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Meng PP, Xiong FX, Chen JL, Zhou Y, Liu XL, Ji XM, Jiang YY, Hou YX. Establish and validate an artificial neural networks model used for predicting portal vein thrombosis risk in hepatitis B-related cirrhosis patients. World J Hepatol 2025; 17:97767. [PMID: 40177194 PMCID: PMC11959667 DOI: 10.4254/wjh.v17.i3.97767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Revised: 11/24/2024] [Accepted: 02/24/2025] [Indexed: 03/26/2025] Open
Abstract
BACKGROUND The portal vein thrombosis (PVT) can exacerbate portal hypertension and lead to complications, increasing the risk of mortality. AIM To evaluate the predictive capacity of artificial neural networks (ANNs) in quantifying the likelihood of developing PVT in individuals afflicted with hepatitis B-induced cirrhosis. METHODS A retrospective study was conducted at Beijing Ditan Hospital, affiliated with Capital Medical University, including 986 hospitalized patients. Patients admitted between January 2011 and December 2014 were assigned to the training set (685 cases), while those hospitalized from January 2015 to December 2016 were divided into the validation cohort (301 cases). Independent risk factors for PVT were identified using COX univariate analysis and used to construct an ANN model. Model performance was evaluated through metrics such as the area under the receiver operating characteristic curve (AUC) and concordance index. RESULTS In the training set, PVT occurred in 19.0% of patients within three years and 23.7% within five years. In the validation cohort, PVT developed in 16.7% of patients within three years and 24.0% within five years. The ANN model incorporated nine independent risk factors: Age, ascites, hepatic encephalopathy, gastrointestinal varices with bleeding, Child-Pugh classification, alanine aminotransferase levels, albumin levels, neutrophil-to-lymphocyte ratio, and platelet. The model achieved an AUC of 0.967 (95%CI: 0.960-0.974) at three years and 0.975 (95%CI: 0.955-0.992) at five years, significantly outperforming existing models such as model for end-stage liver disease and Child-Pugh-Turcotte (all P < 0.001). CONCLUSION The ANN model demonstrated effective stratification of patients into high- and low-risk groups for PVT development over three and five years. Validation in an independent cohort confirmed the model's predictive accuracy.
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Affiliation(s)
- Pei-Pei Meng
- Center of Integrative Chinese and Western Medicine, Beijing Ditan Hospital affiliated to Capital Medical University, Beijing 100102, China
| | - Fei-Xiang Xiong
- Center of Integrative Chinese and Western Medicine, Beijing Ditan Hospital affiliated to Capital Medical University, Beijing 100102, China
| | - Jia-Liang Chen
- Center of Integrative Chinese and Western Medicine, Beijing Ditan Hospital affiliated to Capital Medical University, Beijing 100102, China
| | - Yang Zhou
- Center of Integrative Chinese and Western Medicine, Beijing Ditan Hospital affiliated to Capital Medical University, Beijing 100102, China
| | - Xiao-Li Liu
- Center of Integrative Medicine, Beijing Ditan Hospital Affiliated to Capital Medical, Beijing 100015, China
| | - Xiao-Min Ji
- Center of Integrative Chinese and Western Medicine, Beijing Ditan Hospital affiliated to Capital Medical University, Beijing 100102, China
| | - Yu-Yong Jiang
- Center of Integrative Chinese and Western Medicine, Beijing Ditan Hospital affiliated to Capital Medical University, Beijing 100102, China
| | - Yi-Xin Hou
- Center of Integrative Chinese and Western Medicine, Beijing Ditan Hospital affiliated to Capital Medical University, Beijing 100102, China.
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Premkumar M, Bhujade H, Sharma P, Nain J, Ahluwalia J, Sandhu A, Kumar Y, Rathi S, Taneja S, Duseja AK, Kulkarni AV, Singh C, Naseem S, Karki T, Gupta P, Chaluvashetty SB, Lad D, Reddy KR. Experience With Dabigatran on Rate of Portal Vein Thrombosis Recanalization, Disease Progression and Survival. Aliment Pharmacol Ther 2025; 61:971-987. [PMID: 39748673 DOI: 10.1111/apt.18474] [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: 10/24/2024] [Revised: 11/22/2024] [Accepted: 12/21/2024] [Indexed: 01/04/2025]
Abstract
BACKGROUND AND AIMS We assessed clinical, procoagulant and genetic risk factors and clinical outcomes in dabigatran-treated patients with non-tumoural acute and acute-on-chronic portal vein thrombosis (PVT). METHODS Patients with a new diagnosis of non-tumoural acute and acute-on-chronic PVT between January 2021 and January 2024 (aged ≥ 18 years) in those without/with cirrhosis (Child-Pugh (CP)-A/B/C ≤ 10) were started on dabigatran and followed and compared with those on vitamin K antagonist (VKA) and untreated individuals. RESULTS Dabigatran was prescribed in 119 patients with PVT type 1 (61, 51.3%), type 2 (34, 28.6%), type 3 (24, 20.2%); 72 (60.5%) with cirrhosis [CP-A (27, 37.5%), CP-B (43, 59.7%) and CP-C10 (2, 2.8%)]. Procoagulant factors noted were JAK2V617F (10.1%), CALR (2.5%) and factor V Leiden (1.6%) mutations, antiphospholipid syndrome (APS, 15.2%), isolated Protein C (14.3%) and Protein S (16.8%) deficiency. COMPARATORS 28 patients who declined anticoagulation/were unable to come for follow-up, and six with CP-C received VKA. Overall recanalization rate (RR) on dabigatran was 56 (47.1%); 25 (21%) complete recanalization, 31 (26%) partial recanalization and 63 (52.9%) stable PVT over median follow-up of 32 months. Patients not anticoagulated had a spontaneous RR in 21.4% (28 patients; p = 0.005 compared with dabigatran group) and none recanalized on VKA. On multivariable analysis, predictors of recanalization on dabigatran were Factor VIII Antigen level (FVIII:Ag, HR 0.6; 95% CI 0.3-0.9, p = 0.032), non-occlusive PVT (HR 3.5, 95% CI 1.9-5.6, p = 0.025) and acute PVT (HR 2.1; 95% CI 1.5-3.2, p = 0.003). Mortality was 14 (11.8%). CONCLUSION On dabigatran, 47% of 119 patients achieved portal vein recanalization over 32 months of follow-up which was higher than the spontaneous RR (21.4%) in an untreated cohort. High Factor VIII:Ag was a predictor of non-recanalization. Dabigatran was safe in cirrhosis (CP-A and B) while further work is needed in CP-C.
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Affiliation(s)
- Madhumita Premkumar
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Harish Bhujade
- Department of Radiodiagnosis and Interventional Radiology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Prerna Sharma
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Jasvinder Nain
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Jasmina Ahluwalia
- Department of Hematopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Anchal Sandhu
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Yogendra Kumar
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Sahaj Rathi
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Sunil Taneja
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Ajay Kumar Duseja
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Anand V Kulkarni
- Department of Hepatology, Asian Institute of Gastroenterology, Hyderabad, India
| | - Charanpreet Singh
- Clinical Hematology and Medical Oncology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Shano Naseem
- Department of Hematopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Tanka Karki
- Department of Radiodiagnosis and Interventional Radiology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Pankaj Gupta
- Department of Radiodiagnosis and Interventional Radiology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Sreedhara B Chaluvashetty
- Department of Radiodiagnosis and Interventional Radiology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Deepesh Lad
- Clinical Hematology and Medical Oncology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - K Rajender Reddy
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania, Philadelphia, USA
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van Dievoet MA, David C, Dieu A, Hermans C, Pirotte T, Douxfils J, Lisman T, Stephenne X. Persisting thrombomodulin resistance at 3 months after liver transplantation in children with cirrhosis. Res Pract Thromb Haemost 2025; 9:102709. [PMID: 40290349 PMCID: PMC12034219 DOI: 10.1016/j.rpth.2025.102709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2024] [Revised: 02/03/2025] [Accepted: 02/19/2025] [Indexed: 04/30/2025] Open
Abstract
Background The coagulation cascade in pediatric cirrhotic patients appears rebalanced, similar to adults, with few true hemostasis-related bleeds or thromboembolic events before liver transplantation. Vascular thrombosis is an important post-liver transplantation complication. Few papers have addressed the recovery of the coagulation cascade after liver transplantation. Objectives We aimed to assess the coagulation cascade, with both measurement of individual factors and a global hemostasis assay, before living donor liver transplantation and to investigate its recovery 3 months after transplantation, when liver function has normalized. Methods From January 2022 to July 2023, pediatric cirrhotic patients were prospectively enrolled 1 day before liver transplantation. An age-matched control group was included for comparison. Routine hemostasis tests, levels of coagulation factors and natural anticoagulants, and thrombomodulin-modified thrombin generation were determined on automated coagulation analyzers at inclusion and 3 months after liver transplantation. Results Twenty-seven pediatric patients with cirrhosis, primarily of cholestatic origin, and 10 controls were enrolled. Sixteen patients were sampled 3 months after liver transplantation. Pediatric end-stage liver disease scores ranged from -10 to 44. A rebalanced coagulation cascade was confirmed in cirrhotic children, indicated by a thrombomodulin-modified thrombin generation assay similar to controls, although with higher interpatient variability. Interestingly, 3 months posttransplant, coagulation was not completely normalized. In the majority of patients resistance to thrombomodulin persisted. Conclusion This study confirmed a rebalanced coagulation system in pediatric cirrhotic patients before liver transplantation. Three months posttransplant thrombomodulin resistance persisted. Whereas this contributes to thrombotic complications observed after liver transplantation, remains to be elucidated.
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Affiliation(s)
- Marie-Astrid van Dievoet
- Laboratory of Pediatric Hepatology and Cell Therapy, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, Brussels, Belgium
- Laboratory Department, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - Clara David
- Clinical Pharmacology and Toxicology Research Unit, Namur Research Institute for Life Sciences (NARILIS), University of Namur, Namur, Belgium
- Research and Development Department, QUALIblood s.a., QUALIresearch, Liège, Belgium
| | - Audrey Dieu
- Department of Anesthesiology, Cliniques Universitaires Saint-Luc, 1200 Brussels, Belgium
| | - Cedric Hermans
- Haemostasis and Thrombosis Unit, Division of Haematology, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - Thierry Pirotte
- Department of Anesthesiology, Cliniques Universitaires Saint-Luc, 1200 Brussels, Belgium
| | - Jonathan Douxfils
- Clinical Pharmacology and Toxicology Research Unit, Namur Research Institute for Life Sciences (NARILIS), University of Namur, Namur, Belgium
- Research and Development Department, QUALIblood s.a., QUALIresearch, Liège, Belgium
| | - Ton Lisman
- Surgical Research Laboratory and Section of Hepatobiliary Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Xavier Stephenne
- Laboratory of Pediatric Hepatology and Cell Therapy, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, Brussels, Belgium
- Division of Pediatric Gastroenterology and Hepatology, Department of Pediatrics, Cliniques Universitaires Saint-Luc, Rare Liver ERN, Transplantchild ERN, Brussels, Belgium
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Zanetto A, Campello E, Bulato C, Willems R, Konings J, Roest M, Gavasso S, Nuozzi G, Toffanin S, Burra P, Russo FP, Senzolo M, de Laat B, Simioni P. Impaired whole blood thrombin generation is associated with procedure-related bleeding in acutely decompensated cirrhosis. J Hepatol 2024:S0168-8278(24)02762-4. [PMID: 39672204 DOI: 10.1016/j.jhep.2024.12.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 12/03/2024] [Accepted: 12/03/2024] [Indexed: 12/15/2024]
Abstract
BACKGROUND & AIMS The clinical utility of thrombomodulin-modified thrombin generation (TM-TG) in cirrhosis is uncertain. We conducted a prospective study to evaluate the prognostic value of TM-TG in cirrhosis. METHODS Patients were recruited during outpatient clinics (compensated and stable decompensated cirrhosis) or if admitted to our inpatient service (acutely decompensated cirrhosis). We performed whole blood (WB) and platelet-poor plasma (PPP) TM-TG at recruitment. All patients were prospectively followed-up for bleeding/thrombosis, hepatic decompensation, and liver-related death. RESULTS We included 231 patients: 80 with compensated, 70 with stable decompensated, and 81 with acutely decompensated cirrhosis. Median follow-up was 414 days (range: 77-668). Eleven patients, all with acutely decompensated cirrhosis, experienced procedure-related bleeding. Both WB-TG and PPP-TG were more altered in bleeding vs. non-bleeding individuals (lower endogenous thrombin potential [ETP] and peak-height). However, only WB-TG could identify - at the individual patient level - those experiencing major bleeding (all having pre-procedural ETP <350 nmol/L∗min). In acutely decompensated cirrhosis, the AUC of WB-TG ETP for bleeding was 0.854 (95% CI 0.732-0.976), which was higher than that of PPP-TG ETP (0.676; 95% CI 0.524-0.809). Neither WB-TG nor PPP-TG could predict development of thrombosis, mostly portal vein thrombosis (n = 15). In compensated cirrhosis, WB-TG and PPP-TG were comparable between patients who experienced decompensation and those who did not. In decompensated cirrhosis, WB-TG and PPP-TG were more significantly altered in patients experiencing further decompensation/ACLF/liver-related death. A higher WB-TG ETP was linked to a lower risk of progression independently of MELD, Child-Pugh, and C-reactive protein (hazard ratio 0.4, 95% CI 0.21-0.79, p <0.01). CONCLUSIONS In compensated cirrhosis, WB-TG and PPP-TG do not improve risk stratification. In decompensated cirrhosis, WB-TG may be a promising tool for estimating procedure-related bleeding risk. IMPACT AND IMPLICATIONS Thrombomodulin-modified thrombin generation (TM-TG) in cirrhosis is a well-established research tool to assess the complex coagulopathy of cirrhosis; however, its clinical utility is uncertain. In acutely decompensated cirrhosis, a TM-modified whole blood (WB)-TG ETP <350 nmol/L∗min predicted major bleeding after invasive procedures, whereas platelet-poor plasma TG indicated a hypo-coagulable state in bleeding patients but could not identify those at risk. Neither WB-TG nor platelet-poor plasma-TG could predict development of portal vein thrombosis, which was predicted by cirrhosis and portal hypertension severity. In decompensated cirrhosis, a better WB-TG capacity was associated with a lower risk of further decompensation, acute-on-chronic liver failure, and liver-related death independently of MELD score/Child-Pugh stage and C-reactive protein.
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Affiliation(s)
- Alberto Zanetto
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Italy; Gastroenterology and Multivisceral Transplant Unit, Padova University Hospital, Padova, Italy
| | - Elena Campello
- Department of Medicine (DIMED), University of Padova, Italy; First Chair of Internal Medicine and Thrombotic and Haemorrhagic Disease Unit, Padova University Hospital, Padova, Italy
| | | | - Ruth Willems
- Department of Functional Coagulation, Synapse Research Institute, Maastricht, The Netherlands; Department of Internal Medicine, Section Vascular Medicine, Maastricht University Medical Center, Maastricht, the Netherlands; CARIM, School for Cardiovascular Diseases, Maastricht, the Netherlands
| | - Joke Konings
- Department of Functional Coagulation, Synapse Research Institute, Maastricht, The Netherlands
| | - Mark Roest
- Department of Functional Coagulation, Synapse Research Institute, Maastricht, The Netherlands
| | | | - Giorgia Nuozzi
- Department of Medicine (DIMED), University of Padova, Italy
| | | | - Patrizia Burra
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Italy; Gastroenterology and Multivisceral Transplant Unit, Padova University Hospital, Padova, Italy
| | - Francesco Paolo Russo
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Italy; Gastroenterology and Multivisceral Transplant Unit, Padova University Hospital, Padova, Italy
| | - Marco Senzolo
- Gastroenterology and Multivisceral Transplant Unit, Padova University Hospital, Padova, Italy
| | - Bas de Laat
- Department of Functional Coagulation, Synapse Research Institute, Maastricht, The Netherlands
| | - Paolo Simioni
- Department of Medicine (DIMED), University of Padova, Italy; First Chair of Internal Medicine and Thrombotic and Haemorrhagic Disease Unit, Padova University Hospital, Padova, Italy.
