Skip to main content
Log in

Modelling Thrombin Generation in Human Ovarian Follicular Fluid

  • Original Paper
  • Published:
Bulletin of Mathematical Biology Aims and scope Submit manuscript

Abstract

A mathematical model is constructed to study thrombin production in human ovarian follicular fluid. The model results show that the amount of thrombin that can be produced in ovarian follicular fluid is much lower than that in blood plasma, failing to reach the level required for fibrin formation, and thereby supporting the hypothesis that in follicular fluid thrombin functions to initiate cellular activities via intracellular signalling receptors. It is also concluded that the absence of the amplification pathway to thrombin production in follicular fluid is a major factor in restricting the amount of thrombin that can be produced. Titration of the initial concentrations of the various reactants in the model lead to predictions for the amount of tissue factor and phospholipid that is required to maintain thrombin production in the follicle, as well as to the conclusion that tissue factor pathway inhibitor has little effect on the time that thrombin generation is sustained. Numerical experiments to determine the effect of factor V, which is at a much reduced level in follicular fluid compared to plasma, and thrombomodulin, illustrate the importance for further experimental work to determine values for several parameters that have yet to be reported in the literature.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  • Andersen, M.M., Króll, J., Byskov, A.G., Faber, M., 1976. Protein composition in the fluid of individual bovine follicles. J. Reprod. Fert. 48, 109–118.

    Article  Google Scholar 

  • Broze, G.J., 1992. The role of tissue factor pathway inhibitor in a revised coagulation cascade. Semin. Hematol. 29, 159–169.

    Google Scholar 

  • Broze, G.J., 2003. The rediscovery and isolation of TFPI. J. Throm. Haemost. 1(8), 1671– 1675.

    Article  Google Scholar 

  • Bungay, S.D., Gentry, P.A., Gentry, R.D., 2003. A mathematical model of lipid-mediated thrombin generation. Math. Med. Biol. 20, 105–129.

    Article  MATH  Google Scholar 

  • Carmeliet, P., 2001. Clotting factors build blood vessels. Science 293, 1602–1604.

    Article  Google Scholar 

  • Carmeliet, P., Collen, D., 1996. Genetic analysis of the plasminogen and coagulation system in mice. Haemostasis 26(Suppl. 4), 132–153.

    Google Scholar 

  • Carney, D.H., Redin, W., McCroskey, L., 1992. Role of high-affinity thrombin receptors in postclotting cellular effects of thrombin. Semin. Thromb. Hemost. 18, 91–103.

    Article  Google Scholar 

  • Cawthern, K.M., van ’t Veer, C., Lock, J.B., DiLorenzo, M.E., Branda, R.F., Mann, K.G., 1998. Blood coagulation in hemophilia A and hemophilia C. Blood 91(12), 4581–4592.

    Google Scholar 

  • Coughlin, S.R., 2000. Thrombin signalling and protease-activated receptors. Nature 407, 258–264.

    Article  Google Scholar 

  • Eaton, D., Rodriguez, H., Vehar, G.A., 1986. Proteolytic processing of human factor VIII. Correlation of specific cleavages by thrombin, factor Xa, and activated protein C with activation and inactivation of factor VIII coagulant activity. Biochemistry 25, 505–512.

    Article  Google Scholar 

  • Gentry, P.A., 2004. Comparative aspects of blood coagulation. Vet. J. 168(3), 238–251.

    Article  Google Scholar 

  • Gentry, P., Plante, L., Schroeder, M., LaMarre, J., Young, J., Dodds, W., 2000. Human ovarian follicular fluid has functional systems for the generation and modulation of thrombin. Fertil. Steril. 73, 848–854.

    Article  Google Scholar 

  • Gentry, R., Ye, L., Nemerson, Y., 1995. Surface-mediated enzymatic reactions: Simulations of tissue factor activation of factor X on a lipid surface. Biophys. J. 69, 362–371.

    Google Scholar 

  • Goldsack, N.R., Chambers, R.C., Dabbagh, K., Laurent, G.J., 1998. Thrombin. Int. J. Biochem. Cell Biol. 30, 641–646.

    Article  Google Scholar 

  • Golino, P., Ragni, M., Cimmino, G., Forte, L., 2002. Role of tissue factor pathway inhibitor in the regulation of tissue factor-dependent blood coagulation. Cardiovasc. Drug Rev. 20, 67– 80.

