Models for reaction mechanisms in haemostasis – Contributions from the study of prothrombin activation

Summary

A brief history of the development of the contemporary model for the mechanism of prothrombin activation is presented.The focus is on the advances in understanding structure-function relationships in the molecules that comprise “prothrombinase” that occurred primarily during the 1970s. A link between the “classical theory” of hemostasis and the conceptual development of activation complexes as the activators of the precursors of coagulation proteases is developed. It is argued that advances occurred when new ideas arose that could be tested and new technologies enabled more definitive experiments to be performed.

Keywords

Prothrombinase - prothrombin - structure-function - coagulation models - models - history

 

• References

• 1 Milstone JH. On the evolution of blood clotting theory. Medicine 1952; 31: 411-447.
• 2 Quick AJ, Stanley-Brown M, Bancroft FW. A study of the coagulation defect in hemophilia and in jaundice. Am J Med Sci 1935; 190: 501.
• 3 Quick AJ. The coagulation defect in sweet clover diseasearestorative effects of normal, hypofibrinogenemi cnd in the hemorrhagic chick disease of dietary origin. Am J Physiol 1937; 118: 260-271.
• 4 Owren PA. The fifth coagulation factor (‘FactorV’). Preparation and properties. Biochem J 1948; 43: 136-139.
• 5 Owren PA. Prothrombin and accessory factors; clinical significance. Am J Med 1953; 14: 201-215.
• 6 Owren PA. Thrombotest. A new method for controlling anticoagulant therapy. Lancet 1959; 2: 754-758.
• 7 Duckert F, Koller F, Matter M. Purification and physiological properties of factor VII from plasma and serum; separation from prothrombin. Proc Soc Exp Biol Med 1953; 82: 259-261.
• 8 Duckert F, Fluckiger P, Koller F. The role of factor X in the formation of blood thromboplastin. Rev Hematol 1954; 9: 489-492.
• 9 Duckert F, Fluckiger P, Matter M. et al. Clotting factor X; physiologic and physico-chemical properties. Proc Soc Exp Biol Med 1955; 90: 17-22.
• 10 AleX ander B, De Vries A, Addelson E. Human prothrombin: Quantitative studies on the plasma labile factor and the restorative effects of normal, hypofibrinogenemic, and hemophilic plasma on the prothrombin of stored plasma. J Clin Invest 1949; 28: 24-31.
• 11 Gonyea LM, Hjort P, Owren PA. A study of the relationship of concentrations of prothrombin, proconvertin, and proaccelerin to three methods for measuring prothrombintime. J Lab Clin Med 1956; 48: 624-633.
• 12 Pechet L, AleX ander B, Tishkoff GH. Separation, interaction and properties of clotting components essential for prothrombin activation with special reference to Stuart factor. Thromb Diath Haemorrh 1960; 4 Suppl 47-57.
• 13 Telfer TP, Denson KW, Wright DR. Anew coagulation defect. Br J Haematol 1956; 2: 308-316.
• 14 Hougie C, Barrow EM, Graham JB. The Stuart factor: a hitherto unrecognized blood coagulation factor. Bibl Haematol 1958; 7: 336-340.
• 15 Beck EA. Historical development of the prothrombin concept. In: Prothrombin and Related Coagulation Factors. Leiden: Leiden University Press; 1975: 15-24.
• 16 Esnouf MP, Macfarlane RG. Enzymology and the blood clotting mechanism. Adv Enzymol Related Areas Mol Biol 1968; 30: 255-315.
• 17 Esnouf MP. The nature of prothrombinase. Boer-haave Course 1968. University of Leiden
• 18 Milstone J. Fractionation of plasma globulin for prothrombin, thrombokinase, and accessory thromboplastin. J Gen Physiol 1951; 35: 67-87.
• 19 Milstone JH. Protein thrombokinase and lipoid thromboplastin as distinct factors with complementary functions. Yale J Biol Med 1952; 25: 19-33.
• 20 Milstone JH. Thrombokinase as prime activator of prothrombin: Historical perspectives and present status. Fed Proc 1964; 23: 742-748.
• 21 Milstone J. Fractionation of plasma globulin for prothrombin, thrombokinase, and accessory thromboplastin. J Gen Physiol 1951; 35: 67-87.
• 22 Suttie JW, Jackson CM. Prothrombin structure, activation and biosynthesis. Physiol Rev 1977; 57: 1-70.
• 23 Seegers WH. A personal perspective on hemostasis and thrombosis(1937-1981). Semin Thromb Hemost 1981; 7: 177-307.
• 24 Seegers WH. Prothrombinase: Recognition and developments. Adv Exp Med Biol 1990; 281: 93-96.
