Diurnal changes of fibrinolysis in patients with liver cirrhosis and esophageal varices

Abstract

Variceal bleeding, whose triggering mechanisms are largely unknown, occurs with a circadian rhythmicity, with 2 peaks, one greater, in the evening, and one smaller, in the early morning. We assessed some clotting and hemodynamic parameters, possibly involved in variceal hemorrhage, over a 24-hour period, at 4-hour intervals, in 16 patients with cirrhosis and esophageal varices and in 9 controls. At each time interval, tissue plasminogen activator (tPA) and tPA inhibitor-1 (PAI-1) antigens and activities and total euglobulin fibrinolytic activity were determined and portal-vein flow velocity, volume, and congestion index were measured by duplex-Doppler. Significant circadian rhythms were searched for by least-squares and cosinor methods. tPA activity showed a circadian rhythm in cirrhosis, with a peak of 2.85 times the trough value, calculated at 18:42, and remained over 2.5-fold until shortly after 22:00. Total fibrinolytic activity showed a similar pattern, which was statistically significant also in controls. tPA and PAI antigens also showed significant circadian rhythm both in controls and cirrhotics, with higher values in the morning. Among the portal hemodynamic parameters only the congestion index showed significant rhythmic changes and only in cirrhosis, with the highest values in the late evening, but with limited diurnal excursion (Ϯ 5.5%). In conclusion, we showed the existence of a circadian rhythm of fibrinolysis in cirrhosis, whose temporal distribution might suggest a role of fibrinolysis in variceal hemorrhage on the basis of the comparison to the known chronorisk of variceal bleeding. (HEPATOLOGY 2000;31:349-357.)Several biological processes are driven by rhythms possessing a circadian, infradian, or ultradian frequency. 1 Similarly, some clinical manifestations of chronic diseases also appear according to a distinct temporal rhythm. 2,3 Discovering the time points of maximal risk favors the identification of the events triggering the onset of clinical manifestations. This was the case for hemostatic, coagulative, and hemodynamic factors for myocardial infarction and cerebrovascular events. 2,4,5 Hemorrhage from gastroesophageal varices is one of the most harmful complications of portal hypertension, but the pathophysiology of the acute event is still unclear. In fact, although portal hypertension is the cause for the development of esophageal varices, the relationship between the level of portal pressure, as measured by the hepatic venous pressure gradient and the individual risk of variceal bleeding, has not been definitively established. [6][7][8][9][10]

Facteurs prédictifs de l’hémorragie par rupture de varices œsophagiennes

“…[8]. This was first suggested by the study by Vinel et al [9], showing a relationship between portal [16,17]. Although …”

“…L'augmentation de fr6quence de l'hyperfibrinolyse, de troubles du thrombo-61estogramme, li6e h la pr6sence d'infections et/ou d'h6morragie variqueuse a 6t6 rapport6e [16,17]. Bien que dans le pass6, on ait accord6 peu d'attention ~ ces facteurs, la disponibilit6 de m6dicaments qui peuvent am61iorer de fa~on significative et rapide le profil de coagulation des patients porteurs de cirrhose a permis de noter maintenant un regain d'int6r~t darts ce domaine.…”

Coagulopathy and clotting disorders

“…This may due to the particular in vitro assay used. In contrast, in vivo correlation between hyperfibrinolysis and an increased risk of variceal bleeding, compatible with the circadian rhythm of hyperfibrinolytic activity has been shown [83]. In addition, increased fibrinolytic activity during liver transplantation and hepatic resection correlates with blood loss [84].…”

Assessment of Bleeding Risk in Patients with Cirrhosis

“…In a prospective study, it was demonstrated that patients with positive fibrinogen degradation products or class C had a significantly higher risk of gastrointestinal bleeding [24]. Moreover, it has been demonstrated that fibrinolysis follows a circadian rhythm in cirrhosis, whose temporal distribution coincides with episodes of variceal bleeding, suggesting a possible role of hyperfibrinolysis in the variceal hemorrhage [30].…”