    Article  Google Scholar 

  • Gonzalès, J., Lesourd, S., Dreden, P.V., Richard, P., Lefèbvre, G., Brouzes, D.V., 1992. Protein composition of follicular fluid and oocyte cleavage occurrence in in vitro fertilization (IVF). J. Assist. Reprod. Genet. 9, 211–216.

    Article  Google Scholar 

  • Grand, R. J.A., Turnell, A.S., Grabham, P.W., 1996. Cellular consequences of thrombin-receptor activation. Biochem. J. 313, 353–368.

    Google Scholar 

  • Hasan, S., Hosseini, G., Princivalle, M., Dong, J.-C., Birsan, D., Cagide, C., de Agostini, A.I., 2002. Coordinate expression of anticoagulant heparan sulfate proteoglycans and serine protease inhibitors in the rat ovary: A potent system of proteolysis control. Biol. Reprod. 66, 144–158.

    Article  Google Scholar 

  • Hirota, Y., Osuga, Y., Yoshino, O., Koga, K., Yano, T., Hirata, T., Nose, E., Ayabe, T., Namba, A., Tsutsumi, O., Taketani, Y., 2003. Possible roles of thrombin-induced activation of protease-activated receptor 1 in human luteinized granulosa cells. J. Clin. Endocrinol. Metab. 88, 3952–3957.

    Article  Google Scholar 

  • Jaspard, B., Fournier, N., Vieitez, G., Atger, V., Barbaras, R., Vieu, C., Manent, J., Chap, H., Perret, B., Collet, X., 1997. Structural and functional comparison of HDL from homologous human plasma and follicular fluid. Arterioscler. Thromb. Vasc. Biol. 17, 1605–1613.

    Google Scholar 

  • Jehle, P.M., Fussgaenger, R.D., Angelus, N.K., Jungwirth, R.J., Saile, B., Lutz, M.P., 1999. Proinsulin stimulates growth of small intestinal crypt-like cells acting via specific receptors. Am. J. Pathol. 276, E262–E268.

    Google Scholar 

  • Jesty, J., 1985. The kinetics of inhibition of thrombin by antithrombin in the presence of components of the hemostatic system. Blood 66, 1189–1195.

    Google Scholar 

  • Kalafatis, M., Swords, N.A., Rand, M.D., Mann, K.G., 1994. Membrane-dependent reactions in blood coagulation: Role of the vitamin K dependent complexes. Biochim. Biophys. Acta 1227, 113–129.

    Google Scholar 

  • Macfarlane, S.R., Seatter, M.J., Kanke, T., Hunter, G.D., Plevin, R., 2001. Proteinase-activated receptors. Pharmcol. Rev. 53, 245–282.

    Google Scholar 

  • Mann, K.G., Brummel, K., Butenas, S., 2003. What is all that thrombin for? J. Throm. Haemost. 1, 1504–1514.

    Article  Google Scholar 

  • Mann, K.G., Butenas, S., Brummel, K., 2003. The dynamics of thrombin formation. Arterioscler. Thromb. Vasc. Biol. 23, 17–25.

    Article  Google Scholar 

  • Meijers, J. C.M., Tijburg, P. N.M., Bouma, B.N., 1987. Inhibition of human blood coagulation factor Xa by α2-macroglobulin. Biochemistry 26, 5932–5937.

    Article  Google Scholar 

  • Nagy, B., Pulay, T., Szarka, G., Csomor, S., 1989. The serum protein content of human follicular fluid and its correlation with the maturity of oocytes. Acta Physiol. Hung. 73(1), 71–75.

    Google Scholar 

  • Narayanan, S., 1999. Multifunctional roles of thrombin. Ann. Clin. Lab. Sci. 29, 275–280.

    Google Scholar 

  • Nesheim, M.E., Eid, S., Mann, K.G., 1981. Assembly of the prothrombinase complex in the absence of prothrombin. J. Biol. Chem. 256, 9874–9882.

    Google Scholar 

  • Nesheim, M.E., Taswell, J.B., Mann, K.G., 1979. The contribution of bovine factor V and factor Va to the activity of prothrombinase. J. Biol. Chem. 254, 10952–10962.

