Plasmin pathway

The coagulation system that generates thrombin consists of intrinsic and extrinsic pathways. Both pathways are composed of a series of enzymatic reactions eventually producing thrombin, fibrin, and a stable clot. In parallel with the coagulation, the fibrinolytic system is activated locally. Plasminogen is converted to plasmin, which dissolves the fibrin mesh1 2 3 (Fig. 64—1). 

Although the fibrinolytic pathway is activated when thrombin binds to thrombomodulin, the thrombin-thrombomodulin complex, in addition to activating protein C (APC), activates a fibrinolysis inhibitor called the thrombin-activatable fibrinolysis inhibitor (TAFIa). Thus plasmin generation and, in turn, fibrinolysis are... 

Why do we have the intrinsic pathway when the tissue factor pathway provides rapid clot formation The answer seems to be that the tissue factor pathway is needed immediately after injury but that it is turned off quickly by the anticoagulation systems of the body. As a result the protease plasmin begins to dissolve (lyse) the clot within a few hours. The intrinsic pathway is apparently needed to maintain the clot for a longer period.514... 

During platelet plug formation, the fibrinolytic pathway is locally activated. Plasminogen is enzymatically processed to plasmin (fibri-nolysin) by plasminogen activators present in the tissue. Plasmin interferes in clot propagation and dissolves the fibrin network as wounds heal. At present, a number of fibrinolytic enzymes are available for treatment of myocardial infarctions or pulmonary emboli (see p. 201). 

Proteases contribute to the inflammatory response to injury, forming a final common pathway that leads to BBB breakdown, hemorrhage, and cell death. After traumatic and ischemic injuries, there is a buildup of lactate, which is increased with hyperglycemia. Acidosis leads to release of acid hydrolases, which are destructive enzymes that attack cellular components, including membranes, resulting in cell necrosis. In situations where the pH remains neutral, increases in intracellular calcium and cytokines cause induction of neutral proteases. The main neutral proteases are the extracellular matrix-degrading MMPs, plasminogen activator/plasmin, and caspases. 

Fig. 19.1 Exogenous and endogenous plasmic coagulation cascade (with inhibition by antithrombin III and protein Cj,) and the fibrinolysis pathway through plasminogen-plasmin. Proteolytic plasmin principally hydrolyzes the cross-linked fibrin clot into high molecular weight fragments and D fragment dimers (s. tab. 5.12)...

G9. Gong, R., Rifai, A., Tolbert, E. M., Centracchio, J. N., and Dworkin, L. D., Hepatocyte growth factor modulates matrix metalloproteinases and plasminogen activator/plasmin proteolytic pathways in progressive renal interstitial fibrosis. J. Am. Soc. Nephrol 14, 3047-3060 (2003). 

Fig. 1. Metabolic pathway converting linoleic acid to arachidonic acid and hence, eicosanoids. COX, cyclooxygenase PA-1, plasmin activator-l 2-AQ, 2-arachidonyl glycerol PC, prostaglandin.

In later studies, McFadden and Lomas demonstrated that the myxoma virus-encoded Serp-1 has sequence similarity to serpins, and the protein inhibits tPA, uPA and plasmin in the thrombolytic pathways as well as factor Xa in the thrombotic pathway. However, despite the marked effects of Serp-1 on viral pathogenesis, the Kj, for Serp-1 is a lower affinity reaction at 7-8.6 x 10 M s, whereas the manunalian serpin PAI-1 has higher affinity and activity with on the order... 

Spi-3 is a related but distina viral protein expressed by orthopoxviruses like vaccinia virus and rabbitpox, which unfortunately has a confosing nomenclature with similarity to the unrelated PI6/SPI3 mammalian scrpin nomenclature. Ihe poxviral Spi-3 binds to and inhibits uPA and tPA and plasmin. Spi-3 is also capable of formii weaker complexes with thrombin and factor Xa as measured by gel shifi assays. Spi-3 from vaccinia/rabbitpox and Serp-1 from myxoma virus share only 30% sequence similarity despite targeting similar host protease pathways. The Ki s for Spi-3 was measured as 0.51,1.9 and 0.64 nM for uPA, tPa and plasmin, respectively. The KjS for Serp-1 were similar at 0.16,0.14 and 0.44 nM, respectively for uPa, tPa and plasmin. However, whereas Serp-1 is secreted into the surrounding envirormient, Spi-3 remains tethered to the cell surface and exhibits a secondary function in the inhibition of cell fusion that is independent of its serpin-based activities. 

It should be noted that many viral proteins exhibit more than one frmetion, often targeting two or more host response pathways. Serp-1 targets tPA, uPA, plasmin in the thrombolytic cascade and also foctor in the thrombotic cascade which represent more than one receptor and signaling pathway. It is certainly possible that this h hly potent viral serpin may have acquired other... 

Sousa, L. R, B. M. Silva, B. S. Brasil et al. Plasminogen/plasmin regulates alpha-enolase expression through the MEK/ERK pathway. Biochem Bionhvx Rex Commun 337(4), 2005 1065-71. 

XII Hageman factor The first factor in the intrinsic pathway. A/, 74000 (bovine), 76000 (human). Single chain glycoprotein. Activated by plasmin, kallikrein and XII,. Inhibited by antithrombin III (inhibition accelerated by heparin). Cl esterase inhibitor and lima bean trypsin inhibitor. Activation of XII initiated by contact with abnormal surfaces. 

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