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Effects of Hyperthermic Isolated Limb Perfusion with Recombinant Tumor Necrosis Factor and Melphalan on the Human Fibrinolytic System

Divisions of Intensive Care [J. H. Z. J. K. M., A. R. J. G.] and Surgical Oncology [R. J. v. G., H. S. K., H. J. H.], Department of Surgery, and Division of Hemostasis, Thrombosis and Rheology, Department of Internal Medicine [A. B. M., V. J. J. B., J. v. d. M.], University Hospital Groningen, Hanzeplein 1, P. O. Box 30.001, 9700 RB Groningen, the Netherlands

This study was undertaken to determine the effects on systemic fibrinolysis of hyperthermic isolated limb perfusion with recombinant tumor necrosis factor (r-TNF-) and melphalan, with or without pretreatment with recombinant IFN- (r-IFN-). Twenty patients were treated with r-TNF- and melphalan; four patients, treated with melphalan only, served as controls. Of the twenty patients treated with both r-TNF- and melphalan, eight received r-IFN- for two days before the perfusion and as a bolus into the perfusion circuit. A significant leak of r-TNF- from the perfusion circuit to the systemic circulation was observed in all r-TNF--treated patients (mean maximum TNF-, 87,227 ng/liter versus 31 ng/liter in controls; P < 0.002). In these patients, but not in controls, there was an almost instantaneous rise in systemic tissue plasminogen activator activity (from 0.26 to 5.28 IU/ml in 90 min), causing activation of fibrinolysis. After a delay of 90 min, plasminogen activator inhibitor-1 (PAI-1) antigen rose to high levels in the r-TNF--treated group (mean maximum PAI-1, 1652 ng/ml versus 211 ng/ml in controis; P < 0.02), associated with a sharp decrease of tissue plasminogen activator activity and a slower decrease of plasminogen-antiplasminogen complexes (from 5.28 to 0.02 IU/ml in 2 h and from 1573 to 347 µg/liter in 22 h, respectively). No additional effect of IFN- pretreatment on fibrinolysis could be demonstrated. These results suggest that in isolated limb perfusion with r-TNF- and melphalan an initial activation of systemic fibrinolysis, induced by leakage of r-TNF- from the perfusion circuit, is set off by a subsequent inhibition of the fibrinolytic system by PAI-1. This large increase in PAI-1 could place the patient at risk for deposition of microthrombi in the systemic circulation.

¹ To whom requests for reprints should be addressed.

Received 1/12/96. Accepted 7/ 2/96.

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