, Department of Medicine (DIMED), University of Padova, Italy
| | - Patrizia Burra
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padova University Hospital, Padova, Italy
| | - Francesco Paolo Russo
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padova University Hospital, Padova, Italy
| | - Marco Senzolo
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padova University Hospital, Padova, Italy
| | - Paolo Simioni
- Thrombotic and Haemorrhagic Disease Unit and Haemophilia Center, Department of Medicine (DIMED), University of Padova, Italy; General Internal Medicine Unit, Azienda Ospedale - Università Padova, Padova, Italy.
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Lim HI, Cuker A. Thrombocytopenia and liver disease: pathophysiology and periprocedural management. HEMATOLOGY. AMERICAN SOCIETY OF HEMATOLOGY. EDUCATION PROGRAM 2022; 2022:296-302. [PMID: 36485111 PMCID: PMC9820432 DOI: 10.1182/hematology.2022000408] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/17/2023]
Abstract
Abnormal bleeding in patients with liver disease may result from elevated portal pressure and varix formation, reduced hepatic synthesis of coagulation proteins, qualitative platelet dysfunction, and/or thrombocytopenia. Major mechanisms of thrombocytopenia in liver disease include splenic sequestration and impaired platelet production due to reduced thrombopoietin production. Alcohol and certain viruses may induce marrow suppression. Immune thrombocytopenia (ITP) may co-occur in patients with liver disease, particularly those with autoimmune liver disease or chronic hepatitis C. Drugs used for the treatment of liver disease or its complications, such as interferon, immunosuppressants, and antibiotics, may cause thrombocytopenia. Periprocedural management of thrombocytopenia of liver disease depends on both individual patient characteristics and the bleeding risk of the procedure. Patients with a platelet count higher than or equal to 50 000/µL and those requiring low-risk procedures rarely require platelet-directed therapy. For those with a platelet count below 50 000/µL who require a high-risk procedure, platelet-directed therapy should be considered, especially if the patient has other risk factors for bleeding, such as abnormal bleeding with past hemostatic challenges. We often target a platelet count higher than or equal to 50 000/µL in such patients. If the procedure is elective, we prefer treatment with a thrombopoietin receptor agonist; if it is urgent, we use platelet transfusion. In high-risk patients who have an inadequate response to or are otherwise unable to receive these therapies, other strategies may be considered, such as a trial of empiric ITP therapy, spleen-directed therapy, or transjugular intrahepatic portosystemic shunt placement.
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Affiliation(s)
- Hana I Lim
- Department of Medicine, Weill Cornell Medicine, New York, NY
| | - Adam Cuker
- Department of Medicine and Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
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Ding JN, Feng TT, Sun W, Cai XY, Zhang Y, Zhao WF. Recombinant human thrombopoietin treatment in patients with chronic liver disease-related thrombocytopenia undergoing invasive procedures: A retrospective study. World J Gastrointest Surg 2022; 14:1260-1271. [PMID: 36504518 PMCID: PMC9727570 DOI: 10.4240/wjgs.v14.i11.1260] [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: 09/19/2022] [Revised: 10/30/2022] [Accepted: 11/16/2022] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND Chronic liver disease (CLD) related thrombocytopenia increases the risk of bleeding and poor prognosis. Many liver disease patients require invasive procedures or surgeries, such as liver biopsy or endoscopic variceal ligation, and most of them have lower platelet counts, which could aggravate the risk of bleeding due to liver dysfunction and coagulation disorders. Unfortunately, there is no defined treatment modality for CLD-induced thrombocytopenia. Recombinant human thrombopoietin (rhTPO) is commonly used to treat primary immune thrombocytopenic purpura and thrombocytopenia caused by solid tumor chemotherapy; however, there are few reports on the use of rhTPO in the treatment of CLD-related thrombocytopenia. AIM To evaluate the efficacy of rhTPO in the treatment of patients with CLD-associated thrombocytopenia undergoing invasive procedures. METHODS All analyses were based on the retrospective