Enhancement of endogenous fibrinolysis does not reduce local fibrin deposition, but modulates inflammation upon intestinal ischemia and reperfusion

Ivo G. Schoots; Marcel Levi; Arlène K. van Vliet; Paul J. Declerck; Adrie M. Maas; Thomas M. van Gulik

doi:10.1160/TH03-08-0529

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2004; 91(03): 497-505
DOI: 10.1160/TH03-08-0529

Theme Issue Article

Schattauer GmbH

Enhancement of endogenous fibrinolysis does not reduce local fibrin deposition, but modulates inflammation upon intestinal ischemia and reperfusion

Ivo G. Schoots

¹Departments of Surgery, Academic Medical Center, University of Amsterdam, The Netherlands

²Vascular and Internal Medicine, Academic Medical Center, University of Amsterdam, The Netherlands

,

Marcel Levi

²Vascular and Internal Medicine, Academic Medical Center, University of Amsterdam, The Netherlands

,

Arlène K. van Vliet

¹Departments of Surgery, Academic Medical Center, University of Amsterdam, The Netherlands

,

Paul J. Declerck

³Laboratory for Pharmaceutical Biology and Phytopharmacology, Faculty of Pharmaceutical Sciences, University of Leuven, Belgium

,

Adrie M. Maas

¹Departments of Surgery, Academic Medical Center, University of Amsterdam, The Netherlands

,

Thomas M. van Gulik

¹Departments of Surgery, Academic Medical Center, University of Amsterdam, The Netherlands

› Author Affiliations

Abstract

Summary

This study investigated the contribution of endogenous suppression of fibrinolysis and increased fibrin deposition to intestinal dysfunction and injury in a rat model of intestinal ischemia/ reperfusion (I/R), as fibrinolytic inhibition may lead to thrombotic obstructions that compromise microcirculation and promote intestinal injury. Circulatory fibrinolysis was enhanced by intravenous administration of recombinant tissue plasminogen activator (rt-PA) or by inhibition of PAI-1 by administration of MA-33H1F7. Coagulation and fibrinolysis parameters obtained from portal blood were correlated to fibrin deposition (determined by anti-rat fibrin antibody staining), intestinal function (glucose/water clearance) and intestinal injury (histological evaluation by Park/Chiu score).

Enhanced circulatory fibrinolytic activity, as evidenced by increased portal plasma plasminogen activator activity, elevated fibrin degradation products and decreased levels of PAI-1, did not reduce mucosal fibrin deposition and microthrombosis in postischemic intestinal tissue. Furthermore, rt-PA or anti-PAI-1 antibody administration did not attenuate I/R-induced intestinal injury or dysfunction, as demonstrated by intestinal histopathology scores of 4.8±0.2 and 4.7±0.3 (control I/R group 4.7±0.2) and glucose clearances of 47±6 and 46±9 µL/min · g (control I/R group 30±8 µL/min · g) after 40 minutes of intestinal ischemia and 3 hours of reperfusion, respectively. However, both interventions resulted in decreased levels of interleukin-6, which may indicate fibrin-induced modulation of inflammation. Attempts to enhance the fibrinolytic activity (either by rt-PA or by anti-PAI-1 administration), indicated by increased portal plasma levels of released FDP, failed to decrease mucosal fibrin deposition and to attenuate intestinal I/R injury. Based on our observations and previous reports, the contribution of suppressed endogenous fibrinolysis to microcirculatory fibrin deposition and I/R-injury may be of limited importance.

Keywords

Intestine - ischemia and reperfusion - fibrinolysis - plasminogen activator - plasminogen activator inhibitor

Full Text

References

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