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

Authors

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

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

References
1 Arvidsson D, Rasmussen I, Almqvist P. et al. Splanchnic oxygen consumption in septic and hemorrhagic shock. Surgery 1991; 109: 190-7.
2 Dahn MS, Lange P, Lobdell K. et al. Splanchnic and total body oxygen consumption differences in septic and injured patients. Surgery 1987; 101: 69-80.
3 Biffl WL, Moore EE. Splanchnic ischaemia/ reperfusion and multiple organ failure. Br J Anaesth 1996; 77: 59-70.
4 Pastores SM, Katz DP, Kvetan V. Splanchnic ischemia and gut mucosal injury in sepsis and the multiple organ dysfunction syndrome. Am J Gastroenterol 1996; 91: 1697-710.
5 Meakins JL, Marshall JC. The gut as the motor of multiple system organ failure. In: Marston A, Bulkley GB, Fiddian-Green RG, Haglund UH. eds. Splanchnic Ischemia and Multiple Organ Failure. London: Edward Arnold; 1989: 339-48.
6 Levi M, de Jonge E, van der Poll T. et al. Disseminated intravascular coagulation. Thromb Haemost 1999; 82: 695-705.
7 Margaretten W, McKay DG. Thrombotic ulcerations of the gastrointestinal tract. Arch Intern Med 1971; 127: 250-3.
8 Whitehead R. Ischaemic enterocolitis: an expression of the intravascular coagulation syndrome. Gut 1971; 12: 912-7.
9 Brandt LJ, Gomery P, Mitsudo SM. et al. Disseminated intravascular coagulation in nonocclusive mesenteric ischemia: the lack of specificity of fibrin thrombi in intestinal infarction. Gastroenterology 1976; 71: 954-7.
10 Schoots IG, Levi M, Roossink EH. et al. Local intravascular coagulation and fibrin deposition on intestinal ischemia-reperfusion in rats. Surgery 2003; 133: 411-9.
11 Marder VJ, Sherry S. Thrombolytic therapy: current status (1). N Engl J Med 1988; 318: 1512-20.
12 The Thrombolysis in Myocardial Infarction (TIMI) trial. Phase I findings TIMI Study Group. N Engl J Med 1985; 312: 932-6.
13 Yamaguchi T, Saeki M, Iwasaki Y. et al. Local thrombolytic therapy for superior mesenteric artery embolism: complications and long-term clinical follow-up. Radiat Med 1999; 17: 27-33.
14 Paloma MJ, Páramo JA, Rocha E. Endotoxininduced intravascular coagulation in rabbits: effect of tissue plasminogen activator vs urokinase of PAI generation, fibrin deposits and mortality. Thromb Haemost 1995; 74: 1578-82.
15 Krishnamurti C, Keyt B, Maglasang P. et al. PAI-1-resistant t-PA: low doses prevent fibrin deposition in rabbits with increased PAI-1 activity. Blood 1996; 87: 14-9.
16 Munoz MC, Montes R, Hermida J. et al. Effect of the administration of recombinant hirudin and/or tissue-plasminogen activator (t-PA) on endotoxin-induced disseminated intravascular coagulation model in rabbits. Br J Haematol 1999; 105: 117-21.
17 Becker RC. Reocclusion following successful thrombolysis Emerging concepts. Cardiology 1993; 82: 265-73.
18 Hudson MP, Granger CB, Topol EJ. et al. Early reinfarction after fibrinolysis: experience from the global utilization of streptokinase and tissue plasminogen activator (alteplase) for occluded coronary arteries (GUSTO I) and global use of strategies to open occluded coronary arteries (GUSTO III) trials. Circulation 2001; 104: 1229-35.
19 Anderson JL. Why does thrombolysis fail? Breaking through the reperfusion ceiling. Am J Cardiol 1997; 80: 1588-90.
20 Chesebro JH, Knatterud G, Roberts R. et al. Thrombolysis in Myocardial Infarction (TIMI) Trial, Phase I: A comparison between intravenous tissue plasminogen activator and intravenous streptokinase Clinical findings through hospital discharge. Circulation 1987; 76: 142-54.
21 Topol EJ, Califf RM, George BS. et al. A randomized trial of immediate versus delayed elective angioplasty after intravenous tissue plasminogen activator in acute myocardial infarction. N Engl J Med 1987; 317: 581-8.
22 Erickson LA, Ginsberg MH, Loskutoff DJ. Detection and partial characterization of an inhibitor of plasminogen activator in human platelets. J Clin Invest 1984; 74: 1465-72.
23 Kruithof EK, Tran-Thang C, Ransijn A. et al. Demonstration of a fast-acting inhibitor of plasminogen activators in human plasma. Blood 1984; 64: 907-13.
24 Levi M, Biemond BJ, van Zonneveld AJ, ten Cate JW. et al. Inhibition of plasminogen activator inhibitor-1 activity results in promotion of endogenous thrombolysis and inhibition of thrombus extension in models of experimental thrombosis. Circulation 1992; 85: 305-12.
25 Biemond BJ, Levi M, Coronel R. et al. Thrombolysis and reocclusion in experimental jugular vein and coronary artery thrombosis Effects of a plasminogen activator inhibitor type 1-neutralizing monoclonal antibody. Circulation 1995; 91: 1175-81.