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Zanetto A, Campello E, Bulato C, Willems R, Konings J, Roest M, Gavasso S, Nuozzi G, Toffanin S, Zanaga P, Burra P, Russo FP, Senzolo M, de Laat B, Simioni P. Whole blood thrombin generation shows a significant hypocoagulable state in patients with decompensated cirrhosis. J Thromb Haemost 2024; 22:480-492. [PMID: 37866518 DOI: 10.1016/j.jtha.2023.10.008] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 09/20/2023] [Accepted: 10/09/2023] [Indexed: 10/24/2023]
Abstract
BACKGROUND Patients with cirrhosis have a normal to increased thrombin generation (TG) capacity in platelet-poor plasma (PPP). By reflecting the contribution of all circulating blood cells, whole blood (WB) TG may allow a more physiological assessment of coagulation. OBJECTIVES We compared WB-TG vs PPP-TG in patients with cirrhosis. METHODS Assessment of coagulation included routine tests, factor VIII, natural anticoagulants, PPP-TG, and WB-TG. TG assays were performed with and without thrombomodulin. Twenty-five healthy subjects were included as controls. RESULTS We included 108 patients (Child-Pugh A/B/C, 44/24/40). Compared with controls, patients had significantly lower platelet count, longer international normalized ratio, higher FVIII, and lower levels of protein C/S and antithrombin. Regarding thrombomodulin-modified TG assays, in compensated cirrhosis, both PPP-TG and WB-TG indicated an increased TG capacity, as reflected by an endogenous thrombin potential (ETP) significantly higher than controls. In contrast, in decompensated cirrhosis, PPP-TG indicated a hypercoagulable state with increased ETP, higher peak height, and shorter time-to-peak than controls, whereas WB-TG revealed a progressive impairment of TG kinetics and total capacity, ultimately resulting in a profound hypocoagulable state in patients with Child-Pugh C cirrhosis (ie, significant prolongation of lag time and time-to-peak with reduction of both ETP and peak height). In decompensated patients, bacterial infections and severity of anemia were associated with a further reduction of both ETP and peak height. CONCLUSION Compensated cirrhosis is associated with an increased TG capacity. In decompensated cirrhosis, contrary to PPP-TG, which indicates hypercoagulability, WB-TG shows a significant hypocoagulable state. The clinical value of these findings deserves further investigation.
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Affiliation(s)
- Alberto Zanetto
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padova University Hospital, Padova, Italy. https://twitter.com/azanetto
| | - Elena Campello
- General Internal Medicine Unit, Azienda Ospedale - Università Padova, Padova, Italy; Thrombotic and Haemorrhagic Disease Unit and Haemophilia Center, Department of Medicine, University of Padova, Italy
| | - Cristiana Bulato
- Thrombotic and Haemorrhagic Disease Unit and Haemophilia Center, Department of Medicine, University of Padova, Italy
| | - Ruth Willems
- Department of Functional Coagulation, Synapse Research Institute, Maastricht, The Netherlands; Department of Internal Medicine, Section Vascular Medicine, Maastricht University Medical Center, Maastricht, The Netherlands; Cardiovascular Research Institute Maastricht, School for Cardiovascular Diseases, Maastricht, The Netherlands
| | - Joke Konings
- Department of Functional Coagulation, Synapse Research Institute, Maastricht, The Netherlands
| | - Mark Roest
- Department of Functional Coagulation, Synapse Research Institute, Maastricht, The Netherlands
| | - Sabrina Gavasso
- Thrombotic and Haemorrhagic Disease Unit and Haemophilia Center, Department of Medicine, University of Padova, Italy
| | - Giorgia Nuozzi
- Thrombotic and Haemorrhagic Disease Unit and Haemophilia Center, Department of Medicine, University of Padova, Italy
| | - Serena Toffanin
- Thrombotic and Haemorrhagic Disease Unit and Haemophilia Center, Department of Medicine, University of Padova, Italy
| | - Paola Zanaga
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padova University Hospital, Padova, Italy
| | - Patrizia Burra
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padova University Hospital, Padova, Italy
| | - Francesco Paolo Russo
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padova University Hospital, Padova, Italy
| | - Marco Senzolo
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padova University Hospital, Padova, Italy
| | - Bas de Laat
- Department of Functional Coagulation, Synapse Research Institute, Maastricht, The Netherlands
| | - Paolo Simioni
- General Internal Medicine Unit, Azienda Ospedale - Università Padova, Padova, Italy; Thrombotic and Haemorrhagic Disease Unit and Haemophilia Center, Department of Medicine, University of Padova, Italy.
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Tripodi A, Primignani M, D'Ambrosio R, Tosetti G, La Mura V, Lampertico P, Peyvandi F. Reappraisal of the conventional hemostasis tests as predictors of perioperative bleeding in the era of rebalanced hemostasis in cirrhosis. Hepatology 2024:01515467-990000000-00718. [PMID: 38214562 DOI: 10.1097/hep.0000000000000756] [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: 09/11/2023] [Accepted: 11/24/2023] [Indexed: 01/13/2024]
Abstract
New global laboratory procedures mimicking the in vivo hemostasis process led to the changing paradigm of cirrhosis from the prototype of hemorrhagic diseases to a condition in which hemostasis is normal but fragile, thus justifying the hemorrhagic/thrombotic tendencies that affect these patients. The new paradigm was instrumental to change the management of cirrhosis. For example, international guidelines warn against the entrenched practice of testing patients with conventional hemostasis tests and infusing those with abnormalities with fresh-frozen plasma, coagulation factor concentrates, or platelets, prior to surgery/invasive procedures. These recommendations are, however, largely disattended. The practice of testing patients with the prothrombin time or viscoelastometry and using arbitrary cutoffs to make decisions on perioperative prophylaxis is still common and probably driven by medicolegal issues. There is no doubt that prothrombin time and congeners tests are unable to predict bleeding in cirrhosis. However, it cannot be excluded that some tests may be useful in patients who are severely decompensated. Large prospective collaborative studies are warranted. Enrolled patients should be randomized to receive perioperative prophylaxis based on laboratory testing (eg, viscoelastometry, thrombomodulin-modified thrombin generation) or to usual care. However, for these trials to be useful, a third group of patients who do not receive prophylaxis should be included. In conclusion, until results from these studies are available, physicians attending cirrhosis should refrain from using laboratory tests with arbitrary cutoffs to make decision on perioperative prophylaxis. Decision should be made by considering the clinical history of individual patients and the risk of hemorrhage of specific procedures.
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Affiliation(s)
- Armando Tripodi
- IRCCS Ca' Granda Ospedale Maggiore Policlinico Foundation, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milano, Italy
| | - Massimo Primignani
- Division of Gastroenterology and Hepatology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Roberta D'Ambrosio
- Division of Gastroenterology and Hepatology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Giulia Tosetti
- Division of Gastroenterology and Hepatology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Vincenzo La Mura
- IRCCS Ca' Granda Ospedale Maggiore Policlinico Foundation, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milano, Italy
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy
| | - Pietro Lampertico
- Division of Gastroenterology and Hepatology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Pathophysiology and Transplantation, CRC "A. M. and A. Migliavacca" Center for Liver Disease, University of Milan, Milan, Italy
| | - Flora Peyvandi
- IRCCS Ca' Granda Ospedale Maggiore Policlinico Foundation, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milano, Italy
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy
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Wu Z, Xiao Y, Wang Y. Portal vein thrombosis in liver cirrhosis: An updated overview. PORTAL HYPERTENSION & CIRRHOSIS 2023; 2:78-91. [DOI: 10.1002/poh2.46] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Accepted: 04/11/2023] [Indexed: 01/03/2025]
Abstract
AbstractPortal vein thrombosis (PVT) is a frequent and severe complication in patients with cirrhosis; however, the pathophysiology of PVT needs to be better clarified. There are few significant predictive factors in clinical practice, and the impact of PVT on cirrhosis progression and its complications, such as gastrointestinal bleeding, hepatic encephalopathy, and hepatorenal syndrome, remains uncertain. In recent years, the understanding of the mechanisms of PVT has become more profound with the publication of related literature. Therefore, in this review, we aim to summarize the advanced progress in the epidemiology, hazards, risk factors, diagnosis and classification, and treatment of PVT to provide insight into clinical management.
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Affiliation(s)
- Zhinian Wu
- Department of Infectious Diseases The Third Affiliated Hospital of Hebei Medical University Shijiazhuang Hebei China
| | - Ying Xiao
- Department of Infectious Diseases The Third Affiliated Hospital of Hebei Medical University Shijiazhuang Hebei China
| | - Yadong Wang
- Department of Infectious Diseases The Third Affiliated Hospital of Hebei Medical University Shijiazhuang Hebei China
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Intraindividual variability over time of thrombin generation in patients with cirrhosis. J Thromb Haemost 2023; 21:1441-1452. [PMID: 36758726 DOI: 10.1016/j.jtha.2023.02.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 02/02/2023] [Accepted: 02/02/2023] [Indexed: 02/10/2023]
Abstract
BACKGROUND Patients with cirrhosis are at high risk of thrombotic events, including portal vein thrombosis and venous thromboembolism. In such patients, hypercoagulability is not detected by conventional coagulation tests, but only by the thrombin generation assay (TGA) that integrates the role of pro- and anticoagulant factors. However, TGA use to predict clinical events depends on thrombin generation variability over time. OBJECTIVES The aim of this study was to compare TGA intraindividual variability over time in patients with cirrhosis and in healthy controls. METHODS Blood samples were prospectively collected from 34 healthy controls and 52 patients with cirrhosis at week 0 (inclusion), 6, and 12. TGA was performed with the calibrated automated thrombogram method, tissue factor (5 pM), phospholipids, and with and without thrombomodulin (4 nM) or activated protein C (1 nM). RESULTS When TGA was performed with thrombomodulin, endogenous thrombin potential in patients with cirrhosis was higher compared with controls and increased with cirrhosis severity. Stability over time of all thrombin generation parameters was excellent in healthy controls, good in Child-Turcotte-Pugh (CTP)-A patients, and poor in CTP-B/C patients (severe cirrhosis). In CTP-B/C patients, the phenotype was more variable because one-third of patients switched to normal or hypercoagulability during the 3-month follow-up. CONCLUSION A study with longer monitoring is needed to correlate the hypercoagulable phenotype of patients with cirrhosis with the occurrence of thrombotic events.
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9
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Swersky A, Borja-Cacho D, Deitch Z, Thornburg B, Salem R. Portal Vein Recanalization-Transjugular Intrahepatic Portosystemic Shunt (PVR-TIPS) Facilitates Liver Transplantation in Cirrhotic Patients with Occlusive Portal Vein Thrombosis. Semin Intervent Radiol 2023; 40:38-43. [PMID: 37152801 PMCID: PMC10159708 DOI: 10.1055/s-0043-1764409] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/09/2023]
Abstract
Portal vein thrombosis (PVT) is a heterogeneous condition with multiple possible etiologies and to varying degrees has historically limited candidacy for liver transplant (LT) in the cirrhotic patient population due to resultant difficulties in constructing a robust portal vein anastomosis. While intraoperative approaches to managing PVT are well-described, methods which approximate normal portal physiology are not always feasible depending on the extent of PVT, and other nonphysiologic techniques are linked with substantial morbidity and poor long-term outcomes. Portal vein recanalization-transjugular intrahepatic portosystemic shunt (PVR-TIPS) creation is an efficacious method of restoring physiologic portal flow in cirrhotic patients prior to LT allowing for end-to-end PV anastomosis, and is the product of decades-long institutional expertise in TIPS/LT and the support of a multidisciplinary liver tumor board. To follow is a review of the pertinent pathophysiology of PVT in cirrhosis, the rationale leading to the development and subsequent evolution of the PVR-TIPS procedure, technical lessons learned, and a summary of outcomes to date.
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Affiliation(s)
- Adam Swersky
- Section of Interventional Radiology, Department of Radiology, Northwestern Feinberg School of Medicine, Chicago, Illinois
| | | | | | - Bartley Thornburg
- Section of Interventional Radiology, Department of Radiology, Northwestern Feinberg School of Medicine, Chicago, Illinois
| | - Riad Salem
- Section of Interventional Radiology, Department of Radiology, Northwestern Feinberg School of Medicine, Chicago, Illinois
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10
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Bitto N, Ghigliazza G, Lavorato S, Caputo C, La Mura V. Improving Management of Portal Hypertension: The Potential Benefit of Non-Etiological Therapies in Cirrhosis. J Clin Med 2023; 12:934. [PMID: 36769582 PMCID: PMC9917703 DOI: 10.3390/jcm12030934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 01/17/2023] [Accepted: 01/20/2023] [Indexed: 01/27/2023] Open
Abstract
Portal hypertension is the consequence of cirrhosis and results from increased sinusoidal vascular resistance and hepatic blood inflow. Etiological therapies represent the first intervention to prevent a significant increase in portal pressure due to chronic liver damage. However, other superimposed pathophysiological drivers may worsen liver disease, including inflammation, bacterial translocation, endothelial dysfunction, and hyperactivation of hemostasis. These mechanisms can be targeted by a specific class of drugs already used in clinical practice. Albumin, rifaximin, statins, aspirin, and anticoagulants have been tested in cirrhosis and were a topic of discussion in the last Baveno consensus as non-etiological therapies. Based on the pathogenesis of portal hypertension in cirrhosis, our review summarizes the main mechanisms targeted by these drugs as well as the clinical evidence that considers them a valid complementary option to manage patients with cirrhosis and portal hypertension.
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Affiliation(s)
- Niccolò Bitto
- Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, 20122 Milan, Italy
| | - Gabriele Ghigliazza
- Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Division of Sub-Intensive Care Medicine, 20122 Milan, Italy
| | - Stanislao Lavorato
- Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, 20122 Milan, Italy
| | - Camilla Caputo
- Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, 20122 Milan, Italy
| | - Vincenzo La Mura
- Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, 20122 Milan, Italy
- Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, Italy
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11
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Camerlo S, Ligato J, Rosati G, Carrà G, Russo I, De Gobbi M, Morotti A. Shedding Light on the Pathogenesis of Splanchnic Vein Thrombosis. Int J Mol Sci 2023; 24:ijms24032262. [PMID: 36768584 PMCID: PMC9916478 DOI: 10.3390/ijms24032262] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 01/15/2023] [Accepted: 01/18/2023] [Indexed: 01/26/2023] Open
Abstract
Splanchnic vein thrombosis is a rare but potentially life-threatening manifestation of venous thromboembolism, with challenging implications both at the pathological and therapeutic level. It is frequently associated with liver cirrhosis, but it could also be provoked by myeloproliferative disorders, cancer of various gastroenterological origin, abdominal infections and thrombophilia. A portion of splanchnic vein thrombosis is still classified as idiopathic. Here, we review the mechanisms of splanchnic vein thrombosis, including new insights on the role of clonal hematopoiesis in idiopathic SVT pathogenesis, with important implications from the therapeutic standpoint.
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12
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Violi F, Pignatelli P, Castellani V, Carnevale R, Cammisotto V. Gut dysbiosis, endotoxemia and clotting activation: A dangerous trio for portal vein thrombosis in cirrhosis. Blood Rev 2023; 57:100998. [PMID: 35985881 DOI: 10.1016/j.blre.2022.100998] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 08/04/2022] [Accepted: 08/06/2022] [Indexed: 01/28/2023]
Abstract
Liver cirrhosis (LC) is associated with portal venous thrombosis (PVT) in roughly 20% of cirrhotic patients but the underlying mechanism is still unclear. Low-grade endotoxemia by lipopolysaccharides (LPS), a component of outer gut microbiota membrane, is detectable in the portal circulation of LC and could predispose to PVT. LPS may translocate into systemic circulation upon microbiota dysbiosis-induced gut barrier dysfunction, that is a prerequisite for enhanced gut permeability and ensuing endotoxemia. Experimental and clinical studies provided evidence that LPS behaves a pro-thrombotic molecule so promoting clotting and platelet activation. Experiments conducted in the portal circulation of cirrhotic patients showed the existence of LPS-related enhanced thrombin generation as well as endothelial dysfunction, venous stasis, and platelet activation. The review will analyze 1) the pro-thrombotic role of endotoxemia in the context of LC 2) the biological plausibility linking endotoxemia with PVT and 3) the potentially interventional tools to lower endotoxemia and eventually hypercoagulation.