• 25 Seegers WH. Solving the Riddle of Blood Clotting. In: Thrombosis: Mechanisms and Control. Stuttgart-New York: F. K. Schattauer Verlag; 1973. pp. 9-30.
• 26 Marcum J. Constructing a scientific paper: Howell’s prothrombin laboratory notebook and paper. Int Studies Philos Sci 2001; 15: 293-310.
• 27 Marcum JA. Defending the priority of ‘remarkable researches’: the discovery of fibrin ferment. Hist Philos Life Sci 1998; 20: 51-76.
• 28 Medawar P. Pluto’s Republic, Incorporating The Art of the Soluble and Induction and Intuition in Scientific Thought. Oxford: Oxford University Press; 1984
• 29 Popper K. The Logic of Scientific Discovery. London: Routledge Classics; 1952
• 30 Kuhn TS. The Structure of Scientific Revolutions. 2^nd Ed. University of Chicago Press; 1962. pp. 1-223.
• 31 Clifford WK. The Ethics of Belief. In: Gateway to the Great Books, Philosophical Essays. Chicago: Encyclopaedia Britannica, Inc.; 1963. pp. 14-36.
• 32 Cervantes M. Commendatory Verses. The History of Don Quixote de la Mancha. Britannica Great Books of the Western World. Vol. 29. Chicago: Encyclopaedia Britannica, Inc.; 1952: xiv-xvi.
• 33 Saxe John Godfrey. The Blind Men and the Elephant. Available at http://www.wordinfo.info/words/index/info/view_unit/1/?letter=B&spage=3 Accessed 4-April-2007, American Poet, 1816-1887.
• 34 Frankfurt H. On Bullshit. Princeton: Princeton University Press; 2005: 01-67.
• 35 Pirie NW. Purification and Crystallization of Proteins. Biol. Rev. Cambridge Philos. Soc. 1940; 15: 377 (Reprinted in Ann NY Acad Sci 1979; 325: 21-36.)
• 36 Sober HA, Peterson EA. Protein chromatography on ion exchange cellulose. Fed Proc 1958; 17: 1116-1126.
• 37 Aronson DL. N-Terminal amino-acids formed during the activation of prothrombin. Nature 1962; 194: 475-476.
• 38 Aronson DL, Preiss JW. Molecular weights of human prothrombin and thrombin by electron irradiation. Radiat Res 1962; 16: 138-143.
• 39 Aronson DL, Menache D. Chromatographic analysis of the activation of human prothrombin with human thrombokinase. Biochemistry 1966; 5: 2635-2640.
• 40 Ware AG, Lanchantin GF. Purification of fibrinogen, prothrombin and thrombin. J Biol Chem 1954; 34: 714-721.
• 41 Lanchantin GF, Friedmann JA, Hart DW. The Conversion of Human Prothrombin to Thrombin By Sodium Citrate: Analysis of the Activation Mixture. J Biol Chem 1965; 240: 3276-3282.
• 42 Lanchantin GF, Hart DW, Friedmann JA. et al. Amino acid composition of human plasma prothrombin. J Biol Chem 1968; 243: 5479-5485.
• 43 Lanchantin GF, Friedmann JA, Hart DW. Interaction of soybean trypsin inhibitor with thrombin and its effect on prothrombin activation. J Biol Chem 1969; 244: 865-875.
• 44 Seegers WH, Marciniak E, Kipfer RK. et al. Isolation and Some Properties of Prethrombin and Autoprothrombin III. Arch Biochem Biophys 1967; 121: 372-383.
• 45 Ingwall JS, Scheraga HA. Purification and properties of bovine prothrombin. Biochemistry 1969; 8: 1860-1869.
• 46 Lamy F, Waugh DF. Certain physical properties of bovine prothrombin. J Biol Chem 1953; 203: 489-499.
• 47 Lamy F, Waugh DF. Transformation of prothrombin into thrombin. Physiol Rev 1954; 34: 722-729.
• 48 Shapiro SS, Waugh DF. The purification of human prothrombin. Thromb Diath Haemorrh 1966; 16: 468-490.
• 49 Rosenberg RD, Waugh DF. Multiple bovine thrombin components. J Biol Chem 1970; 245: 5049-5056.
• 50 Waugh DF, Rosenberg RD. Specific activities of bovine thrombin and thrombin components. Thromb Diath Haemorrh 1972; 27: 183-195.
• 51 Magnusson S. Preparation and carbohydrate analysis of bovine prothrombin. Arkiv Kemi 1964; 23: 285-298.
• 52 Magnusson S. Preparation of highly purified bovine thrombin (E. C.3.4.4.13) and determination of its N-terminal amino acid residues. Arkiv Kemi 1965; 24: 349-358.
