"Plasminogen steal" and clot lysis

Cardiovascular Division, Washington University School of Medicine, Saint Louis, Missouri 63110.

Although initially developed to reduce the risk of bleeding, second-generation (clot-selective) thrombolytic agents have been found to induce more prompt and frequent recanalization than do nonselective, first-generation agents. To determine whether they do so in part by preserving clot-associated plasminogen, human whole blood clots formed in Chandler tubes were studied. Addition of suprapharmacologic concentrations of recombinant tissue-type plasminogen activator (rt-PA) to the media bathing mature clots led to a paradoxic impairment of clot lysis and a concomitant concentration-dependent depletion of clot-associated plasminogen (Western blot analysis). In contrast, supplementation of the plasma with plasminogen (0.27 mg/ml) led to significant conservation of both plasma and clot-associated plasminogen (p less than or equal to 0.05, n = 4), and prevented the diminution of clot lysis (p less than or equal to 0.05; n = 4). Fibrinogen degradation products did not account for the attenuation of lysis with the highest concentrations of rt-PA. In concentrations equivalent to those that were induced by the highest concentrations of rt-PA evaluated, fibrinogen degradation products potentiated rather than inhibited lysis (p less than or equal to 0.05, n = 4), probably by stimulating rt-PA activity directly. When preformed clots were incubated with plasminogen-depleted plasma plus 1,000 ng/ml rt-PA, the plasminogen content in residual clot declined (9.36 +/- 0.46 versus 12.39 +/- 0.69 ng/mg clot found in nondepleted plasma; p less than or equal to 0.05; n = 6). Furthermore, clot lysis was attenuated completely.(ABSTRACT TRUNCATED AT 250 WORDS)

This article has been cited by other articles:

				R. Chang, C. C. Chen, A. Kam, E. Mao, T. H. Shawker, and M. K. Horne III Deep Vein Thrombosis of Lower Extremity: Direct Intraclot Injection of Alteplase Once Daily with Systemic Anticoagulation--Results of Pilot Study Radiology, February 1, 2008; 246(2): 619 - 629. [Abstract] [Full Text] [PDF]

				L. V. Mundada, M. Prorok, M. E. DeFord, M. Figuera, F. J. Castellino, and W. P. Fay Structure-Function Analysis of the Streptokinase Amino Terminus (Residues 1-59) J. Biol. Chem., June 27, 2003; 278(27): 24421 - 24427. [Abstract] [Full Text] [PDF]

				P. A. Lapchak, D. M. Araujo, S. Pakola, D. Song, J. Wei, and J. A. Zivin Microplasmin: A Novel Thrombolytic That Improves Behavioral Outcome After Embolic Strokes in Rabbits Stroke, September 1, 2002; 33(9): 2279 - 2284. [Abstract] [Full Text] [PDF]

				J.-N. Liu, J.-X. Liu, B.-f. Liu, Z. Sun, J.-L. Zuo, P.-x. Zhang, J. Zhang, Y.-h. Chen, and V. Gurewich Prourokinase Mutant That Induces Highly Effective Clot Lysis Without Interfering With Hemostasis Circ. Res., April 19, 2002; 90(7): 757 - 763. [Abstract] [Full Text] [PDF]

				D. F. Chapman, P. Lyden, P. A. Lapchak, S. Nunez, H. Thibodeaux, and J. Zivin Comparison of TNK With Wild-Type Tissue Plasminogen Activator in a Rabbit Embolic Stroke Model Stroke, March 1, 2001; 32(3): 748 - 752. [Abstract] [Full Text] [PDF]

				E. M. Ohman, R. A. Harrington, C. P. Cannon, G. Agnelli, J. A. Cairns, and J.W. Kennedy Intravenous Thrombolysis in Acute Myocardial Infarction Chest, January 1, 2001; 119(1_suppl): 253S - 277S. [Full Text] [PDF]

				G. L. Reed, A. K. Houng, L. Liu, B. Parhami-Seren, L. H. Matsueda, S. Wang, and L. Hedstrom A catalytic switch and the conversion of streptokinase to a fibrin-targeted plasminogen activator PNAS, August 3, 1999; 96(16): 8879 - 8883. [Abstract] [Full Text] [PDF]

				C. P. Cannon, C. M. Gibson, C. H. McCabe, A. A. J. Adgey, M. J. Schweiger, R. F. Sequeira, G. Grollier, R. P. Giugliano, M. Frey, H. S. Mueller, et al. TNK–Tissue Plasminogen Activator Compared With Front-Loaded Alteplase in Acute Myocardial Infarction : Results of the TIMI 10B Trial Circulation, December 22, 1998; 98(25): 2805 - 2814. [Abstract] [Full Text] [PDF]

				C. P. Cannon, C. H. McCabe, C. M. Gibson, M. Ghali, R. F. Sequeira, G. R. McKendall, J. Breed, N. B. Modi, N. L. Fox, R. P. Tracy, et al. TNK-Tissue Plasminogen Activator in Acute Myocardial Infarction: Results of the Thrombolysis in Myocardial Infarction (TIMI) 10A Dose-Ranging Trial Circulation, January 21, 1997; 95(2): 351 - 356. [Abstract] [Full Text]

				J.-N. Liu, J.-X. Liu, B.-f. Liu, Z. Sun, J.-L. Zuo, P.-x. Zhang, J. Zhang, Y.-h. Chen, and V. Gurewich Prourokinase Mutant That Induces Highly Effective Clot Lysis Without Interfering With Hemostasis Circ. Res., April 19, 2002; 90(7): 757 - 763. [Abstract] [Full Text] [PDF]