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Affiliation(s)
- Francesco Violi
- Department of Clinical Internal, Anaesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico, 155, Rome 00161, Italy; Mediterranea Cardiocentro-Napoli, Via Orazio, 2, 80122, Naples, Italy.
| | - Pasquale Pignatelli
- Department of Clinical Internal, Anaesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico, 155, Rome 00161, Italy; Mediterranea Cardiocentro-Napoli, Via Orazio, 2, 80122, Naples, Italy
| | - Valentina Castellani
- Department of General and Specialized Surgery "Paride Stefanini", Sapienza University of Rome, Italy
| | - Roberto Carnevale
- Mediterranea Cardiocentro-Napoli, Via Orazio, 2, 80122, Naples, Italy; Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Corso della Repubblica 79, 40100, Latina, Italy
| | - Vittoria Cammisotto
- Department of Clinical Internal, Anaesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico, 155, Rome 00161, Italy
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13
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Zhou G, Liu J, Zhang H, Wang X, Liu D. Elevated endothelial dysfunction-related biomarker levels indicate the severity and predict sepsis incidence. Sci Rep 2022; 12:21935. [PMID: 36536028 PMCID: PMC9763325 DOI: 10.1038/s41598-022-26623-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 12/16/2022] [Indexed: 12/23/2022] Open
Abstract
This study was conducted to investigate the relationship between serum endothelial dysfunction-related biomarker levels and organ dysfunction severity in septic patients and the predictive value of these levels during sepsis. In total, 105 patients admitted to the Department of Critical Care Medicine were enrolled between September 2020 and November 2021. Serum syndecan-1 and soluble thrombomodulin(sTM) levels were measured by enzyme-linked immunosorbent assay, and clinical and laboratory data were recorded. Enroll patients were divided into the infection (n = 28), septic nonshock (n = 31), and septic shock (n = 46) groups . Serum syndecan-1 (102.84 ± 16.53 vs. 55.38 ± 12.34 ng/ml), and sTM(6.60 ± 1.44 ng/ml vs. 5.23 ± 1.23 ng/ml, P < 0.01) levels were increased in the septic group compared with those in the infection group. Serum syndecan-1 levels were closely positively correlated with serum sTM (rs = 0.712, r2 = 0.507, P < 0.001). Additionally, serum syndecan-1(rs = 0.687, r2 = 0.472, P < 0.001) and sTM levels (rs = 0.6, r2 = 0.36, P < 0.01) levels were significantly positively correlated with the sequential organ failure assessment scores respectively. Syndecan-1 (AUC 0.95 ± 0.02, P < 0.0001) was more valuable for prediction sepsis than was sTM (AUC 0.87 ± 0.04, P < 0.0001). Compared with sTM (AUC 0.88 ± 0.03, P < 0.001), syndecan-1 (AUC 0.95 ± 0.02, P < 0.001) and SOFA score (AUC 0.95 ± 0.02, P < 0.001) were better predictors of septic shock. Serum syndecan-1 and sTM levels were associated with organ dysfunction severity in septic patients, and both were good predictors for early identification of sepsis, particularly in patients undergoing septic shock.
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Affiliation(s)
- Gaosheng Zhou
- grid.506261.60000 0001 0706 7839Department of Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 1# Shuai Fu Yuan, Dong Cheng District, Beijing, 100730 China
| | - Jingjing Liu
- grid.506261.60000 0001 0706 7839Department of Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 1# Shuai Fu Yuan, Dong Cheng District, Beijing, 100730 China
| | - Hongmin Zhang
- grid.506261.60000 0001 0706 7839Department of Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 1# Shuai Fu Yuan, Dong Cheng District, Beijing, 100730 China
| | - Xiaoting Wang
- grid.506261.60000 0001 0706 7839Department of Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 1# Shuai Fu Yuan, Dong Cheng District, Beijing, 100730 China
| | - Dawei Liu
- grid.506261.60000 0001 0706 7839Department of Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 1# Shuai Fu Yuan, Dong Cheng District, Beijing, 100730 China
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14
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Calvo A, Torrente MA, Görlinger K, Fernandez J, Reverter E, Vidal J, Tassies D, Colmenero J, Blasi A, Reverter JC. Haemostasis patterns in patients with acute-on-chronic liver failure and acute decompensation of cirrhosis including thromboelastometric tests with and without the addition of Protac: a pilot study. Thromb J 2022; 20:75. [PMID: 36510196 PMCID: PMC9744590 DOI: 10.1186/s12959-022-00438-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 12/05/2022] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Thromboelastometry is considered the best method to assesses hemostasis in liver disease. Diagnostic performance could be improved by adding protein C activators such as thrombomodulin or Protac®. We assessed changes in ROTEM parameters after the addition of Protac® in patients with acute-on-chronic liver failure (ACLF), acute decompensation (AD), and healthy individuals (HI) to define different hemostasis patterns, considering standard and velocity ROTEM parameters, and assess whether Protac® can improve the definition of the pattern. METHODS Pre-test, we investigated whether diluted EXTEM reagent improved the effect of Protac® on the clotting time (CT)-ratio with and without Protac®. Ten ACLF and 20 AD patients and 21 HI were included in the main study. RESULTS Standard EXTEM was used in the main study. INTEM CFT, INTEM A5 (inverse), and INTEM TPI (inverse) were the parameters that best differentiated liver disease from HI (ROC AUC, 0.921, 0.906, and 0.928, respectively; all P-values < 0.001). Combining INTEM CFT with EXTEM LI60-ratio only slightly improved the diagnostic performance (ROC AUC, 0.948; P < 0.001). EXTEM LI60 and INTEM maxV-t were the parameters that best differentiated between ACLF and AD patients (ROC AUC, 0.743, P = 0.033; and 0.723, P = 0.050; respectively). Combining EXTEM LI60 + INTEM maxV-t moderately improved the diagnostic performance (ROC AUC, 0.81, P < 0.001). CONCLUSIONS ROTEM velocity, fibrinolysis parameters and the indices calculated improve the diagnosis in combination with standard parameters (e.g., CFT and A5). Ratios calculated with and without Protac® (e.g., EXTEM LI60-ratio) only slightly increased the diagnostic performance in discriminating hemostasis patterns.
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Affiliation(s)
- Andrea Calvo
- grid.5841.80000 0004 1937 0247Anaesthesiology and Critical Care Department, Hospital Clínic, Institute d’Investigacions Biomédica AgustPi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Miguel Angel Torrente
- grid.410458.c0000 0000 9635 9413Haematology Department, Hospital Clínic and University of Barcelona, Barcelona, Spain
| | - Klaus Görlinger
- grid.5718.b0000 0001 2187 5445Department of Anaesthesiology and Intensive Care Medicine, University Hospital Essen, University Duisburg-Essen, Essen, Germany ,Medical Department, Tem Innovations GmbH, Munich, Germany
| | - Javier Fernandez
- grid.410458.c0000 0000 9635 9413Institut 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, Barcelona, Spain
| | - Enric Reverter
- grid.410458.c0000 0000 9635 9413Institut 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, Barcelona, Spain
| | - Julia Vidal
- grid.410458.c0000 0000 9635 9413Anaesthesiology Department, Hospital Clínic, Barcelona, Spain
| | - Dolors Tassies
- grid.410458.c0000 0000 9635 9413Haematology Department, Hospital Clínic and University of Barcelona, Barcelona, Spain
| | - Jordi Colmenero
- grid.410458.c0000 0000 9635 9413Institut 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, Barcelona, Spain
| | - Annabel Blasi
- grid.10403.360000000091771775Anaesthesiology Department, Hospital Clínic and University of Barcelona, Spain, Institut d’Investigacions Biomèdiques August Pi-Sunyer (IDIBAPS) Y Ciber de Enfermedades Hepáticas Y Digestivas (CIBEREHD), 08036 Barcelona, Spain
| | - Juan Carlos Reverter
- grid.410458.c0000 0000 9635 9413Haematology Department, Hospital Clínic and University of Barcelona, Barcelona, Spain
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15
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La Mura V, Bitto N, Tripodi A. Rational hemostatic management in cirrhosis: from old paradigms to new clinical challenges. Expert Rev Hematol 2022; 15:1031-1044. [PMID: 36342412 DOI: 10.1080/17474086.2022.2144217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 11/01/2022] [Indexed: 11/09/2022]
Abstract
INTRODUCTION Patients with cirrhosis are at risk of both thrombotic and hemorrhagic events. Traditional hemostatic tests are inadequate to assess the complex and fragile balance of hemostasis in this setting, especially in advanced stages of disease such as decompensated cirrhosis or acute on chronic liver failure (ACLF). Furthermore, the indiscriminate use of pro-hemostatic agents for prophylaxis and treatment of bleeding episodes is still debated and often contraindicated. Alongside, splanchnic, and peripheral thrombotic events are frequent in this population and require management that involves a careful balance between risks and benefits of antithrombotic therapy. AREAS COVERED This review aims to address the state of the art on the clinical management of the hemostatic balance of cirrhosis in terms of established knowledge and future challenges. EXPERT OPINION The old paradigm of cirrhosis as a naturally anticoagulated condition has been challenged by more sophisticated global tests of hemostasis. Integrating this information in the clinical decision-making is still challenging for physicians and experts in hemostasis.
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Affiliation(s)
- Vincenzo La Mura
- Fondazione I.R.C.C.S. Ca' Granda, Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Niccolò Bitto
- Fondazione I.R.C.C.S. Ca' Granda, Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy
- Department of Biomedical Sciences for Health, Università degli studi di Milano, Milan, Italy
| | - Armando Tripodi
- Fondazione I.R.C.C.S. Ca' Granda, Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy
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16
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Driever EG, Magaz M, Adelmeijer J, Turon F, Baiges A, Olivas P, Pérez‐Campuzano V, Hernandez‐Gea V, Blasi A, Garcia‐Pagan J, Lisman T. The portal vein in patients with cirrhosis is not an excessively inflammatory or hypercoagulable vascular bed, a prospective cohort study. J Thromb Haemost 2022; 20:2075-2082. [PMID: 35748022 PMCID: PMC9545607 DOI: 10.1111/jth.15797] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 06/02/2022] [Accepted: 06/21/2022] [Indexed: 11/29/2022]
Abstract
BACKGROUND A hypercoagulable state is not associated with development of portal vein thrombosis in cirrhosis, as we previously demonstrated. However, some groups demonstrated elevated levels of inflammatory markers and activation of hemostasis in the portal vein (PV) compared to posthepatic veins, but because the liver is involved in clearance of these markers, we hypothesize that interpretation of these data is not straightforward. AIM To determine whether the PV has particular proinflammatory/hypercoagulable characteristics by comparing plasma sampled in the PV, hepatic vein (HV), and the systemic circulation. METHODS Plasma samples from 51 cirrhotic patients with portal hypertension undergoing transjugular intrahepatic portosystemic shunt placement, were taken from the PV, HV, and jugular vein (JV). Markers of inflammation (lipopolysaccharide, tumor necrosis factor-α, interleukin-6, thiobarbituric acid-reactive substances), neutrophil-extracellular-traps (cfDNA, MPO-DNA), endothelial damage (von Willebrand factor [VWF]), and hemostasis were determined and compared among the three vascular beds. RESULTS Markers of inflammation were slightly, but significantly higher in the PV than in the HV and systemic circulation. VWF and markers of hemostasis were modestly elevated in the PV. Levels of multiple markers were lower in the HV compared with the PV and systemic circulation. Higher model for end-stage liver disease score was associated with a more prothrombotic state in all three sample sites. CONCLUSION In contrast to published studies, we did not detect a clear proinflammatory or prothrombotic environment in the PV of cirrhotic patients. Many markers are lowest in the HV, indicating that the low levels of these markers in the HV, at least in part, reflect clearance of those markers in the liver.
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Affiliation(s)
- Ellen G. Driever
- Surgical Research Laboratory and Section of Hepatobiliary Surgery and Liver Transplantation, Department of SurgeryUniversity Medical Center Groningen, University of GroningenGroningenThe Netherlands
| | - Marta Magaz
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital ClínicInstitut de Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of BarcelonaBarcelonaSpain
- CIBEREHD (Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas), Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN‐Liver)BarcelonaSpain
| | - Jelle Adelmeijer
- Surgical Research Laboratory and Section of Hepatobiliary Surgery and Liver Transplantation, Department of SurgeryUniversity Medical Center Groningen, University of GroningenGroningenThe Netherlands
| | - Fanny Turon
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital ClínicInstitut de Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of BarcelonaBarcelonaSpain
- CIBEREHD (Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas), Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN‐Liver)BarcelonaSpain
| | - Anna Baiges
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital ClínicInstitut de Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of BarcelonaBarcelonaSpain
- CIBEREHD (Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas), Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN‐Liver)BarcelonaSpain
| | - Pol Olivas
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital ClínicInstitut de Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of BarcelonaBarcelonaSpain
- CIBEREHD (Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas), Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN‐Liver)BarcelonaSpain
| | - Valeria Pérez‐Campuzano
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital ClínicInstitut de Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of BarcelonaBarcelonaSpain
- CIBEREHD (Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas), Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN‐Liver)BarcelonaSpain
| | - Virginia Hernandez‐Gea
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital ClínicInstitut de Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of BarcelonaBarcelonaSpain
- CIBEREHD (Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas), Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN‐Liver)BarcelonaSpain
| | - Annabel Blasi
- Anesthesiology Department, Hospital ClínicInstitute d'Investigacions Biomèdica Agustí Pi i Sunyer (IDIBAPS), University of BarcelonaBarcelonaSpain
| | - Juan‐Carlos Garcia‐Pagan
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital ClínicInstitut de Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of BarcelonaBarcelonaSpain
- CIBEREHD (Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas), Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN‐Liver)BarcelonaSpain
| | - Ton Lisman
- Surgical Research Laboratory and Section of Hepatobiliary Surgery and Liver Transplantation, Department of SurgeryUniversity Medical Center Groningen, University of GroningenGroningenThe Netherlands
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Tripodi A, Mannucci PM. Patients with chronic liver disease. Are they naturally anticoagulated? Thromb Res 2022; 218:1-4. [PMID: 35939886 DOI: 10.1016/j.thromres.2022.07.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 07/25/2022] [Accepted: 07/27/2022] [Indexed: 11/29/2022]
Affiliation(s)
- Armando Tripodi
- IRCCS Ca' Granda Maggiore Policlinico Hospital Foundation, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center and Fondazione Luigi Villa, Milano, Italy.
| | - Pier Mannuccio Mannucci
- IRCCS Ca' Granda Maggiore Policlinico Hospital Foundation, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center and Fondazione Luigi Villa, Milano, Italy
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18
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Abstract
Patients with cirrhosis of the liver are at high risk of developing portal vein thrombosis (PVT), which has a complex, multifactorial cause. The condition may present with a myriad of symptoms and can occasionally cause severe complications. Contrast-enhanced computed tomography (CT) is the gold standard for the diagnosis of PVT. There are uncertainties regarding the effect on PVT and its treatment outcome in patients with cirrhosis. The main challenge for managing PVT in cirrhosis is analyzing the risk of hemorrhage compared to the risk of thrombus extension leading to complications. All current knowledge regarding non-tumor PVT in cirrhosis, including epidemiology, risk factors, classification, clinical presentation, diagnosis, impact on natural history, and treatment, is discussed in the present article.
