Association of Heparin-Like Effect, Factor VII/XIII Deficiency and Fibrinolysis with Rebleeding Risk in Cirrhosis with Acute Variceal Bleeding.
Acute-on-chronic liver failure
Endogenous heparinoids
Portal hypertension
Sonoclot
Transfusion algorithms
Journal
Digestive diseases and sciences
ISSN: 1573-2568
Titre abrégé: Dig Dis Sci
Pays: United States
ID NLM: 7902782
Informations de publication
Date de publication:
02 2023
02 2023
Historique:
received:
11
05
2022
accepted:
31
07
2022
pubmed:
20
8
2022
medline:
10
2
2023
entrez:
19
8
2022
Statut:
ppublish
Résumé
Hyperfibrinolysis and coagulation dysfunction may occur in cirrhotic patients with acute variceal bleed (AVB) despite successful endotherapy. To prospectively study the association of endogenous heparinoids and coagulation dysfunction with variceal rebleeding and outcome in cirrhosis. Consecutive patients were assessed with conventional coagulation tests, SONOCLOT™ [(global(gb) and heparinase(h) treated] and factors VII, VIII, XIII, X, tissue plasminogen activator, and plasminogen activator inhibitor ELISA assays in a university hospital. Heparin-like-effect (HLE) was defined as ≥ 20% difference in paired gb/h-SONOCLOT™ traces for activated clotting time (ACT). Of 143 patients screened, 90 (46.4 ± 11.7 years, males 82.2%, ethanol-related 58.8%) were recruited, who bled from esophageal varices (81,90.0%), gastric varices (6,6.6%), or esophageal varices with portal hypertensive gastropathy (3,3.3%). Twenty (21.7%) had early rebleeding, mainly post-variceal ligation ulcer related (70%). Patients who rebled had low Factor XIII [1.6 (1.2-2.1) vs 2.4 ng/ml (2.0-2.8) P = 0.035] and Factor VII (94.1 ± 46.9 vs. 124.0 ± 50.4, P = 0.023). On receiver operating curve analysis, the gbACT > 252 s (sensitivity 86.8%, specificity 76.9%, P < 0.001), hACT > 215 s (sensitivity 71.1%, specificity 70.3%, P < 0.001), and HLE > 50% (sensitivity 69.5%, specificity 70.3%, P = 0.006) predicted rebleeding. Baseline Factor VIII (HR 1.26; 95% CI 1.17-1.34, P < 0.001), low factor VII (HR 0.89; 95% CI 0.76-0.98, P = 0.035), and lysis (HR 1.25, 95% CI 1.17-1.33, P < 0.001) predicted mortality. Endogenous heparinoids at baseline predicted sepsis (HR 1.8; 95% CI 1.4-6.5; P = 0.022), rebleeding events (HR 1.2; 95% CI 1.1-6.3; P = 0.030), and mortality (HR 1.1; 95% CI 1.0-4.6; P = 0.030). Hyperfibrinolysis, Factor VII/XIII deficiency, and HLE are associated with rebleeding after AVB. Trial Registration NCT04111120 available from https://clinicaltrials.gov/ct2/show/NCT04111120 .
Sections du résumé
BACKGROUND
Hyperfibrinolysis and coagulation dysfunction may occur in cirrhotic patients with acute variceal bleed (AVB) despite successful endotherapy.
AIMS
To prospectively study the association of endogenous heparinoids and coagulation dysfunction with variceal rebleeding and outcome in cirrhosis.
METHODS
Consecutive patients were assessed with conventional coagulation tests, SONOCLOT™ [(global(gb) and heparinase(h) treated] and factors VII, VIII, XIII, X, tissue plasminogen activator, and plasminogen activator inhibitor ELISA assays in a university hospital. Heparin-like-effect (HLE) was defined as ≥ 20% difference in paired gb/h-SONOCLOT™ traces for activated clotting time (ACT).
RESULTS
Of 143 patients screened, 90 (46.4 ± 11.7 years, males 82.2%, ethanol-related 58.8%) were recruited, who bled from esophageal varices (81,90.0%), gastric varices (6,6.6%), or esophageal varices with portal hypertensive gastropathy (3,3.3%). Twenty (21.7%) had early rebleeding, mainly post-variceal ligation ulcer related (70%). Patients who rebled had low Factor XIII [1.6 (1.2-2.1) vs 2.4 ng/ml (2.0-2.8) P = 0.035] and Factor VII (94.1 ± 46.9 vs. 124.0 ± 50.4, P = 0.023). On receiver operating curve analysis, the gbACT > 252 s (sensitivity 86.8%, specificity 76.9%, P < 0.001), hACT > 215 s (sensitivity 71.1%, specificity 70.3%, P < 0.001), and HLE > 50% (sensitivity 69.5%, specificity 70.3%, P = 0.006) predicted rebleeding. Baseline Factor VIII (HR 1.26; 95% CI 1.17-1.34, P < 0.001), low factor VII (HR 0.89; 95% CI 0.76-0.98, P = 0.035), and lysis (HR 1.25, 95% CI 1.17-1.33, P < 0.001) predicted mortality. Endogenous heparinoids at baseline predicted sepsis (HR 1.8; 95% CI 1.4-6.5; P = 0.022), rebleeding events (HR 1.2; 95% CI 1.1-6.3; P = 0.030), and mortality (HR 1.1; 95% CI 1.0-4.6; P = 0.030).
