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Yu M, Zheng C, Wang X, Peng R, Lu G, Zhang J. Phosphatidylserine induce thrombotic tendency and liver damage in obstructive jaundice. BMC Gastroenterol 2025; 25:146. [PMID: 40050731 PMCID: PMC11884107 DOI: 10.1186/s12876-025-03739-9] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Accepted: 02/27/2025] [Indexed: 03/10/2025] Open
Abstract
INTRODUCTION Hypercoagulability contributes to the majority of deaths and organ failure associated with obstructive jaundice (OJ). However, the exact mechanism of the coagulopathy in OJ remains elusive. Our objectives were to demonstrate whether phosphatidylserine (PS) exposure on blood cells (BCs), microparticles (MPs), and endothelial cells (ECs) can account for the hypercoagulability and liver damage in OJ patients. METHODS We evaluated OJ patients at two time point, which before (Day 0) and 7 days (Day 7) after the endoscopic retrograde cholangiopancreatography procedure (ERCP), and compared with healthy controls. Lactadherin was used to quantify PS exposure on BCs, MPs and ECs. Human umbilical vein endothelial cells (HUVECs) were incubated with serum of OJ patients and the expression of PS were evaluated. Meanwhile, healthy BCs and HUVECs were treated with 0, 25, 50 or 100µM unconjugated bilirubin (UCB) and PS exposure on cells were evaluated. Procoagulant activity was evaluated by purified coagulation complex assays, clotting time, and fibrin turbidity. In addition, we established a cholestatic mouse model by bile duct ligation to determine the potential role of PS in intrahepatic coagulation and liver damage. RESULTS Using flow cytometry, we found that OJ patients exhibited elevated levels of PS + BCs and associated MPs compared to the controls. Furthermore, the number of PS + BCs and MPs in patients at Day 0 were significantly higher than in patients at Day 7. Similarly, we observed markedly elevated PS exposure on HUVECs cultured with serum from patients at Day 0 versus serum from patients at Day 7. In vitro assays, PS exposure on BCs and HUVECs progressively increased with the concentration of UCB. Moreover, PS + BCs and MPs contributed to greatly shortened coagulation time and markedly enhanced coagulation factor Xa, thrombin, and fibrin generation. This procoagulant activity could be blocked approximately 80%, by the addition of lactadherin. Moreover, cholestatic mice exhibited significantly increased levels of liver tissue necrosis, fibrin deposition, and thrombophilia compared to sham mice. The enhanced intrahepatic coagulation and liver injury could be reversed by inhibiting PS with lactadherin. CONCLUSIONS These results highlight the pathogenic activity of PS + cells and MPs in promoting a prothrombotic environment and liver damage in OJ. As such, lactadherin, a PS blockade, may be a viable therapeutic strategy for treating such patients.
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Affiliation(s)
- Muxin Yu
- Department of Medicine, Jiaxing University, Jiaxing, 314001, China
| | - Chuwei Zheng
- Department of Gastroenterology, The Second Affiliated Hospital of Jiaxing University, Jiaxing, 314001, China
| | - Xiaoguang Wang
- Department of Hepatic Surgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, 314001, China
| | - Rong Peng
- Department of Medicine, Jiaxing University, Jiaxing, 314001, China
| | - Guoming Lu
- Department of Medicine, Jiaxing University, Jiaxing, 314001, China
| | - Jinming Zhang
- Department of Gastroenterology, The Second Affiliated Hospital of Jiaxing University, Jiaxing, 314001, China.
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Li S, Zhou C, Li W, Kang L, Mu H. The effects of coagulation factors on the risk of autoimmune diseases: A Mendelian randomization study. Medicine (Baltimore) 2024; 103:e40893. [PMID: 39969330 PMCID: PMC11688059 DOI: 10.1097/md.0000000000040893] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Accepted: 11/22/2024] [Indexed: 02/20/2025] Open
Abstract
The objective of this study was to investigate the potential causal relationship between coagulation factors and autoimmune diseases (ADs). We employed Mendelian randomization to investigate the associations between selected 7 coagulation factors and 10 ADs, leveraging genetic variants as instrumental variables to assess causal relationships between exposures of interest and outcomes. Within the scope of this investigation, coagulation factors were designated as the exposure source, while ADs were observed to manifest as the consequent outcome. Our analysis using the inverse-variance weighted (IVW) method revealed that Factor VIII (FVIII) (P = .0067) exhibited significant causal associations with a reduced risk of multiple sclerosis. In contrast, fibrinogen (P = .0004) was associated with an increased risk of multiple sclerosis. The analysis also indicated that activated partial thromboplastin time (P = .0047) was implicated in elevating the risk of urticaria. The results also showed that protein C (P = .0188) was inversely associated with the risk of systemic lupus erythematosus. The results unveiled a significant positive correlation between fibrinogen (P = .0318) and the risk of rheumatoid arthritis. Similarly, Factor VII (P = .0119), FVIII (P = .0141), and von Willebrand Factor (P = .0494) were also found to be positively associated with the risk of inflammatory bowel disease. The IVW analysis demonstrated a causal relationship between von Willebrand Factor (P = .0316) and FVIII (P = .0408) and a decreased risk of primary sclerosing cholangitis. IVW results confirmed that protein C (P = .0409) had a protective effect on vitiligo. No significant associations were found between psoriatic arthritis, rosacea, and the 7 coagulation factors in this study. This is of significant importance for advancing the prevention, diagnosis, and treatment of ADs.
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Affiliation(s)
- Shuxuan Li
- Clinical Laboratory, Tianjin First Center Hospital, Tianjin, China
| | - Chunlei Zhou
- Clinical Laboratory, Tianjin First Center Hospital, Tianjin, China
| | - Wenjing Li
- Clinical Laboratory, Tianjin First Center Hospital, Tianjin, China
| | - Lichun Kang
- Clinical Laboratory, Tianjin First Center Hospital, Tianjin, China
| | - Hong Mu
- Clinical Laboratory, Tianjin First Center Hospital, Tianjin, China
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Koh A, Bull N, Brown L, Thomson B, Loveday BPT. Prospective cohort study of rotational thromboelastometry in established biliary obstruction: dispelling the myth of auto-anticoagulation. HPB (Oxford) 2024:S1365-182X(24)02321-9. [PMID: 39353846 DOI: 10.1016/j.hpb.2024.09.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Revised: 07/26/2024] [Accepted: 09/10/2024] [Indexed: 10/04/2024]
Abstract
BACKGROUND Patients with obstructive jaundice are conventionally described as hypocoagulable due to vitamin K malabsorption. However, associated underlying malignancy and synthetic liver dysfunction are mediators of hypercoagulability. The actual effect of biliary obstruction on the coagulation profile is not well characterised. This study aimed to define the coagulation status of patients with established biliary obstruction using rotational thromboelastometry (ROTEM). METHODS This prospective cohort study, conducted in an Australian metropolitan hospital, included patients with a total bilirubin level of >150 umol/L and biliary obstruction on imaging. The primary outcome was the coagulation profile assessed using ROTEM. RESULTS 20 patients were included (median age 74.5 years), 15 were male and 17 had a malignant cause for biliary obstruction. The median bilirubin level was 209 umol/L (IQR: 175.0 umol/L - 255.8 umol/L). On ROTEM, all patients had normal or reduced clot formation times, and normal or increased maximum clot firmness. This confirmed all patients had a normal or hypercoagulable clotting profile, and none were auto-anticoagulated. Vitamin K administration before ROTEM did not vary the coagulation profile. DISCUSSION Patients with established biliary obstruction and jaundice, predominantly due to malignancy, were normo or hypercoagulable. The belief that obstructive jaundice is associated with a hypocoagulable state should be questioned.
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Affiliation(s)
- Angelina Koh
- Department of General Surgical Specialties, The Royal Melbourne Hospital, Melbourne, VIC 3052, Australia.
| | - Nicholas Bull
- Department of General Surgical Specialties, The Royal Melbourne Hospital, Melbourne, VIC 3052, Australia; Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, VIC 3052, Australia
| | - Lisa Brown
- Department of General Surgical Specialties, The Royal Melbourne Hospital, Melbourne, VIC 3052, Australia; The University of Melbourne, Melbourne, VIC 3052, Australia; Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, VIC 3052, Australia
| | - Benjamin Thomson
- Department of General Surgical Specialties, The Royal Melbourne Hospital, Melbourne, VIC 3052, Australia; The University of Melbourne, Melbourne, VIC 3052, Australia; Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, VIC 3052, Australia
| | - Benjamin Paul Timothy Loveday
- Department of General Surgical Specialties, The Royal Melbourne Hospital, Melbourne, VIC 3052, Australia; The University of Melbourne, Melbourne, VIC 3052, Australia; Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, VIC 3052, Australia; Department of Surgery, University of Auckland, Auckland, New Zealand
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Lin YL, Yao T, Wang YW, Yu JS, Zhen C, Lin JF, Chen SB. Association between primary biliary cholangitis with diabetes and cardiovascular diseases: A bidirectional multivariable Mendelian randomization study. Clin Res Hepatol Gastroenterol 2024; 48:102419. [PMID: 38992425 DOI: 10.1016/j.clinre.2024.102419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 07/04/2024] [Accepted: 07/09/2024] [Indexed: 07/13/2024]
Abstract
BACKGROUND AND AIMS Primary biliary cholangitis (PBC) is an autoimmune disease often accompanied by multisystem damage. This study aimed to explore the causal association between genetically predicted PBC and diabetes, as well as multiple cardiovascular diseases (CVDs). METHODS Genome-wide association studies (GWAS) summary data of PBC in 24,510 individuals of European ancestry from the European Association for the Study of the Liver was used to identify genetically predicted PBC. We conducted 2-sample single-variable Mendelian randomization (SVMR) and multivariable Mendelian randomization (MVMR) to estimate the impacts of PBC on diabetes (N = 17,685 to 318,014) and 20 CVDs from the genetic consortium (N = 171,875 to 1,030,836). RESULTS SVMR provided evidence that genetically predicted PBC is associated with an increased risk of type 1 diabetes (T1D), type 2 diabetes (T2D), myocardial infarction (MI), heart failure (HF), hypertension, atrial fibrillation (AF), stroke, ischemic stroke, and small-vessel ischemic stroke. Additionally, there was no evidence of a causal association between PBC and coronary atherosclerosis. In the MVMR analysis, PBC maintained independent effects on T1D, HF, MI, and small-vessel ischemic stroke in most models. CONCLUSION Our findings revealed the causal effects of PBC on diabetes and 7 CVDs, and no causal relationship was detected between PBC and coronary atherosclerosis.
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Affiliation(s)
- Yun-Lu Lin
- The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, PR China
| | - Tao Yao
- The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, PR China
| | - Ying-Wei Wang
- The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, PR China
| | - Jia-Sheng Yu
- The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, PR China
| | - Cheng Zhen
- The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, PR China
| | - Jia-Feng Lin
- The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, PR China
| | - Shui-Bing Chen
- The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, PR China.
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Di Y, Li J, Ye C, Wang Z, Zhu Q. Thromboelastography parameters in chronic viral liver disease and liver resection: a retrospective study. Singapore Med J 2024; 65:438-443. [PMID: 37077056 PMCID: PMC11382816 DOI: 10.4103/singaporemedj.smj-2021-404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Accepted: 07/26/2022] [Indexed: 04/21/2023]
Abstract
INTRODUCTION Thromboelastography (TEG) provides a global assessment of haemostasis and is potentially applicable to liver disease. The present study aimed to explore the utility of TEG for the evaluation of patients with chronic viral liver disease, which has previously not been investigated. METHODS Demographic characteristics and TEG parameters were collected before surgery. Child-Turcotte-Pugh (CTP) and model for end-stage liver disease (MELD) scores were used to categorise stages of liver cirrhosis. Liver resections were classified as low, medium and high complexity. RESULTS A total of 344 patients were included. Results showed significantly longer K-time, smaller α-angle and lower maximum amplitude (MA) with increasing liver disease severity as measured by the CTP and MELD scores ( P < 0.05 for all). After multivariable adjustment (including age, sex, liver disease aetiology, alanine aminotransferase [ALT], aspartate aminotransferase [AST], albumin, total bilirubin, haemoglobin and platelet count), TEG parameters (except R-times) were either weakly or inversely related to the severity of liver disease as defined by the MELD score (absolute r < 0.2 and P < 0.05 for all except R-times). R-times obtained before surgery were weakly correlated with perioperative blood loss ( r < 0.2 and P < 0.05 for all). CONCLUSIONS The correlation between TEG parameters and severity of liver disease was weak. In addition, R-times obtained before liver resection were weakly associated with perioperative blood loss after multivariable adjustments. TEG utility for haemostasis assessment and prediction of blood loss during liver resection should be further explored in high-quality studies.
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Affiliation(s)
- Ying Di
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an City, Shaanxi Province, China
| | - Jialu Li
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an City, Shaanxi Province, China
| | - Chunjuan Ye
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an City, Shaanxi Province, China
| | - Zheng Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an City, Shaanxi Province, China
| | - Qianqian Zhu
- Department of Anesthesiology, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen City, People's Republic of China
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Yu M, Li X, Xu L, Zheng C, Pan W, Chen H, Liu X, Zhang X, Zhang J. Neutrophil extracellular traps induce intrahepatic thrombotic tendency and liver damage in cholestatic liver disease. Hepatol Commun 2024; 8:e0513. [PMID: 39101776 PMCID: PMC11299992 DOI: 10.1097/hc9.0000000000000513] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Accepted: 06/28/2024] [Indexed: 08/06/2024] Open
Abstract
BACKGROUND Cholestatic liver diseases induce local and systemic hypercoagulation, with neutrophil extracellular traps (NETs) serving as major drivers. These NETs have been linked to decreased liver function in patients with obstructive jaundice. However, the impact of NETs on liver hypercoagulation in cholestatic liver disease remains unknown. METHODS We utilized bile duct ligation to create experimental mice and analyzed NETs formation in the liver. Fibrin deposition, tissue factor expression, and inflammation in the liver were visualized through western blot and immunohistochemical techniques. LSECs were incubated with isolated NETs, and we detected endothelial procoagulant activity using coagulation protein production assays and measuring endothelial permeability. In both in vivo and in vitro settings, DNase I was applied to clarify the effect of NETs on intrahepatic hypercoagulability, hepatotoxicity, LSEC, and macrophage activation or injury. RESULTS Bile duct ligation mice exhibited significantly increased levels of NETs in liver tissue, accompanied by neutrophil infiltration, tissue necrosis, fibrin deposition, and thrombophilia compared to sham mice. Notably, NETs resulted in phosphatidylserine and tissue factor exposure on LSEC, enhancing coagulation Factor Xa and thrombin production. The enhanced procoagulant activity could be reversed by degrading NETs with DNase I. Additionally, NETs-induced permeability changes in LSECs, characterized by increased VE-cadherin expression and F-actin retraction, which could be rescued by DNase I. Meanwhile, NET formation is associated with KC activation and the formation of inflammatory factors. CONCLUSIONS NETs promote intrahepatic activation of coagulation and inflammation, leading to liver tissue injury. Strategies targeting NET formation may offer a potential therapeutic approach for treating cholestatic liver disease.