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Key Words
- ACLF, acute-on-chronic liver failure
- BCS, Budd–Chiari syndrome
- DOACs, direct-acting oral anticoagulants
- EASL, European Association for the Study of the Liver
- HCC, hepatocellular carcinoma
- HVPG, hepatic venous pressure gradient
- INR, international normalized ratio
- JAK2, Janus Kinase 2
- LMWH, low molecular weight heparin
- LT, liver transplant
- MELD, Model for End-Stage Liver Disease
- MTHFR, methyltetrahydrofolate reductase
- NASH, non-alcoholic steatohepatitis
- NO, nitric oxide
- NSBBs, non-selective beta-blockers
- PV, portal vein
- PVT, Portal vein thrombosis
- RCT, randomized controlled trial
- SMA, superior mesenteric artery
- SMV, superior mesenteric vein
- SVT, splanchnic vein thrombosis
- TIPS, Transjugular intrahepatic portosystemic shunt
- UNOS, United Network for Organ Sharing
- VEGF, vascular endothelial growth factors
- VKAs, vitamin K antagonists
- VKORC1, vitamin K epoxide reductase complex 1
- anticoagulation
- cirrhosis
- eNOS, endothelial nitric oxide synthase
- non-tumoral portal vein thrombosis
- portal hypertension
- rTPA, recombinant tissue plasminogen activator
- transjugular intrahepatic portosystemic shunt
- vWF, von Willebrand factor
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Affiliation(s)
- Akash Shukla
- Department of Gastroenterology, Seth GS Medical College and KEM Hospital, Mumbai, India
| | - Suprabhat Giri
- Department of Gastroenterology, Seth GS Medical College and KEM Hospital, Mumbai, India
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19
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The Pathophysiology of Portal Vein Thrombosis in Cirrhosis: Getting Deeper into Virchow's Triad. J Clin Med 2022; 11:jcm11030800. [PMID: 35160251 PMCID: PMC8837039 DOI: 10.3390/jcm11030800] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 01/21/2022] [Accepted: 01/28/2022] [Indexed: 02/07/2023] Open
Abstract
Portal vein thrombosis (PVT) is a common complication among patients with cirrhosis. However, its pathophysiology is not well established and there are currently very few predictive factors, none of which are actually useful, from a clinical perspective. The contribution of each of the vertices of Virchow’s triad, e.g., blood hypercoagulability, blood flow, and portal vein endothelial damage in the development of PVT is not clear. In this review, we aim to recapitulate the latest studies on the field of PVT development in order to understand its mechanisms and discuss some of the future directions in the study of this important complication of cirrhosis.
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20
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Roberts LN. Rebalanced hemostasis in liver disease: a misunderstood coagulopathy. HEMATOLOGY. AMERICAN SOCIETY OF HEMATOLOGY. EDUCATION PROGRAM 2021; 2021:485-491. [PMID: 34889414 PMCID: PMC8791121 DOI: 10.1182/hematology.2021000283] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/06/2023]
Abstract
The combination of frequently abnormal hemostatic markers and catastrophic bleeding as seen with variceal hemorrhage has contributed to the longstanding misperception that chronic liver disease (CLD) constitutes a bleeding diathesis. Laboratory studies of hemostasis in liver disease consistently challenge this with global coagulation assays incorporating activation of the protein C pathway demonstrating rebalanced hemostasis. It is now recognized that bleeding in CLD is predominantly secondary to portal hypertension (rather than a coagulopathy) and additionally that these patients are at increased risk of venous thrombosis, particularly in the portal venous system. This narrative review describes the current understanding of hemostasis in liver disease, as well as the periprocedural management of hemostasis and anticoagulation for management of venous thromboembolism in patients with CLD.
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Affiliation(s)
- Lara N. Roberts
- Correspondence Lara N. Roberts, King's Thrombosis Centre, Department of Haematological Medicine, King's College Hospital NHS Foundation Trust, Denmark Hill, London SE5 9RS, UK; e-mail:
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21
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Zanetto A, Campello E, Bulato C, Gavasso S, Saggiorato G, Shalaby S, Spiezia L, Cillo U, Farinati F, Russo FP, Burra P, Senzolo M, Simioni P. More Pronounced Hypercoagulable State and Hypofibrinolysis in Patients With Cirrhosis With Versus Without HCC. Hepatol Commun 2021; 5:1987-2000. [PMID: 34558850 PMCID: PMC8631093 DOI: 10.1002/hep4.1781] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 06/05/2021] [Accepted: 06/17/2021] [Indexed: 12/12/2022] Open
Abstract
In patients with cirrhosis, particularly those with hepatocellular carcinoma (HCC), hypercoagulability may be associated with purported increased risks of portal vein thrombosis and cirrhosis progression. In this study, we extensively investigated hemostatic alterations potentially responsible for the thrombotic tendency in HCC, and evaluated whether such alterations were predictive of hepatic decompensation. Patients with cirrhosis at all stages were prospectively recruited and underwent an extensive hemostatic assessment, including all procoagulant factors and inhibitors, thrombin generation with and without thrombomodulin (TG), profibrinolytic and antifibrinolytic factors, and plasmin-antiplasmin complex. In study part 1 (case control), we compared alterations of coagulation and fibrinolysis in patients with cirrhosis with versus without HCC. In study part 2 (prospective), the subgroup of patients with decompensated cirrhosis was followed for development of further decompensation, and predictors of outcome were assessed by multivariate analysis. One-hundred patients were recruited (50 each with and without HCC). Severity of cirrhosis was comparable between groups. Median HCC volume was 9 cm3 (range: 5-16). Compared with controls, patients with HCC demonstrated a significantly more prothrombotic hemostatic profile due to increased TG and reduced activation of fibrinolysis, independent of cirrhosis stage. During a median follow-up of 175 days, 20 patients with decompensated cirrhosis developed further episodes of decompensation that were predicted by low FVII and high plasminogen activator inhibitor-1 levels, independent of Model for End-Stage Liver Disease score. Conclusion: Patients with cirrhosis with HCC have profound hyper-coagulable changes that can account for their increased thrombotic tendency. In contrast, hypercoagulability in patients with decompensated cirrhosis is more likely a consequence of chronic liver disease rather than a driver for cirrhosis progression.
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Affiliation(s)
- Alberto Zanetto
- GastroenterologyDepartment of Surgery, Oncology, and GastroenterologyPadova University HospitalPadovaItaly
- Multivisceral Transplant UnitDepartment of Surgery, Oncology, and GastroenterologyPadova University HospitalPadovaItaly
| | - Elena Campello
- Thrombotic and Hemorrhagic Diseases UnitGeneral Internal MedicinePadova University HospitalPadovaItaly
| | - Cristiana Bulato
- Thrombotic and Hemorrhagic Diseases UnitGeneral Internal MedicinePadova University HospitalPadovaItaly
| | - Sabrina Gavasso
- Thrombotic and Hemorrhagic Diseases UnitGeneral Internal MedicinePadova University HospitalPadovaItaly
| | - Graziella Saggiorato
- Thrombotic and Hemorrhagic Diseases UnitGeneral Internal MedicinePadova University HospitalPadovaItaly
| | - Sarah Shalaby
- GastroenterologyDepartment of Surgery, Oncology, and GastroenterologyPadova University HospitalPadovaItaly
- Multivisceral Transplant UnitDepartment of Surgery, Oncology, and GastroenterologyPadova University HospitalPadovaItaly
| | - Luca Spiezia
- Thrombotic and Hemorrhagic Diseases UnitGeneral Internal MedicinePadova University HospitalPadovaItaly
| | - Umberto Cillo
- Hepatobiliary Surgery and Liver Transplantation CenterDepartment of Surgery, Oncology, and GastroenterologyPadova University HospitalPadovaItaly
| | - Fabio Farinati
- GastroenterologyDepartment of Surgery, Oncology, and GastroenterologyPadova University HospitalPadovaItaly
| | - Francesco Paolo Russo
- GastroenterologyDepartment of Surgery, Oncology, and GastroenterologyPadova University HospitalPadovaItaly
- Multivisceral Transplant UnitDepartment of Surgery, Oncology, and GastroenterologyPadova University HospitalPadovaItaly
| | - Patrizia Burra
- GastroenterologyDepartment of Surgery, Oncology, and GastroenterologyPadova University HospitalPadovaItaly
- Multivisceral Transplant UnitDepartment of Surgery, Oncology, and GastroenterologyPadova University HospitalPadovaItaly
| | - Marco Senzolo
- GastroenterologyDepartment of Surgery, Oncology, and GastroenterologyPadova University HospitalPadovaItaly
- Multivisceral Transplant UnitDepartment of Surgery, Oncology, and GastroenterologyPadova University HospitalPadovaItaly
| | - Paolo Simioni
- Thrombotic and Hemorrhagic Diseases UnitGeneral Internal MedicinePadova University HospitalPadovaItaly
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22
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Turon F, Driever EG, Baiges A, Cerda E, García-Criado Á, Gilabert R, Bru C, Berzigotti A, Nuñez I, Orts L, Reverter JC, Magaz M, Camprecios G, Olivas P, Betancourt-Sanchez F, Perez-Campuzano V, Blasi A, Seijo S, Reverter E, Bosch J, Borràs R, Hernandez-Gea V, Lisman T, Garcia-Pagan JC. Predicting portal thrombosis in cirrhosis: A prospective study of clinical, ultrasonographic and hemostatic factors. J Hepatol 2021; 75:1367-1376. [PMID: 34333101 DOI: 10.1016/j.jhep.2021.07.020] [Citation(s) in RCA: 100] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 06/25/2021] [Accepted: 07/08/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS Portal vein thrombosis (PVT) is a relatively frequent event in patients with cirrhosis. While different risk factors for PVT have been reported, such as decreased portal blood flow velocity (PBFV) and parameters related with severity of portal hypertension, these are based on retrospective studies assessing only a discrete number of parameters. The aim of the current study was to evaluate the incidence and risks factors for non-tumoral PVT development in a large prospective cohort of patients with cirrhosis. METHODS We performed an exhaustive evaluation of clinical, biochemical, inflammatory and acquired/hereditary hemostatic profiles in 369 patients with cirrhosis without PVT who were prospectively followed-up. Doppler ultrasound was performed at baseline and every 6 months or whenever clinically indicated. PVT development was always confirmed by computed tomography. RESULTS Twenty-nine patients developed non-tumoral PVT, with an incidence of 1.6%, 6% and 8.4% at 1, 3 and 5 years, respectively. Low platelet count, PBFV <15 cm/sec and history of variceal bleeding were factors independently associated with a high PVT risk. No relationship between PVT development and any other clinical biochemical, inflammatory and acquired or hereditary hemostatic parameter was found. CONCLUSIONS In patients with cirrhosis, the factors predictive of PVT development were mainly those related to the severity of portal hypertension. Our results do not support the role of hemostatic alterations (inherited or acquired) and inflammatory markers in the prediction of PVT in patients with cirrhosis. LAY SUMMARY Patients with cirrhosis and more severe portal hypertension are at higher risk of non-tumoral portal vein thrombosis development. Acquired or inherited hemostatic disorders, as well as inflammatory status, do not seem to predict the development of portal vein thrombosis in patients with cirrhosis.
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Affiliation(s)
- Fanny Turon
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain(†); Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - Ellen G Driever
- Surgical Research Laboratory, Department of Surgery, University of Groningen, University Medical Center Groningen, The Netherlands
| | - Anna Baiges
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain(†); Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - Eira Cerda
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain(†)
| | | | - Rosa Gilabert
- Centre de Diagnostic per l'Imatge, Hospital Clínic, Barcelona, Spain
| | - Concepció Bru
- Centre de Diagnostic per l'Imatge, Hospital Clínic, Barcelona, Spain
| | - Annalisa Berzigotti
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain(†); Centre de Diagnostic per l'Imatge, Hospital Clínic, Barcelona, Spain; Hepatologie, University Clinic for Visceral Surgery and Medicin, Inselspital, Bern, Switzerland
| | - Isabel Nuñez
- Centre de Diagnostic per l'Imatge, Hospital Clínic, Barcelona, Spain
| | - Lara Orts
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain(†); Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | | | - Marta Magaz
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain(†); Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - Genis Camprecios
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain(†); Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - Pol Olivas
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain(†)
| | - Fabian Betancourt-Sanchez
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain(†)
| | - Valeria Perez-Campuzano
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain(†)
| | - Annabel Blasi
- Servei d'Anestesiologia i reanimació, Hospital Clínic, Barcelona, Spain
| | - Susana Seijo
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain(†)
| | - Enric Reverter
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain(†); Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - Jaume Bosch
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain(†); Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain; Hepatologie, University Clinic for Visceral Surgery and Medicin, Inselspital, Bern, Switzerland
| | - Roger Borràs
- Arrhythmia Section, Cardiovascular Clinic Institute, Hospital Clínic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Virginia Hernandez-Gea
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain(†); Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - Ton Lisman
- Surgical Research Laboratory, Department of Surgery, University of Groningen, University Medical Center Groningen, The Netherlands
| | - Juan Carlos Garcia-Pagan
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain(†); Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.
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23
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Brodard J, Calzavarini S, Quarroz C, Berzigotti A, De Gottardi A, Angelillo-Scherrer A. Resistance to thrombomodulin correlates with liver stiffness in chronic liver disease a prospective single-center cohort study. Thromb Res 2021; 207:40-49. [PMID: 34536665 DOI: 10.1016/j.thromres.2021.09.007] [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: 06/28/2021] [Revised: 08/19/2021] [Accepted: 09/10/2021] [Indexed: 11/16/2022]
Abstract
INTRODUCTION Chronic liver disease (CLD) is characterized by changes in haemostasis, embracing both hypo- and hypercoagulability. Global hemostatic tests such as thrombin generation assays evaluate the hemostatic balance, to better assess bleeding and thrombotic risks. In addition, procoagulant state in patients with CLD has been demonstrated using modified thrombin generation assays with thrombomodulin, a cofactor for protein C activation. In this study, we prospectively determined thrombin generation and thrombomodulin resistance in patients with CLD staged with liver stiffness measurement (LSM), using both the fully automated analyzer ST Genesia® Thrombin Generation System (STG) and the calibrated automated thrombogram assay (CAT). MATERIALS AND METHODS Demographic, clinical and laboratory characteristics, and blood samples were collected from 65 patients with CLD. Liver stiffness was measured by transient elastography, and thrombin generation and thrombomodulin resistance, by STG and CAT. RESULTS Patients were separated based on LSM of <21 and ≥21 kilopascals (kPa). The propagation rate of thrombin generation was higher in patients with LSM ≥21 kPa and the thrombin generation rate increased as LSM increased. In addition, thrombomodulin resistance assessed by STG and CAT was higher in patients with LSM ≥21 kPa. However, ETP inhibition by activated protein C was comparable in patients with LSM <21 and ≥21 kPa. Finally, LSM correlated with most thrombin generation parameters. CONCLUSION The STG automated system may have value in the assessment of patients with chronic liver disease in the routine coagulation laboratory. LSM ≥21 kPa identify a procoagulant phenotype in these patients, including thrombomodulin resistance.
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Affiliation(s)
- Justine Brodard
- Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, University of Bern, Switzerland; Department for BioMedical Research, University of Bern, Switzerland
| | - Sara Calzavarini
- Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, University of Bern, Switzerland; Department for BioMedical Research, University of Bern, Switzerland
| | - Claudia Quarroz
- Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, University of Bern, Switzerland; Department for BioMedical Research, University of Bern, Switzerland
| | - Annalisa Berzigotti
- Hepatology, Clinic of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland; Gastroenterology and Hepatology, Ente Ospedaliero Cantonale and Università della Svizzera Italiana, Lugano, Switzerland
| | - Andrea De Gottardi
- Department for BioMedical Research, University of Bern, Switzerland; Hepatology, Clinic of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland; Gastroenterology and Hepatology, Ente Ospedaliero Cantonale and Università della Svizzera Italiana, Lugano, Switzerland
| | - Anne Angelillo-Scherrer
- Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, University of Bern, Switzerland; Department for BioMedical Research, University of Bern, Switzerland.