• 53 Magnusson S, Sottrup-Jensen L, Petersen TE. et al. The primary structure of prothrombin, the role of vitamin K in blood coagulation and a thrombin-catalyzed ‘negative feedback’ control mechanism for limiting the activation of prothrombin. In: Prothrombin and Related Coagulation Factors. Leiden: Leiden University Press; 1975. pp. 25-46.
• 54 Sherry S, Troll W, Glueck H. Thrombin as a proteolytic enzyme. Physiol Rev 1954; 34: 736-741.
• 55 Miller KD, Copeland WH. Human thrombin: isolation and stability. Exp Mol Pathol 1965; 26: 431-437.
• 56 Fenton JW, Fasco MJ, Stackrow AB. Human thrombins. Production, evaluation, and properties of alphathrombin. J Biol Chem 1977; 252: 3587-3598.
• 57 Fenton JW, Campbell WP, Harrington JC. et al. Large-scale preparation and preliminary characterization of human thrombin. Biochim Biophys Acta 1971; 229: 26-32.
• 58 Mann KG, Batt CW. The molecular weights of bovine thrombin and its primary autolysis products. J Biol Chem 1969; 244: 6555-6557.
• 59 Seegers WH, Murano G, McCoy L. Structural changes in prothrombin during activation: A theory. Thromb Diath Haemorrh 1970; 23: 26-36.
• 60 Williams WJ, Esnouf MP. The fractionation of Russell’s-viper (Vipera russellii) venom with special reference to the coagulant protein. Biochem J 1962; 84: 52-61.
• 61 Esnouf MP, Williams WJ. The isolation and purification of a bovine-plasma protein which is a substrate for the coagulant fraction of Russell’s viper venom. Biochem J 1962; 84: 62-71.
• 62 Esnouf MP, Jobin F. Lipids in prothrombin conversion. Thromb Diath Haemorrh 1965; 17: 103-111.
• 63 Esnouf MP, Jobin F. The isolation of factor V from bovine plasma. Biochem J 1967; 102: 660-665.
• 64 Jobin F, Esnouf MP. Studies on the formation of the prothrombin-converting complex. Biochem J 1967; 102: 666-674.
• 65 Papahadjopoulos D, Hougie C, Hanahan D. Influence of surface charge of phospholipids on their clot-promoting activity. Proc Soc Exp Biol Med 1962; 111: 412-415.
• 66 Papahadjopoulos D, Hougie C, Hanahan DJ. Purification and properties of bovine factor V: A change of molecular size during blood coagulation. Biochemistry 1964; 3: 264-270.
• 67 Papahadjopoulos D, Yin ET, Hanahan DJ. Purification and properties of bovine factor X: Molecular changes during activation. Biochemistry 1964; 3: 1931-1939.
• 68 Papahadjopoulos D, Hanahan DJ. Observations on the interaction of phospholipids and certain clotting factors in prothrombin activator formation. Biochim Biophys Acta 1964; 90: 436-439.
• 69 Hanahan DJ, Papahadjopoulos D. Interactions of phospholipids with coagulation factors. Thromb Diath Haemorrh 1965; 17: 71-84.
• 70 Barton PG, Hanahan DJ. The Preparation and Properties of a Stable Factor V from Bovine Plasma. Biochim Biophys Acta 1967; 133: 506-518.
• 71 Barton P, Hanahan D. Some lipid-protein interactions involved in prothrombin activation. Biochim Biophys Acta 1969; 187: 319-327.
• 72 Cole ER, Koppel JL, Olwin JH. Phospholipid-protein interactions in the formation of prothrombin activator. Thromb Diath Haemorrh 1965; 14: 431-444.
• 73 Rouser G, Schloredt D. Phospholipid structure and thromboplastic activity II. The fatty acid composition of the active phosphatidyl ethanolamines. Biochim Biophys Acta 1958; 28: 81-87.
• 74 Barton P, Jackson CM, Hanahan D. Relationship between factor V and activated factor X in the generation of prothrombinase. Nature 1967; 214: 923-924.
• 75 Hemker HC, Esnouf MP, Hemker PW. et al. Formation of prothrombin converting activity. Nature 1967; 215: 248-251.
• 76 Esnouf MP. Biochemical aspects of blood coagulation. Proc RSoc Lond B Biol Sci 1969; 173: 269-275.
• 77 Macfarlane RG. An enzyme cascade in the blood clotting mechanism and its function as a biochemical amplifier. Nature 1964; 202: 498-499.
• 78 Macfarlane RG. A clotting scheme for 1964. Thromb Diath Haemorrh 1965; Suppl: 45-52.
• 79 Macfarlane RG. The basis of the cascade hypothesis of blood clotting. Thromb Diath Haemorrh 1965; 15: 591-602.
• 80 Davie EW, Ratnoff OD. Waterfall sequence for intrinsic blood clotting. Science 1964; 145: 1310-1311.