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Affiliation(s)
- Muxin Yu
- Department of Clinical Medical Sciences, College of Medicine, Jiaxing University, Jiaxing, China
| | - Xiaowen Li
- Department of Pathology, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Long Xu
- Department of Clinical Medical Sciences, College of Medicine, Jiaxing University, Jiaxing, China
| | - Chuwei Zheng
- Department of Gastroenterology, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Weiwei Pan
- Department of Clinical Medical Sciences, College of Medicine, Jiaxing University, Jiaxing, China
| | - Hui Chen
- Department of Clinical Medical Sciences, College of Medicine, Jiaxing University, Jiaxing, China
| | - Xiaoyu Liu
- Department of Clinical Medical Sciences, College of Medicine, Jiaxing University, Jiaxing, China
| | - Xianshan Zhang
- Department of Clinical Medical Sciences, College of Medicine, Jiaxing University, Jiaxing, China
| | - Jinming Zhang
- Department of Gastroenterology, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China
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Zanetto A, Campello E, Senzolo M, Simioni P. The evolving knowledge on primary hemostasis in patients with cirrhosis: A comprehensive review. Hepatology 2024; 79:460-481. [PMID: 36825598 DOI: 10.1097/hep.0000000000000349] [Citation(s) in RCA: 17] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Accepted: 02/13/2023] [Indexed: 02/25/2023]
Abstract
Patients with cirrhosis develop complex alterations in primary hemostasis that include both hypocoagulable and hypercoagulable features. This includes thrombocytopenia, multiple alterations of platelet function, and increased plasma levels of von Willebrand factor. Contrary to the historical view that platelet dysfunction in cirrhosis might be responsible for an increased bleeding tendency, the current theory posits a rebalanced hemostasis in patients with cirrhosis. Severe thrombocytopenia is not indicative of the bleeding risk in patients undergoing invasive procedures and does not dictate per se the need for pre-procedural prophylaxis. A more comprehensive and individualized risk assessment should combine hemostatic impairment, the severity of decompensation and systemic inflammation, and the presence of additional factors that may impair platelet function, such as acute kidney injury and bacterial infections. Although there are multiple, complex alterations of platelet function in cirrhosis, their net effect is not yet fully understood. More investigations evaluating the association between alterations of platelet function and bleeding/thrombosis may improve risk stratification in patients with decompensated cirrhosis. Besides hemostasis, the assessment of von Willebrand factor Ag and ADP-induced, whole-blood platelet aggregation normalized by platelet count (VITRO score and PLT ratio) are promising biomarkers to predict the risk of hepatic decompensation and survival in both compensated and decompensated patients. Further investigations into the in vivo interplay between platelets, circulating blood elements, and endothelial cells may help advance our understanding of cirrhotic coagulopathy. Here, we review the complex changes in platelets and primary hemostasis in cirrhosis and their potential clinical implications.
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Affiliation(s)
- Alberto Zanetto
- Gastroenterology and Multivisceral Transplant Unit, Azienda Ospedale-Università Padova, Padova, Italy
- Department of Surgery, Oncology, and Gastroenterology, University of Padova, Padova, Italy
| | - Elena Campello
- Department of Medicine, General Internal Medicine and Thrombotic and Hemorrhagic Diseases Unit, Padova University Hospital, Padova, Italy
| | - Marco Senzolo
- Gastroenterology and Multivisceral Transplant Unit, Azienda Ospedale-Università Padova, Padova, Italy
- Department of Surgery, Oncology, and Gastroenterology, University of Padova, Padova, Italy
| | - Paolo Simioni
- Department of Medicine, General Internal Medicine and Thrombotic and Hemorrhagic Diseases Unit, Padova University Hospital, Padova, Italy
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Akbari Aghdam M, Romecín P, García-Estañ J, Atucha NM. Role of Nitric Oxide in the Altered Calcium Homeostasis of Platelets from Rats with Biliary Cirrhosis. Int J Mol Sci 2023; 24:10948. [PMID: 37446122 DOI: 10.3390/ijms241310948] [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: 06/01/2023] [Revised: 06/26/2023] [Accepted: 06/26/2023] [Indexed: 07/15/2023] Open
Abstract
INTRODUCTION Previously, we found that intracellular calcium (Ca2+) homeostasis is altered in platelets from an experimental model of liver cirrhosis, namely the bile-duct-ligated (BDL) rat. These alterations are compatible with the existence of a hypercoagulable state. OBJECTIVE In the present study, we analyzed the role of nitric oxide in the abnormal calcium signaling responses of an experimental cirrhosis model, the bile duct-ligated rat. METHODS Chronic treatment with L-NAME was used to inhibit NO production in a group of control and BDL animals, and the responses compared to those obtained in a control and BDL untreated group (n = 6 each). The experiments were conducted on isolated platelets loaded with fura-2, using fluorescence spectrometry. RESULTS Chronic treatment with L-NAME increased thrombin-induced Ca2+ release from internal stores in both control and BDL rats. However, the effect was significantly greater in the BDL rats (p < 0.05). Thrombin-induced calcium entry from the extracellular space was also elevated but at lower doses and, similarly in both control and BDL platelets, treated with the NO synthesis inhibitor. Capacitative calcium entry was also enhanced in the control platelets but not in platelets from BDL rats treated with L-NAME. Total calcium in intracellular stores was elevated in untreated platelets from BDL rats, and L-NAME pretreatment significantly (p < 0.05) elevated these values both in controls and in BDL but significantly more in the BDL rats (p < 0.05). CONCLUSIONS Our results suggest that nitric oxide plays a role in the abnormal calcium signaling responses observed in platelets from BDL rats by interfering with the mechanism that releases calcium from the internal stores.
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Affiliation(s)
- Masoud Akbari Aghdam
- Departamento de Fisiología, Facultad de Medicina, Instituto Murciano de Investigación Biosanitaria, Universidad de Murcia, 30120 Murcia, Spain
| | - Paola Romecín
- Departamento de Fisiología, Facultad de Medicina, Instituto Murciano de Investigación Biosanitaria, Universidad de Murcia, 30120 Murcia, Spain
| | - Joaquín García-Estañ
- Departamento de Fisiología, Facultad de Medicina, Instituto Murciano de Investigación Biosanitaria, Universidad de Murcia, 30120 Murcia, Spain
| | - Noemí M Atucha
- Departamento de Fisiología, Facultad de Medicina, Instituto Murciano de Investigación Biosanitaria, Universidad de Murcia, 30120 Murcia, Spain
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Pérez-Calatayud AA, Hofmann A, Pérez-Ferrer A, Escorza-Molina C, Torres-Pérez B, Zaccarias-Ezzat JR, Sanchez-Cedillo A, Manuel Paez-Zayas V, Carrillo-Esper R, Görlinger K. Patient Blood Management in Liver Transplant—A Concise Review. Biomedicines 2023; 11:biomedicines11041093. [PMID: 37189710 DOI: 10.3390/biomedicines11041093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 03/09/2023] [Accepted: 03/13/2023] [Indexed: 04/07/2023] Open
Abstract
Transfusion of blood products in orthotopic liver transplantation (OLT) significantly increases post-transplant morbidity and mortality and is associated with reduced graft survival. Based on these results, an active effort to prevent and minimize blood transfusion is required. Patient blood management is a revolutionary approach defined as a patient-centered, systematic, evidence-based approach to improve patient outcomes by managing and preserving a patient’s own blood while promoting patient safety and empowerment. This approach is based on three pillars of treatment: (1) detecting and correcting anemia and thrombocytopenia, (2) minimizing iatrogenic blood loss, detecting, and correcting coagulopathy, and (3) harnessing and increasing anemia tolerance. This review emphasizes the importance of the three-pillar nine-field matrix of patient blood management to improve patient outcomes in liver transplant recipients.
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Affiliation(s)
| | - Axel Hofmann
- Faculty of Health and Medical Sciences, Discipline of Surgery, The University of Western Australia, Perth 6907, WA, Australia
- Institute of Anesthesiology, University of Zurich and University Hospital Zurich, 8057 Zurich, Switzerland
| | - Antonio Pérez-Ferrer
- Department of Anesthesiology, Infanta Sofia University Hospital, 28700 San Sebastián de los Reyes, Spain
- Department of Anesthesiology, European University of Madrid, 28702 Madrid, Spain
| | - Carla Escorza-Molina
- Departmen of Anesthesiology, Hospital General de México Dr. Eduardo Liceaga, Mexico City 06720, Mexico
| | - Bettina Torres-Pérez
- Department of Anesthesiology, Pediatric Transplant, Centro Medico de Occidente, Instituto Mexicano del Seguro Social, Guadalajara 44329, Mexico
| | | | - Aczel Sanchez-Cedillo
- Transplant Department Hospital General de México Dr. Eduardo Liceaga, Mexico City 06720, Mexico
| | - Victor Manuel Paez-Zayas
- Gastroenterology Department Hospital General de México Dr. Eduardo Liceaga, Mexico City 06720, Mexico
| | | | - Klaus Görlinger
- Department of Anesthesiology and Intensive Care Medicine, University Hospital Essen, University Duisburg-Essen, 45131 Essen, Germany
- TEM Innovations GmbH, 81829 Munich, Germany
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Rogalski P, Bogdanowska-Charkiewicz D, Rogalska-Plonska M, Lukaszewicz-Zajac M, Kostecka-Roslen I, Mroczko B, Dabrowska M, Wasielica-Berger J, Aleksiejuk E, Antonowicz S, Dabrowski A, Daniluk J, Janica J. Elevated levels of soluble glycoprotein V - The plasma marker of platelet activation by thrombin in patients with early stage primary biliary cholangitis (PBC). Adv Med Sci 2023; 68:71-78. [PMID: 36758500 DOI: 10.1016/j.advms.2023.01.002] [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: 07/14/2022] [Revised: 10/30/2022] [Accepted: 01/19/2023] [Indexed: 02/09/2023]
Abstract
PURPOSE There is a growing body of evidence for a prothrombotic tendency in patients with primary biliary cholangitis (PBC). The aim of the study was to evaluate coagulation disorders in patients with early stage PBC compared to healthy controls and evaluation of their relationship with clinical data, with particular emphasis on minimal hepatic encephalopathy (MHE). PATIENTS AND METHODS Fifty-one participants (PBC group - 38 patients, all patients but one Child-Pugh A; control group - 13 healthy controls) were included in our prospective, single center study. We assessed the plasma levels of sGPV, plasma procoagulant phospholipids (PPL) and rotational thromboelastometry (ROTEM) profiles in all study participants. Porto-systemic encephalopathy syndrome test was used to assess MHE. RESULTS The sGPV levels were higher in the PBC group compared to the controls: 36.07 ± 11.32 ng/mL vs 27.04 ± 11.72 ng/mL, p = 0.031. The PPL level was lower in the PBC group compared to controls resulting in increased clotting time in a factor Xa-based coagulation assay: 54.65 (47.83-58.83) sec. vs 45.90 (43.3-50.5) sec., p = 0.0065. PPL levels were correlated with platelet count (rho = -0.46, p = 0.001). ROTEM parameters did not differ significantly between groups. Coagulation parameters did not differ significantly between patients with and without MHE. CONCLUSIONS We have showed increased levels of sGPV - a plasma marker of platelet activation by thrombin in patients with early stage PBC compared to healthy controls. We found no relationship between the coagulation disorders and the occurrence of MHE. The PPL level was lower in the PBC group.
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Affiliation(s)
- Pawel Rogalski
- Department of Gastroenterology and Internal Medicine, Medical University of Bialystok, Bialystok, Poland.
| | | | | | | | - Ines Kostecka-Roslen
- Department of Haematological Diagnostics, Medical University of Bialystok, Bialystok, Poland
| | - Barbara Mroczko
- Department of Biochemical Diagnostics, Medical University of Bialystok, Bialystok, Poland
| | - Milena Dabrowska
- Department of Haematological Diagnostics, Medical University of Bialystok, Bialystok, Poland
| | - Justyna Wasielica-Berger
- Department of Gastroenterology and Internal Medicine, Medical University of Bialystok, Bialystok, Poland
| | - Elzbieta Aleksiejuk
- Department of Gastroenterology and Internal Medicine, Medical University of Bialystok, Bialystok, Poland
| | - Stefania Antonowicz
- Department of Gastroenterology and Internal Medicine, Medical University of Bialystok, Bialystok, Poland
| | - Andrzej Dabrowski
- Department of Gastroenterology and Internal Medicine, Medical University of Bialystok, Bialystok, Poland
| | - Jaroslaw Daniluk
- Department of Gastroenterology and Internal Medicine, Medical University of Bialystok, Bialystok, Poland
| | - Jacek Janica
- Department of Radiology, Medical University of Bialystok, Bialystok, Poland; Department of Paediatric Radiology, Medical University of Bialystok, Bialystok, Poland
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11
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He Y, Yao H, Ageno W, Méndez-Sánchez N, Guo X, Qi X. Review article: thromboelastography in liver diseases. Aliment Pharmacol Ther 2022; 56:580-591. [PMID: 35698893 DOI: 10.1111/apt.17080] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 05/16/2022] [Accepted: 05/29/2022] [Indexed: 12/09/2022]
Abstract
BACKGROUND Patients with liver diseases have complicated haemostatic alternations, resulting in both bleeding and thromboembolic complications, which cannot be sufficiently evaluated by conventional coagulation tests (CCTs), such as platelet count or prothrombin time. Thromboelastography (TEG) is a whole blood viscoelastic test which globally reflects changes in the haemostatic system, and its utility in evaluating patients with liver disease is increasingly recognised. AIMS To review the current evidence and clinical significance of TEG in liver diseases. METHODS Literature regarding TEG and liver diseases was comprehensively searched. RESULTS TEG is associated closely with the severity and aetiology of liver disease, the course of infection and the risk of bleeding and death, but not the risk of portal venous system thrombosis. Additionally, TEG-guided transfusion protocols can significantly decrease the requirement for blood products compared to those guided by CCTs. CONCLUSION TEG can reflect the haemostatic status of liver diseases more comprehensively than CCTs. It has the potential to assess the severity of liver diseases, predict the risk of bleeding and death in patients with liver disease and guide blood product transfusion. Future studies should standardise the use of TEG for assessing disease severity and development of clinical events and guiding blood product transfusion in patients with liver diseases.