collection of clinical data of patients with CLD who were treated in the Department of Infectious Diseases at The First Affiliated Hospital of Soochow University between June 2020 and December 2021. Fifty-nine male and 41 female patients with liver disease were enrolled in this study to assess the changes in platelet counts and parameters before and after the use of rhTPO for thrombocytopenia. Adverse events related to treatment, such as bleeding, thrombosis, and disseminated intravascular coagulation, were also investigated. RESULTS Among the enrolled patients, 78 (78%) showed a platelet count increase after rhTPO use, while 22 (22%) showed no significant change in platelet count. The mean platelet count after rhTPO treatment in all patients was 101.53 ± 81.81 × 109/L, which was significantly improved compared to that at baseline (42.88 ± 16.72 × 109/L), and this difference was statistically significant (P < 0.001). In addition, patients were further divided into three subgroups according to their baseline platelet counts (< 30 × 109/L, 30-50 × 109/L, > 50 × 109/L). Subgroup analyses showed that the median platelet counts after treatment were significantly higher (P < 0.001, all). Ninety (90%) patients did not require platelet transfusion partially due to an increase in platelet count after treatment with rhTPO. No serious adverse events related to rhTPO treatment were observed. Overall, rhTPO demonstrated good clinical efficacy for treating CLD-associated thrombocytopenia. CONCLUSION rhTPO can improve platelet count, reduce the risk of bleeding, and decrease the platelet transfusion rate, which may promote the safety of invasive procedures and improve overall survival of patients with CLD.
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Affiliation(s)
- Jing-Nuo Ding
- Department of Infectious Diseases, The First Affiliated Hospital of Soochow University, Suzhou 215000, Jiangsu Province, China
| | - Ting-Ting Feng
- Department of Infectious Diseases, The First Affiliated Hospital of Soochow University, Suzhou 215000, Jiangsu Province, China
| | - Wei Sun
- Department of Infectious Diseases, The First Affiliated Hospital of Soochow University, Suzhou 215000, Jiangsu Province, China
| | - Xin-Yi Cai
- Department of Infectious Diseases, The First Affiliated Hospital of Soochow University, Suzhou 215000, Jiangsu Province, China
| | - Yun Zhang
- Department of Infectious Diseases, The First Affiliated Hospital of Soochow University, Suzhou 215000, Jiangsu Province, China
| | - Wei-Feng Zhao
- Department of Infectious Diseases, The First Affiliated Hospital of Soochow University, Suzhou 215000, Jiangsu Province, China
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Chen SH, Tsai SC, Lu HC. Platelets as a Gauge of Liver Disease Kinetics? Int J Mol Sci 2022; 23:11460. [PMID: 36232759 PMCID: PMC9569526 DOI: 10.3390/ijms231911460] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 09/22/2022] [Accepted: 09/25/2022] [Indexed: 11/18/2022] Open
Abstract
A multitude of laboratory and clinical interferences influence the utility of platelet-based diagnostic indices, including immature platelet fraction, in longitudinal monitoring and prognostication of patients with chronic liver disease (CLD). The complex yet highly regulated molecular basis of platelet production and clearance kinetics becomes dysregulated in liver pathogenesis. These underlying molecular mechanisms, including premature platelet clearance and bone marrow suppression in parallel with the progressive (e.g., treatment-naïve) or regressive (e.g., on-treatment and off-treatment) disease courses, involved in CLDs, may further confound the changes in platelet-liver correlations over time. Platelet count and function are commonly and secondarily altered in vivo in CLDs. However, the precise characterization of platelet functions during cirrhosis, including in vitro platelet aggregation, has proven challenging due to interferences such as thrombocytopenia. A flow cytometric approach may help monitor the unstably rebalanced hyper- and hypoaggregable states in patients with cirrhosis at risk of hyperaggregable, prothrombotic, or bleeding events. Studies have attempted to stratify patients with cirrhosis by substages and prognosis through the use of novel indices such as the ratio of in vitro endogenous platelet aggregation to platelet count. This review attempts to highlight clinical and laboratory precautions in the context of platelet-assisted CLD monitoring.
