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Fibrin-specific and effective clot lysis requires both plasminogen activators and for them to be in a sequential rather than simultaneous combination

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Abstract

Thrombolysis with tissue plasminogen activator (tPA) has been a disappointment and has now been replaced by an endovascular procedure whenever possible. Nevertheless, thrombolysis remains the only means by which circulation in a thrombosed artery can be restored rapidly. In contrast to tPA monotherapy, endogenous fibrinolysis uses both tPA and urokinase plasminogen activator (uPA), whose native form is a proenzyme, prouPA. This combination is remarkably effective as evidenced by the fibrin degradation product, d-dimer, which is invariably present in plasma. The two activators have complementary mechanisms of plasminogen activation and are synergistic in combination. Since tPA initiates fibrinolysis when released from the vessel wall and prouPA is in the blood, they induce fibrinolysis sequentially. It was postulated that this may be more effective and fibrin-specific. The hypothesis was tested in a model of clot lysis in plasma in which a clot was first exposed to tPA for 5 min, washed and incubated with prouPA. Lysis was compared with that of clots incubated with both activators simultaneously. The sequential combination was almost twice as effective and caused less fibrinogenolysis than the simultaneous combination (p < 0.0001) despite having significantly less tPA, as a result of the wash. A mechanism is described by which this phenomenon can be explained. The findings are believed to have significant therapeutic implications.

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Funding

The study was funded by a grant from Vascular Laboratory Inc, a non-profit vascular research fund registered in the state of Massachusetts in 1984; Federal Identification No. 23-7375422.

Author information

Correspondence to V. Gurewich.

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Conflict of interest

Victor Gurewich, MD, is Scientific Director and Founder of TSI, a company that is developing mutant prouPA (His-300 prouPA). Ralph Pannell, Ph. D and Shelley Li have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants performed by any of the authors.

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Pannell, R., Li, S. & Gurewich, V. Fibrin-specific and effective clot lysis requires both plasminogen activators and for them to be in a sequential rather than simultaneous combination. J Thromb Thrombolysis 44, 210–215 (2017). https://doi.org/10.1007/s11239-017-1514-0

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Keywords

  • Fibrinolysis
  • tPA
  • ProuPA
  • Synergy
  • Sequential lysis