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Plasminogen Activator in Dogs with Femoral Vein Thrombosis

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Plasminogen Activator in Dogs with Femoral Vein Thrombosis Thrombolysis with human extrinsic (tissue-type) plasminogen activator in dogs with femoral vein thrombosis. C Korninger, … , J M Stassen, D Collen J Clin Invest. 1982;69(3):573-580. https://doi.org/10.1172/JCI110483. Research Article Extrinsic (tissue-type) plasminogen activator (plasminogen activator) was isolated either as a single-chain or as a two- chain molecule from the culture medium of a human melanoma cell line. The thrombolytic activity of both molecular forms of activator was investigated in beagle dogs with an experimental femoral vein thrombosis and compared with that of urokinase. The 125I-fibrinogen-labeled thrombus was formed in an isolated 4-cm segment of the vein, aged for 30 min, and the thrombolytic substances were infused over a 4-h period. The degree of thrombolysis was measured 2 h later as the difference between the injected and recovered 125I. In six control animals with a saline infusion the extent of thrombolysis was 16.3 +/- 3.8% (mean +/- SEM), in five dogs receiving 100,000 IU urokinase, 17.4 +/- 3.7% (P less than 0.4) and in four dogs with 1,000,000 IU urokinase 40.6 +/- 4.8% (P less than 0.001). Infusion of 100.000 IU single-chain plasminogen activator in five dogs resulted in 3.5 +/- 7.8% lysis (P less than 0.05) and of 100,000 IU two-chain plasminogen activator in five dogs in 60.1 +/- 10.8% (P less than 0.001). Infusion of 300,000 IU one-chain plasminogen activator yielded 57.5% lysis and of the same amount of two-chain plasminogen activator 72.9%. Significant activation of plasminogen, consumption of alpha 2-antiplasmin, and fibrinogen breakdown in plasma was only observed […] Find the latest version: https://jci.me/110483/pdf Thrombolysis with Human Extrinsic (Tissue-type) Plasminogen Activator in Dogs with Femoral Vein Thrombosis C. KORNINGER, 0. MATSUO, R. Suy, J. M. STASSEN, and D. COLLEN, Center for Thrombosis and Vascular Research, Department of Medical Research, University of Leuven, Belgium A B S T R A C T Extrinsic (tissue-type) plasminogen ac- INTRODUCTION tivator (plasminogen activator) was isolated either as a single-chain or as a two-chain molecule from the Pharmacological dissolution of thrombi has been at- culture medium of a human melanoma cell line. The tempted in several ways, e.g., by infusion of plasmin thrombolytic activity of both molecular forms of ac- (1), urokinase (2), streptokinase (3), streptokinase-plas- tivator was investigated in beagle dogs with an ex- minogen complex (4), and the protease extracted from perimental femoral vein thrombosis and compared Aspergillus oryzae (5, 6). Extensive clinical experience with that of urokinase. The '251-fibrinogen-labeled has mainly been obtained with urokinase, a plasmin- thrombus was formed in an isolated 4-cm segment of ogen activator of urinary origin and with streptoki- the vein, aged for 30 min, and the thrombolytic sub- nase, a bacterial protein that activates the human fi- stances were infused over a 4-h period. The degree of brinolytic system indirectly (7). Thrombolysis with thrombolysis was measured 2 h later as the difference either of these substances is, however, associated with between the injected and recovered 1251. systemic activation of the fibrinolytic system and with In six control animals with a saline infusion the ex- hemostatic breakdown, which may occasionally lead tent of thrombolysis was 16.3±3.8% (mean±SEM), in to serious hemorrhages. The side effects of these five dogs receiving 100,000 IU urokinase, 17.4±3.7% thrombolytic agents apparently relate to the fact that (P > 0.4) and in four dogs with 1,000,000 IU urokinase they activate both circulating and fibrin-bound plas- 40.6±4.8% (P < 0.001). Infusion of 100,000 IU single- minogen relatively indiscriminately, leading to sys- chain plasminogen activator in five dogs resulted in temic fibrinolytic activation. 33.5±7.8% lysis (P < 0.05) and of 100,000 IU two- "Extrinsic" or "tissue-type" plasminogen activators chain plasminogen activator in five dogs in 60.1±10.8% extracted from blood (8, 9), vessel perfusates (10), or (P < 0.001). Infusion of 300,000 IU one-chain plas- from tissues (11-13) have the property to preferen- minogen activator yielded 57.5% lysis and of the same tially activate plasminogen in the presence of fibrin amount of two-chain plasminogen activator 72.9%. (14-16), thereby confining the activation process to the Significant activation of plasminogen, consumption immediate environment of a formed thrombus. of a2-antiplasmin, and fibrinogen breakdown in plasma Recently, we have purified extrinsic (tissue-type) was only observed in the animals receiving the high plasminogen activator from a human melanoma cell doses of urokinase but not in the saline, plasminogen culture (17) in sufficiently large amounts to allow more