• 81 Davie EW, Fujikawa K. Basic mechanisms in blood coagulation. Annu Rev Biochem 1975; 44: 799-829.
• 82 Bangham AD. A correlation between surface charge and coagulant action of phospholipids. Nature 1961; 192: 1197-1198.
• 83 Marcus A. The role of lipids in blood coagulation. Adv Lip Res 1966; 4: 1-33.
• 84 Jackson CM, Hanahan DJ. Studies on bovine Factor X: I. Large scale purification of the bovine plasma protein possessing factor X activity. Biochemistry 1968; 7: 4492-4505.
• 85 Jackson CM, Hanahan D. Studies on bovine factor X: II. Characterization of purified factor X observations on some alterations in zone electrophoretic and chromatographic behavior occurring during purification. Biochemistry 1968; 7: 4506-4517.
• 86 Gitel SN, Owen WG, Esmon CT. et al. A polypeptide region of bovine prothrombin specific for binding to phospholipids. Proc Natl Acad Sci USA 1973; 70: 1344-1348.
• 87 Jackson CM, Gordon JG, Hanahan DJ. Separation of the tosyl arginine esterase activity from the factor X activating enzyme of Russell’s viper venom. Biochim Biophys Acta 1971; 252: 255-261.
• 88 Esmon CT, Owen WG, Duiguid D. et al. The action of thrombin on blood clotting factor V: Conversion of factor V to a prothrombin-binding protein. Biochim Biophys Acta 1973; 310: 289-294.
• 89 Freeman JP, Guillin M-C, Bezeaud A. et al. Activation of bovine blood coagulation factor V. A prerequisite for it to bind both pothrombin and factor Xa. Fed Proc 1977; 36: 675.
• 90 Stenn K, Blout E. Mechanism of bovine prothrombin activation by an insoluble preparation of bovine factor Xa (thrombokinase). Biochemistry 1972; 11: 4502-4515.
• 91 Jackson CM, Esmon CT, Gitel SN. et al. The conversion of prothrombin to thrombin: The function of the propiece of prothrombin. In: Prothrombin and related coagulation factors. Leiden: Leiden University Press; 1974. pp. 59-88.
• 92 Jackson CM, Esmon CT, Owen WG. The activation of bovine prothrombin. In: Cold Spring Harbor Conferences on Cell Proliferation 2: Proteases and Biological Control. New York: Cold Sprint Harbor Laboratory; 1975. pp. 95-109.
• 93 Owen WG, Esmon CT, Jackson CM. The conversion of prothrombin to thrombin: I. Characterization of the reaction products formed during the activation of bovine prothrombin. J Biol Chem 1974; 249: 594-605.
• 94 Jackson CM. Report of the Task Force on Blood Clotting Zymogens and Zymogen Intermediates. Thromb Haemost 1978; 38: 567-577.
• 95 Morita T, Iwanaga S, Suzuki T. The mechanism of activation of bovine prothrombin by an activator isolated from Echis carinatus venom and characterization of the new active intermediates. J Biochem 1976; 79: 1089-1108.
• 96 Esmon CT, Owen WG, Jackson CM. The conversion of prothrombin to thrombin II. Differentiation between thrombin and factor Xa catalyzed proteolyses. J Biol Chem 1974; 249: 606-611.
• 97 Esmon CT, Jackson CM. The conversion of prothrombin to thrombin. III. The factor Xa catalyzed activation of prothrombin. J Biol Chem 1974; 249: 7782-7790.
• 98 Carlisle TL, Jackson CM. The two peptide bonds in bovine prethrombin 1 are cleaved at equal rates by bovine Factor Xa. Thromb Haemost 1985; 54: 46.
• 99 Carlisle TL, Bock PE, Jackson CM. Kinetic intermediates in prothrombin activation: Bovine prethrombin 1 conversion to thrombin by factor X. J Biol Chem 1990; 265: 22044-22055.
• 100 Bock PE. Active site-selective labeling of thrombin with fluorescence probes using thioester derivatives of peptide-chloromethyl ketones. Thromb Haemost 1987; 58: 506.
• 101 Bock PE. Active-site-selective labeling of blood coagulation proteinases with fluorescence probes by the use of thioester peptide chloromethyl ketones: II. Properties of thrombin derivatives as reporters of prothrombin fragment 2 binding and specificity of the labeling approach for other proteinases. J Biol Chem 1992; 267: 14974-14981.
• 102 Esmon CT, Jackson CM. The conversion of prothrombin to thrombin. IV. The function of the fragment 2 region during activation in the presence of factor V. J Biol Chem 1974; 249: 7791-7797.
• 103 Esmon CT, Owen WG, Jackson CM. The conversion of prothrombin to thrombin V: The activation of prothrombin by factor Xa in the presence of phospholipid. J Biol Chem 1974; 249: 7798-7807.
