Coagulation and Fibrinolysis in Amniotic Fluid: Physiology and Observations on Amniotic Fluid Embolism, Preterm Fetal Membrane Rupture, and Pre-Eclampsia

ABSTRACT

Two dangerous obstetric complications, amniotic fluid embolism and preterm prelabor rupture of membranes (PROM), can be caused by amniotic fluid (AF) constituents. Disseminated intravascular coagulation (DIC) is related to the former complication, whereas local thrombin/plasmin-dependent collagenolysis in the decidua and fetal membranes is associated with the latter. In AF, most proteins of the coagulation and fibrinolysis system, known as plasma constituents, have been identified based on the activity and/or presence of antigen. The AF levels of most of these proteins are low (< 2 to 5% of the respective maternal plasma levels). However, there are some exceptions: tissue factor (TF), urokinase plasminogen activator (uPA) and its receptor (uPAR), as well as plasminogen activator inhibitors. The AF level of fetal fibrinogen is trace, which is a particular exception. The key enzymes of coagulation and fibrinolysis, thrombin and plasmin, are generated in AF. Thrombin generation is four- to fivefold higher than in maternal plasma as measured by the concentration of the prothrombin fragments 1 + 2 (F 1 + 2) and thrombin-antithrombin complexes, whereas plasmin generation is relatively low as measured by the plasmin–α-2-antiplasmin complexes. Phosphatidylserine, a phospholipid, and thrombin-activatable fibrinolysis inhibitor (TAFI) are novel components of AF. Phosphatidylserine contributes to DIC in AF embolism; TAFI is considered a link between coagulation and fibrinolysis. uPA and uPAR are the factors contributing to PROM via plasmin-dependent proteolysis. Intriguing is the assumption that TF and its inhibitor can be risk factors for PROM through thrombin-dependent activation of matrix prometalloproteinases in the decidua and fetal membranes. It is unknown whether the amniotic pool of hemostatic components is involved in pre-eclampsia pathogenesis.