CONCLUSIONS
Hyperfibrinolysis, Factor VII/XIII deficiency, and HLE are associated with rebleeding after AVB. Trial Registration NCT04111120 available from https://clinicaltrials.gov/ct2/show/NCT04111120 .
Identifiants
pubmed: 35984611
doi: 10.1007/s10620-022-07656-9
pii: 10.1007/s10620-022-07656-9
pmc: PMC9389477
doi:
Substances chimiques
Factor VII
9001-25-6
Tissue Plasminogen Activator
EC 3.4.21.68
Heparin
9005-49-6
Heparinoids
0
Banques de données
ClinicalTrials.gov
['NCT04111120']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
497-513Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
Références
Premkumar M, Bihari C, Saxena P et al. Heparin-like Effect Associated With Risk of Bleeding, Sepsis, and Death in Patients With Severe Alcohol-Associated Hepatitis. Clin Gastroenterol Hepatol. 2020;18:486-495.e3.
doi: 10.1016/j.cgh.2019.04.057
Premkumar M, Sarin SK. Current Concepts in Coagulation Profile in Cirrhosis and Acute-on-Chronic Liver Failure. Clin Liver Dis (Hoboken). 2020;16:158–167.
doi: 10.1002/cld.976
Thalheimer U, Triantos C, Samonakis D et al. Endogenous heparinoids in acute variceal bleeding. Gut. 2005;54:310–311.
doi: 10.1136/gut.2004.051474
Premkumar M, Saxena P, Rangegowda D et al. Coagulation failure is associated with bleeding events and clinical outcome during systemic inflammatory response and sepsis in acute-on-chronic liver failure: An observational cohort study. Liver Int. 2019;39:694–704.
doi: 10.1111/liv.14034
Bernard B, Cadranel JF, Valla D et al. Prognostic significance of bacterial infection in bleeding cirrhotic patients: a prospective study. Gastroenterology. 1995;108:1828–1834.
doi: 10.1016/0016-5085(95)90146-9
Mehta R, Shapiro AD. Plasminogen activator inhibitor type 1 deficiency. Haemophilia. 2008;14:1255–1260.
doi: 10.1111/j.1365-2516.2008.01834.x
Uemura M, Fujimura Y, Ko S et al. Pivotal role of ADAMTS13 function in liver diseases. Int J Hematol. 2010;91:20–29.
doi: 10.1007/s12185-009-0481-4
Ishikawa M, Uemura M, Matsuyama T et al. Potential role of enhanced cytokinemia and plasma inhibitor on the decreased activity of plasma ADAMTS13 in patients with alcoholic hepatitis: relationship to endotoxemia. Alcohol Clin Exp Res. 2010;34:S25-33.
doi: 10.1111/j.1530-0277.2008.00850.x
de Laat-Kremers RMW, Yan Q, Ninivaggi M et al. Deciphering the coagulation profile through the dynamics of thrombin activity. Sci Rep. 2020;10:12544.
doi: 10.1038/s41598-020-69415-y
Neuenschwander PF, Jesty J. Thrombin-activated and factor Xa-activated human factor VIII: differences in cofactor activity and decay rate. Arch Biochem Biophys. 1992;296:426–434.
doi: 10.1016/0003-9861(92)90593-L
Bedreli S, Sowa JP, Malek S. Rotational thromboelastometry can detect factor XIII deficiency and bleeding diathesis in patients with cirrhosis. Liver Int. 2017;37:562–568.
doi: 10.1111/liv.13254
Agarwal S, Senzolo M, Melikian C et al. The prevalence of a heparin-like effect shown on the thromboelastograph in patients undergoing liver transplantation. Liver Transpl. 2008;14:855–860.
doi: 10.1002/lt.21437
Small C, Attridge RL, Franco-Martinez C et al. Prothrombin Complex Concentrate Use in Intracranial Hemorrhage Patients With Cirrhosis Not on Prior Anticoagulation. J Intensive Care Med. 2021. https://doi.org/10.1177/08850666211012650 .
doi: 10.1177/08850666211012650
Tischendorf M, Fuchs A, Zeuzem S, Lange CM. Use of prothrombin complex concentrates in patients with decompensated liver cirrhosis is associated with thromboembolic events. J Hepatol. 2019;70:800–801.
doi: 10.1016/j.jhep.2018.11.019
Tsochatzis E, Papatheodoridis GV et al. Prophylactic and therapeutic use of recombinant activated factor VII in patients with cirrhosis and coagulation impairment. Dig Liver Dis. 2007;39:490–494.
doi: 10.1016/j.dld.2006.05.015
Premkumar M, Loganathan S, Kajal K et al. COVID-19-related dynamic coagulation disturbances and anticoagulation strategies using conventional D-dimer and point-of-care Sonoclot tests: a prospective cohort study. BMJ Open. 2022;12:e051971. https://doi.org/10.1136/bmjopen-2021-051971 .