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24
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Molvar C, Amin P. Portal Vein Thrombosis In Cirrhosis: Interventional Treatment Options. Curr Gastroenterol Rep 2021; 23:24. [PMID: 34654971 DOI: 10.1007/s11894-021-00826-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/24/2021] [Indexed: 02/07/2023]
Abstract
PURPOSE OF REVIEW Portal vein thrombosis (PVT) is a frequent consequence of cirrhosis and its management is variable and controversial. Herein we highlight interventional treatment options and outcomes, together with mention of the physiology, presentation and imaging of PVT. RECENT FINDINGS Utilization of transjugular intrahepatic portosystemic shunt (TIPS) for acute and chronic PVT is expanding. In acute PVT, TIPS improves hepatopetal flow which promotes thrombus resorption and prevents rethrombosis. The TIPS also functions as a conduit for thrombectomy devices and allows for embolization of variceal shunts. Chronic PVT is a relative contraindication to liver transplant. Portal vein recanalization (PVR) TIPS restores flow in a previously occluded portal vein, allowing for a conventional end-to-end portal vein anastomosis at transplant. PVR TIPS is technically demanding and often requires percutaneous splenic vein access for portal venous recanalization. Selection of endovascular PVT treatment varies with the age (acute or chronic) and the extent of thrombus, along with presenting symptoms and transplant candidacy.
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Affiliation(s)
- Christopher Molvar
- Department of Radiology, Loyola University Medical Center, Maywood, IL, USA.
| | - Parag Amin
- Department of Imaging, Cleveland Clinic Florida, Weston, FL, USA
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25
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Senzolo M, Garcia-Tsao G, García-Pagán JC. Current knowledge and management of portal vein thrombosis in cirrhosis. J Hepatol 2021; 75:442-453. [PMID: 33930474 DOI: 10.1016/j.jhep.2021.04.029] [Citation(s) in RCA: 119] [Impact Index Per Article: 29.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 04/20/2021] [Accepted: 04/20/2021] [Indexed: 12/13/2022]
Abstract
Portal vein thrombosis (PVT) is an increasingly recognised complication of cirrhosis whose incidence increases in parallel with the severity of cirrhosis. Several risk factors have been associated with the occurrence and progression of PVT. Although the negative effect of complete PVT on the surgical outcome of liver transplant recipients is clear, its impact on cirrhosis progression remains uncertain. Treatment options include anticoagulants and interventional thrombolytic therapies, which are chosen almost on a case-by-case basis depending on the characteristics of the patient and the thrombus. In this manuscript, we review current knowledge regarding the epidemiology, risk factors, diagnosis and classification, natural history, clinical consequences and treatment of non-neoplastic PVT in cirrhosis.
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Affiliation(s)
- Marco Senzolo
- Multivisceral Transplant Unit-Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy(†).
| | - Guadalupe Garcia-Tsao
- Section of Digestive Diseases, VA-Connecticut Healthcare System, West Haven, CT, USA; Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA
| | - Juan Carlos García-Pagán
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Barcelona, Spain; Institut de Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Spain; CIBEREHD (Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas), Spain(†)
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26
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Anticoagulant Treatment for Splanchnic Vein Thrombosis in Liver Cirrhosis: A Systematic Review and Meta-Analysis. Thromb Haemost 2021; 121:867-876. [PMID: 33525037 DOI: 10.1055/s-0040-1722192] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Splanchnic vein thrombosis (SVT) is a common complication in patients with liver cirrhosis. The aim of this study was to evaluate the efficacy and safety of anticoagulant therapy for SVT in cirrhotic patients. METHODS In this systematic review and meta-analysis, studies reporting on SVT recanalization and progression, recurrent venous thromboembolism (VTE), major bleeding, and overall mortality were searched in MEDLINE, EMBASE, and ClinicalTrial.gov up to December 2019. Pooled proportions and risk ratios (RRs) with corresponding 95% confidence intervals (CIs) were calculated. RESULTS A total of 1,475 patients were included in 26 studies (23 observational and 3 randomized controlled trials). In patients receiving anticoagulant therapy, SVT recanalization occurred in 68% (95% CI, 62-74; 571/842 patients; 22 studies), SVT progression in 6% (95% CI, 4-9; 25/748 patients; 22 studies), recurrent VTE in 10% (95% CI, 4-22; 48/399 patients; 7 studies), major bleeding in 6% (95% CI, 4-10; 58/785 patients; 18 studies), and overall mortality in 9% (95% CI, 6-14; 68/787 patients; 17 studies). Anticoagulant treatment was associated with higher SVT recanalization (RR 3.19; 95% CI, 1.42-7.17), lower thrombosis progression (RR 0.28; 95% CI, 0.15-0.52), major bleeding (RR 0.52; 95% CI, 0.28-0.97), and overall mortality (RR 0.42; 95% CI, 0.24-0.73) compared with no treatment. CONCLUSION Anticoagulant therapy seems to improve vein recanalization and to reduce SVT progression, major bleeding, and overall mortality in cirrhotic patients with SVT. The incidence of recurrent VTE during anticoagulation remains substantial.
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27
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Rugivarodom M, Charatcharoenwitthaya P. Nontumoral Portal Vein Thrombosis: A Challenging Consequence of Liver Cirrhosis. J Clin Transl Hepatol 2020; 8:432-444. [PMID: 33447527 PMCID: PMC7782107 DOI: 10.14218/jcth.2020.00067] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 09/27/2020] [Accepted: 10/18/2020] [Indexed: 12/13/2022] Open
Abstract
Nontumoral portal vein thrombosis (PVT) is an increasingly recognized complication in patients with cirrhosis. Substantial evidence shows that portal flow stasis, complex thrombophilic disorders, and exogenous factors leading to endothelial dysfunction have emerged as key factors in the pathogenesis of PVT. The contribution of PVT to hepatic decompensation and mortality in cirrhosis is debatable; however, the presence of an advanced PVT increases operative complexity and decreases survival after transplantation. The therapeutic decision for PVT is often determined by the duration and extent of thrombosis, the presence of symptoms, and liver transplant eligibility. Evidence from several cohorts has demonstrated that anticoagulation treatment with vitamin K antagonist or low molecular weight heparin can achieve recanalization of the portal vein, which is associated with a reduction in portal hypertension-related events and improved survival in cirrhotic patients with PVT. Consequently, interest in direct oral anticoagulants for PVT is increasing, but clinical data in cirrhosis are limited. Although the most feared consequence of anticoagulation is bleeding, most studies indicate that anticoagulation therapy for PVT in cirrhosis appears relatively safe. Interestingly, the data showed that transjugular intrahepatic portosystemic shunt represents an effective adjunctive therapy for PVT in cirrhotic patients with symptomatic portal hypertension if anticoagulation is ineffective. Insufficient evidence regarding the optimal timing, modality, and duration of therapy makes nontumoral PVT a challenging consequence of cirrhosis. In this review, we summarize the current literature and provide a potential algorithm for the management of PVT in patients with cirrhosis.
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Affiliation(s)
- Manus Rugivarodom
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Phunchai Charatcharoenwitthaya
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
- Correspondence to: Phunchai Charatcharoenwitthaya, Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Wang-Lang Road, Bangkoknoi, Bangkok 10700, Thailand. Tel: +662-419-7282, Fax: +662-411-5013, E-mail:
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28
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Rafiq M, Liaquat A, Saeed N, Shamshad GU, Mumtaz S, Khan MJ. Gene expression of thrombomodulin, TNF-α and NF-KB in coronary artery disease patients of Pakistan. Mol Biol Rep 2020; 47:7575-7582. [PMID: 32930934 DOI: 10.1007/s11033-020-05824-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Accepted: 09/07/2020] [Indexed: 11/28/2022]
Abstract
Thrombomodulin (THBD) is an endothelial surface glycoprotein receptor, having a pivotal role in maintaining laminar blood flow. It functions to protect endothelial integrity by exhibiting anti-coagulation and anti-inflammatory properties thereby playing a key role in cardiovascular disease (CVD) pathology. Cholesterol lowering drugs have shown to alter the anti-inflammatory effects of cytokines. Understanding the molecular aspects of THBD gene and its relation to inflammatory cytokines is important to identify new prognostic and therapeutic targets for the CVD treatments. The present study was conducted to measure the expression of THBD, TNF-α and NF-kB genes in coronary artery disease patients (CAD) in Pakistani population. Lipid profile and BMI was compared both on fifty CAD patients and fifty healthy individuals. Expression analysis for THBD, TNF-α and NF-kB was carried out using real time PCR. The effect of lipid lowering drugs on cardiometabolic risk variables especially gene expression was analyzed. Our results indicated that the difference in BMI was marginal; however LDL-cholesterol and triglycerides levels in CAD patients were significantly higher than healthy individuals. THBD gene was significantly up-regulated whereas TNF-α and NF-kB were significantly down regulated in CAD individuals. Further exploration revealed that these variations were accounted to the use of statins by the patients. The use of statins by CAD patients up-regulated the mRNA expression of THBD by down-regulation of inflammatory mediators. The enhanced expression of endothelial THBD in response to cholesterol lowering drugs establishes a novel pleiotropic target that can be of clinical significance in thromboembolic and inflammatory disorders.
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Affiliation(s)
- Muhammad Rafiq
- Department of Biosciences, COMSATS University Islamabad (CUI), Islamabad, 45550, Pakistan.,Shifa College of Medicine, Shifa Tameer-E-Millat University, Islamabad, 45550, Pakistan
| | - Afrose Liaquat
- Shifa College of Medicine, Shifa Tameer-E-Millat University, Islamabad, 45550, Pakistan.
| | - Nadia Saeed
- Shifa College of Medicine, Shifa Tameer-E-Millat University, Islamabad, 45550, Pakistan
| | | | - Sana Mumtaz
- Shifa College of Medicine, Shifa Tameer-E-Millat University, Islamabad, 45550, Pakistan.,Department of Psychosomatic Medicine and Psychotherapy, University Medical Center, 37075, Gottingen, Germany
| | - Muhammad Jawad Khan
- Department of Biosciences, COMSATS University Islamabad (CUI), Islamabad, 45550, Pakistan.
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29
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Extrahepatic portal vein obstruction (EHPVO) in cirrhosis. Clin Res Hepatol Gastroenterol 2020; 44:497-502. [PMID: 32312599 DOI: 10.1016/j.clinre.2020.03.014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Accepted: 03/03/2020] [Indexed: 02/04/2023]
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30
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Talon L, Sinegre T, Lecompte T, Pereira B, Massoulié S, Abergel A, Lebreton A. Hypercoagulability (thrombin generation) in patients with cirrhosis is detected with ST-Genesia. J Thromb Haemost 2020; 18:2177-2190. [PMID: 32558351 DOI: 10.1111/jth.14963] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2020] [Revised: 05/06/2020] [Accepted: 06/03/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND Thrombin generation assays (TGAs) performed with calibrated automated thrombography (CAT) in the presence of thrombomodulin (TM) indicate plasma hypercoagulability in cirrhosis. OBJECTIVE To evaluate, in the presence of TM, the new ST-Genesia automated device developed for improving TGA vs the previously used CAT method, with plasma samples of patients with cirrhosis. PATIENTS/METHODS Platelet-poor plasma samples were prepared from citrated blood samples of 52 healthy controls and 85 patients with cirrhosis (severity evaluated using the Child-Pugh score [CP]). TGAs were performed using CAT with PPP-Reagent and ST-Genesia with the STG-ThromboScreen reagent, in the presence of TM. Endogenous thrombin potential (ETP) was chosen as the main parameter. RESULTS Whatever the method, ETP values were higher in patients than in healthy controls. All patients identified as hypercoagulable with ST-Genesia and STG-ThromboScreen were found hypercoagulable with CAT and PPP-Reagent. Conversely, eight and ten patients in the CP-A and CP-B classes respectively were identified as hypercoagulable only with CAT. The use of ST-Genesia with the STG-ThromboScreen reagent with TM led to a bias, with higher ETP values for healthy controls and lower for patients compared with CAT. Crossover analysis (CAT with the STG-ThromboScreen reagent) evidenced a substantial effect of the STG-ThromboScreen reagent; the analyzer (including calibration and data analysis) plays a lesser role. CONCLUSION ST-Genesia evidences hypercoagulability in patients with cirrhosis when TG is studied in the presence of TM, but the results are not interchangeable with those obtained with CAT.
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Affiliation(s)
- Laurie Talon
- Service d'hématologie biologique, CHU Clermont-Ferrand, Clermont-Ferrand, France
| | - Thomas Sinegre
- Service d'hématologie biologique, CHU Clermont-Ferrand, Clermont-Ferrand, France
| | - Thomas Lecompte
- Hôpitaux Universitaires de Genève, Unité d'hémostase, Département de médecine, faculté de Médecine - GpG, Université de Genève, Geneva, Switzerland
| | - Bruno Pereira
- Unité de Biostatistiques (Direction de la recherche clinique et de l'innovation), CHU Clermont-Ferrand, Clermont-Ferrand, France
| | - Sylvie Massoulié
- Service d'Hépato-Gastro-Entérologie, CHU Clermont-Ferrand, Clermont-Ferrand, France
| | - Armand Abergel
- Service d'Hépato-Gastro-Entérologie, CHU Clermont-Ferrand, Clermont-Ferrand, France
| | - Aurélien Lebreton
- Service d'hématologie biologique, CHU Clermont-Ferrand, Clermont-Ferrand, France
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31
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Nicoară-Farcău O, Soy G, Magaz M, Baiges A, Turon F, Garcia-Criado A, Barrufet M, Burrel M, Hernández-Gea V, García-Pagán JC. New Insights into the Pathogenesis, Risk Factors, and Treatment of Portal Vein Thrombosis in Patients with Cirrhosis. Semin Thromb Hemost 2020; 46:673-681. [PMID: 32820481 DOI: 10.1055/s-0040-1715473] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Portal vein thrombosis (PVT) is a frequent event in patients with cirrhosis regardless of etiology. Notwithstanding the commonality of the problem, the pathophysiology and risk factors for PVT in cirrhosis are largely unknown. The clinical impact of PVT in the natural history of cirrhosis is unclear, indications for PVT treatment are not well defined, and treatment recommendations are based on experts' opinion and consensus only. Therefore, this review aims to summarize current knowledge of mechanisms and risk factors for PVT development and assess the current evidence of PVT management, with a special focus on strategies of anticoagulation and transjugular intrahepatic portosystemic shunt placement.
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Affiliation(s)
- Oana Nicoară-Farcău
- Department of Hepatology, Regional Institute of Gastroenterology and Hepatology "Octavian Fodor," "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania.,Liver Unit, Barcelona Hepatic Hemodynamic Laboratory, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi I i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Guillem Soy
- Liver Unit, Barcelona Hepatic Hemodynamic Laboratory, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi I i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain.,Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN-Liver)
| | - Marta Magaz
- Liver Unit, Barcelona Hepatic Hemodynamic Laboratory, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi I i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain.,Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN-Liver)
| | - Anna Baiges
- Liver Unit, Barcelona Hepatic Hemodynamic Laboratory, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi I i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain.,Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN-Liver)
| | - Fanny Turon
- Liver Unit, Barcelona Hepatic Hemodynamic Laboratory, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi I i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain.,Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN-Liver)
| | - Angeles Garcia-Criado
- Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN-Liver).,Department of Radiology, Hospital Clinic de Barcelona, Barcelona, Spain
| | - Marta Barrufet
- Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN-Liver).,Department of Radiology, Hospital Clinic de Barcelona, Barcelona, Spain
| | - Marta Burrel
- Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN-Liver).,Department of Radiology, Hospital Clinic de Barcelona, Barcelona, Spain
| | - Virginia Hernández-Gea
- Liver Unit, Barcelona Hepatic Hemodynamic Laboratory, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi I i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain.,Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN-Liver)
| | - Juan Carlos García-Pagán
- Liver Unit, Barcelona Hepatic Hemodynamic Laboratory, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi I i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain.,Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN-Liver)
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Lebreton A, Sinegre T, Lecompte T, Talon L, Abergel A, Lisman T. Thrombin Generation and Cirrhosis: State of the Art and Perspectives. Semin Thromb Hemost 2020; 46:693-703. [PMID: 32820480 DOI: 10.1055/s-0040-1715102] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Epidemiological and laboratory studies performed in the last decades have changed our understanding of coagulopathy in cirrhosis, from a condition at increased risk of hemorrhagic events to one at higher thrombotic risk. However, it is not clear whether the decrease in factors that promote (except factor [F] VIII) versus inhibit coagulation in patients with cirrhosis results in a rebalanced state or in a hypercoagulable phenotype. This issue can be partially addressed using thrombin generation assays (TGA), which unlike routine clotting tests (prothrombin time or activated partial thromboplastin time) are sensitive to both procoagulant factors and coagulation inhibitors. However, many preanalytical issues and variable analytical methodologies used in TGAs complicate data analysis and interlaboratory comparisons. The introduction of TGAs in which activators of the protein C pathway (particularly soluble forms of thrombomodulin [TM]) are added has allowed detection of a reduced anticoagulant effect of TM or even a hypercoagulable phenotype as judged by endogenous thrombin potential. However, inter- and intra-assay variability may be greater with this TGA variant compared with "standard" TGAs. TGAs also allowed identifying main determinants of the hypercoagulability phenotype in the presence of TM: acquired antithrombin and protein C deficiencies, and elevated FVIII levels. The aim of this narrative review is to summarize the preanalytical and methodological variables of TGAs and also the findings of the main studies that have evaluated TGAs in patients with cirrhosis. The review also provides some propositions for future studies and outlines some perspectives on the potential implementation of this promising tool in clinical practice for the study of coagulation in patients with cirrhosis.