KEYWORDS

Amniotic fluid - procoagulants - anticoagulants - fibrinolysis - PROM

REFERENCES

• 1 Albrechtsen O K, Trolle D. A fibrinolytic system in human amniotic fluid.  Acta Haematol. 1955;  14 (6) 376-382
• 2 Uszyński M, Maciejewski K, Uszyński W, Kuczyński J. Placenta and myometrium—the two main sources of fibrinolytic components during pregnancy.  Gynecol Obstet Invest. 2001;  52 (3) 189-193
• 3 Lockwood C J, Krikun G, Rahman M, Caze R, Buchwalder L, Schatz F. The role of decidualization in regulating endometrial hemostasis during the menstrual cycle, gestation, and in pathological states.  Semin Thromb Hemost. 2007;  33 (1) 111-117
• 4 Watanabe T, Araki M, Mimuro J, Tamada T, Sakata Y. Fibrinolytic components in fetal membranes and amniotic fluid.  Am J Obstet Gynecol. 1993;  168 (4) 1283-1289
• 5 Gulbis B, Jauniaux E, Jurkovic D, Thiry P, Campbell S, Ooms H A. Determination of protein pattern in embryonic cavities of human early pregnancies: a means to understand materno-embryonic exchanges.  Hum Reprod. 1992;  7 (6) 886-889
• 6 Michel P E, Crettaz D, Morier P et al. Proteome analysis of human plasma and amniotic fluid by Off-Gel isoelectric focusing followed by nano-LC-MS/MS.  Electrophoresis. 2006;  27 (5–6) 1169-1181
• 7 Mavrou A, Anagnostopoulos A K, Kolialexi A et al. Proteomic analysis of amniotic fluid in pregnancies with Turner syndrome fetuses.  J Proteome Res. 2008;  7 (5) 1862-1866
• 8 Tisi D K, Emard J J, Koski K G. Total protein concentration in human amniotic fluid is negatively associated with infant birth weight.  J Nutr. 2004;  134 (7) 1754-1758
• 9 Cade J F, Hirsh J, Martin M. Placental barrier to coagulation factors: its relevance to the coagulation defect at birth and to haemorrhage in the newborn.  BMJ. 1969;  2 (5652) 281-283
• 10 Brace R A. Physiology of amniotic fluid volume regulation. In: Rao K A, Ross M G, eds. Amniotic Fluid. Bangalore, India: Prism Books; 1999: 110-132
• 11 Köttgen E, Hell B, Müller C, Tauber R. Demonstration of glycosylation variants of human fibrinogen, using the new technique of glycoprotein lectin immunosorbent assay (GLIA).  Biol Chem Hoppe Seyler. 1988;  369 (10) 1157-1166
• 12 Kimball M E, Milunsky A, Giannusa P, Carvalho A C. Amniotic fluid fibrinogen degradation products in the prenatal diagnosis of neural tube defects.  Am J Obstet Gynecol. 1977;  128 (3) 294-299
• 13 Lockwood C J, Bach R, Guha A, Zhou X D, Miller W A, Nemerson Y. Amniotic fluid contains tissue factor, a potent initiator of coagulation.  Am J Obstet Gynecol. 1991;  165 (5 Pt 1) 1335-1341
• 14 Erez O, Gotsch F, Mazaki-Tovi S et al. Evidence of maternal platelet activation, excessive thrombin generation, and high amniotic fluid tissue factor immunoreactivity and functional activity in patients with fetal death.  J Matern Fetal Neonatal Med. 2009;  22 (8) 672-687
• 15 Uszyński M, Żekanowska E, Uszyński W, Kuczyński J. Tissue factor (TF) and tissue factor pathway inhibitor (TFPI) in amniotic fluid and blood plasma: implications for the mechanism of amniotic fluid embolism.  Eur J Obstet Gynecol Reprod Biol. 2001;  95 (2) 163-166
• 16 González-Quintero V H, Jiménez J J, Jy W et al. Elevated plasma endothelial microparticles in preeclampsia.  Am J Obstet Gynecol. 2003;  189 (2) 589-593
• 17 Thompson A R. Factor IX and prothrombin in amniotic fluid and fetal plasma: constraints on prenatal diagnosis of hemophilia B and evidence of proteolysis.  Blood. 1984;  64 (4) 867-874
• 18 Ludwig H, Metzger H. Das uterine Placentarbett post partum in Rasterelektronenmikroskop, zugleich ein Beitrag zur Frage der extravasalen Fibrinbildung.  Arch Gynakol. 1971;  210 251-266
• 19 McVey J H. Tissue factor pathway.  Baillieres Clin Haematol. 1999;  12 361-372
• 20 Zhou J, Liu S, Ma M et al. Procoagulant activity and phosphatidylserine of amniotic fluid cells.  Thromb Haemost. 2009;  101 (5) 845-851
• 21 Steiner P E, Lushbaugh C C. Maternal pulmonary embolism by amniotic fluid as a cause of obstetric shock and unexpected deaths in obstetrics.  JAMA. 1941;  117 1245-1254
• 22 Uszyński W, Uszyński M, Zekanowska E. Thrombin markers in pregnant women: measurements of prothrombin fragments F 1 + 2 and thrombin-antithrombin III complexes (TAT) in the cord blood, the mother's blood and in amniotic fluid.  [in Polish] Ginekol Pol. 2004;  75 (8) 595-602
• 23 Uszyński M, Zekanowska E, Kotzbach M, Uszyński W, Kotzbach R. Protein C, protein S, and thrombomodulin in amniotic fluid. A preliminary study.  J Perinat Med. 2006;  34 (4) 289-292
• 24 Uszyński W, Zekanowska E, Uszyński M, Rystok D. Concentration of annezin in gestational tissues: placenta, fetal membranes, myometrium, and amniotic fluid.  [in Polish] Gin Pol. 2006;  77 603-610
• 25 Uszyński M, Kłyszejko A, Zekanowska E. Plasminogen, α(2)-antiplasmin and complexes of plasmin-α(2)-antiplasmin (PAP) in amniotic fluid and blood plasma of parturient women.  Eur J Obstet Gynecol Reprod Biol. 2000;  93 (2) 167-171
• 26 Uszyński M, Perlik M, Uszyński W, Zekanowska E. Urokinase plasminogen activator (uPA) and its receptor (uPAR) in gestational tissues; measurements and clinical implications.  Eur J Obstet Gynecol Reprod Biol. 2004;  114 (1) 54-58
• 27 Hajjar K A. Cellular receptors in the regulation of plasmin generation.  Thromb Haemost. 1995;  74 (1) 294-301
• 28 Uszyński W, Uszyński M, Zekanowska E. Thrombin activatable fibrinolysis inhibitor (TAFI) in human amniotic fluid. A preliminary study.  Thromb Res. 2007;  119 (2) 241-245
• 29 Nesheim M, Wang W, Boffa M, Nagashima M, Morser J, Bajzar L. Thrombin, thrombomodulin and TAFI in the molecular link between coagulation and fibrinolysis.  Thromb Haemost. 1997;  78 (1) 386-391
• 30 Wang W, Boffa M B, Bajzar L, Walker J B, Nesheim M E. A study of the mechanism of fibrynolysis by activated thrombin-activatable inhibitor.  J Biol Chem. 1998;  273 27176-27181
• 31 Gris J C, Neveu S, Tailland M L, Courtieu C, Marès P, Schved J F. Use of a low-molecular weight heparin (enoxaparin) or of a phenformin-like substance (moroxydine chloride) in primary early recurrent aborters with an impaired fibrinolytic capacity.  Thromb Haemost. 1995;  73 (3) 362-367
• 32 Vassalli J D. The urokinase receptor.  Fibrinolysis. 1994;  8 172-181
• 33 Vadillo-Ortega F, Hernandez A, Gonzalez-Avila G, Bermejo L, Iwata K, Strauss III JF. Increased matrix metalloproteinase activity and reduced tissue inhibitor of metalloproteinases-1 levels in amniotic fluids from pregnancies complicated by premature rupture of membranes.  Am J Obstet Gynecol. 1996;  174 (4) 1371-1376
• 34 Lijnen H R. Plasmin and matrix metalloproteinases in vascular remodeling.  Thromb Haemost. 2001;  86 (1) 324-333
• 35 Erez O, Espinoza J, Chaiworapongsa T et al. A link between a hemostatic disorder and preterm PROM: a role for tissue factor and tissue factor pathway inhibitor.  J Matern Fetal Neonatal Med. 2008;  21 (10) 732-744
• 36 Stephenson C D, Lockwood C J, Ma Y, Guller S. Thrombin-dependent regulation of matrix metalloproteinase (MMP)-9 levels in human fetal membranes.  J Matern Fetal Neonatal Med. 2005;  18 (1) 17-22
• 37 Adachi T, Nakabayashi M, Sakwra M, Ando K. Involvement of fibrinolytic factors in mid trimester amniotic fluid with development of severe early-onset preeclampsia.  Semin Thromb Hemost. 1999;  25 (5) 447-450
• 38 Tanjung M, Siddik H Z, Hariman H et al.. Coagulation and fibrinolysis in preeclampsia and neometes.  Clin Appl Thromb/Hemost. 2005;  11 (4) 467-473
• 39 Hathaway W, Corrigan J. Report of Scientific and Standardization Subcommitee on Neonatal Hemostasis.  Thromb Haemost. 1991;  65 323-325