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Affiliation(s)
- Yanglan He
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang, China.,Postgraduate College, China Medical University, Shenyang, China
| | - Haijuan Yao
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang, China
| | - Walter Ageno
- Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Nahum Méndez-Sánchez
- Liver Research Unit Medica Sur Clinic & Foundation and Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico
| | - Xiaozhong Guo
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang, China
| | - Xingshun Qi
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang, China
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12
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Validation of 5 models predicting transfusion, bleeding, and mortality in liver transplantation: an observational cohort study. HPB (Oxford) 2022; 24:1305-1315. [PMID: 35131142 DOI: 10.1016/j.hpb.2022.01.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 12/08/2021] [Accepted: 01/03/2022] [Indexed: 12/12/2022]
Abstract
BACKGROUND Historically, orthotopic liver transplantation (OLT) has been associated with massive blood loss, blood transfusion and morbidity. In order to predict such outcomes five nomograms have been published relating to transfusions and morbidity associated with OLTs. These nomograms, developed on the basis of three cohorts of patients consisting of 406, 750, and 800 having undergone OLTs, aimed to predict a transfusion of ≥1 red blood cell unit (RBC), a transfusion of >2 RBC units, a blood loss of >900 ml, as well as one-month and one-year survival rates. The aim of this study was to validate these five nomograms in a contemporary, independent cohort of patients. METHODS Five nomograms were previously developed based on 406, 750, and 800 OLTs. In this study we performed a temporal validation of these nomograms on contemporary patients that consisted of three cohorts of 800, 250, and 200 OLTs. Logistic regression coefficients from the historic development cohorts were applied to the three contemporary temporal validation cohorts. RESULTS The most accurate nomogram was able to predict transfusion of ≥1 RBC units with an area under the curve (AUC) was 0.91. The second-best nomogram was able to predict bleeding of >900 ml with an AUC of 0.70. T he AUC of the third nomogram (transfusion of >2 RBC units) was 0.70. However, is temporal validation was suboptimal, due to a low prevalence of OLTs transfused with >2 RBC units. The last 2 nomograms exhibited clearly suboptimal AUC values of 0.54 and 0.61. CONCLUSION Two of the five nomograms predict blood transfusion and blood loss with excellent accuracy. Transfusion of ≥1 RBC unit and blood loss of >900 ml can be predicted on the basis of these nomograms. However, these nomograms are not accurate to predict one-month and one-year survival rates. These results should be further cross-validated, ideally prospectively, in additional external independent cohorts.
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13
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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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14
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Poole LG, Fournier AK, Cline-Fedewa HM, Kopec AK, Luyendyk JP, Groeneveld DJ. Von Willebrand factor exerts hepatoprotective effects in acute but not chronic cholestatic liver injury in mice. Toxicology 2021; 463:152968. [PMID: 34619301 PMCID: PMC8585719 DOI: 10.1016/j.tox.2021.152968] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 09/17/2021] [Accepted: 09/29/2021] [Indexed: 02/06/2023]
Abstract
Acute and chronic liver disease are associated with substantial alterations in the hemostatic system, including elevated levels of the platelet-adhesive protein von Willebrand factor (VWF). Carbon tetrachloride-induced liver fibrosis is reduced in VWF-deficient mice, but it is unclear if VWF plays a pathologic role in all settings of liver fibrosis. Indeed, several studies suggest an anti-fibrotic role for components of the hemostatic system, including platelets, in experimental settings of bile duct fibrosis. However, the role of VWF in this specific pathology has not been examined. We tested the hypothesis that VWF exerts hepatoprotective effects in experimental bile duct injury. Wild-type and VWF-deficient (VWF-/-) mice were challenged with the bile duct toxicant alpha-naphthylisothiocyanate (ANIT) and the impact of VWF deficiency on acute cholestatic liver injury and chronic liver fibrosis was determined. Acute ANIT (60 mg/kg, po)-induced cholestatic liver injury was associated with increased VWF plasma antigen and activity levels. VWF deficiency enhanced ANIT-induced hepatocellular injury, evidenced by increased plasma ALT activity and area of hepatocellular necrosis. Surprisingly, platelet accumulation within necrotic areas was increased in ANIT-challenged VWF-/- mice compared to wild-type mice. Compared to acute ANIT challenge, hepatic platelet accumulation was modest and appeared to be VWF-dependent in mice exposed to ANIT diet (0.05 %) for 6 weeks. However, contrasting the role of VWF after acute ANIT challenge, VWF deficiency did not impact biliary fibrosis induced by chronic ANIT exposure. The results suggest that VWF plays dichotomous roles in experimental acute and chronic ANIT-induced cholestatic liver injury.
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Affiliation(s)
- Lauren G. Poole
- Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, MI, USA.,Institute for Integrative Toxicology, Michigan State University, East Lansing, MI, USA
| | - Anna-Katherine Fournier
- Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, MI, USA
| | - Holly M. Cline-Fedewa
- Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, MI, USA
| | - Anna K. Kopec
- Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, MI, USA.,Institute for Integrative Toxicology, Michigan State University, East Lansing, MI, USA
| | - James P. Luyendyk
- Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, MI, USA.,Institute for Integrative Toxicology, Michigan State University, East Lansing, MI, USA.,Department of Pharmacology & Toxicology, Michigan State University, East Lansing, MI, USA
| | - Dafna J. Groeneveld
- Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, MI, USA
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15
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Tantry US, Hartmann J, Neal MD, Schöechl H, Bliden KP, Agarwal S, Mason D, Dias JD, Mahla E, Gurbel PA. The role of viscoelastic testing in assessing peri-interventional platelet function and coagulation. Platelets 2021; 33:520-530. [PMID: 34369848 DOI: 10.1080/09537104.2021.1961709] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
We carried out a literature search in MEDLINE (PubMed) and EMBASE literature databases to provide a concise review of the role of viscoelastic testing in assessing peri-interventional platelet function and coagulation. The search identified 130 articles that were relevant for the review, covering the basic science of VHA and VHA in clinical settings including cardiac surgery, cardiology, neurology, trauma, non-cardiac surgery, obstetrics, liver disease, and COVID-19. Evidence from these articles is used to describe the important role of VHAs and platelet function testing in various peri-interventional setups. VHAs can help us to comprehensively assess the contribution of platelets and coagulation dynamics to clotting at the site-of-care much faster than standard laboratory measures. In addition to standard coagulation tests, VHAs are beneficial in reducing allogeneic transfusion requirements and bleeding, in predicting ischemic events, and improving outcomes in several peri-interventional care settings. Further focused studies are needed to confirm their utility in the peri-interventional case.
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Affiliation(s)
- Udaya S Tantry
- Sinai Center for Thrombosis Research and Drug Development, Sinai Hospital of Baltimore, Baltimore, MD, USA
| | - Jan Hartmann
- Medical Affairs and Clinical Development, Haemonetics Corporation, Boston, MA, USA
| | - Matthew D Neal
- Department of General Surgery, The University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Herbert Schöechl
- Department of Anesthesiology and Intensive Care Medicine, AUVA Trauma Centre Salzburg, Academic Teaching Hospital of the Paracelsus Medical University, Salzburg, Austria.,AUVA Trauma Research Centre, Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Vienna, Austria
| | - Kevin P Bliden
- Sinai Center for Thrombosis Research and Drug Development, Sinai Hospital of Baltimore, Baltimore, MD, USA
| | - Seema Agarwal
- Department of Anaesthesia, Manchester University Foundation Trust, Manchester, UK
| | - Dan Mason
- Medical Affairs and Clinical Development, Haemonetics Corporation, Boston, MA, USA
| | - Joao D Dias
- Medical Affairs and Clinical Development, Haemonetics Corporation, Boston, MA, USA
| | - Elisabeth Mahla
- Department of Anaesthesiology and Intensive Care Medicine, Medical University of Graz, Graz, Austria
| | - Paul A Gurbel
- Sinai Center for Thrombosis Research and Drug Development, Sinai Hospital of Baltimore, Baltimore, MD, USA
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16
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Pavlick M, DeLaforcade A, Penninck DG, Webster CRL. Evaluation of coagulation parameters in dogs with gallbladder mucoceles. J Vet Intern Med 2021; 35:1763-1772. [PMID: 34196054 PMCID: PMC8295708 DOI: 10.1111/jvim.16203] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 06/05/2021] [Accepted: 06/15/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Gallbladder mucocele (GBM) is a common biliary disorder in dogs. Limited information is available on the coagulation status of dogs with GBM. HYPOTHESIS/OBJECTIVES To determine patterns of coagulation alterations in dogs with GBM and correlate them with clinicopathologic abnormalities and ultrasonographic findings of disease severity. ANIMALS Twenty-three dogs with GBM identified on ultrasound examination were prospectively enrolled. METHODS At the time of GBM identification, blood and urine were collected for CBC, serum biochemical panel, urinalysis, prothrombin time, activated partial thromboplastin time (aPTT), factor VIII, protein C (PC), von Willebrand's factor (vWF), antithrombin activity, fibrinogen, D-dimers, and thromboelastrography (TEG). Gallbladder mucoceles were classified into ultrasound types 1 to 5. Medical records were reviewed for clinical presentation, underlying conditions and to determine if systemic inflammatory response syndrome (SIRS) was present. RESULTS Based on TEG parameters, maximal amplitude, and G, 19/23 (83%) of dogs with GBM had evaluations consistent with hypercoagulability. On plasma-based coagulation testing, dogs with GBM had increased total PC activity (20/23, 87%), fibrinogen (9/23, 39%), platelet count (9/23, 39%), and D-dimers (6/15, 40%) as well as prolongations in aPTT (9/22, 41%) and low vWF activity (5/21, 24%). No correlation was found between TEG G value and any coagulation or clinical pathology variables, ultrasound stage of GBM or disease severity as assessed by the presence of SIRS. CONCLUSIONS AND CLINICAL IMPORTANCE Dogs with ultrasonographically identified GBM have changes in whole blood kaolin-activated TEG supporting a hypercoagulable state although traditional plasma-based coagulation testing suggests that a complex state of hemostasis exists.
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Affiliation(s)
- Michelle Pavlick
- Cummings School of Veterinary Medicine at Tufts University, Grafton, Massachusetts, USA
| | - Armelle DeLaforcade
- Cummings School of Veterinary Medicine at Tufts University, Grafton, Massachusetts, USA
| | - Dominique G Penninck
- Cummings School of Veterinary Medicine at Tufts University, Grafton, Massachusetts, USA
| | - Cynthia R L Webster
- Cummings School of Veterinary Medicine at Tufts University, Grafton, Massachusetts, USA
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17
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Buliarca A, Horhat A, Mocan T, Craciun R, Procopet B, Sparchez Z. Viscoelastic tests in liver disease: where do we stand now? World J Gastroenterol 2021; 27:3290-3302. [PMID: 34163112 PMCID: PMC8218367 DOI: 10.3748/wjg.v27.i23.3290] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 03/17/2021] [Accepted: 05/20/2021] [Indexed: 02/06/2023] Open
Abstract
Hemostasis is a complex physiological process based on the balance between pro-coagulant and anticoagulant systems to avoid pathological bleeding or thrombosis. The changes in standard coagulation tests in liver disease were assumed to reflect an acquired bleeding disorder, and cirrhotic patients were considered naturally anticoagulated. In the light of the new evidence, the theory of rebalanced hemostasis replaced the old concept. According to this model, the hemostatic alteration leads to a unique balance between pro-coagulant, anticoagulant, and fibrinolytic systems. But the balance is fragile and may prone to bleeding or thrombosis depending on various risk factors. The standard coagulation tests [INR (international normalized ratio), platelet count and fibrinogen] only explore parts of the hemostasis, not offering an entire image of the process. Rotational thromboelastometry (ROTEM) and thromboelastography (TEG) are both point of care viscoelastic tests (VET) that provide real-time and dynamic information about the entire hemostasis process, including clot initiation (thrombin generation), clot kinetics, clot strength, and clot stability (lysis). Despite prolonged PT/INR (international normalized ratio of prothrombin time) and low platelet counts, VET is within the normal range in many patients with both acute and chronic liver disease. However, bleeding remains the dominant clinical issue in patients with liver diseases, especially when invasive interventions are required. VET has been shown to asses more appropriately the risk of bleeding than conventional laboratory tests, leading to decrial use of blood products transfusion. Inappropriate clotting is common but often subtle and may be challenging to predict even with the help of VET. Although VET has shown its benefit, more studies are needed to establish cut-off values for TEG and ROTEM in these populations and standardization of transfusion guidelines before invasive interventions in cirrhotic patients/orthotopic liver transplantation.
