Serine-proteases as plasminogen activators in terms of fibrinolysis

Abstract

Objectives This review should give an overview about the natural human plasminogen activators and their various modified variants as well as similar substances isolated from animals, microorganisms and plants. When a blood clot is formed in a blood vessel, it avoids the oxygen supply of the surrounding tissue. A fast fibrinolytic therapy should redissolve the blood vessel and reduce the degradation of the tissue. All proteases that are part of the human blood coagulation and fibrinolytic system belong to the serine protease family. t-PA (tissue plasminogen activator) and u-PA (urokinase plasminogen activator) are the naturally occurring fibrinolytic agents that are also used in therapy. Key findings Despite many years of research, t-PA is still the gold standard in fibrinolytic therapy. But it has to be given as an infusion, which needs time. Modified fibrinolytic substances are, were, or perhaps will be in the market. They have different advantages over t-PA, but often the disadvantages predominate. Conclusion Many substances have been developed but an optimal fibrinolytic agent combined with a simple administration is not in therapeutic use to date.

The evolution of recombinant thrombolytics: Current status and future directions

“…Thus, the loss of the kringle 1 domain in r-PA increased the half-life of this molecule from 4 to »15 min with mainly renal form of elimination. 23,83 Further, other characteristics, like inhibition by PAI-1, activity in the absence of fibrin and conversion between single-chain and 2-chain forms seems to be similar to alteplase. 81,82 However, its fibrin binding affinity is 5-fold lesser than alteplase because of the absence of the fibrin-binding finger domain.…”

“…Amino acid alterations in the F domain between residues 42-49 also played a major role in drug clearance. 23 The sequence Lys 296 -His 297 -Arg 298 -Arg 299 is required for rapid inhibition by PAI-1. 72 An advantage of t-PA over other plasminogen activators is its specificity toward fibrin.…”

“…Therefore, it causes a systemic fibrinolytic state leading to bleeding complications. 23 The choice of thrombolytic therapy depends on several factors, including the cost of the drug, side effects, stability, half-life as well as specificity toward fibrin and immunogenicity (Table 2). 17 Thus, till today in the developing countries of the world the first generation plasminogen activator, streptokinase, remains the mainstay of thrombolytic therapy due to its costeffectiveness (US $200 per treatment).…”

“…Further, the rate of synthesis can be enhanced by bradykinin, substance P, TNF-a, desmopressin and is reduced in the presence of plasmin. 23 Rijken and Collen (1981) purified and characterized t-PA secreted by a human melanoma cell line (Bowes). 66 This cell line efficiently secreted t-PA.…”

“…Degradation of cross-linked fibrin produces D-dimers instead of D fragments. 23 (iii) Fibrinolytic system inhibitors Regulation of the fibrinolytic system occurs via the action of inhibitors both at the level of plasminogen activation and plasmin action. They are specific, fastacting inactivators of the serine protease inhibitor (SERPIN) superfamily.…”