Bedeutung der Thrombozyten für die Entwicklung und Funktion der Plazenta

Zusammenfassung

Die Verfügbarkeit von Mäusen mit genetischen Defekten des hämostatischen Systems (Knock-out- und transgene Mäuse) hat es ermöglicht, die Bedeutung des Gerinnungssystems für die Entwicklung des Embryos und der Plazenta zu charakterisieren. Dabei wurde die Funktion der Thrombozyten erst kürzlich experimental untersucht. Diese Studien haben neue Einblicke in die Funktion von Thrombozyten für die Reproduktion gegeben. Das Fehlen embryonaler Thrombozyten infolge einer genetischen Ablation des Transkriptionsfaktors NF-E2 führt zu einer embryonalen Wachstumsverzögerung und verminderten Vaskularisation der Plazenta. Ein maternaler Thrombozytenmangel ist mit Plazentablutungen assoziiert, die jedoch keinen Einfluss auf das Überleben des Embryos oder der Mutter haben. Thrombozyten oder thrombozytäre Mediatoren regulieren die invasiven Eigenschaften und den Phänotyp humaner extravillöser Trophoblastenzellen. Im Gegensatz hierzu sind Thrombozyten und Fibrinogen, und somit die Fähigkeit Thrombozyten-Fibrin-Aggregate zu bilden, für die embryonale Entwicklung nicht erforderlich. Diese Daten beweisen, dass Thrombozyten eine Funktion für die Plazentaentwicklung und/oder -funktion haben, wohingegen Thrombozyten nicht für die Entwicklung des Embryos selber erforderlich sind. Das bedeutet, dass die embryonale Letalität von Mäusen mit genetischen Gerinnungsdefekten nicht auf das Fehlen einer Thrombzyten-Fibrin-Interaktion zurückgeführt werden kann, und das Gerinnungssystem durch andere Mechanismen, z. B. Regulation der intrazellulären Signaltransduktion durch Protease-aktivierbare Rezeptoren (PARs), die Entwicklung des Embryos reguliert.

Summary

The availability of mice with defined defects within the hemostatic system enabled researchers to identify a role the coagulation system for embryonic and placental development. However, the role of platelets during development has only recently been experimentally addressed, giving some insight into potential functions of platelets during development. Thus, a quantitative embryonic platelet defect (severe thrombopenia secondary to NF-E2 deficiency) is associated with an embryonic growth retardation and reduced vascularisation of the placenta. Maternal platelet deficiency is associated with placental haemorrhage, which, however, does not impair embryonic or maternal survival. In vitro studies established that platelets or platelet conditioned medium regulate the invasive properties of human extravillous trophoblast cells and induce a phenotypical switch of trophoblast cells. These data imply that platelets are of relevance during placentation. Conversely, platelets and the formation of platelet-fibrin aggregates are dispensable for the development of the embryo proper, establishing that the lethal phenotypes observed in some embryos lacking coagulation regulators does not result from an inability to form platelet-fibrin aggregates, but likely reflects altered protease dependent signaling during vascular development.