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Affiliation(s)
- Sheng-Hung Chen
- Department of Medicine, China Medical University, No. 91, Xueshi Road, Taichung 404333, Taiwan
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, No. 2, Yude Road, Taichung 404327, Taiwan
| | - Shih-Chang Tsai
- Department of Biological Science and Technology, China Medical University, Taichung 404333, Taiwan
| | - Hsiu-Chen Lu
- Department of Education, China Medical University Hospital, Taichung 404327, Taiwan
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Hamad MA, Krauel K, Schanze N, Gauchel N, Stachon P, Nuehrenberg T, Zurek M, Duerschmied D. Platelet Subtypes in Inflammatory Settings. Front Cardiovasc Med 2022; 9:823549. [PMID: 35463762 PMCID: PMC9021412 DOI: 10.3389/fcvm.2022.823549] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Accepted: 03/09/2022] [Indexed: 12/24/2022] Open
Abstract
In addition to their essential role in hemostasis and thrombosis, platelets also modulate inflammatory reactions and immune responses. This is achieved by specialized surface receptors as well as secretory products including inflammatory mediators and cytokines. Platelets can support and facilitate the recruitment of leukocytes into inflamed tissue. The various properties of platelet function make it less surprising that circulating platelets are different within one individual. Platelets have different physical properties leading to distinct subtypes of platelets based either on their function (procoagulant, aggregatory, secretory) or their age (reticulated/immature, non-reticulated/mature). To understand the significance of platelet phenotypic variation, qualitatively distinguishable platelet phenotypes should be studied in a variety of physiological and pathological circumstances. The advancement in proteomics instrumentation and tools (such as mass spectrometry-driven approaches) improved the ability to perform studies beyond that of foundational work. Despite the wealth of knowledge around molecular processes in platelets, knowledge gaps in understanding platelet phenotypes in health and disease exist. In this review, we report an overview of the role of platelet subpopulations in inflammation and a selection of tools for investigating the role of platelet subpopulations in inflammation.
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Affiliation(s)
- Muataz Ali Hamad
- Department of Cardiology and Angiology I, Heart Center, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany
- Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, Freiburg im Breisgau, Germany
- Faculty of Biology, University of Freiburg, Freiburg im Breisgau, Germany
| | - Krystin Krauel
- Department of Cardiology and Angiology I, Heart Center, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany
- Department of Cardiology, Angiology, Haemostaseology, and Medical Intensive Care, University Medical Centre Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Nancy Schanze
- Department of Cardiology and Angiology I, Heart Center, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany
- Department of Cardiology, Angiology, Haemostaseology, and Medical Intensive Care, University Medical Centre Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Nadine Gauchel
- Department of Cardiology and Angiology I, Heart Center, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany
| | - Peter Stachon
- Department of Cardiology and Angiology I, Heart Center, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany
| | - Thomas Nuehrenberg
- Department of Cardiology and Angiology II, Heart Center, Faculty of Medicine, University of Freiburg, Bad Krozingen, Germany
| | - Mark Zurek
- Department of Cardiology and Angiology II, Heart Center, Faculty of Medicine, University of Freiburg, Bad Krozingen, Germany
| | - Daniel Duerschmied
- Department of Cardiology and Angiology I, Heart Center, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany
- Department of Cardiology, Angiology, Haemostaseology, and Medical Intensive Care, University Medical Centre Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- European Center for AngioScience (ECAS) and German Center for Cardiovascular Research (DZHK) Partner Site Heidelberg/Mannheim, Mannheim, Germany
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Hamad MA, Schanze N, Schommer N, Nührenberg T, Duerschmied D. Reticulated Platelets-Which Functions Have Been Established by In Vivo and In Vitro Data? Cells 2021; 10:cells10051172. [PMID: 34065800 PMCID: PMC8150321 DOI: 10.3390/cells10051172] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 04/29/2021] [Accepted: 05/10/2021] [Indexed: 12/18/2022] Open
Abstract
Reticulated platelets (RP) are the youngest platelet fraction released into the circulation. These immature platelets have increased RNA content, a larger cell volume, more dense granules, higher levels of surface activation markers and are thought to be more reactive compared to their mature counterparts. RP have been associated with cardiovascular disease, diabetes and increased mortality. Yet only a few animal studies investigating RP have been conducted so far and further investigations are warranted. Established methods to count RP are flow cytometry (staining with thiazole orange or SYTO13) or fully automated hematology analyzers (immature platelet fraction, IPF). IPF has been established as a diagnostic parameter in thrombocytopenia, cardiovascular disease and, in particular, the response to antiplatelet therapy. This review seeks to provide an overview of the key features of RP as well as preanalytical and analytical aspects that need to be considered when working with this platelet population.