• 104 Dombrose FA, Gitel SN, Zawalich K. et al. The association of bovine prothrombin fragment 1 with phospholipid quantitative characterization of the Ca2+ ion-mediated binding of prothrombin fragment 1 to phospholipid vesicles and a molecular model for its association with phospholipids. J Biol Chem 1979; 254: 5027-5040.
• 105 Stenflo J, Ganrot PO. Vitamin K and the biosynthesis of prothrombin. I. Identification and purification of a dicoumarol-induced abnormal prothrombin from bovine plasma. J Biol Chem 1972; 247: 8160-8166.
• 106 Stenflo J, Ganrot P. Binding of Ca2+ to normal and dicoumarol-induced prothrombin. Biochem Biophys Res Comm 1972; 50: 98-104.
• 107 Stenflo J. Structural comparison of normal and dicoumarol-induced prothrombin. In: Prothrombin and Related Coagulation Factors. Leiden: Leiden University Press; 1975. pp. 152-158.
• 108 Stenflo J, Fernlund P, Roepstorff P. Structure of a vitamin K-dependent portion of prothrombin. In: Proteases and Biological Control. Cold Spring Harbor: Cold Spring Harbor: Conference on Cell Proliferation; 1975. pp. 111-122.
• 109 Stenflo J, Suttie JW. Vitamin K-dependent formation of γ-carboxyglutamic acid. Annu Rev Biochem 1977; 46: 157-172.
• 110 Esmon CT, Suttie JW, Jackson CM. The functional significance of vitamin K action. Difference in phospholipid binding between normal and abnormal prothrombin. J Biol Chem 1975; 250: 4095-4099.
• 111 Guillin MC, Aronson DL, Bezeaud A. et al. The purification of human acarboxy prothrombin. Characterization of its derivatives after thrombin cleavage. Thromb Res 1977; 10: 223-233.
• 112 Morita T, Jackson CM. Localization of the structural difference between bovine blood coagulation Factors X1 and X2 to tyrosine 18 in the activation peptide. J Biol Chem 1986; 261: 4008-4015.
• 113 Morita T, Jackson CM. Preparation and properties of derivatives of bovine factor X and factor Xa from which the γ-carboxyglutamic acid containing domain has been removed. J Biol Chem 1986; 261: 4015-4023.
• 114 Esmon CT, Owen WG, Jackson CM. A plausible mechanism for prothrombin activation by factor Xa, factor Va, phospholipid, and calcium ions. J Biol Chem 1974; 249: 8045-8047.
• 115 Esnouf MP. The blood clotting mechanism. Prog Clin Biol Res 1976; 5: 69-84.
• 116 Esnouf MP. Biochemistry of blood coagulation. Br Med Bull 1977; 33: 213-218.
• 117 Jesty J, Esnouf MP. The preparation of activated factor X and its action on prothrombin. Biochem J 1973; 131: 791-799.
• 118 Morita T, Iwanaga S, Suzuki T. et al. Characterization of amino-terminal fragment liberated from bovine prothrombin by activated factor X. FEBS Lett 1973; 36: 313-317.
• 119 Morita T, Nishibe H, Iwanaga S. et al. Studies on the activation of bovine prothrombin isolation and characterization of the fragments released from the prothrombin by activated factor X. J Biochem 1974; 76: 1031-1048.
• 120 Seegers WH, Sakuragawa N, McCoy LE. et al. Prothrombin activation: Ac-globulin, lipid, platelet membrane, and autoprothrombin C (factor Xa) requirements. Thromb Res 1972; 1: 293-310.
• 121 Seegers WH, McCoy LE, Sakuragawa N. Mechanisms of thrombin formation. In: Physiology and Biochemistry of Prothrombin Conversion. Stuttgart: F. K. Schattauer Verlag; 1974. pp. 255-272.
• 122 Seegers WH, McCoy LE, Walz DA. Properties of Bovine Prothrombin. In: Physiology and Biochemistry of Prothrombin Converstion. Stuttgart-New York: F. K. Schattauer Verlag; 1974. pp. 1-5.
• 123 Seegers WH, Novoa E, Walz DA. et al. Effects of prothrombin fragments on thrombin, on thrombin formation, and separation from Ac-globulin (factor V). Thromb Res 1976; 8: 83-97.
• 124 Ball AP, Fenton J, Aronson DL. et al. Proceedings: Purification and characterization of activation fragments F1 and F2 from human prothrombin. Thromb Diath Haemorrh 1975; 34: 591.
• 125 Aronson DL, Stevan L, Ball AP. et al. Generation of the combined prothrombin activation peptide(F1-2) during the clotting of blood and plasma. J Clin Invest 1977; 60: 1410-1418.