doi: 10.1136/bmjopen-2021-051971
Sarin SK, Kumar A, Angus PW et al. Asian Pacific Association for the Study of the Liver (APASL) Working Party on Portal Hypertension. Diagnosis and management of acute variceal bleeding: Asian Pacific Association for Study of the Liver recommendations. Hepatol Int. 2011;5:607–624.
doi: 10.1007/s12072-010-9236-9
Schulman S, Kearon C. Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005;3:692–694.
doi: 10.1111/j.1538-7836.2005.01204.x
Singer M, Deutschman CS, Seymour CW et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315:801–810.
doi: 10.1001/jama.2016.0287
O’Leary JG, Greenberg CS, Patton HM, Caldwell SH. AGA Clinical Practice Update: Coagulation in Cirrhosis. Gastroenterology. 2019;157:34-43.e1.
doi: 10.1053/j.gastro.2019.03.070
Premkumar M, Mehtani R, Divyaveer S et al. Clinical Validation of Global Coagulation Tests to Guide Blood Component Transfusions in Cirrhosis and ACLF. J Clin Transl Hepatol. 2021;9:210–219.
Premkumar M, Kulkarni AV, Kajal K et al. Principles, Interpretation, and Evidence-Based Role of Viscoelastic Point-of-Care Coagulation Assays in Cirrhosis and Liver Failure. Journal of Clinical and Experimental Hepatology. 2021. https://doi.org/10.1016/j.jceh.2021.05.001 .
doi: 10.1016/j.jceh.2021.05.001
Ferguson JW, Helmy A, Ludlam C, Webb DJ, Hayes PC, Newby DC. Hyperfibrinolysis in alcoholic cirrhosis: relative plasminogen activator inhibitor type 1 deficiency. Thromb Res. 2008;121:675–680.
doi: 10.1016/j.thromres.2007.07.008
Saxena P, Bihari C, Rastogi A, Agarwal S, Anand L, Sarin SK. Sonoclot Signature Analysis in Patients with Liver Disease and Its Correlation with Conventional Coagulation Studies. Advances in Hematology. 2013. https://doi.org/10.1155/2013/237351 .
doi: 10.1155/2013/237351
Violi F, Ferro D, Basili S et al. Hyperfibrinolysis resulting from clotting activation in patients with different degrees of cirrhosis. Hepatology. 1993;17:78–83.
doi: 10.1002/hep.1840170115
Takaya H, Yoshiji H, Kawaratani H et al. Decreased activity of plasma ADAMTS13 are related to enhanced cytokinemia and endotoxemia in patients with acute liver failure. Biomed Rep. 2017;7:277–285.
doi: 10.3892/br.2017.945
Reuken PA, Kussmann A, Kiehntopf M et al. Imbalance of von Willebrand factor and its cleaving protease ADAMTS13 during systemic inflammation superimposed on advanced cirrhosis. Liver Int. 2015;35:37–45.
doi: 10.1111/liv.12657
Carnevale R, Raparelli V, Nocella C et al. Gut-derived endotoxin stimulates factor VIII secretion from endothelial cells. Implications for hypercoagulability in cirrhosis. J Hepatol. 2017;67:950–956.
doi: 10.1016/j.jhep.2017.07.002
Kumar M, Ahmad J, Maiwall R et al. Thromboelastography-Guided Blood Component Use in Patients With Cirrhosis With Nonvariceal Bleeding: A Randomized Controlled Trial. Hepatology. 2020;71:235–246.
doi: 10.1002/hep.30794
de Franchis R, Bosch J, Garcia-Tsao G, Reiberger T, Ripoll C. Baveno VII Faculty. Baveno VII - Renewing consensus in portal hypertension. J Hepatol. 2022;76:959–974. https://doi.org/10.1016/j.jhep.2021.12.022 .
doi: 10.1016/j.jhep.2021.12.022
Mohanty A, Kapuria D, Canakis A et al. Fresh frozen plasma transfusion in acute variceal haemorrhage: Results from a multicentre cohort study. Liver Int. 2021;41:1901–1908.
doi: 10.1111/liv.14936
Mahmud N, Hubbard RA, Kaplan DE, Serper M. Declining Cirrhosis Hospitalizations in the Wake of the COVID-19 Pandemic: A National Cohort Study. Gastroenterology. 2020;159:1134-1136.e3.
doi: 10.1053/j.gastro.2020.05.005
Zanetto A, Rinder HM, Campello E et al. Acute Kidney Injury in Decompensated Cirrhosis Is Associated With Both Hypo-coagulable and Hyper-coagulable Features. Hepatology. 2020;72:1327–1340. https://doi.org/10.1002/hep.31443 .
doi: 10.1002/hep.31443
Zanetto A, Campello E, Bulato C et al. Global hemostatic profiling in patients with decompensated cirrhosis and bacterial infections. JHEP Rep. 2022;4:100493. https://doi.org/10.1016/j.jhepr.2022.100493 .
doi: 10.1016/j.jhepr.2022.100493