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Affiliation(s)
- Alina Buliarca
- The Third Medical Department, “Iuliu Hatieganu” University of Medicine and Pharmacy, Institute for Gastroenterology and Hepatology “Prof. Dr. O. Fodor”, Cluj-Napoca 400162, Romania
| | - Adelina Horhat
- The Third Medical Department, “Iuliu Hatieganu” University of Medicine and Pharmacy, Institute for Gastroenterology and Hepatology “Prof. Dr. O. Fodor”, Cluj-Napoca 400162, Romania
| | - Tudor Mocan
- The Third Medical Department, “Iuliu Hatieganu” University of Medicine and Pharmacy, Institute for Gastroenterology and Hepatology “Prof. Dr. O. Fodor”, Cluj-Napoca 400162, Romania
| | - Rares Craciun
- The Third Medical Department, “Iuliu Hatieganu” University of Medicine and Pharmacy, Institute for Gastroenterology and Hepatology “Prof. Dr. O. Fodor”, Cluj-Napoca 400162, Romania
| | - Bogdan Procopet
- The Third Medical Department, “Iuliu Hatieganu” University of Medicine and Pharmacy, Institute for Gastroenterology and Hepatology “Prof. Dr. O. Fodor”, Cluj-Napoca 400162, Romania
| | - Zeno Sparchez
- The Third Medical Department, “Iuliu Hatieganu” University of Medicine and Pharmacy, Institute for Gastroenterology and Hepatology “Prof. Dr. O. Fodor”, Cluj-Napoca 400162, Romania
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18
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Hegazy S, Elsabaawy M, Eltabakh M, Hammad R, Bedair H. CD62P (P-selectin) expression as a platelet activation marker in patients with liver cirrhosis with and without cholestasis. Clin Exp Hepatol 2021; 7:231-240. [PMID: 34295992 PMCID: PMC8284161 DOI: 10.5114/ceh.2021.107566] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Accepted: 03/24/2021] [Indexed: 11/25/2022] Open
Abstract
AIM OF THE STUDY P-selectin (CD62P) is a platelet activation marker that was claimed to mediate the accumulation of platelets induced by cholestasis. The nature of platelet dysfunction and hemostasis abnormalities in cholestatic liver disease needs to be more explored. The aim of this study was to assess platelet CD62P expression in cirrhotic patients with and without cholestasis, and to evaluate its relationship with a bleeding tendency. MATERIAL AND METHODS 150 patients were included in this case-control study. Participants were divided into 84 patients with liver cirrhosis (group I), 44 of whom had cholestasis (Group Ia) and 40 patients were without cholestasis (group Ib); 36 patients who were cholestatic without liver cirrhosis (group II); and 30 healthy subjects who formed the control group (group III). Platelet CD62P expression was assessed by a flow cytometer. RESULTS Platelets expressing CD62P were significantly increased in all patient groups compared to controls (p < 0.001). Platelets expressing CD62P were significantly increased in gastrointestinal (GIT) bleeders compared to non-bleeders in cirrhotic and cholestatic groups (p < 0.001 each). Among group I patients at cut-off > 12.4, up-regulation of platelet CD62P yielded 72% sensitivity and 44.1% specificity to discriminate bleeders from non-bleeders (p = 0.01), while among group II at cut-off > 12.9, it yielded 90% sensitivity and 80.8% specificity (p < 0.001). In cirrhotic patients, platelet CD62P expression was significantly increased in patients with an advanced Child-Pugh class (p < 0.001). Platelet expressing CD62P was shown as an independent risk factor for bleeding among cirrhotic cases with an odds ratio of 1.07 and CI 0.99-1.15. CONCLUSIONS Up-regulation of platelet CD62P expression can serve as a GIT bleeding predictor in liver cirrhosis.
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19
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Groeneveld DJ, Poole LG, Luyendyk JP. Targeting von Willebrand factor in liver diseases: A novel therapeutic strategy? J Thromb Haemost 2021; 19:1390-1408. [PMID: 33774926 PMCID: PMC8582603 DOI: 10.1111/jth.15312] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 03/08/2021] [Accepted: 03/22/2021] [Indexed: 12/11/2022]
Abstract
Acute and chronic liver disease are associated with substantial alterations in the hemostatic system. Evidence from both experimental and clinical studies suggests that anticoagulants slow the progression of liver disease. Efficacy of those anticoagulant drugs is, in part, attributed to a reduction of microthrombi formation within the liver. Although anticoagulant drugs show promising results, bleeding risk associated with these drugs is an obvious drawback, particularly in patients with a complex coagulopathy driven by decreased liver function. Identifying therapies that reduce intrahepatic thrombosis with minimal bleeding risk would significantly advance the field. Among the hemostatic alterations observed in patients are substantially increased levels of the platelet-adhesive protein von Willebrand factor (VWF). In contrast, levels of A Disintegrin and Metalloproteinase with Thrombospondin motifs, the enzyme that regulates VWF activity, are significantly reduced in patients with liver disease. Highly elevated VWF levels are proposed to accelerate intrahepatic thrombus formation and thus be a driver of disease progression. Strong clinical evidence suggesting a link between liver disease and changes in VWF is now being matched by emerging mechanistic data showing a detrimental role for VWF in the progression of liver disease. This review focuses on clinical and experimental evidence supporting a connection between VWF function and the progression of acute and chronic liver diseases. Furthermore, with the recent anticipated approval of several novel therapies targeting VWF, we discuss potential strategies and benefits of targeting VWF as an innovative therapy for patients with liver disease.
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Affiliation(s)
- Dafna J Groeneveld
- Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, MI, USA
| | - Lauren G Poole
- Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, MI, USA
| | - James P Luyendyk
- Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, MI, USA
- Institute for Integrative Toxicology, Michigan State University, East Lansing, MI, USA
- Department of Pharmacology & Toxicology, Michigan State University, East Lansing, MI, USA
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20
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Wilkinson A, Panciera D, DeMonaco S, Boes K, Leib M, Clapp K, Ruth J, Cecere T, McClendon D. Platelet function in dogs with chronic liver disease. J Small Anim Pract 2021; 63:120-127. [PMID: 33900656 DOI: 10.1111/jsap.13342] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 03/15/2021] [Accepted: 03/29/2021] [Indexed: 12/29/2022]
Abstract
OBJECTIVES To assess platelet function, buccal mucosal bleeding time and plasma von Willebrand factor concentration in dogs with chronic inflammatory and/or fibrotic liver disease and to compare results with those obtained in healthy dogs. MATERIALS AND METHODS Preliminary study including 18 dogs with chronic inflammatory and/or fibrotic liver disease undergoing liver biopsy and 18 healthy age-matched control dogs. Platelet function was assessed by measuring closure time with the PFA-100® analyser using adenosine diphosphate (ADP) as an agonist. Buccal mucosal bleeding time, closure time and plasma von Willebrand factor antigen were measured in dogs in both groups. After undergoing ultrasound-guided needle biopsy, dogs were monitored for haemorrhage to determine if there was an association of any measurement with post-biopsy bleeding. RESULTS The closure time was not different between the liver disease group (median 76.3; range 53 to 118.5 seconds) and control group (72.8; 57 to 89.5 seconds). The buccal mucosal bleeding time was longer in the liver disease group (median 138; range 95 to 229 seconds) than the control group (103; 63 to 200 seconds). The plasma von Willebrand factor antigen concentration was not different between the liver disease group (median 203; range 109 to 351%) and control group (165.5; 63 to 246%). CLINICAL SIGNIFICANCE In this study, dogs with chronic necroinflammatory and/or fibrotic liver disease did not have overt, clinically relevant derangements in platelet function as assessed by buccal mucosal bleeding time, closure time and von Willebrand factor analysis. In addition, none of the dogs undergoing percutaneous ultrasound-guided biopsy in the study exhibited bleeding complications post-biopsy procedure.
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Affiliation(s)
- A Wilkinson
- Department of Small Animal Clinical Sciences, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, 24061, USA
| | - D Panciera
- Department of Small Animal Clinical Sciences, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, 24061, USA
| | - S DeMonaco
- Department of Small Animal Clinical Sciences, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, 24061, USA
| | - K Boes
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, 24061, USA
| | - M Leib
- Department of Small Animal Clinical Sciences, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, 24061, USA
| | - K Clapp
- Department of Small Animal Clinical Sciences, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, 24061, USA
| | - J Ruth
- Department of Small Animal Clinical Sciences, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, 24061, USA
| | - T Cecere
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, 24061, USA
| | - D McClendon
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, 24061, USA
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21
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Thrombocytopenia and Hemostatic Changes in Acute and Chronic Liver Disease: Pathophysiology, Clinical and Laboratory Features, and Management. J Clin Med 2021; 10:jcm10071530. [PMID: 33917431 PMCID: PMC8038677 DOI: 10.3390/jcm10071530] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 03/22/2021] [Accepted: 03/24/2021] [Indexed: 12/12/2022] Open
Abstract
Thrombocytopenia, defined as a platelet count <150,000/μL, is the most common complication of advanced liver disease or cirrhosis with an incidence of up to 75%. A decrease in platelet count can be the first presenting sign and tends to be proportionally related to the severity of hepatic failure. The pathophysiology of thrombocytopenia in liver disease is multifactorial, including (i) splenomegaly and subsequently increased splenic sequestration of circulating platelets, (ii) reduced hepatic synthesis of thrombopoietin with missing stimulation both of megakaryocytopoiesis and thrombocytopoiesis, resulting in diminished platelet production and release from the bone marrow, and (iii) increased platelet destruction or consumption. Among these pathologies, the decrease in thrombopoietin synthesis has been identified as a central mechanism. Two newly licensed oral thrombopoietin mimetics/receptor agonists, avatrombopag and lusutrombopag, are now available for targeted treatment of thrombocytopenia in patients with advanced liver disease, who are undergoing invasive procedures. This review summarizes recent advances in the understanding of defective but at low level rebalanced hemostasis in stable cirrhosis, discusses clinical consequences and persistent controversial issues related to the inherent bleeding risk, and is focused on a risk-adapted management of thrombocytopenia in patients with chronic liver disease, including a restrictive transfusion regimen.
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Vlachogiannakos J, Binas J, Siakavellas S, Karagiannakis DS, Voulgaris T, Papatheodoridis GV, Ladas SD. Platelet activation and hypercoagulability in patients with early primary biliary cholangitis compared with healthy controls. Ann Gastroenterol 2021; 34:229-234. [PMID: 33654364 PMCID: PMC7903578 DOI: 10.20524/aog.2021.0572] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Accepted: 09/23/2020] [Indexed: 11/23/2022] Open
Abstract
Background Patients with primary biliary cholangitis (PBC) who have advanced disease are hypercoagulable, with no thrombophilic factors compared to non-cholestatic cirrhotics. We investigated whether hypercoagulability is present in early-stage PBC. Methods PBC patients with biopsy-documented early disease and healthy controls matched by sex and age were asked to participate in the study. All were evaluated using rotational thromboelastometry (ROTEM), platelet aggregation, and flow cytometry. Four ROTEM parameters were evaluated (clotting time, clotting formation time, α-angle, and maximum clot firmness [MCF]). Platelet aggregation was determined as the maximal change in light transmission after the addition of adenosine diphosphate, collagen and epinephrine. Flow cytometry was used to evaluate the expression of glycoprotein (GP) IIb, GPIIa, and P-selectin on the platelet surface. Results We enrolled 50 individuals in the study (25 PBC patients, 25 controls). Prothrombin time and activated partial thromboplastin time did not differ significantly between PBC patients and controls (P-value not significant). In ROTEM, aaaaaaaa-angle and MCF parameters were abnormally elevated in 9 (36%) PBC patients compared to 3 (12%) healthy controls and the difference was statistically significant (P=0.026). Platelet aggregation in PBC patients was not significantly different from controls. In flow cytometry, GPIIb and P-selectin expression was greater in PBC patients than in the control group and the difference was statistically significant (P=0.005 and P=0.006 respectively). Conclusion In this study, we used a combination of sophisticated methods to detect evidence of platelet activation and hypercoagulability in patients with early PBC. Our findings may have important clinical implications and merit further investigation.
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Affiliation(s)
- Jiannis Vlachogiannakos
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, "Laiko" General Hospital, Athens, Greece (Jiannis Vlachogiannakos, Jiannis Binas, Spyros Siakavellas, Dimitrios S. Karagiannakis, Theodoros Voulgaris, George V. Papatheodoridis, Spiros D. Ladas)
| | - Jiannis Binas
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, "Laiko" General Hospital, Athens, Greece (Jiannis Vlachogiannakos, Jiannis Binas, Spyros Siakavellas, Dimitrios S. Karagiannakis, Theodoros Voulgaris, George V. Papatheodoridis, Spiros D. Ladas)
| | - Spyros Siakavellas
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, "Laiko" General Hospital, Athens, Greece (Jiannis Vlachogiannakos, Jiannis Binas, Spyros Siakavellas, Dimitrios S. Karagiannakis, Theodoros Voulgaris, George V. Papatheodoridis, Spiros D. Ladas)
| | - Dimitrios S Karagiannakis
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, "Laiko" General Hospital, Athens, Greece (Jiannis Vlachogiannakos, Jiannis Binas, Spyros Siakavellas, Dimitrios S. Karagiannakis, Theodoros Voulgaris, George V. Papatheodoridis, Spiros D. Ladas)
| | - Theodoros Voulgaris
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, "Laiko" General Hospital, Athens, Greece (Jiannis Vlachogiannakos, Jiannis Binas, Spyros Siakavellas, Dimitrios S. Karagiannakis, Theodoros Voulgaris, George V. Papatheodoridis, Spiros D. Ladas)
| | - George V Papatheodoridis
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, "Laiko" General Hospital, Athens, Greece (Jiannis Vlachogiannakos, Jiannis Binas, Spyros Siakavellas, Dimitrios S. Karagiannakis, Theodoros Voulgaris, George V. Papatheodoridis, Spiros D. Ladas)
| | - Spiros D Ladas
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, "Laiko" General Hospital, Athens, Greece (Jiannis Vlachogiannakos, Jiannis Binas, Spyros Siakavellas, Dimitrios S. Karagiannakis, Theodoros Voulgaris, George V. Papatheodoridis, Spiros D. Ladas)
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Visweshwar N, Jaglal M, Patel A, Laber D, Sokol L. Should we integrate viscoelastic assays with standard coagulation screening? J Clin Pathol 2021; 74:141-143. [PMID: 33436484 DOI: 10.1136/jclinpath-2020-207099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 10/05/2020] [Accepted: 10/07/2020] [Indexed: 11/04/2022]
Affiliation(s)
- Nathan Visweshwar
- Department of Hematology, University of South Florida, Tampa, Florida, USA
| | - Michael Jaglal
- Department of Hematology/Oncology, Tampa General Hospital, Tampa, Florida, USA
| | - Ankita Patel
- Department of Hematology/Oncology, Tampa General Hospital, Tampa, Florida, USA
| | - Damian Laber
- Department of Hematology/Oncology, Tampa General Hospital, Tampa, Florida, USA
| | - Lubomir Sokol
- Department of Malignant Hematology, Moffitt Cancer Center, Tampa, Florida, USA
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Portal vein thrombosis prevalence and mortality among alcoholic cirrhosis in a nationwide inpatient cohort. Eur J Gastroenterol Hepatol 2020; 32:1160-1167. [PMID: 31834054 DOI: 10.1097/meg.0000000000001624] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Portal vein thrombosis is commonly associated with cirrhosis. The effect of alcoholic cirrhosis on portal vein thrombosis prevalence and mortality has not been well studied. METHODS We conducted a retrospective cohort study utilizing the 2000-2014 National Inpatient Sample Database. We included patients older than 18 years with decompensated cirrhosis without a history of liver transplantation or hepatocellular carcinoma. We further identified patients with alcoholic cirrhosis vs. non-alcoholic cirrhosis. Primary outcomes included the risk and mortality of portal vein thrombosis in alcoholic cirrhosis. Secondary outcomes included trends of portal vein thrombosis prevalence and mortality in alcoholic cirrhosis, implications of portal vein thrombosis on complications in alcoholic cirrhosis vs. non-alcoholic cirrhosis, and risk of venous thromboembolism in alcoholic cirrhosis. RESULTS Among 1 892 271 patients with decompensated alcoholic cirrhosis, portal vein thrombosis prevalence was 1.3%. Alcoholic cirrhosis was associated with lower risk of portal vein thrombosis (odds ratio 0.76, P < 0.001) and venous thromboembolism (odds ratio 0.69, P < 0.001) compared to non-alcoholic cirrhosis. Portal vein thrombosis contributed to increased mortality (odds ratio 1.19, P < 0.001) in alcoholic cirrhosis. Portal vein thrombosis prevalence among alcoholic cirrhosis increased while mortality declined during the study period. CONCLUSION Thrombotic events including portal vein thrombosis and venous thromboembolism were found in less frequent association with alcoholic cirrhosis compared with non-alcoholic cirrhosis. Despite this, the higher in-hospital mortality found among portal vein thrombosis with alcoholic cirrhosis should prompt careful consideration of management.