• 126 Franza Jr BR, Aronson DL, Finlayson JS. Activation of human prothrombin by a procoagulant fraction from the venom of Echis carinatus. Identification of a high molecular weight intermediate with thrombin activity. J Biol Chem 1975; 250: 7057-7068.
• 127 Heldebrant CM, Mann KG. The activation of prothrombin. I. Isolation and preliminary characterization of intermediates. J Biol Chem 1973; 248: 3642-3652.
• 128 Mann KG, Heldebrant CM, Fass DN. Multiple active forms of thrombin. II. Mechanism of production from prothrombin. J Biol Chem 1971; 246: 6106-6114.
• 129 Fass DN, Mann KG. Activation of fluorescein-labeled prothrombin. J Biol Chem 1973; 248: 3280-3287.
• 130 Heldebrant CM, Butkowski RJ, Bajaj SP. et al. The activation of prothrombin. II. Partial reactions, physical and chemical characterization of the intermediates of activation. J Biol Chem 1973; 248: 7149-7163.
• 131 Heldebrant CM, Noyes C, Kingdon HS. et al. The activation of prothrombin. III. The partial amino acid sequences at the amino terminal of prothrombin and the intermediates of activation. Biochem Biophys Res Commun 1973; 54: 155-160.
• 132 Butkowski RJ, Bajaj SP, Mann KG. The preparation and activation of (sialyl-3H) prothrombin. J Biol Chem 1974; 249: 6562-6569.
• 133 Bajaj SP, Butkowski RJ, Mann KG. Prothrombin fragments. Ca2+ binding and activation kinetics. J Biol Chem 1975; 250: 2150-2156.
• 134 Downing MR, Butkowski RJ, Clark MM. et al. Human prothrombin activation. J Biol Chem 1975; 250: 8897-8906.
• 135 Myrmel KH, Lundblad RL, Mann KG. Characteristics of the association between prothrombin fragment 2 and alpha-thrombin. Biochemistry 1976; 15: 1767-1773.
• 136 Butkowski RJ, Elion J, Downing MR. et al. Primary structure of human prethrombin 2 and alpha-thrombin. J Biol Chem 1977; 252: 4942-4957.
• 137 Kisiel W, Hanahan DJ. Purification and characterization of human factor II. Biochim Biophys Acta 1973; 304: 103-113.
• 138 Kisiel W, Hanahan DJ. The action of factor Xa, thrombin and trypsin on human factor II. Biochim Biophys Acta 1973; 329: 221-232.
• 139 Kisiel W, Hanahan DJ. Proteolysis of human factor II by factor Xa in the presence of hirudin. Biochem Biophys Res Comm 1974; 59: 570-577.
• 140 Miletich JP, Jackson CM, Majerus PW. Interaction of coagulation factor Xa with human platelets. Proc Natl Acad Sci USA 1977; 74: 4033-4036.
• 141 Miletich JP, Jackson CM, Majerus PW. Properties of the factor Xa binding site on human platelets. J Biol Chem 1978; 253: 6908-6916.
• 142 Kane W, Lindhout M, Jackson CM. et al. Factor Va-dependent binding of factor Xa to human platelets. J Biol Chem 1978; 255: 1170-1174.
• 143 Zwaal RFA, Comfurius P, vanDeenen LLM. Membrane asymmetry and blood coagulation. Nature 1977; 268: 358-360.
• 144 Bevers EM, Comfuriue P, Zwaal RFA. Changes in membrane phospholipid distribution during platelet activation. Biochim Biophys Acta 1983; 736: 57-66.
• 145 Marciniak E. Factor-Xa inactivation by antithrombin III: Evidence for biological stabilization of factor Xa by factor V-phospholipid complex. Br J Haematol 1973; 24: 391-400.
• 146 Miletich J, Kane W, Hofmann S. Deficiency of factor Xa -factor Va binding sites on the platelets of a patient with a bleeding disorder. Blood 1979; 54: 1015-1022.
• 147 Tracy PB, Peterson JM, Nesheim ME. et al. Interaction of coagulation factor V and factor Va with platelets. J Biol Chem 1979; 254: 10354-10361.
• 148 Tracy PB, Nesheim ME, Mann KG. Coordinate binding of factor Va and factor Xa to the unstimulated platelet. J Biol Chem 1981; 256: 743-751.
• 149 Tracy PB, Rohrbach MS, Mann KG. Functional prothrombinase complex assembly on isolated monocytes and lymphocytes. J Biol Chem 1983; 258: 7264-7267.
• 150 Tracy PB, Nesheim ME, Mann KG. Platelet factor Xa receptor. Methods Enzymol 1992; 215: 329-360.
• 151 Swords NA, Mann KG. The assembly of the prothrombinase complex on adherent platelets. Arterioscler Thromb 1993; 13: 1602-1612.