activator, or the low-dose urokinase groups. detailed investigation of its biochemical and biological It is thus concluded that in this thrombosis model properties (16, 18, 19). In the present study this en- human extrinsic plasminogen activator has a higher zyme will be designated plasminogen activator. Plas- specific thrombolytic effect than urokinase. Plasmin- minogen activator was isolated as a one-chain mole- ogen activator also appears to induce thrombolysis cule, which probably represents the vascular or blood without systemic fibrinolytic activation and fibrinogen plasminogen activator, or as a two-chain molecule, breakdown. which is most probably a proteolytic degradation prod- uct of the former (14, 17). This study was undertaken to further investigate the thrombolytic effect of plas- Received for publication 18 August 1981 and in revised minogen activator in vivo. Dogs with experimental form 5 November 1981. femoral vein thrombosis were chosen because this J. Clin. Invest. © The American Society for Clinical Investigation, Inc. - 0021-9738/82/03/0573/08 $1.00 573 Volume 69 March 1982 573-580 model has proved to be suitable for the evaluation of stitutes of Health (NIH) U/ml] was quickly injected, fol- various thrombolytic agents (20-23). lowed at once by the volume of blood containing the radio- Because the effect ac- active fibrinogen. Care was taken to avoid injection of air thrombolytic of plasminogen bubbles. Cotton swabs were then placed over the vessel to tivator in vitro is -10 times higher than that of uro- absorb blood leaking from the vein segment. In most in- kinase (18), a dose of 100,000 IU of plasminogen ac- stances, the clot formed quickly and was allowed to age for tivator (- 1 mg purified activator) was compared to 30 min. Then both vessel clamps were removed and venog- 100,000 and 1,000,000 IU of urokinase. Additionally, raphy was carried out using a standard portable x-ray unit. 5 ml of Urographin 60% (Schering Corp., Berlin, West Ger- single experiments were performed in which 300,000 many) contrast medium was infused over 15 s, through the IU of one-chain or two-chain plasminogen activator ipsilateral dorsal pedal vein and the exposure was made to- were infused. wards the end of the infusion. After demonstration of a suit- able thrombus the leg wound was temporarily closed. The cotton swabs were removed for radioisotope counting and METHODS the amount of radioactivity delivered to the clot was cal- culated by subtracting the swab losses, the radioactivity re- Purified proteins. One-chain and two-chain plasminogen maining in the syringe, and the total blood radioactivity activator were highly purified from the culture fluid of a after venography from the original amount of radioactivity human melanoma cell line by a method described elsewhere in the syringe. 4-ml blood samples were drawn on citrate (17). The activity was expressed in international units of (final concentration 0.01 M) and 1-ml samples on mixtures urokinase by comparison of its fibrinolytic activity on plas- of 40 NIH U thrombin and 1,000 U aprotinin (trasylol, the minogen-enriched bovine fibrin films (17). Because the spe- Bayer Co., Leverkusen, West Germany) immediately after cific activity of plasminogen activator is -90,000 IU/mg venography and then at hourly intervals for 6 h. The plasma and its mol wt 72,000 (17), equal amounts of units of plas- samples were used for measurement of radioactivity, fibrin- minogen activator and urokinase (Mr 56,000; sp act - 100,000 ogen (28), plasminogen (29), a2-antiplasmin (30), and fi- IU/mg) correspond to equal molar quantities. Urokinase was brin(ogen) degradation products (31). a gift from Institut Choay, Paris, France (courtesy of Dr. The thrombolysis experiments were carried out under Toulemonde). Human fibrinogen was prepared according minimal heparinization once the initial x ray confirmed ad- to Blombiick and Blomback (24) and labeled with 1251 ac- equate thrombus formation. Heparin (100 U/kg) was in- cording to McFarlane (25). Human thrombin was purified jected intravenously, and during the experiment 50-U/kg as described by Fenton et al. (26). amounts were given when the whole blood clotting time Experimental procedure. The thrombolytic effect of one- approached normal values. The bladder was emptied every or two-chain plasminogen activator, as compared with uro- hour, the urine volume was measured, and an aliquot was kinase was evaluated in a dog femoral vein thrombosis model taken for radioisotope counting. developed by Smith et al. (23, 27). Beagle dogs (9-11 kg) Immediately after the result of venography had been ob- were premedicated with ketamine hydrochloride (10 mg in tained (i.e., -15 min after removal of the vessel clamps), 1 ml, i.m.) and atropine sulfate (500 ,ug in 1 ml, i.m.). Anes- intravenous infusion of saline, plasminogen activator, or thesia was induced with sodium pentobarbital (5 ml of a 6% urokinase was started.
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