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Affiliation(s)
- Aurélien Lebreton
- Service d'hématologie biologique, CHU Clermont-Ferrand, Clermont-Ferrand, France.,Université Clermont Auvergne, INRA, UNH, Unité de Nutrition Humaine, CRNH Auvergne, Clermont-Ferrand, France
| | - Thomas Sinegre
- Service d'hématologie biologique, CHU Clermont-Ferrand, Clermont-Ferrand, France.,Université Clermont Auvergne, INRA, UNH, Unité de Nutrition Humaine, CRNH Auvergne, Clermont-Ferrand, France
| | - Thomas Lecompte
- Hôpitaux Universitaires de Genève, Unité d'hémostase, Département de médecine, Genève; Université de Genève, faculté de Médecine - GpG, Switzerland
| | - Laurie Talon
- Service d'hématologie biologique, CHU Clermont-Ferrand, Clermont-Ferrand, France
| | - Armand Abergel
- Service d'Hépato-Gastro-Entérologie, CHU Clermont-Ferrand, Clermont-Ferrand, France
| | - Ton Lisman
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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33
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Scheiner B, Northup PG, Gruber AB, Semmler G, Leitner G, Quehenberger P, Thaler J, Ay C, Trauner M, Reiberger T, Lisman T, Mandorfer M. The impact of ABO blood type on the prevalence of portal vein thrombosis in patients with advanced chronic liver disease. Liver Int 2020; 40:1415-1426. [PMID: 32052552 PMCID: PMC7317432 DOI: 10.1111/liv.14404] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2019] [Revised: 01/11/2020] [Accepted: 02/06/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Non-O blood type (BT) is a risk factor for thromboses, which has been attributed to its effects on von Willebrand factor (VWF)/factor VIII (FVIII) levels. Although high VWF/FVIII may be risk factors for portal vein thrombosis (PVT) in patients with advanced chronic liver disease (ACLD), the impact of BT on PVT is unknown. We aimed to assess (I) whether non-O-BT is a risk factor for PVT and (II) whether non-O-BT impacts VWF/factor VIII in patients with ACLD. METHODS Retrospective analysis comprising two cohorts: (I) "US" including all adult liver transplantations in the US in the MELD era and (II) "Vienna" comprising patients with a hepatic venous pressure gradient (HVPG) ≥6 mmHg. RESULTS (I) The "US cohort" included 84 947 patients (non-O: 55.43%). The prevalence of PVT at the time of listing (4.37% vs 4.56%; P = .1762) and at liver transplantation (9.56% vs 9.33%; P = .2546) was similar in patients with O- and non-O-BT. (II) 411 patients were included in the "Vienna cohort" (non-O: 64%). Mean HVPG was 18(9) mmHg and 90% had an HVPG ≥10 mmHg. Patients with non-O-BT had slightly increased VWF levels (318(164)% vs 309(176)%; P = .048; increase of 23.8%-23.9% in adjusted analyses), but this difference was driven by patients with less advanced disease. However, non-O-BT explained only 1% of the variation in VWF and had no effect on FVIII. CONCLUSIONS Although non-O-BT impacts VWF in patients with early stage ACLD, its contribution to VWF variation is considerably smaller than in the general population. Moreover, non-O-BT had no impact on FVIII. These findings may explain the absence of an association between non-O-BT and PVT in patients with advanced cirrhosis.
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Affiliation(s)
- Bernhard Scheiner
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
- Vienna Hepatic Hemodynamic LaboratoryMedical University of ViennaViennaAustria
| | - Patrick G. Northup
- Center for the Study of Hemostasis in Liver DiseaseDivision of Gastroenterology and HepatologyUniversity of VirginiaCharlottesvilleVAUSA
| | - Anselm B. Gruber
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
- Vienna Hepatic Hemodynamic LaboratoryMedical University of ViennaViennaAustria
| | - Georg Semmler
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
- Vienna Hepatic Hemodynamic LaboratoryMedical University of ViennaViennaAustria
| | - Gerda Leitner
- Department of Blood Group Serology and Transfusion MedicineMedical University of ViennaViennaAustria
| | - Peter Quehenberger
- Department of Laboratory MedicineMedical University of ViennaViennaAustria
| | - Johannes Thaler
- Division of Hematology and HemostaseologyDepartment of Medicine IMedical University of ViennaViennaAustria
| | - Cihan Ay
- Division of Hematology and HemostaseologyDepartment of Medicine IMedical University of ViennaViennaAustria
| | - Michael Trauner
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
- Vienna Hepatic Hemodynamic LaboratoryMedical University of ViennaViennaAustria
| | - Thomas Reiberger
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
- Vienna Hepatic Hemodynamic LaboratoryMedical University of ViennaViennaAustria
| | - Ton Lisman
- Surgical Research Laboratory and Section of Hepatobiliary Surgery and Liver TransplantationDepartment of SurgeryUniversity of GroningenUniversity Medical Center GroningenGroningenThe Netherlands
| | - Mattias Mandorfer
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
- Vienna Hepatic Hemodynamic LaboratoryMedical University of ViennaViennaAustria
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Zermatten MG, Fraga M, Calderara DB, Aliotta A, Moradpour D, Alberio L. Biomarkers of liver dysfunction correlate with a prothrombotic and not with a prohaemorrhagic profile in patients with cirrhosis. JHEP Rep 2020; 2:100120. [PMID: 32715285 PMCID: PMC7369360 DOI: 10.1016/j.jhepr.2020.100120] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 04/08/2020] [Accepted: 04/21/2020] [Indexed: 02/07/2023] Open
Abstract
Background & Aims Different liver dysfunction biomarkers are used to assess the bleeding risk of patients with cirrhosis, either as such or included in bleeding risk assessment scores. Since the current model of coagulation in patients with cirrhosis describes a procoagulant tendency with increasing severity according to Child-Pugh stage, we decided to investigate the relation between liver dysfunction biomarkers and thrombin generation. Our aim was to verify their adequacy for bleeding risk assessment. Methods We performed a prospective single-centre study including 260 patients with liver cirrhosis. Thrombin generation was measured using ST Genesia® Thrombin Generation System without and with thrombomodulin in order to assess the role of proteins C and S. Relations between thrombin generation and Child-Pugh/model for end-stage liver disease (MELD) scores, prothrombin time (PT)/international normalised ratio (INR), activated partial thromboplastin time (aPTT), factor V activity, albumin, and total bilirubin were assessed. Results Thrombomodulin-mediated inhibition of thrombin generation was significantly decreased in patients with liver cirrhosis compared with healthy donors (p <0.0001) and in Child-Pugh B and C compared with A (p <0.0001 [A–B], 0.4515 [B–C], <0.0001 [A–C]). Thrombomodulin-mediated inhibition significantly decreased with increasing PT/INR, aPTT, and total bilirubin levels and with decreasing factor V activity and albumin levels. Conclusions Worsening liver dysfunction biomarkers reflect an increasing prothrombotic profile in patients with liver cirrhosis. In particular, prolonged PT/INR and aPTT as well as decreasing factor V activity are related to an increasing thrombotic risk and not to an increasing bleeding risk. These parameters should not be used to assess bleeding risk due to haemostatic anomalies in patients with liver cirrhosis. Alternative biomarkers for bleeding risk assessment in patients with liver cirrhosis need to be developed. Lay summary We demonstrate that the laboratory parameters used to assess bleeding risk of patients with liver disease, e.g. prothrombin time/international normalised ratio (PT/INR) and activated partial thromboplastin time (aPTT), are inadequate for this purpose because they are correlated with a prothrombotic coagulation profile. In this article, we highlight the need for alternative parameters to assess bleeding risk in patients with liver disease.
Patients with cirrhosis display a prothrombotic coagulation profile. This is due to a relative decrease of natural anticoagulants compared with procoagulants. In cirrhosis, PT and aPTT correlate with a prothrombotic state, and are inadequate as bleeding risk biomarkers.
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Affiliation(s)
- Maxime G Zermatten
- Division of Hematology and Central Hematology Laboratory, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland
| | - Montserrat Fraga
- Division of Gastroenterology and Hepatology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland
| | - Debora Bertaggia Calderara
- Division of Hematology and Central Hematology Laboratory, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland
| | - Alessandro Aliotta
- Division of Hematology and Central Hematology Laboratory, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland
| | - Darius Moradpour
- Division of Gastroenterology and Hepatology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland
| | - Lorenzo Alberio
- Division of Hematology and Central Hematology Laboratory, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland
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Acute Portal Vein Thrombosis Treated with Recombinant Human Soluble Thrombomodulin Combined with Antithrombin III. Case Rep Med 2020; 2020:8268016. [PMID: 32328109 PMCID: PMC7174955 DOI: 10.1155/2020/8268016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Accepted: 03/23/2020] [Indexed: 11/18/2022] Open
Abstract
Portal vein thrombosis is a major complication associated with liver cirrhosis. In cirrhotic patients, a decrease in procoagulant and anticoagulant factors and an unstable balance between them is observed, and a relative decrease in the activation of anticoagulant drivers is one of the main causes of portal vein thrombosis (PVT). Herein, we report a case of acute portal thrombosis associated with liver cirrhosis and treated with a recombinant form of soluble thrombomodulin (thrombomodulin alpha, TM-α) in combination with antithrombin III. TM-α was administered in accordance with the dosage and route of administration for disseminated intravascular coagulation therapy and resulted in dissolution of PVT with a gradual decrease in D-dimer levels. No adverse events were observed during the course of treatment. In the future, in addition to conventional anticoagulation therapy using heparin or antivitamin K drugs, novel therapies targeting protein C activation using a recombinant form of soluble thrombomodulin may play an important role in the treatment of acute PVT.
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Abstract
OBJECTIVES Critically ill patients with deranged conventional coagulation tests are often perceived to have an increased bleeding risk. Whether anticoagulant prophylaxis for these patients should be withheld is contentious. This study assessed the ability of using in vitro clot strength, as measured by thromboelastography, to predict thromboembolism in patients with abnormal coagulation profiles. DESIGN Prospective cohort study. SETTING A tertiary ICU. PATIENTS Two-hundred and fifteen critically ill coagulopathic patients with thrombocytopenia and/or a derangement in at least one conventional coagulation test (international normalized ratio or activated partial thromboplastin time) within 48 hours of ICU admission. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Thromboelastography was performed for all study patients, and plasma thrombotic biomarkers were measured in a nested cohort (n = 40). Of the 215 patients included, 34 patients (16%) developed subsequent thromboembolism-predominantly among those with a normal (maximum amplitude, 54-72 mm) or increased (maximum amplitude, > 72 mm) in vitro clot strength on thromboelastography (91%; area under the receiver-operating characteristic curve, 0.74; 95% CI, 0.64-0.83). The ability of the maximum amplitude to predict thromboembolism was comparable to plasma P-selectin concentrations (thromboembolism, 78.3 ng/mL vs no thromboembolism, 59.5 ng/mL; p = 0.031; area under the receiver-operating characteristic curve, 0.73; 95% CI, 0.52-0.95). In addition, patients with an increased maximum amplitude were also less likely to receive blood product transfusions within 24 hours of testing compared with those with a subnormal maximum amplitude (12.8% vs 69.2%, respectively; area under the receiver-operating characteristic curve, 0.74; 95% CI, 0.67-0.80). CONCLUSIONS In patients with abnormal coagulation profiles, an increased in vitro clot strength on thromboelastography was associated with an increased risk of thromboembolism, and a reduced risk of requiring transfusion compared with those with a normal or reduced in vitro clot strength.
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Thromboelastography-guided Blood Product Transfusion in Cirrhosis Patients With Variceal Bleeding: A Randomized Controlled Trial. J Clin Gastroenterol 2020; 54:255-262. [PMID: 31008867 DOI: 10.1097/mcg.0000000000001214] [Citation(s) in RCA: 85] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
GOALS The aim of this study was to assess the use of thromboelastography (TEG)-directed blood product transfusion in cirrhotic patients with acute variceal bleeding compared with conventional transfusion for correction of coagulopathy. BACKGROUND Coagulopathy is common in patients with cirrhosis. Recommendations for correction of conventional parameters of coagulation-platelets and the international normalized ratio before endoscopy in patients with acute variceal bleeding-need more validation. STUDY In this randomized controlled trial, cirrhotic patients with severe coagulopathy and acute variceal bleeding were randomized to either TEG-guided blood product transfusion or conventional transfusion from March 2017 to December 2017. The primary outcome was the difference in the amount of fresh frozen plasma and platelet units transfused between the groups. Secondary outcomes were rebleeding at 5 days and 42 days, and 6-week mortality. RESULTS Of the 60 recruited patients, 30 each were randomized to the TEG and conventional transfusion groups. There were no differences in baseline characteristic and endoscopic findings between the 2 groups. Four subjects in the TEG group received blood product transfusions versus all in the conventional transfusion group (13.3% vs. 100%; P<0.001). The control of bleeding on initial endoscopy was similar in the 2 groups. Rebleeding in the TEG and conventional transfusion groups at 5 days was similar [1 (3.3%) vs. 4 (13.3%), P=0.167], whereas it was significantly less in the TEG group at 42 days [3 (10%) vs. 11 (36.7%), P=0.012]. Mortality at 6 weeks was seen in 4 (13.3%) in the TEG group and in 8 (26.7%) patients in the conventional transfusion group (P=0.176). CONCLUSIONS TEG-guided strategy was associated with reduced blood product transfusion to correct coagulopathy without compromising hemostasis in cirrhotic patients (Clinical trial ID: CTRI/2017/02/007864).
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Abstract
Disorders of the mesenteric, portal, and hepatic veins and mesenteric and hepatic arteries have important clinical consequences and may lead to acute liver failure, chronic liver disease, noncirrhotic portal hypertension, cirrhosis, and hepatocellular carcinoma. Although literature in the field of vascular liver disorders is scant, these disorders are common in clinical practice, and general practitioners, gastroenterologists, and hepatologists may benefit from expert guidance and recommendations for management of these conditions. These guidelines represent the official practice recommendations of the American College of Gastroenterology. Key concept statements based on author expert opinion and review of literature and specific recommendations based on PICO/GRADE analysis have been developed to aid in the management of vascular liver disorders. These recommendations and guidelines should be tailored to individual patients and circumstances in routine clinical practice.
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39
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Intagliata NM, Caldwell SH, Tripodi A. Diagnosis, Development, and Treatment of Portal Vein Thrombosis in Patients With and Without Cirrhosis. Gastroenterology 2019; 156:1582-1599.e1. [PMID: 30771355 DOI: 10.1053/j.gastro.2019.01.265] [Citation(s) in RCA: 239] [Impact Index Per Article: 39.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2018] [Revised: 01/11/2019] [Accepted: 01/21/2019] [Indexed: 02/06/2023]
Abstract
Portal vein thrombosis unrelated to solid malignancy is common in patients with cirrhosis, but less frequently observed in patients without cirrhosis. Prompt diagnosis and management of acute symptomatic portal vein thrombosis are essential. Failure to detect and treat thromboses can result in mesenteric ischemia, chronic cavernous transformation, and complications of portal hypertension. In patients with cirrhosis, development of portal vein thrombosis is often insidious and remains undetected until its incidental detection. Management of portal vein thrombosis in patients with cirrhosis is more controversial. However, there are data to support treatment of specific patients with anticoagulation agents. We review the common and distinct features of portal vein thromboses in patients without liver tumors, with and without cirrhosis.
