What drives “fibrinolysis”?

Summary

The timely removal of blood clots and fibrin deposits is essential in the regulation of haemostasis. This is achieved by the fibrinolytic system, an enzymatic process that regulates the activation of plasminogen into its proteolytic form, plasmin. This is a self-regulated event as the very presence of fibrin initiates plasminogen activation on the fibrin surface due to the presentation of exposed C-terminal lysine residues in fibrin that allow plasminogen to position itself via its lysine binding sites and to be more efficiently cleaved by tissue-type plasminogen activator (t-PA). Hence fibrin, the ultimate substrate of plasmin during fibrinolysis, is indeed an essential cofactor in the cascade. What has now come to light is that the fibrinolytic system is not solely designed to eliminate fibrin. Indeed, it is a broad acting system that processes a variety of proteins, including many in the brain where there is no fibrin. So what drives t-PA-mediated plasminogen activation when fibrin is not available?

This review will describe the broadening role of the fibrinolytic system highlighting the importance of fibrin and other key proteins as facilitators during t-PA-mediated plasminogen activation.

Zusammenfassung

Die rechtzeitige Auflösung von Blutgerinnseln und Fibrinablagerungen trägt maßgeblich zur Regulierung der Hämostase bei. Erreicht wird dies durch das fibrinolytische System, einen enzymatischem Prozess, der die Aktivierung von Plasminogen zu seiner proteolytischen Form Plasmin regelt. Dies ist ein selbst reguliertes Ereignis, insofern die Plasminogen-Aktivierung auf der Fibrinoberfläche alleine durch die Anwesenheit von Fibrin, aufgrund der Präsentation von exponierten C-terminalen Lysinresten im Fibrin, ausgelöst wird; an diesen kann sich Plasminogen über seine Lysinbindungsstellen selbst anlagern und wirksamer durch den gewebespezifischen Plasminogen-Aktivator (tPA) gespalten werden. Somit ist Fibrin, das letzte Substrat des Plasmins im Verlauf der Fibrinolyse, ein wesentlicher Kofaktor in der Kaskade. Wie sich herausstellt, dient das fibrinolytische System nicht nur dazu, Fibrin zu eliminieren. Vielmehr ist es ein umfassend wirkendes System, das eine Reihe von Proteinen verarbeitet, darunter viele im Gehirn, wo es kein Fibrin gibt. Wodurch also wird die tPAvermittelte Plasminogenaktivierung vorangetrieben, wenn kein Fibrin verfügbar ist?

In dieser Übersicht beschreiben wir die umfassendere Rolle des fibrinolytischen Systems, wobei wir vor allem die fördernde Bedeutung von Fibrin und anderen Schlüsselproteinen bei der tPA-vermittelten Plasminogen-Aktivierung beleuchten.

Keywords

Fibrinogen - fibrin - fibrinolysis inhibitors - nervous system - plasminogen activators - plasminogen

Schlüsselwörter

Fibrinogen - Fibrin - Fibrinolyse-Inhibitoren - Nervensystem - Plasminogen-Aktivatoren - Plasminogen

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