• 152 Bevers EM, Comfurius P, van Rijn JLML. et al. Generation of prothrombin-converting activity and the exposure of phosphatidylserine at the outer surface of platelets. Eur J Biochem 1982; 122: 429-436.
• 153 Bevers EM, Tilly RHJ, Senden JMG. et al. Exposure of endogenous phosphatidylserine at the outer surface of stimulated platelets is reversed by restoration of aminophospholipid translocase activity. Biochemistry 1989; 28: 2382-2387.
• 154 Miletich J, Majerus D, Majerus P. Patients with congenital factor V deficiency have decreased factor Xa binding sites on their platelets. J Clin Invest 1978; 62: 824-831.
• 155 Majerus PW, Miletich JP. Relationships between platelets and coagulation factors in hemostasis. Ann Rev Med 1978; 29: 41-49.
• 156 Walsh PN. Platelet coagulation-protein interactions. Semin Thromb Hemost 2004; 30: 461-471.
• 157 Nesheim ME, Prendergast FG, Mann KG. Interactions of a fluorescent active-site-directed inhibitor of thrombin: Dansylarginine n-(3-ethyl-1,5-pentanediyl) amide. Biochemistry 1979; 18: 990-1003.
• 158 Nesheim MW, Tasswell JB, Mann KG. The contribution of bovine factor V and factor Va to the activity of prothrombinase. J Biol Chem 1979; 254: 10952-10962.
• 159 Nesheim ME, Kettner C, Shaw E. et al. Cofactor dependence of factor Xa incorporation into the prothrombinase complex. J Biol Chem 1981; 256: 6537-6540.
• 160 Mann KG, Nesheim ME, Tracy PB. et al. Assembly of the prothrombinase complex. Biophys J 1982; 37: 106-107.
• 161 Nesheim ME, Mann KG. The kinetics and cofactor dependence of the two cleavages involved in prothrombin activation. J Biol Chem 1983; 258: 5386-5391.
• 162 Nesheim ME, Foster WB, Hewick R. et al. Characterization of factor V activation intermediates. J Biol Chem 1984; 259: 3187-3196.
• 163 Krishnaswamy S, Mann KG, Nesheim ME. The prothrombinase-catalyzed activation of prothrombin proceeds through the intermediate meizothrombin in an ordered, sequential reaction. J Biol Chem 1986; 261: 8977-8984.
• 164 Krishnaswamy S, Church WR, Nesheim ME. et al. Activation of human prothrombin by human prothrombinase. Influence of factor Va on the reaction mechanism. J Biol Chem 1987; 262: 3291-3299.
• 165 Mann KG. Biochemistry and physiology of blood coagulation. Thromb Haemost 1999; 82: 165-174.
• 166 Kalafatis M, Swords NA, Rand MD. et al. Membrane-dependent reactions in blood coagulation: role of the vitamin K-dependent enzyme complexes. Biochim Biophys Acta 1994; 1227: 113-129.
• 167 Bovill EG, Tracy RP, Hayes TE. et al. Evidence that meizothrombin is an intermediate product in the clotting of whole blood. Arterioscler Thromb Vasc Biol 1995; 15: 754-758.
• 168 Krishnaswamy S, Nesheim ME, Pryzdial EL. et al. Assembly of prothrombinase complex. Methods Enzymol 1993; 222: 260-280.
• 169 Baugh RJ, Dickinson CD, Ruf W. et al. Exosite interactions determine the affinity of factor X for the extrinsic Xase complex. J Biol Chem 2000; 275: 28826-28833.
• 170 Doyle MF, Mann KG. Multiple active forms of thrombin. IV. Relative activities of meizothrombins. J Biol Chem 1990; 265: 10693-10701.
• 171 Mann KG, Nesheim ME, Church WR. et al. Surface-dependent reactions of the vitamin K-dependent enzyme complexes. Blood 1990; 76: 1-16.
• 172 Rosing J, Tans G, Govers-Riemslag JWP. et al. The role of phospholipids and factor Va in the prothrombinase complex. J Biol Chem 1980; 255: 274-283.
• 173 Lindhout T, Govers-Riemslag JWP, van de Waart P. et al. Factor Va-factor Xa interaction. Effects of phospholipid vesicles of varying composition. Biochemistry 1982; 21: 5494-5502.
• 174 Rosing J, vanRijn JLML, Bevers EM. et al. The role of activated human platelets in prothrombin and factor X activation. Blood 1985; 65: 319-331.
• 175 Rosing J, Zwaal RFA, Tans G. Formation of meizothrombin as intermediate in factor Xa-catalyzed prothrombin activation. J Biol Chem 1986; 261: 4224-4228.
• 176 Rosing J, Tans G. Meizothrombin, a major product of factor Xa-catalyzed prothrombin activation. Thromb Haemost 1988; 60: 355-360.