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Affiliation(s)
- Muataz Ali Hamad
- Department of Cardiology and Angiology I, Heart Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg im Breisgau, Germany; (N.S.); (N.S.); (D.D.)
- Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, 79104 Freiburg im Breisgau, Germany
- Faculty of Biology, University of Freiburg, 79104 Freiburg im Breisgau, Germany
- Correspondence: ; Tel.: +49-761-270-70470
| | - Nancy Schanze
- Department of Cardiology and Angiology I, Heart Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg im Breisgau, Germany; (N.S.); (N.S.); (D.D.)
| | - Nicolas Schommer
- Department of Cardiology and Angiology I, Heart Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg im Breisgau, Germany; (N.S.); (N.S.); (D.D.)
| | - Thomas Nührenberg
- Department of Cardiology and Angiology II, Heart Center, Faculty of Medicine, University of Freiburg, 79189 Bad Krozingen, Germany;
| | - Daniel Duerschmied
- Department of Cardiology and Angiology I, Heart Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg im Breisgau, Germany; (N.S.); (N.S.); (D.D.)
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Benlachgar N, Doghmi K, Masrar A, Mahtat EM, Harmouche H, Tazi Mezalek Z. Immature platelets: a review of the available evidence. Thromb Res 2020; 195:43-50. [PMID: 32652352 DOI: 10.1016/j.thromres.2020.06.048] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Revised: 05/12/2020] [Accepted: 06/30/2020] [Indexed: 12/28/2022]
Abstract
Immature platelets or reticulated platelets are newly released thrombocytes. They can be identified by their large size and high RNA cytoplasm concentration. Immature platelet fraction (IPF) represents the percentage of immature circulative platelets to the total number of platelets. The development of analytical standardization of this hematological parameter by new automated devices allowed a better exploration of its contribution in a context of thrombocytopenia. In fact, several studies had confirmed its clinical utility to differentiate immune thrombocytopenia from other causes of thrombocytopenia. IPF can also predict platelets recovery after chemotherapy and successful engraftment. In addition, immature platelets have shown utility in other diseases such as coronary artery diseases, bacterial infections and liver diseases. Despite all these advantages, immature platelet fraction can be increased in some cases of thrombocytopenia characterized by platelets hypoproduction. The aim of this review is to present the immature platelet fraction contribution in clinical practice.
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Affiliation(s)
- Naoufal Benlachgar
- Department of Clinical Haematology, Military Hospital of Instruction Mohamed V, Rabat, Morocco.