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Affiliation(s)
- Nicolas M Intagliata
- Division of Gastroenterology and Hepatology, University of Virginia Medical CenterCharlottesville, Virginia.
| | - Stephen H Caldwell
- Division of Gastroenterology and Hepatology, University of Virginia Medical CenterCharlottesville, Virginia
| | - Armando Tripodi
- Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Cà Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center and Fondazione Luigi Villa, Milano, Italy
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40
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La Mura V, Primignani M. Reply. Clin Gastroenterol Hepatol 2019; 17:798-799. [PMID: 30218704 DOI: 10.1016/j.cgh.2018.09.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Revised: 09/07/2018] [Accepted: 09/10/2018] [Indexed: 02/07/2023]
Affiliation(s)
- Vincenzo La Mura
- Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, UOC Medicina Generale - Emostasi e Trombosi, Milan, Italy; Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Milan, Italy; Centro di Ricerca Coordinata "A.M. e A. Migliavacca per lo Studio e la Cura delle Malattie del Fegato", Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy
| | - Massimo Primignani
- Centro di Ricerca Coordinata "A.M. e A. Migliavacca per lo Studio e la Cura delle Malattie del Fegato", Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy
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Russo FP, Zanetto A, Campello E, Bulato C, Shalaby S, Spiezia L, Gavasso S, Franceschet E, Radu C, Senzolo M, Burra P, Lisman T, Simioni P. Reversal of hypercoagulability in patients with HCV-related cirrhosis after treatment with direct-acting antivirals. Liver Int 2018; 38:2210-2218. [PMID: 29738632 DOI: 10.1111/liv.13873] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2018] [Accepted: 04/20/2018] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS The long-term impact of sustained virological response (SVR) after direct-acting antivirals (DAAs) on the hypercoagulability associated with HCV cirrhosis is unknown. We longitudinally evaluated the effect of DAAs treatment on cirrhotic coagulopathy. METHODS Pro- and anticoagulant factor levels and thrombin generation were assessed in patients with HCV-related cirrhosis at baseline, end of therapy (EOT), at 12, 24 and 48 weeks (W) after EOT. RESULTS Fifty-eight patients were enrolled (86% Child's A). SVR was 100%. Median factor VIII activity significantly decreased at EOT, 12 weeks and 24 weeks compared with baseline, whereas protein C significantly increased at 24 weeks and 48 weeks. Cirrhotic patients showed a slight but sustained increase in endogenous thrombin potential (ETP) with a statistically significant difference at EOT, 12 weeks, 24 weeks and 48 weeks compared with baseline. Conversely, thrombomodulin-modified ETP was elevated before treatment and decreased over time to normal levels at 24 weeks and 48 weeks. The ETP ratio decreased slowly at EOT and 12 weeks, and was significantly decreased at 24 weeks and 48 weeks compared with baseline (P < .001 for both comparisons), being not statistically different from ETP ratio measured in healthy controls. Child's B patients showed a significantly higher ETP ratio compared to Child's A at baseline and did not show any significant improvement in ETP ratio through 12 weeks. Two Child's B patients developed PVT with an incidence rate of 1.1% p-yrs (95%CI, 0.18 to 3.58). CONCLUSIONS DAAs therapy in HCV-related cirrhotic patients is associated with significant changes in thrombin generation suggesting a reversal of hypercoagulability particularly in Child's A patients.
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Affiliation(s)
- Francesco Paolo Russo
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Alberto Zanetto
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Elena Campello
- Thrombotic and Haemorrhagic Diseases Unit, Department of Medicine, Padua University Hospital, Padua, Italy
| | - Cristiana Bulato
- Thrombotic and Haemorrhagic Diseases Unit, Department of Medicine, Padua University Hospital, Padua, Italy
| | - Sarah Shalaby
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Luca Spiezia
- Thrombotic and Haemorrhagic Diseases Unit, Department of Medicine, Padua University Hospital, Padua, Italy
| | - Sabrina Gavasso
- Thrombotic and Haemorrhagic Diseases Unit, Department of Medicine, Padua University Hospital, Padua, Italy
| | - Enrica Franceschet
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Claudia Radu
- Thrombotic and Haemorrhagic Diseases Unit, Department of Medicine, Padua University Hospital, Padua, Italy
| | - Marco Senzolo
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Patrizia Burra
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Ton Lisman
- Section of Hepatobiliary Surgery and Liver Transplantation, Surgical Research Laboratory, Department of Surgery, University Medical Center Groningen, Groningen, the Netherlands
| | - Paolo Simioni
- Thrombotic and Haemorrhagic Diseases Unit, Department of Medicine, Padua University Hospital, Padua, Italy
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Tu B, Bi J, Wu D, Zhao P, Shi L, Xie Y, Zhang X, Xu Z, Liu S, Wang X, Li X, Wang F, Qin E. Bloodstream infection due to Escherichia coli in liver cirrhosis patients: clinical features and outcomes. Oncotarget 2018; 9:35780-35789. [PMID: 30515269 PMCID: PMC6254670 DOI: 10.18632/oncotarget.23200] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2017] [Accepted: 05/29/2017] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVES The study aimed to investigate the clinical characteristics and antibiotic management, as well as independent indicators for survival within 30 days for Escherichia coli bloodstream infection (BSI) in liver cirrhosis. RESULTS Hospital-acquired BSI accounted for 60.07%, with prolonged hospital stay (P = 0.000). The prevalence of Extended Spectrum Beta-Lactamases (ESBL) producing bacteria was 48.26%, which correlated with ICU admission (P = 0.015) and high model for end-stage liver disease (MELD) score at onset of BSI (P = 0.035). Moreover, ESBL producing pathogens showed a high resistant to the common antibiotic families and 27.5% pathogens were confirmed as multidrug-resistant (MDR). MDR infection was significantly correlated with ESBL production, ICU admission, inappropriate empiric therapy, resistance to firstly selected antibiotic, and infection duration (P < 0.05 for all). In addition, appropriate empiric therapy within 48 h (HR = 2.581, 95% CI = 1.166-5.715), ICU admission (HR = 4.434, 95% CI = 2.130-8.823), HE (HR = 2.379, 95% CI = 1.115-5.073) and final MELD (HR = 1.074, 95% CI = 1.044-1.106) were independent indicators for 30-day mortality. MATERIALS AND METHODS The clinical data were collected from 288 eligible patients, and compared according to survival status and sites of infection acquisition. Drug resistance was recorded according to ESBL. In addition, cox regression analysis model was applied to evaluate the risk factors for 30-day mortality. CONCLUSIONS ESBL production can promote resistance to antibiotics in Escherichia coli. Antibiotic regimens, ICU admission, HE and MELD score can help identify the risk individuals who will benefit from the improved therapeutic regimens.
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Affiliation(s)
- Bo Tu
- Center for Infectious Disease, Beijing 302 Hospital, Beijing 100039, China
| | - Jingfeng Bi
- Center for Clinical Research Management, Beijing 302 Hospital, Beijing 100039, China
| | - Dan Wu
- Center for Infectious Disease, Beijing 302 Hospital, Beijing 100039, China
| | - Peng Zhao
- Center for Infectious Disease, Beijing 302 Hospital, Beijing 100039, China
| | - Lei Shi
- Center for Infectious Disease, Beijing 302 Hospital, Beijing 100039, China
| | - Yangxin Xie
- Center for Infectious Disease, Beijing 302 Hospital, Beijing 100039, China
| | - Xin Zhang
- Center for Infectious Disease, Beijing 302 Hospital, Beijing 100039, China
| | - Zhe Xu
- Center for Infectious Disease, Beijing 302 Hospital, Beijing 100039, China
| | - Suxia Liu
- Center for Liver Failure, Beijing 302 Hospital, Beijing 100039, China
| | - Xinhua Wang
- Center for Obstetrics and Gynecology, Beijing 302 Hospital, Beijing 100039, China
| | - Xiaoxi Li
- Center for Clinical Laboratory, Beijing 302 Hospital, Beijing 100039, China
| | - Fusheng Wang
- Center for Infectious Disease, Beijing 302 Hospital, Beijing 100039, China
| | - Enqiang Qin
- Center for Infectious Disease, Beijing 302 Hospital, Beijing 100039, China
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Girolami A, Cosi E, Ferrari S, Girolami B. Heparin, coumarin, protein C, antithrombin, fibrinolysis and other clotting related resistances: old and new concepts in blood coagulation. J Thromb Thrombolysis 2018; 45:135-141. [PMID: 29063359 DOI: 10.1007/s11239-017-1559-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The concept of resistance in blood coagulation has become important. In the past it was limited to the resistance shown by some patients to heparin, coumarin or aspirin. Subsequently, it was demonstrated that a mutation in a single clotting factor, FV, showed resistance to activated protein C. Since activated protein C is supposed to downregulate aFV and aFVIII, their persistence in the circulation gives origin to a hypercoagulable state. Recently antithrombin resistance has been defined. Several prothrombin abnormalities (dysprothrombinemias) have been shown to be resistant to the action of antithrombin. This is associated with the occurrence of a trombophilic state. Prothrombin may therefore be associated like FV with both a bleeding condition (prothrombin deficiency) and a thrombophilic state (some dysprothrombinemias). Finally, thrombomodulin resistance has been defined in liver cirrhosis. These patients often show an increased ratio between FVIII levels and protein C. This imbalance may be partly responsible for the frequent presence of portal vein thrombosis seen in these patients. All these studies have greatly increased the complexity of the clotting mechanisms and interactions. They have cast light on clinical events which had remained unknown or ill-defined.
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Affiliation(s)
- A Girolami
- Department of Medicine, University of Padua Medical School, Via Ospedale 105, 35128, Padua, Italy.
| | - E Cosi
- Department of Medicine, University of Padua Medical School, Via Ospedale 105, 35128, Padua, Italy
| | - S Ferrari
- Department of Medicine, University of Padua Medical School, Via Ospedale 105, 35128, Padua, Italy
| | - B Girolami
- Division of Medicine, Padua City Hospital, Padua, Italy
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Senzolo M, Riva N, Dentali F, Rodriguez-Castro K, Sartori MT, Bang SM, Martinelli I, Schulman S, Alatri A, Beyer-Westendorf J, Di Minno MND, Ageno W. Long-Term Outcome of Splanchnic Vein Thrombosis in Cirrhosis. Clin Transl Gastroenterol 2018; 9:176. [PMID: 30108204 PMCID: PMC6092393 DOI: 10.1038/s41424-018-0043-2] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Revised: 06/07/2018] [Accepted: 06/16/2018] [Indexed: 02/06/2023] Open
Abstract
Introduction Little is known about the long-term outcome of cirrhotic patients with splanchnic vein thrombosis (SVT). This prospective cohort study aimed to describe the clinical presentation, bleeding incidence, thrombotic events, and mortality in patients with SVT associated with cirrhosis. Methods Among 604 consecutive patients with SVT enrolled over 2 years, 149 had cirrhosis. Major bleeding, thrombotic events, and all-cause mortality were recorded during a 2-year follow-up. In a subgroup, the degree of recanalization with or without anticoagulation therapy, and the correlation between clinical events and liver disease severity were also investigated. Results The most common thrombosis sites were the portal (88%) and mesenteric veins (34%). At presentation, 50% of patients were asymptomatic. Anticoagulation was administered to 92/149 patients for a median of 6.5 months. Vessel recanalization was documented in 47/98 patients with a radiological follow-up. Anticoagulation was associated with a 3.33-fold higher of recanalization rate, and a lower recurrent thrombosis rate, while patients with and without anticoagulation experienced a similar rate of major bleeding episodes. Mortality rates were 6.8 per 100 patient-years for patients with thrombosis completely or partially resolving during the follow-up, and 15.4 per 100 patient-years for those with stable or progressing thrombosis. An impact of SVT on survival was only apparent in patients with more advanced liver disease (Child–Pugh B-C). Conclusions Patients with SVT and cirrhosis have a substantial long-term risk of recurrent thrombotic events, which is reduced by anticoagulation therapy without any increase in bleeding risk. Anticoagulation can improve the likelihood of vessel recanalization, and is associated with a lower risk of death for decompensated patients.
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Affiliation(s)
- Marco Senzolo
- Multivisceral Transplant Unit, University Hospital of Padua, Padua, Italy.
| | - Nicoletta Riva
- Department of Clinical and Experimental Medicine, University of Insubria, Varese, Italy
| | - Francesco Dentali
- Department of Clinical and Experimental Medicine, University of Insubria, Varese, Italy
| | | | - Maria Teresa Sartori
- Clinical Medicine I, Department of Medicine, Padua University Hospital, Padua, Italy
| | - Soo-Mee Bang
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Ida Martinelli
- A. Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy
| | - Sam Schulman
- Department of Medicine, McMaster University, Hamilton, Canada
| | - Adriano Alatri
- Hemostasis and Thrombosis Center, A.O. Istituti Ospitalieri di Cremona, Cremona, Italy
| | - Jan Beyer-Westendorf
- Thrombosis Research, Department of Medicine, 1st Division of Hematology, Dresden University Clinic, Dresden, Germany
| | | | - Walter Ageno
- Department of Clinical and Experimental Medicine, University of Insubria, Varese, Italy
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Bitto N, Liguori E, La Mura V. Coagulation, Microenvironment and Liver Fibrosis. Cells 2018; 7:85. [PMID: 30042349 PMCID: PMC6115868 DOI: 10.3390/cells7080085] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2018] [Revised: 07/19/2018] [Accepted: 07/20/2018] [Indexed: 12/12/2022] Open
Abstract
Fibrosis is the main consequence of any kind of chronic liver damage. Coagulation and thrombin generation are crucial in the physiological response to tissue injury; however, the inappropriate and uncontrolled activation of coagulation cascade may lead to fibrosis development due to the involvement of several cellular types and biochemical pathways in response to thrombin generation. In the liver, hepatic stellate cells and sinusoidal endothelial cells orchestrate fibrogenic response to chronic damage. Thrombin interacts with these cytotypes mainly through protease-activated receptors (PARs), which are expressed by endothelium, platelets and hepatic stellate cells. This review focuses on the impact of coagulation in liver fibrogenesis, describes receptors and pathways involved and explores the potential antifibrotic properties of drugs active in hemostasis in studies with cells, animal models of liver damage and humans.
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Affiliation(s)
- Niccolò Bitto
- Medicina Interna, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Donato, Università Degli Studi di Milano, 20097 San Donato Milanese (MI), Italy.
| | - Eleonora Liguori
- Medicina Interna, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Donato, Università Degli Studi di Milano, 20097 San Donato Milanese (MI), Italy.
| | - Vincenzo La Mura
- Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, UOC Medicina Generale-Emostasi e Trombosi, 20122 Milano, Italy.
- Dipartimento di Scienze biomediche per la Salute, Università degli Studi di Milano, 20122 Milano, Italy.
- A. M. and A. Migliavacca per lo studio delle Malattie del Fegato, 20122 Milano, Italy.