    Google Scholar 

  • Radhakrishnan, K., Hindmarsh, A.C., 1993. Description and use of LSODE, the Livermore solver for ordinary differential equations. Report UCRL-ID-113855, Lawrence Livermore National Laboratory, http://www.llnl.gov/CASC/download/download_home.html.

  • Riewald, M., Ruf, W., 2002. Orchestration of coagulation protease signaling by tissue factor. Trends Cardiovasc. Med. 12, 149–154.

    Article  Google Scholar 

  • Rigler, R., Pramanik, A., Jonasson, P., Kratz, G., Jansson, O.T., Nygren, P., Stahl, S., Ekberg, K., Johansson, B., Uhlen, S., Uhlen, M., Jornvall, H., Wahren, J., 1999. Specific binding of proinsulin C-peptide to human cell membranes. Proc. Natl. Acad. Sci. 96, 13318–13323.

    Article  Google Scholar 

  • Roach, L.E., Petrik, J.J., Plante, L., LaMarre, J., Gentry, P.A., 2002. Thrombin generation and presence of thrombin receptor in ovarian follicles. Biol. Reprod. 66, 1350–1358.

    Article  Google Scholar 

  • Salmassi, A., Lu, S., Hedderich, J., Oettinghaus, C., Jonat, W., Mettler, L., 2001. Interaction of interleukin-6 on human granulosa cell steroid secretion. J. Endocrinol. 170(2), 471–478.

    Article  Google Scholar 

  • Semotok, C.A., Johnson, W.H., LaMarre, J., Gentry, P.A., 2000. Amounts of selected coagulation factors in pre- and post-mortem follicular fluid are similar and do not correlate with molecular mass. Anim. Rep. Sci. 63, 177–185.

    Article  Google Scholar 

  • Shimada, H., Kasakura, S., Shiotani, M., Nakamura, K., Ikeuchi, M., Hoshino, T., Komatsu, T., Ihara, Y., Sohma, M., Maeda, Y., Matsuura, R., Nakamura, S., Hine, C., Ohkura, N., Kato, H., 2001. Hypocoagulable state of human preovulatory ovarian follicular fluid: Role of sulfated proteoglycan and tissue factor pathway inhibitor in the fluid. Biol. Reprod. 64, 1739–1745.

    Article  Google Scholar 

  • Steiner, J.P., Bhattacharya, P., Strickland, D.K., 1985. Thrombin-induced conformational changes of human α2-macroglobulin: Evidence for two functional domains. Biochemistry 24, 2993–3001.

    Article  Google Scholar 

  • Suchanek, E., Mujkic-Klaric, A., Grizelj, V., Simunic, V., Kopjar, B., 1990. Protein concentration in pre-ovulatory follicular fluid related to ovarian stimulation. Int. J. Gynecol. Obstet. 32, 53–59.

    Article  Google Scholar 

  • Thyzel, E., Siegling, S., Götting, C., Tinneberg, H.-R., Brinkmann, T., Kleesiek, K., 2003. Quantification of tissue factor pathway inhibitor in human seminal plasma and in human follicular fluid. Throm. Res. 109, 329–332.

    Article  Google Scholar 

  • Tracy, P.B., Nesheim, M.E., Mann, K.G., 1981. Coordinate binding of factor Va and factor Xa to the unstimulated platelet. J. Biol. Chem. 256, 743–751.

    Google Scholar 

  • Turgeon, V.L., Salman, N., Houenou, L.J., 2000. Thrombin: A neuronal cell modulator. Throm. Res. 99, 417–427.

    Article  Google Scholar 

  • Vergnolle, N., Ferazzini, M., D’Andrea, M.R., Buddenkotte, J., Steinhoff, M., 2003. Proteinase-activated receptors: novel signals for peripheral nerves. Trends Neurosci. 26(9), 496–500.

    Article  Google Scholar 

  • Wielders, S.J., Beguin, S., Hemker, H.C., Lindhout, T., 2004. Factor XI-dependent reciprocal thrombin generation consolidates blood coagulation when tissue factor is not available. Arterioscler. Thromb. Vasc. Biol. 24(6), 1138–1142.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Sharene D. Bungay.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bungay, S.D., Gentry, P.A. & Gentry, R.D. Modelling Thrombin Generation in Human Ovarian Follicular Fluid. Bull. Math. Biol. 68, 2283–2302 (2006). https://doi.org/10.1007/s11538-006-9115-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11538-006-9115-7

Keywords

Navigation