Abstract
Background
Liver cirrhosis is the most common cause of portal hypertension which may end in serious bleeding from gastro-esophageal varices. Recent studies have demonstrated a daily pattern of acute upper gastrointestinal bleeding in patients with liver cirrhosis evidenced by one or two peaks throughout the day.
Aim
The assessment of the circadian rhythm of acute variceal bleeding with the possible participation of circadian changes of the fibrinolytic parameters.
Patients and methods
The study included 264 patients with liver cirrhosis and upper gastrointestinal bleeding in addition to 20 healthy subjects as a control group. A series of hemostatic tests and parameters including prothrombin (PT), activated partial thromboplastin time (APTT), fibrinogen (Fib), Factors II, V, VII, IX, X, XI, platelets counts and fibrinolytic parameters assessement were completed in 60 patients in addition to the control group. The fibrinolytic activity was assessed by estimation of plasminogen, tissue plasminogen activator antigen (tPA: Ag) and plasminogen activator inhibitor antigen (PAI-1: Ag) at hour 09:00 and hour 17:00. The hemostatic tests and liver function tests were assessed once at hour 09.00.
Results
We observed statistically significant two time peaks of upper gastrointestinal bleeding at hour 04:00 and hour 17:00 with a peak of the fibrinolytic parameter, tissue plasminogen activator antigen, with the night peak of bleeding. A significant correlation between the levels of fibrinolytic parameters and hemostatic factors as well as liver function tests were detected.
Conclusion
There are two time peaks of upper gastrointestinal bleeding with a temporal association between the night peak and a relative hyperfibrinolytic state.
Keywords: Circadian pattern, Variceal bleeding, Fibrinolysis, Liver cirrhosis
Full Text
The Full Text of this article is available as a PDF (860.6 KB).
References
- 1.Moore E.M., Czeisler C.A., Richardson G.S. Circadian timekeeping in health and disease. Part 1. Basic properties of circadian pacemakers. N Eng J Med. 1983;309:469–476. doi: 10.1056/NEJM198308253090806. [DOI] [PubMed] [Google Scholar]
- 2.Muller J.E., Stone P.H., Turi Z.G., et al. Circadian variation in the frequency of onset of acute myocardial infarction. N Eng J Med. 1985;313:1315–1322. doi: 10.1056/NEJM198511213132103. [DOI] [PubMed] [Google Scholar]
- 3.Muller J.E., Ludmer P.L., Willich S.N. Circadian variation in the frequency of sudden cardiac death. Circulation. 1987;75:131–138. doi: 10.1161/01.cir.75.1.131. [DOI] [PubMed] [Google Scholar]
- 4.Panza J.A., Epstein S.E., Quyyumi A.A. Circadian variation in vascular tone and its relation to alpha-sympathetic vasoconstrictor activity. N Eng J Med. 1991;325:986–990. doi: 10.1056/NEJM199110033251402. [DOI] [PubMed] [Google Scholar]
- 5.Decousus H., Boissier C., Perpoint B., Page Y., Mismetti P., Laporte S., et al. Circadian dynamics of coagulation and chronopathology of cardiovascular and cerebrovascular events. Future therapeutic implications for the treatment of these disorders? Ann NY Acad Sci. 1991;618:159–165. doi: 10.1111/j.1749-6632.1991.tb27244.x. [DOI] [PubMed] [Google Scholar]
- 6.Schepis F., Cammà C., Niceforo D., Magnano A., Pallio S., Cinquegrani M., et al. Which patients with cirrhosis should undergo endoscopic screening for oesophageal varices detection? Hepatology. 2001;33:333–338. doi: 10.1053/jhep.2001.21410. [DOI] [PubMed] [Google Scholar]
- 7.D’Amico G., Pagliaro L., Bosch J. Pharmacological treatment of portal hypertension: an evidence-based approach. Semin Liver Dis. 1999;19:475–505. doi: 10.1055/s-2007-1007133. [DOI] [PubMed] [Google Scholar]
- 8.García-Pagán J.C., Feu F., Castells A., Luca A., Hermida R.C., Rivera F., et al. Circadian variations of portal pressure and variceal haemorrhage in patients with cirrhosis. Hepatology. 1994;19:595–601. doi: 10.1002/hep.1840190309. [DOI] [PubMed] [Google Scholar]
- 9.Merkel C., Gatta A., Portale T. Circadian variation in the frequency of acute variceal bleeding in cirrhosis. J Hepatol. 1994;21:912–913. doi: 10.1016/S0168-8278(94)80260-2. [DOI] [PubMed] [Google Scholar]
- 10.Merican I., Sprengers D., McCormick P. Diurnal pattern of variceal bleeding in cirrhotic patients. J Hepatol. 1993;19:15–22. doi: 10.1016/S0168-8278(05)80171-0. [DOI] [PubMed] [Google Scholar]
- 11.Siringo S., Bolondi L., Sofia S., Hermida R.C., Gramantieri L., Gaiani S., et al. Circadian occurrence of variceal bleeding in patients with liver cirrhosis. J Gastroenterol Hepatol. 1996;11:1115–1120. doi: 10.1111/j.1440-1746.1996.tb01838.x. [DOI] [PubMed] [Google Scholar]
- 12.Mann N., Hillis A., Mann S. In cirrhotic patients: variceal bleeding is more frequent in the evening and correlates with severity of liver disease. Hepatogastroenterology. 1999;46:391–394. [PubMed] [Google Scholar]