| | - Kamal Doghmi
- Department of Clinical Haematology, Military Hospital of Instruction Mohamed V, Rabat, Morocco
| | - Azlarab Masrar
- Central laboratory of hematology, Ibn Sina Hospital, University Mohamed V of Medicine, Rue Lamfadel Cherkaoui, BP 6527 Rabat, Morocco
| | - El Mehdi Mahtat
- Department of Clinical Haematology, Military Hospital of Instruction Mohamed V, Rabat, Morocco
| | - Hicham Harmouche
- Internal Medicine Department, Ibn Sina Hospital, University Mohamed V of Medicine, Rue Lamfadel Cherkaoui, BP 6527 Rabat, Morocco
| | - Zoubida Tazi Mezalek
- Internal Medicine Department, Ibn Sina Hospital, University Mohamed V of Medicine, Rue Lamfadel Cherkaoui, BP 6527 Rabat, Morocco
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Zermatten MG, Fraga M, Moradpour D, Bertaggia Calderara D, Aliotta A, Stirnimann G, De Gottardi A, Alberio L. Hemostatic Alterations in Patients With Cirrhosis: From Primary Hemostasis to Fibrinolysis. Hepatology 2020; 71:2135-2148. [PMID: 32090357 DOI: 10.1002/hep.31201] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 01/20/2020] [Accepted: 02/11/2020] [Indexed: 12/11/2022]
Abstract
In the setting of liver cirrhosis (LC), profound hemostatic changes occur, which affect primary hemostasis, coagulation, and fibrinolysis. They involve prohemorrhagic and prothrombotic alterations at each of these steps. Patients with cirrhosis exhibit multifactorial thrombocytopenia and in vitro thrombocytopathy, counterbalanced by increased von Willebrand factor. The resultant shift is difficult to assess, but overall these changes probably result in a rebalanced primary hemostasis. Concerning coagulation, the reduced activity of coagulation factors is counterbalanced by an increase in factor VIII (produced by liver sinusoidal endothelial cells), a decrease of the natural anticoagulants, and complex changes, including changes in circulating microparticles, cell-free DNA, and neutrophil extracellular traps. Overall, these alterations result in a procoagulant state. As for fibrinolysis, increased tissue-type and urokinase-type plasminogen activators, a relatively decreased plasminogen activator inhibitor 1, and decreased levels of thrombin-activatable fibrinolysis inhibitor and α2-antiplasmin are counterbalanced by decreased plasminogen and a decreased fibrin clot permeability. Whether and how these changes shift fibrinolysis remains to be determined. Overall, the current consensus is that in patients with cirrhosis, the hemostasis is shifted toward a procoagulant state. We review the published evidence for the concept of LC as a prothrombotic state, discuss discordant data, and highlight the impact of the underlying cause of LC on the resultant imbalance.
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Affiliation(s)
- Maxime G Zermatten
- Division of Hematology and Central Hematology Laboratory, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland
| | - Montserrat Fraga
- Division of Gastroenterology and Hepatology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland
| | - Darius Moradpour
- Division of Gastroenterology and Hepatology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland
| | - Debora Bertaggia Calderara
- Division of Hematology and Central Hematology Laboratory, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland
| | - Alessandro Aliotta
- Division of Hematology and Central Hematology Laboratory, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland
| | - Guido Stirnimann
- University Clinic for Visceral Surgery and Medicine, University Hospital Inselspital and University of Bern, Bern, Switzerland
| | - Andrea De Gottardi
- University Clinic for Visceral Surgery and Medicine, University Hospital Inselspital and University of Bern, Bern, Switzerland.,Gastroenterology and Hepatology, Ente Ospedaliero Cantonale, Università della Svizzera Italiana, Lugano, Switzerland
| | - Lorenzo Alberio
- Division of Hematology and Central Hematology Laboratory, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland
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12
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Sigal SH, Sherman Z, Jesudian A. Clinical Implications of Thrombocytopenia for the Cirrhotic Patient. ACTA ACUST UNITED AC 2020; 12:49-60. [PMID: 32341665 PMCID: PMC7166072 DOI: 10.2147/hmer.s244596] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Accepted: 03/10/2020] [Indexed: 02/06/2023]
Abstract
Thrombocytopenia is a frequent complication in patients with cirrhosis. As many as 84% of patients with cirrhosis have thrombocytopenia, and it is an independent variable indicative of advanced disease and poor prognosis. Although there is great concern that it may aggravate bleeding during surgical procedures, there is limited evidence to inform decisions regarding the treatment of cirrhotic patients with thrombocytopenia undergoing invasive procedures. Finally, there is evidence that platelets play a significant role in liver regeneration. In this report, the clinical implications of thrombocytopenia in cirrhotic patients are reviewed. The utility of platelet counts in the prognosis of cirrhosis and relationship to complications of advanced liver disease, including portal hypertension, esophageal varices, and hepatocellular carcinoma. The impact of low platelet counts on bleeding complications during invasive procedures is outlined. Finally, the role of platelets and potential adverse impact in liver regeneration is reviewed.