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Najafi A, Jafarian A, Makarem J, Barzin G, Salimi J, Nasiri-Toosi M, Moini M, Ebrahimi A, Behboudi B, Mohammadpour Z, Shariat Moharari R. Comparison of Coagulation Conditions in Patients With Liver Cirrhosis Due to Primary Sclerosing Cholangitis and Nonbiliary Causes of Cirrhosis Before Orthotopic Liver Transplant. EXP CLIN TRANSPLANT 2020; 18:696-700. [PMID: 32552627 DOI: 10.6002/ect.2018.0374] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVES Orthotopic liver transplant can be accompanied by an obscure bleeding pattern in patients with severe hepatic malfunction. In the present study, coagulation conditions of patients with cirrhosis of the liver due to primary sclerosing cholangitis and nonbiliary causes of cirrhosis were compared using rotational thromboelastometry assays obtained before orthotopic liver transplant. MATERIALS AND METHODS This case control study analyzed patients who were candidates for orthotopic liver transplant from 2010 to 2016. Eighty patients with cirrhosis of the liver (40 patients with primary sclerosing cholangitis and 40 with nonbiliary causes of cirrhosis) were randomly selected and enrolled into the study. Patients received rotational thromboelastometry assays under anesthesia just before the start of the operation, and results were compared between the 2 patient groups. RESULTS Of 80 patients, 52 were men and 28 were women. In the assays, we found that maximum amplitudes in 10 and in 20 minutes and maximum clot firmness parameters were higher in patients with primary sclerosing cholangitis. The alpha angle and clot formation time were different in the intrinsic and extrinsic assay panels. In the intrinsic assay, we found clotting time to be shorter (P < .05). The average of all parameters in all 3 assays (intrinsic, extrinsic, and fibrinogen contribution) was lower in patients with nonbiliary causes of cirrhosis than in those with primary sclerosing cholangitis. CONCLUSIONS In contrast with previous studies that found that patients with primary sclerosing cholangitis are hypercoagulable, our study observed that they have normal coagulable results. Furthermore, we found that, although mean coagulation indexes in patients with primary sclerosing cholangitis were within normal ranges, in patients with nonbiliary causes of cirrhosis, these indexes were generally lower.
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Affiliation(s)
- Atabak Najafi
- From the Liver Transplantation Research Center, Imam Khomeini Hospital Complex, and the Department of Anesthesiology and Critical Care, Tehran University of Medical Sciences, Sina Hospital, Tehran, Iran
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Adam EH, Möhlmann M, Herrmann E, Schneider S, Zacharowski K, Zeuzem S, Weber CF, Weiler N. Assessment of hemostatic profile in patients with mild to advanced liver cirrhosis. World J Gastroenterol 2020; 26:2097-2110. [PMID: 32536777 PMCID: PMC7267688 DOI: 10.3748/wjg.v26.i17.2097] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 03/26/2020] [Accepted: 04/24/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hemostasis of patients suffering from liver cirrhosis is challenging due to both, pro- and anticoagulatory disorders leading to hemostatic alterations with distinct abnormalities of coagulation. Pathological changes in conventional coagulation analysis and platelet count are common manifestations of decreased liver synthesis of coagulation factors and reduced platelet count in these patients. However, conventional coagulation analysis and platelet count do not reflect in-vivo coagulation status or platelet function. The purpose of this present observational study was therefore to assess the haemostatic profile including plasmatic coagulation using thrombelastometry and impedance aggregometry for platelet function in patients suffering from liver cirrhosis.
AIM To assess the hemostatic profile of cirrhotic patients according to model for end-stage liver disease (MELD) score.
METHODS Our study included both in- and outpatients suffering from liver cirrhosis attending the out- and inpatient care of the department of hepatology. Demographic and biochemical data as well as medical history including cause of liver cirrhosis, end stage kidney failure and medication with anticoagulants were recorded. To assess the hemostatic profile, platelet function was analyzed by multiple electrode aggregometry (MEA) using Multiplate® (ADP-, ASPI- and TRAP-test) and thrombelastometry using ROTEM® (EXTEM, INTEM, FIBTEM). Data were compared using Mann-Whitney U- or χ2-test. Spearman correlation was performed to analyze the association between MELD Score and results of thrombelastometry and MEA.
RESULTS A total of 68 patients attending the out- and inpatient care suffering from liver cirrhosis were screened. Of these, 50 patients were included and assigned to groups according to MELD score 6 to 11 (n = 25) or ≥ 17 (n = 25). Baseline patient characteristics revealed significant differences for MELD score (8 vs 22, P < 0.0001) and underlying laboratory parameters (international normalized ratio, bilirubine, creatinine) as well as fibrinogen level (275 mg/dL vs 209 mg/dL, P = 0.006) and aPTT (30 s vs 35 s, P = 0.047). MEA showed a moderately impaired platelet function (medians: AUCADP = 43U, AUCASPI = 71U, AUCTRAP = 92U) but no significant differences between both groups. Thrombelastometry using ROTEM® (EXTEM, INTEM, FIBTEM) revealed values within normal range in both groups. No significant correlation was observed between MELD score and results of MEA/thrombelastometry.
CONCLUSION Our data demonstrate a partially impaired hemostatic profile in liver cirrhosis patients unrelated to MELD score. An individual assessment of a potential coagulopathy should therefore be considered.
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Affiliation(s)
- Elisabeth Hannah Adam
- Department of Anaesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Goethe-University Frankfurt, Frankfurt 60590, Germany
| | - Madara Möhlmann
- Department of Anaesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Goethe-University Frankfurt, Frankfurt 60590, Germany
| | - Eva Herrmann
- Department of Biostatistics and mathematical modeling, University Hospital Frankfurt, Goethe-University Frankfurt, Frankfurt 60590, Germany
| | - Sonia Schneider
- Department of Anaesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Goethe-University Frankfurt, Frankfurt 60590, Germany
| | - Kai Zacharowski
- Department of Anaesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Goethe-University Frankfurt, Frankfurt 60590, Germany
| | - Stefan Zeuzem
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University Hospital Frankfurt, Goethe-University Frankfurt, Frankfurt 60590, Germany
| | - Christian Friedrich Weber
- Department of Anaesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Goethe-University Frankfurt, Frankfurt 60590, Germany
- Department of Anaesthesiology, Intensive Care Medicine and Emergency Medicine, Asklepios Clinics Hamburg, Hamburg 22043, Germany
| | - Nina Weiler
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University Hospital Frankfurt, Goethe-University Frankfurt, Frankfurt 60590, Germany
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Thromboelastography Parameters Are Associated with Cirrhosis Severity. Dig Dis Sci 2019; 64:2661-2670. [PMID: 30915655 DOI: 10.1007/s10620-019-05597-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Accepted: 03/19/2019] [Indexed: 12/22/2022]
Abstract
BACKGROUND Coagulopathy in cirrhosis represents complex coagulation derangements, and thromboelastography (TEG) measures these complex derangements. AIM We sought to evaluate associations between TEG parameters and validated measures of cirrhosis severity, which have not been previously investigated. MATERIALS AND METHODS Adults with cirrhosis undergoing liver transplant (LT) were identified. Patients had TEG drawn immediately prior to LT. TEG parameters included reaction time (R), kinetic time (K), alpha angle (α), and maximum amplitude (MA). The validated measures of cirrhosis severity were MELD-Na and clinical stage of cirrhosis (classified using history of varices, variceal bleeding, or ascites). Multivariable linear and logistic regression analyses were conducted to evaluate the associations between TEG and stage of cirrhosis and MELD-Na. RESULTS Among 164 patients with cirrhosis, advancing stage of cirrhosis was associated with more hypocoagulable TEG parameters including longer K-time (p = 0.05) and lower MA (p < 0.001). Similarly, with increasing MELD-Na quartiles, K-time was longer (p < 0.001), and both MA and α-angle decreased (p < 0.001, for both). Variceal bleeding within 6 weeks prior to LT was associated with longer R-times (p = 0.02), longer K-times (p = 0.04), smaller α-angle (p = 0.03), and lower MA (p = 0.01). On multivariable analyses, decreasing MA remained statistically significantly associated with advancing stage of cirrhosis and increasing MELD-Na, after adjusting for multiple covariates including platelet count, (p = 0.02 and p < 0.0001, respectively). CONCLUSIONS Hypocoagulable TEG measurements are associated with advancing stage of cirrhosis and increasing MELD-Na among patients with cirrhosis. These data indicate that TEG, as an informative measure of complex hemostatic function, may be a useful objective marker of liver disease severity in cirrhosis.
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Rogalski P, Rogalska-Plonska M, Wroblewski E, Kostecka-Roslen I, Dabrowska M, Swidnicka-Siergiejko A, Wasielica-Berger J, Cydzik M, Hirnle T, Dobrzycki S, Flisiak R, Dabrowski A. Blood platelet function abnormalities in cirrhotic patients with esophageal varices in relation to the variceal bleeding history. Scand J Gastroenterol 2019; 54:311-318. [PMID: 30907172 DOI: 10.1080/00365521.2019.1578822] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Objective: The study aimed at assessing the effect of thrombocytopenia and platelet function abnormalities on the occurrence of variceal bleeding in patients with cirrhosis. Methods: The results of impedance aggregometry, von Willebrand factor antigen level and thromboelastometry (TEM) with and without the addition of a platelet inhibitor (FIBTEM®, EXTEM® test, respectively) were compared in two patient groups: Group 1 (n = 32) - patients with moderate or large esophageal or gastric varices, who had never had symptoms of acute gastrointestinal bleeding and Group 2 (n = 26) - patients with history of variceal bleeding. Results: Standard clotting test indicated more hypocoagulable profile in Group 2 compared to Group 1. However, no differences in any TEM component were observed between groups in EXTEM® test. The contribution of platelets to clot strength was significantly higher in Group 2 than in Group 1 [PLT% = 74.2 (67.5-80.4) versus 68.8 (63.7-76.5) %; p = .039]. The aggregation index was also higher in Group 2 compared to Group 1, although not statistically significant [% of healthy = 96.9 (73.2-140.1) versus 67.6 (52.5-118.8) %, p = .195]. No differences in vWF antigen levels were observed between groups. Conclusions: The results of thromboelastometry and aggregometry indicate increased contribution of platelets in clot formation in patients with a history of variceal bleeding compared to cirrhotic patients who never bled. Comparable effectiveness of hemostasis in both groups is most likely associated with the compensatory role of platelets. Increased platelet activity in this group of patients is probably due to a mechanism independent of the von Willebrand factor antigen level.
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Affiliation(s)
- Pawel Rogalski
- a Department of Gastroenterology and Internal Medicine , Medical University of Bialystok , Bialystok , Poland
| | - Magdalena Rogalska-Plonska
- b Department of Infectious Diseases and Hepatology , Medical University of Bialystok , Bialystok , Poland
| | - Eugeniusz Wroblewski
- a Department of Gastroenterology and Internal Medicine , Medical University of Bialystok , Bialystok , Poland
| | - Ines Kostecka-Roslen
- c Department of Haematological Diagnostics , Medical University of Bialystok , Bialystok , Poland
| | - Milena Dabrowska
- c Department of Haematological Diagnostics , Medical University of Bialystok , Bialystok , Poland
| | | | - Justyna Wasielica-Berger
- a Department of Gastroenterology and Internal Medicine , Medical University of Bialystok , Bialystok , Poland
| | - Mariusz Cydzik
- d Department of Cardiosurgery , Medical University of Bialystok , Bialystok , Poland
| | - Tomasz Hirnle
- d Department of Cardiosurgery , Medical University of Bialystok , Bialystok , Poland
| | - Slawomir Dobrzycki
- e Department of Invasive Cardiology , Medical University of Bialystok , Bialystok , Poland
| | - Robert Flisiak
- b Department of Infectious Diseases and Hepatology , Medical University of Bialystok , Bialystok , Poland
| | - Andrzej Dabrowski
- a Department of Gastroenterology and Internal Medicine , Medical University of Bialystok , Bialystok , Poland
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Campbell RAS, Thomson EM, Beattie C. Effect of Liver Disease Etiology on ROTEM Profiles in Patients Undergoing Liver Transplantation. Transplant Proc 2019; 51:783-789. [PMID: 30979465 DOI: 10.1016/j.transproceed.2018.12.030] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Revised: 12/27/2018] [Accepted: 12/28/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Coagulation abnormalities in liver transplant patients are complex and may be related to the underlying liver disease. We evaluated the effects of disease etiology on whole-blood rotational thromboelastometry (ROTEM; Pentapharm GmbH, Munich, Germany) profile and association with thrombotic complications following liver transplantation. METHODS Analysis of perioperative data from patients undergoing liver transplantation between January 1, 2012 and December 31, 2016. Patients were grouped based on the biology of their underlying liver disease: hepatocellular carcinoma (HCC), biliary etiology, and non-biliary etiology. The primary outcome was the EXTEM A10 value of the pre-incision ROTEM. Secondary outcomes included associations between EXTEM A10 value and incidence of postoperative thrombotic complications. RESULTS Three hundred fifty patients met the eligibility criteria: 60 had biliary etiologies, 203 had non-biliary etiologies, and 87 had HCC. EXTEM A10 values were significantly higher in patients with biliary etiologies than those with non-biliary etiologies (mean difference, 13.8; 95% CI: 10.1 to 17.5; P = .001) and those with HCC (mean difference, 10.4; 95% CI: 6.2 to 14.7; P = .001). Patients with non-biliary etiologies had slightly higher values than those with HCC (mean difference, -3.3; 95% CI: -6.6 to -0.1; P = .04). Higher values for biliary etiologies remained after adjusting for liver disease severity, platelet count, and fibrinogen level. There was no significant difference in EXTEM A10 values between patients who suffered thrombotic complications and those who did not (mean difference: 4.3, 95% CI: -1.3 to 9.9, P = .13). CONCLUSION Patients with biliary diseases demonstrated higher EXTEM A10 values compared to those with non-biliary diseases or HCC. This was not fully explained by differences in disease severity, platelet count, or fibrinogen level. Pre-incision EXTEM A10 values do not predict incidence of postoperative thrombotic complications.