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La Mura V, Braham S, Tosetti G, Branchi F, Bitto N, Moia M, Fracanzani AL, Colombo M, Tripodi A, Primignani M. Harmful and Beneficial Effects of Anticoagulants in Patients With Cirrhosis and Portal Vein Thrombosis. Clin Gastroenterol Hepatol 2018; 16:1146-1152.e4. [PMID: 29066371 DOI: 10.1016/j.cgh.2017.10.016] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Accepted: 10/07/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Vitamin K antagonists (VKAs) promote recanalization of portal vein thrombosis (PVT) in patients with cirrhosis. However, the benefit of PVT recanalization might be offset by major and minor bleeding associated with use of anticoagulants. We evaluated harmful and beneficial effects of VKA in patients with PVT and cirrhosis. METHODS We performed a retrospective study of 63 consecutive patients with cirrhosis given anticoagulants for the first detection of non-neoplastic PVT from 2003 to 2015 in Italy. We collected data on bleeding events in these patients and compared them with those from patients without cirrhosis with venous thromboembolism (VTE) (n = 160) for up to 4 years. Time in the therapeutic range, based on the international normalized ratio, was used to determine the quality of anticoagulation. We also collected data from 139 patients with cirrhosis who did not receive VKAs (controls), to analyze portal hypertension-related events. We performed survival analyses to determine the effects of VKA in patients with PVT vs controls. RESULTS The group with VTE and the group with PVT were comparable in age, sex, and time in the therapeutic range, but patients with VTE received VKAs for a longer time period (31.1 ± 16.9 mo vs 23.3 ± 16.2 mo; P = .002). The incidence of major or minor bleeding was higher in patients with PVT than patients with VTE (major, 24% vs 7%; P = .012; minor, 29% vs 19%; P = .024). Patients with PVT had a higher rate of major bleeding from the upper-gastrointestinal tract than patients with VTE (P = .019), but there were no significant differences in other types of major bleeding (P = .376). Patients with PVT and controls had the same rate of upper-gastrointestinal bleeding. Complete recanalization in patients with PVT receiving VKA (n = 31) was independently associated with increased portal hypertension-related event-free and transplantation-free survival times. CONCLUSIONS In a retrospective analysis of 63 patients with cirrhosis given anticoagulants for PVT, we found VKA use to increase risk of minor bleeding, compared with patients without cirrhosis given VKA. However, this risk is offset by the ability of VKA to increase portal hypertension-related, event-free, and transplantation-free survival of patients with PVT recanalization. Portal hypertension, rather than anticoagulants, could account for the difference in risk of major bleeding between patients with PVT vs patients with VTE.
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Affiliation(s)
- Vincenzo La Mura
- A. M. and A. Migliavacca-Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy; Internal Medicine, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Donato, Department of Biomedical Sciences for Health, University of Milan, San Donato Milanese, Italy.
| | - Simon Braham
- Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Cà Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - Giulia Tosetti
- A. M. and A. Migliavacca-Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - Federica Branchi
- A. M. and A. Migliavacca-Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - Niccolò Bitto
- Internal Medicine, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Donato, Department of Biomedical Sciences for Health, University of Milan, San Donato Milanese, Italy
| | - Marco Moia
- Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Cà Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - Anna Ludovica Fracanzani
- Internal Medicine, Department of Pathophysiology and Transplantation, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Cà Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - Massimo Colombo
- Department of Internal Medicine, Humanitas Clinical and Research Center (MI), Rozzano, Italy
| | - Armando Tripodi
- Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Cà Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - Massimo Primignani
- A. M. and A. Migliavacca-Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
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Sinegre T, Duron C, Lecompte T, Pereira B, Massoulier S, Lamblin G, Abergel A, Lebreton A. Increased factor VIII plays a significant role in plasma hypercoagulability phenotype of patients with cirrhosis. J Thromb Haemost 2018; 16:1132-1140. [PMID: 29577605 DOI: 10.1111/jth.14011] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Indexed: 12/14/2022]
Abstract
Essentials The role of increased factor VIII in cirrhosis-induced hypercoagulability has never been demonstrated. Factor VIII and protein C effects were characterized by thrombin generation with thrombomodulin. Factor VIII elevation plays a significant role in cirrhosis-induced plasma hypercoagulability. Only protein C and factor VIII normalization led to thrombin generation similar to controls. SUMMARY Background In cirrhosis, thrombin generation (TG) studied in the presence of thrombomodulin (TM) indicates plasma hypercoagulability. Although the role of protein C (PC) deficiency has been investigated, the influence of an increase in the factor VIII level has never been addressed. Objectives We investigated the roles of high FVIII and low PC levels in increased TG in the presence of TM. Methods Blood samples were prospectively collected from 35 healthy controls and 93 patients with cirrhosis (Child-Turcotte-Pugh [CTP]-A, n = 61; CTP-B, n = 19; and CTP-C, n = 13) and FVIII levels > 150% (n = 48) and/or PC levels < 70% (n = 88). TG was performed with tissue factor (5 pm), phospholipids, and TM (4 nm). FVIII and PC levels were normalized by adding an inhibitory anti-FVIII antibody and exogenous PC, respectively. Results The endogenous thrombin potential (ETP) in the presence of TM was higher in patients than in controls. After FVIII normalization, the ETP (median) decreased from 929 nm min to 621 nm min (CTP-A), 1122 nm min to 1082 nm min (CTP-B), and 1221 nm min to 1143 nm min (CTP-C); after PC normalization, it decreased from 776 nm min to 566 nm min (CTP-A), 1120 nm min to 790 nm min (CTP-B), and 995 nm min to 790 nm min (CTP-C). The ETP was reduced by 17% and 30%, respectively, but normal TG was not restored. When both FVIII and PC levels were normalized, the ETP decreased from 929 nm min to 340 nm min (CTP-A), 1122 nm min to 506 nm min (CTP-B), and 1226 nm min to 586 nm min (CTP-C), becoming similar to control levels. Conclusion Cirrhosis-induced plasma hypercoagulability, as demonstrated in these experimental conditions, can be partly explained by opposite changes in two factors: PC level (decrease) and FVIII level (increase).
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Affiliation(s)
- T Sinegre
- Service d'Hématologie Biologique, CHU Clermont-Ferrand, Clermont-Ferrand, France
- Université Clermont Auvergne, INRA, UMR 1019, Clermont-Ferrand, France
| | - C Duron
- Service d'Hépato-Gastro-Entérologie, CHU Clermont-Ferrand, Clermont-Ferrand, France
- Université Clermont Auvergne, CNRS, UMR 6284, Clermont-Ferrand, France
| | - T Lecompte
- Hôpitaux Universitaires de Genève, Unité d'hémostase, Département des spécialités de médecine, Geneva, Switzerland
- Université de Genève, GpG, Geneva, Switzerland
| | - B Pereira
- CHU Clermont-Ferrand, Unité de Biostatistiques (Direction de la recherche clinique et de l'innovation), Clermont-Ferrand, France
| | - S Massoulier
- Service d'Hépato-Gastro-Entérologie, CHU Clermont-Ferrand, Clermont-Ferrand, France
| | - G Lamblin
- Service d'Hépato-Gastro-Entérologie, CHU Clermont-Ferrand, Clermont-Ferrand, France
| | - A Abergel
- Service d'Hépato-Gastro-Entérologie, CHU Clermont-Ferrand, Clermont-Ferrand, France
- Université Clermont Auvergne, CNRS, UMR 6284, Clermont-Ferrand, France
| | - A Lebreton
- Service d'Hématologie Biologique, CHU Clermont-Ferrand, Clermont-Ferrand, France
- Université Clermont Auvergne, INRA, UMR 1019, Clermont-Ferrand, France
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Mantaka A, Augoustaki A, Kouroumalis EA, Samonakis DN. Portal vein thrombosis in cirrhosis: diagnosis, natural history, and therapeutic challenges. Ann Gastroenterol 2018; 31:315-329. [PMID: 29720857 PMCID: PMC5924854 DOI: 10.20524/aog.2018.0245] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Accepted: 11/26/2017] [Indexed: 12/13/2022] Open
Abstract
Portal vein thrombosis (PVT) is a frequent complication in cirrhosis and its prevalence increases with disease severity. Several factors are involved in the development and progression of PVT. The challenge for the management of PVT is the precise evaluation of the bleeding risk as opposed to life-threatening extension of thrombosis. Nevertheless, the impact on the progression and outcome of liver disease is unclear. A critical evaluation of the available data discloses that treating PVT in cirrhotics is safe and effective. However, there are open issues, such as which anticoagulant could represent a safer therapeutic option, and when and for how long this treatment should be administered to cirrhotic patients with PVT.
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Affiliation(s)
- Aikaterini Mantaka
- Department of Gastroenterology and Hepatology, University Hospital of Crete, Heraklion, Crete, Greece
| | - Aikaterini Augoustaki
- Department of Gastroenterology and Hepatology, University Hospital of Crete, Heraklion, Crete, Greece
| | - Elias A Kouroumalis
- Department of Gastroenterology and Hepatology, University Hospital of Crete, Heraklion, Crete, Greece
| | - Dimitrios N Samonakis
- Department of Gastroenterology and Hepatology, University Hospital of Crete, Heraklion, Crete, Greece
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Tripodi A, D'Ambrosio R, Padovan L, Tosetti G, Aghemo A, Primignani M, Chantarangkul V, Peyvandi F, Colombo M. Evaluation of coagulation during treatment with directly acting antivirals in patients with hepatitis C virus related cirrhosis. Liver Int 2017; 37:1295-1303. [PMID: 28129465 DOI: 10.1111/liv.13374] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2016] [Accepted: 01/20/2017] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIMS The effect of direct-acting-antivirals (DAA) on coagulation of hepatitis-C-virus (HCV)-related cirrhosis is unknown. METHODS We investigated 28 patients on DAA treatment and performed prothrombin-time, thrombin generation with and without thrombomodulin, whole-blood thromboelastometry, as well as the individual procoagulants (II, VIII, XIII, von Willebrand) and anticoagulants, antithrombin and protein-C. RESULTS Patients had undetectable HCV-RNA at the end-of- treatment and at 12-weeks after end-of-treatment (sustained virological response). Transaminases were significantly decreased at both end-of-treatment and at 12-weeks. Prothrombin-time declined at 12-weeks, but did not reach statistical significance. Factor-II, protein-C and antithrombin increased significantly at end-of-treatment (P<.001) and persisted at 12-weeks. Factor-VIII decreased at end-of-treatment and to a greater extent at 12-weeks when reached statistical significance (P<.05). Factor-VIII/protein-C ratio decreased sharply, reached statistical significance at end-of-treatment (P<.01) and persisted at 12-weeks. Von-Willebrand decreased at end-of-treatment and reached statistical significance at 12-weeks (P<.001). Endogenous-thrombin-potential without thrombomodulin increased significantly at end-of-treatment (P<.01) and persisted at 12-weeks. No changes were observed after addition of thrombomodulin. Endogenous-thrombin-potential ratio (with/without thrombomodulin) decreased and reached statistical significance at 12-weeks (P<.05). Thromboelastometry clotting time decreased sharply, reached statistical significance at end-of treatment (P<.001) and persisted at 12-weeks. CONCLUSIONS Treatment with DAAs in HCV-related cirrhosis results in improvement of the individual pro- and anticoagulants. It can be hypothesised that the net effect does not substantially modify their balance (as shown by the unchanged thrombin generation in the presence of thrombomodulin) but makes it more stable and less amenable to be perturbed as presumably occurs before treatment when there is a partial deficiency for both.
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Affiliation(s)
- Armando Tripodi
- Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milano, Italy.,Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milano, Italy.,IRCCS Cà Granda Maggiore Hospital Foundation, Milano, Italy
| | - Roberta D'Ambrosio
- IRCCS Cà Granda Maggiore Hospital Foundation, Milano, Italy.,Division of Gastroenterology and Hepatology, Milano, Italy
| | - Lidia Padovan
- Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milano, Italy.,IRCCS Cà Granda Maggiore Hospital Foundation, Milano, Italy
| | - Giulia Tosetti
- IRCCS Cà Granda Maggiore Hospital Foundation, Milano, Italy.,Division of Gastroenterology and Hepatology, Milano, Italy
| | - Alessio Aghemo
- IRCCS Cà Granda Maggiore Hospital Foundation, Milano, Italy.,Division of Gastroenterology and Hepatology, Milano, Italy.,Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy
| | - Massimo Primignani
- IRCCS Cà Granda Maggiore Hospital Foundation, Milano, Italy.,Division of Gastroenterology and Hepatology, Milano, Italy
| | | | - Flora Peyvandi
- Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milano, Italy.,IRCCS Cà Granda Maggiore Hospital Foundation, Milano, Italy.,Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy
| | - Massimo Colombo
- IRCCS Cà Granda Maggiore Hospital Foundation, Milano, Italy.,Division of Gastroenterology and Hepatology, Milano, Italy.,Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy.,Humanitas Clinical and Research Center, Milano, Italy
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Wu X, Yao Z, Zhao L, Zhang Y, Cao M, Li T, Ding W, Liu Y, Deng R, Dong Z, Chen H, Novakovic VA, Bi Y, Kou J, Tian Y, Zhou J, Shi J. Phosphatidylserine on blood cells and endothelial cells contributes to the hypercoagulable state in cirrhosis. Liver Int 2016; 36:1800-1810. [PMID: 27206310 DOI: 10.1111/liv.13167] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Accepted: 05/14/2016] [Indexed: 12/24/2022]
Abstract
BACKGROUND & AIMS The mechanism of thrombogenicity in cirrhosis is largely unknown. Our objective was to study the relationship between phosphatidylserine on blood cells and endothelial cells and the hypercoagulable state in cirrhotic patients. METHODS Patients with cirrhosis and healthy controls were studied. Lactadherin was used to quantify phosphatidylserine exposure on blood cells and endothelial cells. Procoagulant activity of cells was evaluated using clotting time and purified coagulation complex assays. Fibrin production was determined by turbidity. Phosphatidylserine exposure, fibrin strands and FVa/Xa binding on cells were observed using confocal microscopy. RESULTS Our study showed that phosphatidylserine exposure on erythrocytes, platelets and leucocytes in cirrhotic patients increased progressively with Child-Pugh categories. In addition, we found that endothelial cells treated with cirrhotic serum in vitro exposed more phosphatidylserine than those exposed to healthy serum. The exposed phosphatidylserine supported a shorter coagulation time and increased FXa, thrombin and fibrin formation. Notably, phosphatidylserine+ erythrocytes also promoted shorter coagulation times and more fibrin generation in cirrhotic microparticle-depleted plasma, regardless of Child-Pugh categories. Confocal microscopy data showed that the FVa/FXa complex and fibrin fibrils colocalized with phosphatidylserine on endothelial cells. Lactadherin significantly inhibited FXa and thrombin generation and consequently decreased fibrin production in normal or cirrhotic plasma. CONCLUSIONS These results lead us to believe that exposed phosphatidylserine on activated or injured erythrocytes, platelets, leucocytes and endothelial cells plays an important role in the hypercoagulable state in cirrhotic patients. Thus, blocking phosphatidylserine binding sites might be a new therapeutic target for preventing thrombosis.
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Affiliation(s)
- Xiaoming Wu
- Departments of Hematology, The First Hospital, Harbin Medical University, Harbin, China
| | - Zhipeng Yao
- Departments of Hematology, The First Hospital, Harbin Medical University, Harbin, China
| | - Lu Zhao
- Departments of Hematology, The First Hospital, Harbin Medical University, Harbin, China
| | - Yan Zhang
- Departments of Hematology, The First Hospital, Harbin Medical University, Harbin, China
| | - Muhua Cao
- Departments of Hematology, The First Hospital, Harbin Medical University, Harbin, China
| | - Tao Li
- Departments of Hematology, The First Hospital, Harbin Medical University, Harbin, China
| | - Wenbo Ding
- Department of Cardiology, The Second Hospital, Harbin Medical University, Harbin, China
| | - Yan Liu
- Departments of Hematology, The First Hospital, Harbin Medical University, Harbin, China
| | - Ruijuan Deng
- Departments of Hematology, The First Hospital, Harbin Medical University, Harbin, China
| | - Zengxiang Dong
- Department of Cardiology, The First Hospital, Harbin Medical University, Harbin, China
| | - He Chen
- Department of Pathology, Harbin Medical University, Harbin, China
| | - Valerie A Novakovic
- Department of Research, VA Boston Healthcare System, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Yayan Bi
- Department of Cardiology, The First Hospital, Harbin Medical University, Harbin, China
| | - Junjie Kou
- Department of Cardiology, The Second Hospital, Harbin Medical University, Harbin, China
| | - Ye Tian
- Department of Cardiology, The First Hospital, Harbin Medical University, Harbin, China
| | - Jin Zhou
- Departments of Hematology, The First Hospital, Harbin Medical University, Harbin, China
| | - Jialan Shi
- Departments of Hematology, The First Hospital, Harbin Medical University, Harbin, China.,Department of Surgery, VA Boston Healthcare System, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
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