Protein C und S

Zusammenfassung

Protein C oder Autoprothrombin II-A ist ein Vitamin-K-abhängiges Glykoprotein mit einem Molekulargewicht von etwa 62000 Dalton. Seine Aminosäurensequenz und andere physikalisch-chemische Eigenschaften haben eine gewisse Ähnlichkeit mit Faktor X. Es kann in vitro durch Thrombin, Trypsin und das Gift der Russell-Viper in seine enzymatische Form, Protein Ca, umgewandelt werden. In seiner aktiven Form ist Protein C ein doppelkettiges Protein, das das aktive enzymatische Zentrum mit Serin in der schweren Kette hat und eine Anzahl γ-Karboxyglutaminsäure-residuen an der leichten Kette.

Die In-vivo-Aktivierung des Protein C durch Thrombin bedarf der Anwesenheit eines gefäßwandständigen Proteins, Thrombomodulin. Das an Thrombomodulin gebundene Thrombin (äquimolare Komplexe) verliert seine Gerinnungsaktivität und seine Plättchenwirkung, nimmt jedoch eine neue Aktivität an, nämlich Protein C in Ca umzuwandeln. Diese Aktivierung erfolgt in Gegenwart von Kalziumionen an Oberflächen. Antithrombin III kann auch das an Thrombomodulin gebundene Thrombin inaktivieren. Eine alternative, jedoch langsamere Protein-C-Aktivie-rung scheint durch Thrombin und Faktor Va möglich zu sein.

Protein Ca hemmt die Gerinnung, indem es proteolytisch die Faktoren Va und Villa zerstört. In dieser Reaktion übernimmt ein weiteres Vitamin-K-abhängiges Protein, Protein S, eine Kofaktorfunktion. Protein Ca aktiviert auch das fibrinolytische System, indem es den Plasminogengewebsakti-vator von der Gefäßwand freisetzt.

Protein Ca wird durch einen spezifischen Protein-Ca-Inhibitor im Plasma inaktiviert, wobei eine ähnliche Komplexbildung zustande kommt, wie sie für Antithrombin und seine zu inaktivierenden Enzyme bekannt ist.

Protein C kann immunologisch (Laureil und ELISA-Technik) und funktionell (synthetische Substrate) bestimmt werden, wobei das Fehlen von Thrombomodulin die funktionellen Methoden unsicher macht.

Protein S, das als Kofaktor für Protein Ca dient, ist auch ein Vitamin-K-abhängiges Glykoprotein mit einem Molekulargewicht von etwa 69000 Dalton. Neben seiner Kofak-toraktivität für Protein Ca kann es offenbar das hochmolekulare C4b-Bindeprotein an Oberflächen binden und somit die Aktivierung des Komplementsystems an Zelloberflächen steuern.

Angeborene und erworbene Pro-tein-C-Mangelzustände führen zu schweren rezidivierenden venösen Thromboembolien, die klinisch dem Antithrombinmangel ähneln. Der angeborene Protein-C-Mangel hat einen autosomal dominanten Erbgang, und die meisten beschriebenen Fälle waren heterozygot. Homozygote Pro-tein-C-Mangelzustände führen zu massiven, tödlichen Thrombosen. Heterozygote Patienten können mit oralen Antikoagulantien und mit Heparin behandelt werden. Einige Patienten erlitten Haut- und Fettnekrosen während der Einleitung der Therapie mit oralen Antikoagulantien. Diese beruhen möglicherweise auf dem schnellen Aktivitätsabfall von Protein C im Plasma.

Der erste Fall von angeborenem Protein-S-Mangel ist ebenfalls durch rezidivierende venöse Thromboembolien gekennzeichnet.

Die Hypothese, daß die autosomal dominanten Faktor-V/VIII-Kombina-tionsdefekte auf einem Mangel von Protein-C-Inhibitor beruhen, hat sich als nicht richtig erwiesen.

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