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Affiliation(s)
| | - E M Thomson
- Department of Anaesthetics, Critical Care and Pain Medicine, Royal Infirmary of Edinburgh, Edinburgh, UK
| | - C Beattie
- Department of Anaesthetics, Critical Care and Pain Medicine, Royal Infirmary of Edinburgh, Edinburgh, UK
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Blasi A, Calvo A, Prado V, Reverter E, Reverter JC, Hernández-Tejero M, Aziz F, Amoros A, Cardenas A, Fernández J. Coagulation Failure in Patients With Acute-on-Chronic Liver Failure and Decompensated Cirrhosis: Beyond the International Normalized Ratio. Hepatology 2018; 68:2325-2337. [PMID: 29790188 DOI: 10.1002/hep.30103] [Citation(s) in RCA: 76] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Accepted: 05/14/2018] [Indexed: 12/22/2022]
Abstract
Balanced hemostasis with hypocoagulable and hypercoagulable features may occur in acute-on-chronic liver failure (ACLF). The characteristics and prognostic impact of the coagulation profile in ACLF are unknown. Consecutive patients with ACLF (n = 36) and acute decompensation (AD; n = 24) were included. Blood samples for thromboelastometry (TE) were obtained at admission and 72 hours thereafter. The coagulation profile was evaluated in patients with and without ACLF and in those with and without systemic inflammatory response syndrome. The impact of the coagulation profile on transfusion requirements, bleeding events, and short-term survival was assessed. At admission, patients with ACLF showed more hypocoagulable characteristics compared to AD subjects, with prolonged time to initial fibrin formation and clot formation time and decreased maximum clot firmness and alpha-angle values. TE parameters worsened at 72 hours in ACLF but improved in patients with AD. Prevalence of a hypocoagulable profile (three or more TE parameters outside range) was significantly higher in patients with ACLF either at admission (61% versus 29% in AD; P = 0.03) or during follow-up. Hypocoagulability correlated with systemic inflammation and was associated with higher 28-day (45% versus 16%; P = 0.02) and 90-day (52% versus 19%; P = 0.01) mortality rates but not with transfusion requirements or bleeding. Prolonged time to initial fibrin formation (extrinsic TE assay >80 seconds) and Model for End-Stage Liver Disease score at baseline were independent predictors of 28-day mortality. Conclusion: Patients with ACLF frequently show hypocoagulable features with prolonged time to initial fibrin formation and clot formation time and reduced clot firmness; these alterations worsen after admission, correlate with systemic inflammation, and translate into higher short-term mortality; hypofibrinolysis could contribute to organ failure in ACLF.
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Affiliation(s)
- Annabel Blasi
- Anesthesiology Department, Hospital Clínic, and University of Barcelona, Spain.,Institut d'Investigacions Biomèdiques August Pi-Sunyer (IDIBAPS) y Ciber de Enfermedades Hepáticas y Digestivas (CIBEREHD)
| | - Andrea Calvo
- Anesthesiology Department, Hospital Clínic, and University of Barcelona, Spain
| | - Verónica Prado
- Liver Unit, Institut de Malalties Digestives i Metabòliques, Hospital Clínic, and University of Barcelona
| | - Enric Reverter
- Institut d'Investigacions Biomèdiques August Pi-Sunyer (IDIBAPS) y Ciber de Enfermedades Hepáticas y Digestivas (CIBEREHD).,Liver Unit, Institut de Malalties Digestives i Metabòliques, Hospital Clínic, and University of Barcelona
| | | | - María Hernández-Tejero
- Liver Unit, Institut de Malalties Digestives i Metabòliques, Hospital Clínic, and University of Barcelona
| | - Fátima Aziz
- Liver Unit, Institut de Malalties Digestives i Metabòliques, Hospital Clínic, and University of Barcelona
| | - Alex Amoros
- European Foundation for the Study of Chronic Liver Failure
| | - Andres Cardenas
- Institut d'Investigacions Biomèdiques August Pi-Sunyer (IDIBAPS) y Ciber de Enfermedades Hepáticas y Digestivas (CIBEREHD).,GI/Liver Unit, Institut de Malalties Digestives i Metabòliques, Hospital Clínic, and University of Barcelona, Barcelona, Spain
| | - Javier Fernández
- Institut d'Investigacions Biomèdiques August Pi-Sunyer (IDIBAPS) y Ciber de Enfermedades Hepáticas y Digestivas (CIBEREHD).,Liver Unit, Institut de Malalties Digestives i Metabòliques, Hospital Clínic, and University of Barcelona.,European Foundation for the Study of Chronic Liver Failure
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Abstract
Platelets are key players in thrombosis and hemostasis. Alterations in platelet count and function are common in liver disease, and may contribute to bleeding or thrombotic complications in liver diseases and during liver surgery. In addition to their hemostatic function, platelets may modulate liver diseases by mechanisms that are incompletely understood. Here, we present clinical evidence for a role of platelets in the progression of chronic and acute liver diseases, including cirrhosis, acute liver failure, and hepatocellular carcinoma. We also present clinical evidence that platelets promote liver regeneration following partial liver resection. Subsequently, we summarize studies in experimental animal models that support these clinical observations, and also highlight studies that are in contrast with clinical observations. The combined results of clinical and experimental studies suggest that platelets may be a therapeutic target in the treatment of liver injury and repair, but the gaps in our understanding of mechanisms involved in platelet-mediated modulation of liver diseases call for caution in clinical application of these findings.
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Affiliation(s)
- Ton Lisman
- Section of Hepatobiliary Surgery and Liver Transplantation and Surgical Research Laboratory, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - James P. Luyendyk
- Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan, USA
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Hugenholtz GC, Lisman T, Stravitz RT. Thromboelastography does not predict outcome in different etiologies of cirrhosis. Res Pract Thromb Haemost 2017; 1:275-285. [PMID: 30046697 PMCID: PMC6058258 DOI: 10.1002/rth2.12037] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2017] [Accepted: 06/28/2017] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND New laboratory tests that measure global hemostasis indicate generally preserved hemostatic function in patients with cirrhosis. It is not known whether normal hemostatic function is maintained across various subsets of patients. OBJECTIVES In the present study, we investigated clot generation and clot lysis kinetics in a large group of patients with different etiologies of disease. PATIENTS/METHODS Blood samples of 270 patients with cirrhosis were studied using thromboelastography (TEG), which measures the dynamic and physical properties of clot formation and lysis in whole blood. TEG parameters of different subsets of the patient population were compared. Correlations with routine laboratory tests as well as clinical outcomes were explored. RESULTS Overall, TEG parameters were normal and similar between underlying disease etiologies. A proportion of subjects showed hypocoagulable features, with the exception of patients with cholestatic cirrhosis in whom TEG readings showed hypercoagulable features. In all groups, K-time, α-Angle, and MA correlated well with platelet counts and fibrinogen plasma levels. After a mean follow-up of 2 years and 11 months, 31 patients had experienced a bleeding event, 8 had developed thrombosis, and 173 patients (64%) had undergone liver transplantation and/or had died. TEG baseline parameters were similar between patients subdivided according to outcome. CONCLUSIONS TEG parameters reflected generally preserved function of the hemostatic system in patients with cirrhosis, with hypo- and hypercoagulable features in subsets of patients with specific underlying disease etiologies. Abnormalities in TEG parameters did however not predict bleeding, thrombosis, or risk of liver transplantation and/or death.
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Affiliation(s)
- Greg C.G. Hugenholtz
- Department of SurgerySurgical Research LaboratoryUniversity of GroningenUniversity of Medical Center GroningenGroningenthe Netherlands
| | - Ton Lisman
- Department of SurgerySurgical Research LaboratoryUniversity of GroningenUniversity of Medical Center GroningenGroningenthe Netherlands
- Department of SurgerySection of Hepatobiliary Surgery and Liver TransplantationUniversity of GroningenUniversity of Medical Center GroningenGroningenthe Netherlands
| | - Richard Todd Stravitz
- Section of Hepatology and Hume‐Lee Transplant CenterVirginia Commonwealth UniversityRichmondVAUSA
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Lisman T, Bernal W. Management of Hemostatic Disorders in Patients With Advanced Liver Disease Admitted to an Intensive Care Unit. Transfus Med Rev 2017; 31:245-251. [DOI: 10.1016/j.tmrv.2017.06.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2017] [Revised: 05/19/2017] [Accepted: 06/20/2017] [Indexed: 02/07/2023]
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Vinholt PJ, Hvas AM, Nielsen C, Söderström AC, Sprogøe U, Fialla AD, Nybo M. Reduced platelet activation and platelet aggregation in patients with alcoholic liver cirrhosis. Platelets 2017; 29:520-527. [PMID: 28895774 DOI: 10.1080/09537104.2017.1349308] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Results from previous studies regarding platelet function in liver cirrhosis are discordant. The aim was to investigate platelet activation and platelet aggregation in patients with alcoholic liver cirrhosis. We included 27 patients with alcoholic liver cirrhosis and 22 healthy individuals. A recently established flow cytometric approach was used to measure platelet activation and platelet aggregation independent of sample platelet count. Platelet aggregation was further investigated using light transmission aggregometry (LTA) (for platelet count >100 × 109/L). Platelet agonists were adenosine diphosphate, thrombin receptor-activating peptide, arachidonic acid, collagen, and collagen-related peptide. Patients had lower median platelet count than healthy individuals, 125 × 109/L (interquartile range [IQR] 90-185) versus 240 × 109 (IQR 204-285), p < 0.001. Platelet activation levels in stimulated samples were lower in patients versus healthy individuals, e.g., after collagen-related peptide stimulation, the median percentage of platelets positive for activated glycoprotein IIb/IIIa was 85% (IQR 70-94) in patients versus 97% (IQR 94-99) in healthy individuals, p < 0.001; lower platelet activation capacity being associated with low platelet count and Child-Pugh class B/C cirrhosis. Flow cytometric platelet aggregation was reduced in patients for collagen-related peptide and for adenosine diphosphate, e.g., platelet aggregation (mean ± standard deviation) was 57% ± 4 in patients versus 70% ± 1 in healthy individuals for collagen-related peptide, p = 0.01. Light LTA showed reduced collagen-induced platelet aggregation in some patients compared with healthy individuals. In conclusion, platelet function was reduced in some patients with alcoholic liver cirrhosis and the severity was associated with platelet count and severity of liver cirrhosis.
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Affiliation(s)
- Pernille Just Vinholt
- a Department of Clinical Biochemistry and Pharmacology , Odense University Hospital , Odense , Denmark
| | - Anne-Mette Hvas
- b Department of Clinical Biochemistry , Aarhus University Hospital , Aarhus , Denmark
| | - Christian Nielsen
- c Department of Clinical Immunology , Odense University Hospital , Odense , Denmark
| | - Anna Cecilia Söderström
- a Department of Clinical Biochemistry and Pharmacology , Odense University Hospital , Odense , Denmark
| | - Ulrik Sprogøe
- c Department of Clinical Immunology , Odense University Hospital , Odense , Denmark
| | - Annette Dam Fialla
- d Department of Gastroenterology , Odense University Hospital , Odense , Denmark
| | - Mads Nybo
- a Department of Clinical Biochemistry and Pharmacology , Odense University Hospital , Odense , Denmark
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Romecín P, Navarro EG, Ortiz MC, Iyú D, García-Estañ J, Atucha NM. Bile Acids Do Not Contribute to the Altered Calcium Homeostasis of Platelets from Rats with Biliary Cirrhosis. Front Physiol 2017. [PMID: 28638347 PMCID: PMC5461275 DOI: 10.3389/fphys.2017.00384] [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] [Indexed: 11/13/2022] Open
Abstract
Previously, we have found that intracellular calcium homeostasis is altered in platelets from an experimental model of liver cirrhosis, the bile-duct ligated (BDL) rat; these alterations are compatible with the existence of a hypercoagulable state and related to an enhanced intracellular calcium release evoked by thrombin and an increased amount of calcium stored in the intracellular organelles. In the present study we have investigated the role of bile acids in those alterations of the BDL cirrhotic model. Cholic acid (CA) or deoxycholic acid (DCA) did not change P-selectin expression or platelet aggregation in any group but elevated baseline platelet calcium levels. Incubation with both bile acids reduced calcium release after stimulation with thrombin in the absence of extracellular calcium. Pretreatment with CA but not with DCA reduced significantly thrombin-induced calcium entry in all three experimental groups. The capacitative calcium entry was also significantly lower in platelets pretreated with both bile acids. The simultaneous addition of thapsigargin and ionomycin to estimate the total amount of calcium in platelet internal stores was decreased by pretreatment with both CA and DCA, although these changes were significantly different in the control rats only with CA and in the BDL platelets with DCA. These results indicate that CA and DCA reduce calcium movements in platelets of control and BDL animals, thus suggesting that bile acids do not participate in the alterations observed in the BDL cirrotic model.
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Thakrar SV, Mallett SV. Thrombocytopenia in cirrhosis: Impact of fibrinogen on bleeding risk. World J Hepatol 2017; 9:318-325. [PMID: 28293381 PMCID: PMC5332421 DOI: 10.4254/wjh.v9.i6.318] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Revised: 11/12/2016] [Accepted: 01/14/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the relationship between baseline platelet count, clauss fibrinogen, maximum amplitude (MA) on thromboelastography, and blood loss in orthotopic liver transplantation (OLT).
METHODS A retrospective analysis of our OLT Database (2006-2015) was performed. Baseline haematological indices and intraoperative blood transfusion requirements, as a combination of cell salvage return and estimation of 300 mls/unit of allogenic blood, was noted as a surrogate for intraoperative bleeding. Two groups: Excessive transfusion (> 1200 mL returned) and No excessive transfusion (< 1200 mL returned) were analysed. All data analyses were conducted using IBM SPSS Statistics version 23.
