Association of Heparin-Like Effect, Factor VII/XIII Deficiency and Fibrinolysis with Rebleeding Risk in Cirrhosis with Acute Variceal Bleeding

Madhumita Premkumar, Rohit Mehtani, Anand V Kulkarni, Ajay Kumar Duseja, Arka De, Sunil Taneja, Virendra Singh, Nipun Verma, Jasmina Ahluwalia, Kamal Kajal, Smita Divyaveer, Akash Roy, Akash Gandotra, Narender Kalson, Kushal Kekan, Harmanpreet Kaur, Harpreet Kaur, Madhumita Premkumar, Rohit Mehtani, Anand V Kulkarni, Ajay Kumar Duseja, Arka De, Sunil Taneja, Virendra Singh, Nipun Verma, Jasmina Ahluwalia, Kamal Kajal, Smita Divyaveer, Akash Roy, Akash Gandotra, Narender Kalson, Kushal Kekan, Harmanpreet Kaur, Harpreet Kaur

Abstract

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://ichgcp.net/clinical-trials-registry/NCT04111120 .

Keywords: Acute-on-chronic liver failure; Endogenous heparinoids; Portal hypertension; Sonoclot; Transfusion algorithms.

Conflict of interest statement

None of the authors have potential conflicts (financial, professional, or personal) which are relevant to this manuscript.

© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Figures

Fig. 1
Fig. 1
Enrollment flowchart of the study
Fig. 2
Fig. 2
Glass bead (gb) and heparinase-treated (h)Sonoclot tests in patients with AVB with calculation of heparin-like effect (HLE) as a predictor of rebleeding and mortality
Fig. 3
Fig. 3
Kaplan–Meier (KM) survival analysis for overall transplant-free survival in patients with and without rebleeding (panel A), risk of mortality in presence of heparin-like effect (HLE) (panel B), and outcomes based on severity of HLE (panel C)
Fig. 4
Fig. 4
Receiver operating Characteristics (ROC) curves for predictors of mortality in patients with cirrhosis and acute variceal bleeding

References

    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. Mehta R, Shapiro AD. Plasminogen activator inhibitor type 1 deficiency. Haemophilia. 2008;14:1255–1260. doi: 10.1111/j.1365-2516.2008.01834.x.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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 doi: 10.1177/08850666211012650.
    1. 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.
    1. 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.
    1. 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. doi: 10.1136/bmjopen-2021-051971.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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 doi: 10.1016/j.jceh.2021.05.001.
    1. 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.
    1. 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 doi: 10.1155/2013/237351.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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. doi: 10.1016/j.jhep.2021.12.022.
    1. 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.
    1. 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.
    1. 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. doi: 10.1002/hep.31443.
    1. Zanetto A, Campello E, Bulato C, et al. Global hemostatic profiling in patients with decompensated cirrhosis and bacterial infections. JHEP Rep. 2022;4:100493. doi: 10.1016/j.jhepr.2022.100493.

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