• 177 Tans G, Janssen-Claessen T, Hemker HC. et al. Meizothrombin formation during factor Xa-catalyzed prothrombin activation. Formation in a purified system and in plasma. J Biol Chem 1991; 266: 21864-21873.
• 178 vanRijn JLML, Govers-Riemslag JWP, Zwaal RFA. et al. Kinetic studies of prothrombin activation: Effect of factor Va and phospholipids on the formation of the enzyme-substrate complex. Biochemistry 1984; 23: 4557-4564.
• 179 Dahlback B, Stenflo J. The activation of prothrombin by platelet-bound factor Xa. Eur J Biochem 1980; 104: 549-557.
• 180 Suzuki K, Dahlback B, Stenflo J. Thrombin-catalyzed activation of human coagulation factor V. J Biol Chem 1982; 257: 6556-6564.
• 181 Autin L, Stehen M, Dahlback B. et al. Proposed structural models of the prothrombinase (FXa-FVa) complex. Proteins 2006; 63: 440-450.
• 182 Brufatto N, Nesheim ME. Analysis of the kinetics of prothrombin activation and evidence that two equilibrating forms of prothrombinase are involved in the process. J Biol Chem 2003; 278: 6755-6764.
• 183 Bukys MA, Blum MA, Kim PY. et al. Incorporation of factor Va into prothrombinase is required for coordinated cleavage of prothrombin by factor Xa. J Biol Chem 2005; 280: 27393-27401.
• 184 Bukys MA, Kim PY, Nesheim ME. et al. A control switch for prothrombinase: characterization of a hirudin-like pentapeptide from the COOH terminus of factor Va heavy chain that regulates the rate and pathway for prothrombin activation. J Biol Chem 2006; 281: 39194-39204.
• 185 Di Cera, Guinto ER, Vindigni A. et al. The Na+ binding site of thrombin. J Biol Chem 1995; 270: 22089-22092.
• 186 Di Cera, Dang QD, Ayala YM. Molecular mechanisms of thrombin function. Cell Mol Life Sci 1997; 53: 701-730.
• 187 Camire RM. Prothrombinase assembly and S1 site occupation restore the catalytic activity of FXa impaired by mutationatthe sodium-binding site. J Biol Chem 2002; 277: 37863-37870.
• 188 Di Cera. A structural perspective on enzymes activated by monovalent cations. J Biol Chem 2006; 281: 1305-1308.
• 189 Bianchini EP, Pike RN, Le Bonniec BF. The elusive role of the potential factor X cation-binding exosite-1 in substrate and inhibitor interactions. J Biol Chem 2004; 279: 3671-3679.
• 190 Jackson CM, Nemerson Y. Blood coagulation. Annu Rev Biochem 1980; 49: 765-781.
• 191 Nesheim ME, Tracy RP, Mann KG. “Clotspeed” a mathematical simulation of the functional properties of prothrombinase. J Biol Chem 1984; 259: 1447-1453.
• 192 Nesheim ME, Tracy RP, Tracy PB. et al. Mathematical simulation of prothrombinase. Methods Enzymol 1992; 215: 316-328.
• 193 Jesty J, Beltrami E, Willems G. Mathematical analysis of a proteolytic positive-feedback loop: dependence of lag time and enzyme yields on the initial conditions and kinetic parameters. Biochemistry 1993; 32: 6266-6274.
• 194 Beltrami E, Jesty J. Mathematical analysis of activation thresholds in enzyme-catalyzed positive feedbacks: application to the feedbacks of blood coagulation. Proc Natl Acad Sci USA 1995; 92: 8744-8748.
• 195 Gir S, Slack SM, Turitto VT. A numerical analysis of factor X activation in the presence of tissue factor--factor VIIa complex in a flow reactor. Ann Biomed Eng 1996; 24: 394-399.
• 196 Beltrami E, Jesty J. The role of membrane patch size and flow in regulating a proteolytic feedback threshold on a membrane: possible application in blood coagulation. Math Biosci 2001; 172: 1-13.
• 197 Jesty J, Beltrami E. Positive feedbacks of coagulation: their role in threshold regulation. Arterioscler Thromb Vasc Biol 2005; 25: 2463-2469.
• 198 Obraztsov IF, Kardakov DV, Kogan AE. et al. A mathematical model of the background state of the blood coagulation system. Dokl Biochem Biophys 2001; 376: 10-12.
• 199 Ataullakhanov FI, Panteleev MA. Mathematical modeling and computer simulation in blood coagulation. Pathophysiol Haemost Thromb 2005; 34: 60-70.
• 200 Orfeo T, Mann KG. Mathematical and biological models of blood coagulation. J Thromb Haemost 2005; 3: 2397-2398.