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Affiliation(s)
- Samuel H Sigal
- Department of Medicine, Montefiore Medical Center, Bronx, NY, USA
| | - Zachary Sherman
- Department of Medicine, Weill Cornell Medical Center, New York, NY, USA
| | - Arun Jesudian
- Department of Medicine, Weill Cornell Medical Center, New York, NY, USA
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13
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Abstract
Abstract
Reticulated platelets are immature platelets freshly released from the bone marrow into the circulation and contain vestigial amounts of ribonucleic acid. Thus, they can serve as an indicator for the activity of thrombopoiesis. Despite the current lack of a standardized reference method, two types of hematology analyzers have incorporated a fully automated measurement of reticulated platelets. The “immature platelet fraction” (IPF; Sysmex XE-/XN-series) has some clinical utility in the differential diagnosis of thrombocytopenia. This is less clear for “reticulated platelets” (retPLT; Abbott CELL-DYN Sapphire/Alinity HQ). The usefulness of these parameters in the prediction of platelet recovery after chemotherapy or stem cell transplantation and as a decision aid for platelet transfusions has not been unequivocally confirmed. Recent findings have shown an association of reticulated platelets with an adverse risk in patients with coronary artery disease and stroke as well as resistance to anti-platelet therapy. Furthermore, a role of reticulated platelets for the prediction of sepsis was indicated. However, validation in larger prospective trials is necessary to establish the clinical benefit of reticulated platelets in these conditions. This review gives an overview of the available analytical methods and summarizes the current knowledge regarding the clinical application of reticulated platelets.
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Affiliation(s)
- Lisa Meintker
- Department of Medicine 5 for Hematology and Oncology , University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg , Erlangen , Germany
| | - Stefan W. Krause
- Department of Medicine 5 for Hematology and Oncology , University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg , Erlangen , Germany
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14
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Smith JD, Narayanan P, Li N. Biomarkers of platelet dysfunction in non-clinical safety studies and humans. CURRENT OPINION IN TOXICOLOGY 2019. [DOI: 10.1016/j.cotox.2019.11.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
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15
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Shi X, Xia H, Zhang W, Li G, Li A. Radiotherapy for one rectal cancer patient with cirrhosis and moderate to severe thrombocytopenia: a case report. Onco Targets Ther 2018; 11:5203-5207. [PMID: 30214226 PMCID: PMC6118332 DOI: 10.2147/ott.s174638] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
When patients with cirrhosis and severe thrombocytopenia suffer malignant tumors, there is usually no effective and feasible treatment method due to the high risk of hemorrhage. Herein, we report a case in which radiotherapy was given to a patient with a strong desire for the treatment. The patient was a 66-year-old man with a 13-year history of cirrhosis and a 10-year history of thrombocytopenia, and was diagnosed with locally advanced rectal cancer (LARC; T4aN1M0, stage IIIB). The platelet count before radiotherapy was 32 × 109/L, and the blood coagulation was normal. The severity of thrombocytopenia increased after 2 Gy × 7 fractions pelvic radiation, with platelet counts dropping to 16 × 109/L. Platelet counts failed to return to pre-therapy levels after supporting therapy including recombinant human interleukin 11 subcutaneous injection and platelet transfusion. Although radiotherapy was discontinued eventually, the data presented here represent a valuable resource that can help inform treatment decisions for tumor patients with cirrhosis and thrombocytopenia.
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Affiliation(s)
- Xinqi Shi
- Department of Radiation Oncology, The First Hospital of China Medical University, Shenyang, Liaoning, China,
| | - Huifang Xia
- Department of Radiation Oncology, The First Hospital of China Medical University, Shenyang, Liaoning, China,
| | - Weiwei Zhang
- Department of Radiation Oncology, The First Hospital of China Medical University, Shenyang, Liaoning, China,
| | - Guang Li
- Department of Radiation Oncology, The First Hospital of China Medical University, Shenyang, Liaoning, China,
| | - Ailin Li
- Department of Radiation Oncology, The First Hospital of China Medical University, Shenyang, Liaoning, China,
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16
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Povital role of platelet count in platelet-lymphocyte count used in distinguishing patients with significant liver fibrosis and insulin resistance. Eur J Gastroenterol Hepatol 2018; 30:807. [PMID: 29847526 DOI: 10.1097/meg.0000000000001138] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
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