RESULTS Of 322 OLT patients, 77 were excluded due to fulminant disease; redo transplant or baseline haemoglobin (Hb) of < 80 g/L. One hundred and fourteen (46.3%) were classified into the excessive transfusion group, 132 (53.7%) in the no excessive transfusion group. Mean age and gender distribution were similar in both groups. Baseline Hb (P ≤ 0.001), platelet count (P = 0.005), clauss fibrinogen (P = 0.004) and heparinase MA (P = 0.001) were all statistically significantly different. Univariate logistic regression with a cut-off of platelets < 50 × 109/L as the predictor and Haemorrhage as the outcome showed an odds ratio of 1.393 (95%CI: 0.758-2.563; P = 0.286). Review of receiver operating characteristic curves showed an area under the curve (AUC) for platelet count of 0.604 (95%CI: 0.534-0.675; P = 0.005) as compared with AUC for fibrinogen level, 0.678 (95%CI: 0.612-0.744; P ≤ 0.001). A multivariate logistic regression shows United Kingdom model for End Stage Liver Disease (P = 0.006), Hb (P = 0.022) and Fibrinogen (P = 0.026) to be statistically significant, whereas Platelet count was not statistically significant.
CONCLUSION Platelet count alone does not predict excessive transfusion. Additional investigations, e.g., clauss fibrinogen and viscoelastic tests, provide more robust assessment of bleeding-risk in thrombocytopenia and cirrhosis.
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Romecín P, Atucha NM, Navarro EG, Ortiz MC, Iyú D, Rosado JA, García-Estañ J. Role of homocysteine and folic acid on the altered calcium homeostasis of platelets from rats with biliary cirrhosis. Platelets 2017; 28:698-705. [PMID: 28150525 DOI: 10.1080/09537104.2016.1265920] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Previously, we have found that intracellular calcium homeostasis is altered in platelets from an experimental model of liver cirrhosis, the bile-duct ligated (BDL) rat; these alterations are compatible with the existence of a hypercoagulable state. Different studies indicate that cholestatic diseases are associated with hyperhomocysteinemia; thus, we hypothetized that it could contribute to those platelet alterations. In the present study, we have investigated the role of homocysteine (HCY) in platelet aggregation and calcium signaling in the BDL model. The effect of chronic folic acid treatment was also analyzed. Acute treatment with HCY increased the aggregation response to ADP and calcium responses to thrombin in platelets of control and BDL rats. Capacitative calcium entry was not altered by HCY. Chronic treatment with folic acid decreased platelet aggregation in control and BDL rats, but this decrease was greater in BDL rats. In folic acid-treated rats, thrombin-induced calcium entry and release were decreased in platelet of control rats but unaltered in BDL rats; however, capacitative calcium entry was decreased in platelets of control and BDL rats treated with folic acid. Reactive oxygen species were produced at higher levels by BDL platelets after stimulation with HCY or thrombin and folic acid normalized these responses. HCY plays a role in the enhanced platelet aggregation response of BDL rats, probably through an enhanced formation of ROS. Folic acid pretreatment normalizes many of the platelet alterations shown by BDL rats.
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Affiliation(s)
- Paola Romecín
- a Depto. Fisiología, Fac. Medicina, Instituto Murciano de Investigación Biosanitaria (IMIB) , Universidad de Murcia, Murcia, Spain
| | - Noemí M Atucha
- a Depto. Fisiología, Fac. Medicina, Instituto Murciano de Investigación Biosanitaria (IMIB) , Universidad de Murcia, Murcia, Spain
| | - Esther G Navarro
- a Depto. Fisiología, Fac. Medicina, Instituto Murciano de Investigación Biosanitaria (IMIB) , Universidad de Murcia, Murcia, Spain
| | - M Clara Ortiz
- a Depto. Fisiología, Fac. Medicina, Instituto Murciano de Investigación Biosanitaria (IMIB) , Universidad de Murcia, Murcia, Spain
| | - David Iyú
- a Depto. Fisiología, Fac. Medicina, Instituto Murciano de Investigación Biosanitaria (IMIB) , Universidad de Murcia, Murcia, Spain
| | - Juan Antonio Rosado
- b Depto. Fisiología, Fac. Veterinaria , Universidad de Extremadura , Cáceres, Spain
| | - Joaquín García-Estañ
- a Depto. Fisiología, Fac. Medicina, Instituto Murciano de Investigación Biosanitaria (IMIB) , Universidad de Murcia, Murcia, Spain
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38
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Peterson TJ, Webb AMB, Vipler BS. Use of thromboelastography in the management of liver cirrhosis and accelerated intravascular coagulation and fibrinolysis (AICF). BMJ Case Rep 2016; 2016:bcr2016218294. [PMID: 27974342 PMCID: PMC5174901 DOI: 10.1136/bcr-2016-218294] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/29/2016] [Indexed: 01/11/2023] Open
Abstract
In the presented case, the authors describe an obese middle-aged man that presented to the emergency department for persistent oedema, scleral icterus and fatigue. He was admitted to the hospital and diagnosed with liver cirrhosis via transjugular liver biopsy. He continued to bleed from the biopsy site for 5 days from accelerated intravascular coagulation and fibrinolysis (AICF) requiring multiple transfusions of packed red blood cells, fresh-frozen plasma and cryoprecipitate. The authors then used thromboelastography (TEG) to further characterise the patient's coagulopathy, which revealed platelet inhibition. The results of the TEG significantly changed future transfusion management. Finally, the authors conducted a literature review to summarise the current literature available for the use of TEG in the management of liver cirrhosis with AICF.
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Affiliation(s)
- Thomas Joseph Peterson
- Uniformed Services University of the Health Sciences, F. Edward Hebert School of Medicine, Bethesda, Maryland, USA
| | - Allison Margaret Brown Webb
- Department of Internal Medicine–Psychiatry, Walter Reed National Military Medical Center, Bethesda, Maryland, USA
| | - Benjamin Samuel Vipler
- Department of Internal Medicine, Naval Medical Center Portsmouth, Portsmouth, Virginia, USA
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De Pietri L, Bianchini M, Rompianesi G, Bertellini E, Begliomini B. Thromboelastographic reference ranges for a cirrhotic patient population undergoing liver transplantation. World J Transplant 2016; 6:583-593. [PMID: 27683637 PMCID: PMC5036128 DOI: 10.5500/wjt.v6.i3.583] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2016] [Revised: 06/21/2016] [Accepted: 08/16/2016] [Indexed: 02/05/2023] Open
Abstract
AIM To describe the thromboelastography (TEG) “reference” values within a population of liver transplant (LT) candidates that underline the differences from healthy patients.
METHODS Between 2000 and 2013, 261 liver transplant patients with a model for end-stage liver disease (MELD) score between 15 and 40 were studied. In particular the adult patients (aged 18-70 years) underwent to a first LT with a MELD score between 15 and 40 were included, while all patients with acute liver failure, congenital bleeding disorders, and anticoagulant and/or antiplatelet drug use were excluded. In this population of cirrhotic patients, preoperative haematological and coagulation laboratory tests were collected, and the pretransplant thromboelastographic parameters were studied and compared with the parameters measured in a previously studied population of 40 healthy subjects. The basal TEG parameters analysed in the cirrhotic population of liver candidates were as follows: Reaction time (r), coagulation time (k), Angle-Rate of polymerization of clot (αAngle), Maximum strenght of clot (MA), Amplitudes of the TEG tracing at 30 min and 60 min after MA is measured (A30 and A60), and Fibrinolysis at 30 and 60 min after MA (Ly30 and Ly60). The possible correlation between the distribution of the reference range and the gender, age, MELD score (higher or lower than 20) and indications for transplantation (liver pathology) were also investigated. In particular, a MELD cut-off value of 20 was chosen to verify the possible correlation between the thromboelastographic reference range and MELD score.
RESULTS Most of the TEG reference values from patients with end-stage liver disease were significantly different from those measured in the healthy population and were outside the suggested normal ranges in up to 79.3% of subjects. Wide differences were found among all TEG variables, including r (41.5% of the values), k (48.6%), α (43.7%), MA (79.3%), A30 (74.4%) and A60 (80.9%), indicating a prevailing trend to hypocoagulability. The differences between the mean TEG values obtained from healthy subjects and the cirrhotic population were statistically significant for r (P = 0.039), k (P < 0.001), MA (P < 0.001), A30 (P < 0.001), A60 (P < 0.001) and Ly60 (P = 0.038), indicating slower and less stable clot formation in the cirrhotic patients. In the cirrhotic population, 9.5% of patients had an r value shorter than normal, indicating a tendency for faster clot formation. Within the cirrhotic patient population, gender, age and the presence of hepatocellular carcinoma or alcoholic cirrhosis were not significantly associated with greater clot firmness or enhanced whole blood clot formation, whereas greater clot strength was associated with a MELD score < 20, hepatitis C virus and cholestatic-related cirrhosis (P < 0.001; P = 0.013; P < 0.001).
CONCLUSION The range and distribution of TEG values in cirrhotic patients differ from those of healthy subjects, suggesting that a specific thromboelastographic reference range is required for liver transplant candidates.
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Kopec AK, Luyendyk JP. Role of Fibrin(ogen) in Progression of Liver Disease: Guilt by Association? Semin Thromb Hemost 2016; 42:397-407. [PMID: 27144445 DOI: 10.1055/s-0036-1579655] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Strong experimental evidence indicates that components of the hemostatic system, including thrombin, exacerbate diverse features of experimental liver disease. Clinical studies have also begun to address this connection and some studies have suggested that anticoagulants can improve outcome in patients with liver disease. Among the evidence of coagulation cascade activation in models of liver injury and disease is the frequent observation of thrombin-driven hepatic fibrin(ogen) deposition. Indeed, hepatic fibrin(ogen) deposition has long been recognized as a consequence of hepatic injury. Although commonly inferred as pathologic due to protective effects of anticoagulants in mouse models, the role of fibrin(ogen) in acute liver injury and chronic liver disease may not be universally detrimental. The localization of hepatic fibrin(ogen) deposits within the liver is connected to the disease stimulus and in animal models of liver toxicity and chronic disease, fibrin(ogen) deposition may not always be synonymous with large vessel thrombosis. Here, we provide a balanced review of the experimental evidence supporting a direct connection between fibrin(ogen) and liver injury/disease pathogenesis, and suggest a path forward bridging experimental and clinical research to improve our knowledge on the nature and function of fibrin(ogen) in liver disease.
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Affiliation(s)
- Anna K Kopec
- Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan
| | - James P Luyendyk
- Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan
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Hemostatic balance in patients with liver cirrhosis: Report of a consensus conference. Dig Liver Dis 2016; 48:455-467. [PMID: 27012444 DOI: 10.1016/j.dld.2016.02.008] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Accepted: 02/18/2016] [Indexed: 12/11/2022]
Abstract
Patients with cirrhosis present with hemostatic alterations secondary to reduced availability of pro-coagulant and anti-coagulant factors. The net effect of these changes is a rebalanced hemostatic system. The Italian Association of the Study of the Liver (AISF) and the Italian Society of Internal Medicine (SIMI) promoted a consensus conference on the hemostatic balance in patients with cirrhosis. The consensus process started with the review of the literature by a scientific board of experts and ended with a formal consensus meeting in Rome in December 2014. The statements were graded according to quality of evidence and strength of recommendations, and approved by an independent jury. The statements presented here highlight strengths and weaknesses of current laboratory tests to assess bleeding and thrombotic risk in cirrhotic patients, the pathophysiology of hemostatic perturbations in this condition, and outline the optimal management of bleeding and thrombosis in patients with liver cirrhosis.
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Yip J, Bruno DA, Burmeister C, Kazimi M, Yoshida A, Abouljoud MS, Schnickel GT. Deep Vein Thrombosis and Pulmonary Embolism in Liver Transplant Patients: Risks and Prevention. Transplant Direct 2016; 2:e68. [PMID: 27500259 PMCID: PMC4946512 DOI: 10.1097/txd.0000000000000578] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2015] [Accepted: 01/05/2016] [Indexed: 01/17/2023] Open
Abstract
Deep vein thrombosis (DVT) and pulmonary embolism (PE) are surgical complications estimated to occur in 5% to 10% of patients. There are limited data regarding DVT/PE in the early postoperative period in liver transplant patients. The aim of this study is to determine risk factors that influence the incidence of DVT/PE and the effectiveness of prophylaxis.
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Affiliation(s)
- James Yip
- Division of Transplant and Hepatobiliary Surgery, Department of Surgery, Henry Ford Hospital, Detroit, MI
| | - David A Bruno
- Division of Transplant and Hepatobiliary Surgery, Department of Surgery, Henry Ford Hospital, Detroit, MI
| | - Charlotte Burmeister
- Division of Transplant and Hepatobiliary Surgery, Department of Surgery, Henry Ford Hospital, Detroit, MI
| | - Marwan Kazimi
- Division of Transplant and Hepatobiliary Surgery, Department of Surgery, Henry Ford Hospital, Detroit, MI
| | - Atsushi Yoshida
- Division of Transplant and Hepatobiliary Surgery, Department of Surgery, Henry Ford Hospital, Detroit, MI
| | - Marwan S Abouljoud
- Division of Transplant and Hepatobiliary Surgery, Department of Surgery, Henry Ford Hospital, Detroit, MI
| | - Gabriel T Schnickel
- Division of Transplant and Hepatobiliary Surgery, Department of Surgery, Henry Ford Hospital, Detroit, MI
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Fibrin deposition following bile duct injury limits fibrosis through an αMβ2-dependent mechanism. Blood 2016; 127:2751-62. [PMID: 26921287 DOI: 10.1182/blood-2015-09-670703] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2015] [Accepted: 02/23/2016] [Indexed: 12/15/2022] Open
Abstract
Coagulation cascade activation and fibrin deposits have been implicated or observed in diverse forms of liver damage. Given that fibrin amplifies pathological inflammation in several diseases through the integrin receptor αMβ2, we tested the hypothesis that disruption of the fibrin(ogen)-αMβ2 interaction in Fibγ(390-396A) mice would reduce hepatic inflammation and fibrosis in an experimental setting of chemical liver injury. Contrary to our hypothesis, α-naphthylisothiocyanate (ANIT)-induced liver fibrosis increased in Fibγ(390-396A) mice, whereas inflammatory cytokine expression and hepatic necrosis were similar to ANIT-challenged wild-type (WT) mice. Increased fibrosis in Fibγ(390-396A) mice appeared to be independent of coagulation factor 13 (FXIII) transglutaminase, as ANIT challenge in FXIII-deficient mice resulted in a distinct pathological phenotype characterized by increased hepatic necrosis. Rather, bile duct proliferation underpinned the increased fibrosis in ANIT-exposed Fibγ(390-396A) mice. The mechanism of fibrin-mediated fibrosis was linked to interferon (IFN)γ induction of inducible nitric oxide synthase (iNOS), a gene linked to bile duct hyperplasia and liver fibrosis. Expression of iNOS messenger RNA was significantly increased in livers of ANIT-exposed Fibγ(390-396A) mice. Fibrin(ogen)-αMβ2 interaction inhibited iNOS induction in macrophages stimulated with IFNγ in vitro and ANIT-challenged IFNγ-deficient mice had reduced iNOS induction, bile duct hyperplasia, and liver fibrosis. Further, ANIT-induced iNOS expression, liver fibrosis, and bile duct hyperplasia were significantly reduced in WT mice administered leukadherin-1, a small molecule that allosterically enhances αMβ2-dependent cell adhesion to fibrin. These studies characterize a novel mechanism whereby the fibrin(ogen)-integrin-αMβ2 interaction reduces biliary fibrosis and suggests a novel putative therapeutic target for this difficult-to-treat fibrotic disease.