- 13.Goulis J., Patch D., Burroughs A. Bacterial infection in the pathogenesis of variceal bleeding. Lancet. 1999;353:139–142. doi: 10.1016/S0140-6736(98)06020-6. [DOI] [PubMed] [Google Scholar]
- 14.Iwao T., Oho K., Sakai T. Upright posture decreases oesophageal varices flow velocity in patients with cirrhosis. J Hepatol. 1998;28:447–453. doi: 10.1016/S0168-8278(98)80319-X. [DOI] [PubMed] [Google Scholar]
- 15.Violi F., Ferro D., Basili S., et al. Hyperfibrinolysis increases the risk of gastrointestinal haemorrhage in patients with advanced cirrhosis. Hepatology. 1992;15:672–676. doi: 10.1002/hep.1840150420. [DOI] [PubMed] [Google Scholar]
- 16.Primignani M, Dell1era A, Bucciarelli P et al. (2008) High-d-dimer plasma levels predict poor outcome in eosphageal variceal bleeding. Dig liver disease(epub ahead of print) [DOI] [PubMed]
- 17.Andreotti F., Kluft C. Circadian variation of fibrinolytic activity in blood. Chronobiol Int. 1991;8:336–351. doi: 10.3109/07420529109059170. [DOI] [PubMed] [Google Scholar]
- 18.Tofler G.H., Brezinski D., Schafer A.I., et al. Concurrent morning increase in platelet aggregability and the risk of myocardial infarction and sudden cardiac death. N Eng J Med. 1987;316:1514–1518. doi: 10.1056/NEJM198706113162405. [DOI] [PubMed] [Google Scholar]
- 19.Grimaudo V., Hauert J., Bachmann F. Diurnal variation of the fibrinolytic system. Thromb Haemost. 1988;59:495–499. [PubMed] [Google Scholar]
- 20.Bridges A.B., McLaren M., Scott N.A. Circadian variation of tissue plasminogen activator and its inhibitor, von Willebrand factor antigen, and prostacyclin stimulating factor in men with ischaemic heart disease. Br Heart J. 1993;69:121–124. doi: 10.1136/hrt.69.2.121. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Haus E., Cusulos M., Sackett L.L. Circadian variations in blood coagulation parameters, alpha-antitrypsin antigen and platelet aggregation and retention in clinically healthy subjects. Chronobiol Int. 1990;7:203–216. doi: 10.3109/07420529009056976. [DOI] [PubMed] [Google Scholar]
- 22.Beppu K., Inokuchi K., Koyanagi N. Prediction of variceal haemorrhage by oesophageal endoscopy. Gastrointest Endosc. 1981;27:213–218. doi: 10.1016/S0016-5107(81)73224-3. [DOI] [PubMed] [Google Scholar]
- 23.North Italian Endoscopic Club Prediction of the first variceal haemorrhage in patients with cirrhosis of the liver and oesophageal varices. A prospective multicenter study. N Eng J Med. 1988;319:983–989. doi: 10.1056/NEJM198810133191505. [DOI] [PubMed] [Google Scholar]
- 24.Siringo S., Bolondi L., Gaiani S. Timing of the first variceal haemorrhage in cirrhotic patients: prospective evaluation of Doppler flowmetry, endoscopy and clinical parameters. Hepatology. 1994;20:66–73. doi: 10.1002/hep.1840200111. [DOI] [PubMed] [Google Scholar]
- 25.Alvarez D., Heras M., Abecasis R. Daily variation in portal blood flow and the effect of propranolol administration in a randomized study of patients with cirrhosis. Hepatology. 1997;25(3):548–550. doi: 10.1002/hep.510250309. [DOI] [PubMed] [Google Scholar]
- 26.Oka K., Tanaka K. Local fibrinolysis of oesophagus and stomach as a cause of haemorrhage in liver cirrhosis. Thrombosis Res. 1979;14:837–844. doi: 10.1016/0049-3848(79)90003-3. [DOI] [PubMed] [Google Scholar]
- 27.Francis R.J., Feinstein D.I. Clinical significance of accelerated fibrinolysis in liver disease. Haemostasis. 1984;14:460–465. doi: 10.1159/000215106. [DOI] [PubMed] [Google Scholar]
- 28.Boks A.L., Brommer E.J., Schalm S.W. Haemostasis and fibrinolysis in severe liver failure and their relation to haemorrhage. Hepatology. 1986;6:79–86. doi: 10.1002/hep.1840060115. [DOI] [PubMed] [Google Scholar]
- 29.Bertaglia E., Belmonte P., Vertolli U. Bleeding in cirrhotic patients: a precipitating factor due to intravascular coagulation or to hepatic failure? Haemostasis. 1983;13:328–334. doi: 10.1159/000214772. [DOI] [PubMed] [Google Scholar]
- 30.Violi F., Ferro D., Basili S. Association between low-grade disseminated intravascular coagulation and endotoxemia in patients with liver cirrhosis. Gastroenterology. 1995;109:531–539. doi: 10.1016/0016-5085(95)90342-9. [DOI] [PubMed] [Google Scholar]
- 31.Ferguson JW, Helmy A, Ludlam C, Webb DJ, Hayes PC, Newby DC (2007) Hyperfibrinolysis in alcoholic cirrhosis: Relative plasminogen activator inhibitor type 1 deficiency. Thromb Res. [Epub ahead of print] [DOI] [PubMed]
- 32.Kahl B.S., Schwartz B.S., Mosher D.F. Profound imbalance of pro-fibrinolytic and anti-fibrinolytic factors (tissue plasminogen activator and plasminogen activator inhibitor type 1) and severe bleeding diathesis in a patient with cirrhosis: correction by liver transplantation. Blood Coagul Fibrinolysis. 2003;14:741–744. doi: 10.1097/00001721-200312000-00008. [DOI] [PubMed] [Google Scholar]