Schlüsselwörter

Thrombozyten - Plazenta

Keywords

Platelets - placenta - trophoblast

• Literatur

• 1 Sherer DM, Lerner R. Glanzmann’s thrombasthenia in pregnancy: a case and review of the literature. Am J Perinatol 1999; 16: 297-301.
• 2 Khalil A, Seoud M, Tannous R. et al. Bernard-Soulier syndrome in pregnancy: case report and review of the literature. Clin Lab Haematol 1998; 20: 125-128.
• 3 Trudinger B, Song JZ, Wu ZH. et al. Placental insufficiency is characterized by platelet activation in the fetus. Obstet Gynecol 2003; 101: 975-981.
• 4 Vincelot A, Nathan N, Collet D. et al. Platelet function during pregnancy: an evaluation using the PFA-100 analyser. Br J Anaesth 2001; 87: 890-893.
• 5 Kam PC, Thompson SA, Liew AC. Thrombocytopenia in the parturient. Anaesthesia 2004; 59: 255-264.
• 6 Xu MJ, Matsuoka S, Yang FC. et al. Evidence for the presence of murine primitive megakaryocytopoiesis in the early yolk sac. Blood 2001; 97: 2016-2022.
• 7 Ohlsson R, Falck P, Hellstrom M. et al. PDGFB regulates the development of the labyrinthine layer of the mouse fetal placenta. Dev Biol 1999; 212: 124-136.
• 8 Smith S, Francis R, Guilbert L. et al. Growth factor rescue of cytokine mediated trophoblast apoptosis. Placenta 2002; 23: 322-330.
• 9 Escalante-Alcalde D, Hernandez L, Le Stunff H. et al. The lipid phosphatase LPP3 regulates extraembryonic vasculogenesis and axis patterning. Development 2003; 130: 4623-4637.
• 10 Suh TT, Holmback K, Jensen NJ. et al. Resolution of spontaneous bleeding events but failure of pregnancy in fibrinogen-deficient mice. Genes Dev 1995; 9: 2020-2033.
• 11 Iwaki T, Sandoval-Cooper MJ, Paiva M. et al. Fibrinogen stabilizes placental-maternal attachment during embryonic development in the mouse. Am J Pathol 2002; 160: 1021-1034.
• 12 Shivdasani RA, Rosenblatt MF, Zucker-Franklin D. et al. Transcription factor NF-E2 is required for platelet formation independent of the actions of thrombopoietin/MGDF in megakaryocyte development. Cell 1995; 81: 695-704.
• 13 Levin J, Peng JP, Baker GR. et al. Pathophysiology of thrombocytopenia and anemia in mice lacking transcription factor NF-E2. Blood 1999; 94: 3037-3047.
• 14 Palumbo JS, Zogg M, Talmage KE. et al. Role of fibrinogen- and platelet-mediated hemostasis in mouse embryogenesis and reproduction. J Thromb Haemost 2004; 2: 1368-1379.
• 15 Erlich J, Parry GC, Fearns C. et al. Tissue factor is required for uterine hemostasis and maintenance of the placental labyrinth during gestation. Proc Natl Acad Sci USA 1999; 96: 8138-8143.
• 16 Offermanns S, Toombs CF, Hu YH. et al. Defective platelet activation in G alpha(q)-deficient mice. Nature 1997; 389: 183-186.
• 17 Kahn ML, Zheng YW, Huang W. et al. A dual thrombin receptor system for platelet activation. Nature 1998; 394: 690-694.
• 18 Sambrano GR, Weiss EJ, Zheng YW. et al. Role of thrombin signalling in platelets in haemostasis and thrombosis. Nature 2001; 413: 74-78.
• 19 Isermann B, Sood R, Pawlinski R. et al. The thrombomodulin- protein C system is essential for the maintenance of pregnancy. Nat Med 2003; 9: 331-337.
• 20 Sood R, Zogg M, Weiler H. A critical role of platelets and the Par4 receptor in developmental growht arrest of thrombomodulin null embryos. ASH 2005 abstract: No 529.
• 21 Sato Y, Fujiwara H, Zeng BX. et al. Platelet-derived soluble factors induce human extravillous trophoblast migration and differentiation: platelets are a possible regulator of trophoblast infiltration into maternal spiral arteries. Blood 2005; 106: 428-435.
• 22 Zhou Y, Damsky CH, Fisher SJ. Preeclampsia is associated with failure of human cytotrophoblasts to mimic a vascular adhesion phenotype. One cause of defective endovascular invasion in this syndrome? J Clin Invest 1997; 99: 2152-2164.
• 23 Carmeliet P, Mackman N, Moons L. et al. Role of tissue factor in embryonic blood vessel development. Nature 1996; 383: 73-75.
• 24 Bugge TH, Xiao Q, Kombrinck KW. et al. Fatal embryonic bleeding events in mice lacking tissue factor, the cell- associated initiator of blood coagulation. Proc Natl Acad Sci USA 1996; 93: 6258-6263.
• 25 Toomey JR, Kratzer KE, Lasky NM. et al. Targeted disruption of the murine tissue factor gene results in embryonic lethality. Blood 1996; 88: 1583-1587.
• 26 Yang TL, Cui J, Taylor JM. et al. Rescue of fatal neonatal hemorrhage in factor V deficient mice by low level transgene expression. Thromb Haemost 2000; 83: 70-77.
• 27 Sun WY, Witte DP, Degen JL. et al. Prothrombin deficiency results in embryonic and neonatal lethality in mice. Proc Natl Acad Sci USA 1998; 95: 7597-7602.
• 28 Xue J, Wu Q, Westfield LA. et al. Incomplete embryonic lethality and fatal neonatal hemorrhage caused by prothrombin deficiency in mice. Proc Natl Acad Sci USA 1998; 95: 7603-7607.
• 29 Huang ZF, Higuchi D, Lasky N. et al. Tissue factor pathway inhibitor gene disruption produces intrauterine lethality in mice. Blood 1997; 90: 944-951.
• 30 Ishiguro K, Kojima T, Kadomatsu K. et al. Complete antithrombin deficiency in mice results in embryonic lethality. J Clin Invest 2000; 106: 873-878.
• 31 Isermann B, Hendrickson SB, Hutley K. et al. Tissue- restricted expression of thrombomodulin in the placenta rescues thrombomodulin-deficient mice from early lethality and reveals a secondary developmental block. Development 2001; 128: 827-838.
• 32 Camerer E, Duong DN, Hamilton JR. et al. Combined deficiency of protease-activated receptor-4 and fibrinogen recapitulates the hemostatic defect but not the embryonic lethality of prothrombin deficiency. Blood 2004; 103: 152-154.
• 33 Griffin CT, Srinivasan Y, Zheng YW. et al. A role for thrombin receptor signaling in endothelial cells during embryonic development. Science 2001; 293: 1666-1670.