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Pre-operative predictors of red blood cell transfusion in liver transplantation. BLOOD TRANSFUSION = TRASFUSIONE DEL SANGUE 2016; 15:53-56. [PMID: 27136440 DOI: 10.2450/2016.0203-15] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Subscribe] [Scholar Register] [Received: 08/10/2015] [Accepted: 10/28/2015] [Indexed: 12/27/2022]
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Joshi N, Kopec AK, O'Brien KM, Towery KL, Cline-Fedewa H, Williams KJ, Copple BL, Flick MJ, Luyendyk JP. Coagulation-driven platelet activation reduces cholestatic liver injury and fibrosis in mice. J Thromb Haemost 2015; 13:57-71. [PMID: 25353084 PMCID: PMC4487795 DOI: 10.1111/jth.12770] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2014] [Accepted: 10/17/2014] [Indexed: 01/14/2023]
Abstract
BACKGROUND The coagulation cascade has been shown to participate in chronic liver injury and fibrosis, but the contribution of various thrombin targets, such as protease activated receptors (PARs) and fibrin(ogen), has not been fully described. Emerging evidence suggests that in some experimental settings of chronic liver injury, platelets can promote liver repair and inhibit liver fibrosis. However, the precise mechanisms linking coagulation and platelet function to hepatic tissue changes following injury remain poorly defined. OBJECTIVES To determine the role of PAR-4, a key thrombin receptor on mouse platelets, and fibrin(ogen) engagement of the platelet αII b β3 integrin (αIIb β3 ) in a model of cholestatic liver injury and fibrosis. METHODS Biliary and hepatic injury was characterized following 4 week administration of the bile duct toxicant α-naphthylisothiocyanate (ANIT) (0.025%) in PAR-4-deficient mice, mice expressing a mutant form of fibrin(ogen) incapable of binding integrin αII b β3 (Fibγ(Δ5) ), and wild-type mice. RESULTS Elevated plasma thrombin-antithrombin and serotonin levels, hepatic fibrin deposition, and platelet accumulation in liver accompanied hepatocellular injury and fibrosis in ANIT-treated wild-type mice. PAR-4 deficiency reduced plasma serotonin levels, increased serum bile acid concentration, and exacerbated ANIT-induced hepatocellular injury and peribiliary fibrosis. Compared with PAR-4-deficient mice, ANIT-treated Fibγ(Δ5) mice displayed more widespread hepatocellular necrosis accompanied by marked inflammation, robust fibroblast activation, and extensive liver fibrosis. CONCLUSIONS Collectively, the results indicate that PAR-4 and fibrin-αII b β3 integrin engagement, pathways coupling coagulation to platelet activation, each exert hepatoprotective effects during chronic cholestasis.
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MESH Headings
- 1-Naphthylisothiocyanate
- Animals
- Antithrombin III
- Bile Acids and Salts/blood
- Blood Coagulation/genetics
- Blood Platelets/metabolism
- Chemical and Drug Induced Liver Injury/blood
- Chemical and Drug Induced Liver Injury/genetics
- Chemical and Drug Induced Liver Injury/pathology
- Chemical and Drug Induced Liver Injury/prevention & control
- Cholestasis/blood
- Cholestasis/chemically induced
- Cholestasis/genetics
- Cholestasis/pathology
- Cholestasis/prevention & control
- Fibrinogens, Abnormal/genetics
- Fibrinogens, Abnormal/metabolism
- Genotype
- Liver/metabolism
- Liver/pathology
- Liver Cirrhosis, Experimental/blood
- Liver Cirrhosis, Experimental/chemically induced
- Liver Cirrhosis, Experimental/genetics
- Liver Cirrhosis, Experimental/pathology
- Liver Cirrhosis, Experimental/prevention & control
- Male
- Mice, Inbred C57BL
- Mice, Knockout
- Mutation
- Necrosis
- Peptide Hydrolases/blood
- Phenotype
- Platelet Activation/genetics
- Platelet Glycoprotein GPIIb-IIIa Complex/metabolism
- Receptors, Thrombin/deficiency
- Receptors, Thrombin/genetics
- Serotonin/blood
- Signal Transduction
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Affiliation(s)
- N Joshi
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA; Center for Integrative Toxicology, Michigan State University, East Lansing, MI, USA
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46
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Effects of increased von Willebrand factor levels on primary hemostasis in thrombocytopenic patients with liver cirrhosis. PLoS One 2014; 9:e112583. [PMID: 25397410 PMCID: PMC4232392 DOI: 10.1371/journal.pone.0112583] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2014] [Accepted: 10/08/2014] [Indexed: 02/07/2023] Open
Abstract
In patients with liver cirrhosis procoagulant and anticoagulant changes occur simultaneously. During primary hemostasis, platelets adhere to subendothelial structures, via von Willebrand factor (vWF). We aimed to investigate the influence of vWF on primary hemostasis in patients with liver cirrhosis. Therefore we assessed in-vitro bleeding time as marker of primary hemostasis in cirrhotic patients, measuring the Platelet Function Analyzer (PFA-100) closure times with collagen and epinephrine (Col-Epi, upper limit of normal ≤ 165 s) or collagen and ADP (Col-ADP, upper limit of normal ≤ 118 s). If Col-Epi and Col-ADP were prolonged, the PFA-100 was considered to be pathological. Effects of vWF on primary hemostasis in thrombocytopenic patients were analyzed and plasma vWF levels were modified by adding recombinant vWF or anti-vWF antibody. Of the 72 included cirrhotic patients, 32 (44.4%) showed a pathological result for the PFA-100. They had mean closure times (± SD) of 180 ± 62 s with Col-Epi and 160 ± 70 s with Col-ADP. Multivariate analysis revealed that hematocrit (P = 0.027) and vWF-antigen levels (P = 0.010) are the predictors of a pathological PFA-100 test in cirrhotic patients. In 21.4% of cirrhotic patients with platelet count ≥ 150/nL and hematocrit ≥ 27.0%, pathological PFA-100 results were found. In thrombocytopenic (< 150/nL) patients with cirrhosis, normal PFA-100 results were associated with higher vWF-antigen levels (462.3 ± 235.9% vs. 338.7 ± 151.6%, P = 0.021). These results were confirmed by multivariate analysis in these patients as well as by adding recombinant vWF or polyclonal anti-vWF antibody that significantly shortened or prolonged closure times, respectively. In conclusion, primary hemostasis is impaired in cirrhotic patients. The effect of reduced platelet count in cirrhotic patients can at least be partly compensated by increased vWF levels. Recombinant vWF could be an alternative to platelet transfusions in the future.
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47
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Klammt S, Mitzner SR, Reisinger EC, Stange J. No sustained impact of intermittent extracorporeal liver support on thrombocyte time course in a randomized controlled albumin dialysis trial. Ther Apher Dial 2014; 18:502-8. [PMID: 25195684 DOI: 10.1111/1744-9987.12124] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Reduction of platelets is a common finding in patients with liver disease and can be aggravated by extracorporeal therapies, e.g. artificial liver support. The impact of extracorporeal albumin dialysis on the time count and time course of platelets in liver failure patients was evaluated in a randomized controlled clinical trial. Mean thrombocyte reduction during a single extracorporeal liver support therapy was -15.1% [95%CI: -17.7; -12.5]. No differences were found between treatments of patients with a more reduced platelet count (<100 GPT/L: -15.6% [-19.5; -11.7%]; n = 43) compared to patients with normal or slightly decreased thrombocytes (-14.6% [-18.3%; -11.0%]; n = 43; P = 0.719). The variation of platelet count within 24 h after onset of extracorporeal therapy treatment was less, albeit significant (-3.5% [-6.3%; -0.7%], P < 0.016). Absolute thrombocyte variability was comparable between both groups (with extracorporeal therapy -5.6 GPT/L [-9.7; -1.4], without extracorporeal therapy -1.3 GPT/L [-7.3; 4.7]; P = 0.243), whereas relative decrease of thrombocytes within a 24-h period of extracorporeal therapy was greater than the changes in patients without extracorporeal therapy (-3.5% [-6.3%; -0.7%] vs. 2.0% [-2.0%; 5.9%]; P = 0.026]. Within a period of two weeks after enrollment, no significant differences of platelet count were observed either between the two groups or in the time course (P(group) = 0.337, P(time) = 0.277). Reduction of platelets during intermittent extracorporeal liver support was less pronounced within a 24-h period as before and after a single treatment and was comparable to variations in the control group without extracorporeal therapy.
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Affiliation(s)
- Sebastian Klammt
- Division of Nephrology, University Rostock, Rostock, Germany; Division of Tropical Medicine and Infectious Diseases, Department of Internal Medicine II, University Rostock, Rostock, Germany
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48
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Weeder PD, Porte RJ, Lisman T. Hemostasis in liver disease: implications of new concepts for perioperative management. Transfus Med Rev 2014; 28:107-13. [PMID: 24721432 DOI: 10.1016/j.tmrv.2014.03.002] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2014] [Revised: 03/09/2014] [Accepted: 03/10/2014] [Indexed: 02/08/2023]
Abstract
The hemostatic profile of patients with liver diseases is frequently profoundly different from that of healthy individuals. These complex alterations lead to abnormal results from routine laboratory tests, but because of the nature of these assays, they fail to accurately represent the patient's hemostatic state. Nevertheless, based on abnormal laboratory coagulation values, it has long been assumed that patients with liver disease have a natural bleeding tendency and are protected from thrombosis. This assumption is false; the average patient with liver disease is actually in a state of "rebalanced hemostasis" that can relatively easily be tipped toward both bleeding and thrombosis. The new paradigm of rebalanced hemostasis has strong implications for the clinic, which are presented in this review. There is no evidence that prophylactic transfusion of plasma helps to prevent procedure-related bleeding. In addition, the presence of independent risk factors such as poor kidney status or infections should be carefully assessed before invasive procedures. Furthermore, central venous pressure plays an important role in the risk of bleeding in patients with liver diseases, so during procedures, a restrictive infusion policy should be applied. Finally, thrombosis prophylaxis should not be withheld from patients with cirrhosis or acute liver failure, and clinicians should be alert to the possibility of thrombosis occurring in these patients.
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Affiliation(s)
- Pepijn D Weeder
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Surgical Research Laboratory, Department of Surgery, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
| | - Robert J Porte
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
| | - Ton Lisman
- Surgical Research Laboratory, Department of Surgery, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
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49
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Xianghong G, Guanping C, Fenghua Y, Jiayin W. Changes in platelet functional parameters and CD62 P expression in liver cirrhosis. Afr Health Sci 2013; 13:1079-83. [PMID: 24940335 DOI: 10.4314/ahs.v13i4.31] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND Hepatic impairment, portal hypertension, and multi-systemic damage could occur during liver cirrhosis's late stage. Bleeding is a complication of hepatic cirrhosis along with several changes including blood platelet count (BPC), mean platelet volume (MPV), platelet crit (PCT) and expression of platelet CD62P. Blood platelet count (BPC), mean platelet volume (MPV), platelet distribution width, and other indices are indirect reflections of CD62P parameters. OBJECTIVE To investigate the changes in platelet functional parameters and CD62 P expression in liver cirrhosis as a possible guide in clinical treatments and prognoses of liver cirrhosis. METHODS CD62P was tested by flow cytometry in liver cirrhosis. BPC, MPV, and PCT in peripheral blood were tested using an auto blood cell analyzer. Data were analyzed using SPSS11.0. RESULTS The values of CD62P and MPV in patients was significantly higher than those of healthy donors (P<0.01), while the values of BPC and PCT were significantly lower than those of the control group (P<0.01). CONCLUSIONS CD62P, BPC, MPV, and platelet crit (PCT) show several changes in liver cirrhosis. It is useful to understand the relationship between hepatic cirrhosis severity and CD62P, BPC, MPV, PCT, timely monitoring of CD62P for treatment of hepatic cirrhosis in clinical treatment and prognosis.
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50
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Mayhew PD, Savigny MR, Otto CM, Brown DC, Brooks MB, Bentley AM, Runge JJ, Callan MB. Evaluation of coagulation in dogs with partial or complete extrahepatic biliary tract obstruction by means of thromboelastography. J Am Vet Med Assoc 2013; 242:778-85. [PMID: 23445288 DOI: 10.2460/javma.242.6.778] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
OBJECTIVE To characterize in vitro coagulation status in a cohort of dogs with extrahepatic biliary tract obstruction (EHBO) and to evaluate these patients for hypercoagulability by means of thromboelastography. DESIGN Prospective cohort study. Animals-10 dogs with EHBO and 19 healthy control dogs. PROCEDURES Partial or complete EHBO was confirmed via exploratory celiotomy. Venous blood samples were collected for evaluation of prothrombin time (PT) and activated partial thromboplastin time (APTT); fibrinogen and D-dimer concentrations; protein C and antithrombin activities; and factor VII, VIII, and XI coagulant activities in plasma as well as thromboelastography in whole blood. Thromboelastography variables were measured from the thromboelastography tracing, and a coagulation index was calculated. Thromboelastography results were compared with those of healthy control dogs previously evaluated by the same laboratory. RESULTS Hypercoagulability was diagnosed in all dogs with EHBO on the basis of a high coagulation index. Thromboelastography variables, including maximal amplitude, α-angle, and coagulation index, were significantly higher, and K (clot formation time) and R (reaction time) were significantly lower in these dogs than in control dogs. All dogs with EHBO had PT and APTT within respective reference ranges. Plasma D-dimer and fibrinogen concentrations were above reference ranges in 8 and 7 dogs, respectively, and protein C and antithrombin activities were below reference ranges in 3 and 1 dogs, respectively. CONCLUSIONS AND CLINICAL RELEVANCE In vitro hypercoagulability was commonly detected in dogs with naturally occurring EHBO. The traditional view of EHBO as a disease that causes hypocoagulability may need to be reconsidered.
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Affiliation(s)
- Philipp D Mayhew
- Department of Clinical Studies-Philadelphia, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
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