26 Montes R, Declerck PJ, Calvo A. et al. Prevention of renal fibrin deposition in endotoxin-induced DIC through inhibition of PAI- 1. Thromb Haemost 2000; 84: 65-70.
27 Debrock S, Declerck PJ. Neutralization of plasminogen activator inhibitor-1 inhibitory properties: identification of two different mechanisms. Biochim Biophys Acta 1997; 1337: 257-66.
28 Craane H, Emeis JJ, Lindeman J. et al. Immunoenzymehistochemical detection of fibrin microthrombi during disseminated intravascular coagulation rats. Histochemistry 1978; 57: 97-105.
29 Ten Cate H, Lamping RJ, Henny CP. et al. Automated amidolytic method for determining heparin, a heparinoid, and a low-Mr heparin fragment, based on their anti-Xa activity. Clin Chem 1984; 30: 860-4.
30 Elms MJ, Bunce IH, Bundesen PG. et al. Measurement of crosslinked fibrin degradation products an immunoassay using monoclonal antibodies. Thromb Haemost 1983; 50: 591-4.
31 Verheijen JH, Mullaart E, Chang GT. et al. A simple, sensitive spectrophotometric assay for extrinsic (tissue-type) plasminogen activator applicable to measurements in plasma. Thromb Haemost 1982; 48: 266-9.
32 Levi M, de Boer JP, Roem D. et al. Plasminogen activation in vivo upon intravenous infusion of DDAVP Quantitative assessment of plasmin-alpha 2-antiplasmin complex with a novel monoclonal antibody based radioimmunoassay. Thromb Haemost 1992; 67: 111-6.
33 Verburg M, Renes IB, Meijer HP. et al. Selective sparing of goblet cells and paneth cells in the intestine of methotrexate-treated rats. Am J Physiol Gastrointest Liver Physiol 2000; 279: G1037-G1047.
34 Park PO, Haglund U, Bulkley GB. et al. The sequence of development of intestinal tissue injury after strangulation ischemia and reperfusion. Surgery 1990; 107: 574-80.
35 Massberg S, Enders G, Matos FC. et al. Fibrinogen deposition at the postischemic vessel wall promotes platelet adhesion during ischemia-reperfusion in vivo. Blood 1999; 94: 3829-38.
36 Salter JW, Krieglstein CF, Issekutz AC. et al. Platelets modulate ischemia/reperfusioninduced leukocyte recruitment in the mesenteric circulation. Am J Physiol Gastrointest Liver Physiol 2001; 281: G1432-G1439.
37 Yan SF, Mackman N, Kisiel W. et al. Hypoxia/ Hypoxemia-Induced activation of the procoagulant pathways and the pathogenesis of ischemia-associated thrombosis. Arterioscler Thromb Vasc Biol 1999; 19: 2029-35.
38 Gross PL, Aird WC. The endothelium and thrombosis. Semin Thromb Hemost 2000; 26: 463-78.
39 Rupin A, Martin F, Vallez MO. et al. Inactivation of plasminogen activator inhibitor-1 accelerates thrombolysis of a platelet-rich thrombus in rat mesenteric arterioles. Thromb Haemost 2001; 86: 1528-31.
40 Pislaru SV, Barrios L, Stassen T. et al. Infarct size, myocardial hemorrhage, and recovery of function after mechanical versus pharmacological reperfusion: effects of lytic state and occlusion time. Circulation 1997; 96: 659-66.
41 Ohnishi Y, Butterfield MC, Saffitz JE. et al. Deleterious effects of a systemic lytic state on reperfused myocardium Minimization of reperfusion injury and enhanced recovery of myocardial function by direct angioplasty. Circulation 1995; 92: 500-10.
42 Levi M, ten Cate H, van der Poll T. Endothelium: interface between coagulation and inflammation. Crit Care Med 2002; 30: S220-S224.
43 Biemond BJ, Levi M, ten Cate H. et al. Plasminogen activator and plasminogen activator inhibitor I release during experimental endotoxaemia in chimpanzees: effect of interventions in the cytokine and coagulation cascades. Clin Sci (Lond) 1995; 88: 587-94.
44 van der Poll T, Coyle SM, Levi M. et al. Effect of a recombinant dimeric tumor necrosis factor receptor on inflammatory responses to intravenous endotoxin in normal humans. Blood 1997; 89: 3727-34.
45 Jansen PM, Boermeester MA, Fischer E. et al. Contribution of interleukin-1 to activation of coagulation and fibrinolysis, neutrophil degranulation, and the release of secretorytype phospholipase A2 in sepsis: studies in nonhuman primates after interleukin-1 alpha administration and during lethal bacteremia. Blood 1995; 86: 1027-34.
46 Carmeliet P, Schoonjans L, Kieckens L. et al. Physiological consequences of loss of plasminogen activator gene function in mice. Nature 1994; 368: 419-24.
47 Yamamoto K, Loskutoff DJ. Fibrin deposition in tissues from endotoxin-treated mice correlates with decreases in the expression of urokinase-type but not tissue-type plasminogen activator. J Clin Invest 1996; 97: 2440-51.
48 Chavakis T, Kanse SM, May AE. et al. Haemostatic factors occupy new territory: the role of the urokinase receptor system and kininogen in inflammation. Biochem Soc Trans 2002; 30: 168-73.