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During the past 20 years contributions from many laboratories have led to the development of isolation procedures, delineation of primary structures, and more recently, to the expression of recombinant proteins associated with the coagulation cascade. In general, studies of coagulation proteins under defined conditions have demonstrated the prescience of Davie and Ratnoff and MacFarlane in their proposals of the coagulation cascade. The more recent discovery of thrombomodulin by Esmon et al has led to the identification and characterization of components of the vitamin K-dependent anticoagulant pathway. In this review we have attempted to analyze and compare the functional properties of each of the vitamin K-dependent enzyme complexes associated with the procoagulant and anticoagulant phases of blood clotting. Although dissimilarities exist, the vitamin K-dependent complexes have analogous requirements and appear to function with a common general mode of organization. Membrane-bound cofactors serve as anchoring sites for the appropriate membrane-binding enzymes. This process localizes the complex on the membrane surface and increases the catalytic efficiency for substrate utilization. Complex formation provides extraordinary improvements in the catalytic efficiency for the complexes as compared with their soluble enzyme components. Membrane- bound complexes provide a mechanism that can be regulated at a site by membrane presentation, zymogen activation, and cofactor activation or presentation. The kinetic constants obtained for the various coagulation reactions determined in vitro provide some insights into how these pathways may function in vivo. The catalytic efficiency (kcat/Km) for factor X activation by factor VIIIa/factor IXa is far in excess of the catalytic efficiency of activation of factor X by tissue factor/factor VIIa (Table 3). This may provide a rational interpretation for the observation that patients with hemophilia A and B bleed even though they appear to have an alternative pathway to factor X activation. In addition, tissue factor is not ordinarily presented by the vascular tissue that has direct access to blood. However, it appears that extravascular constitutive tissue factor is available once the blood vessel becomes disrupted. The efforts to identify the initiating reactions of the blood coagulation process have not been unambiguously successful. We conclude that factor VII is most likely a zymogen, just as are the other proenzymes of the blood clotting process. In addition, it is difficult to rationalize the importance of the intrinsic pathway of coagulation involving factor XII, prekallikrein, and high molecular weight kininogen since the congenital absence of any one of these factors does not result in abnormal bleeding.(ABSTRACT TRUNCATED AT 400 WORDS) Volume 76, Issue 1, pp. 1-16, 07/01/1990 Copyright © 1990 by The American Society of Hematology CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: H. Meems, A. B. Meijer, D. B. Cullinan, K. Mertens, and G. E. Gilbert Factor VIII C1 domain residues Lys 2092 and Phe 2093 contribute to membrane binding and cofactor activity Blood, October 29, 2009; 114(18): 3938 - 3946. [Abstract] [Full Text] [PDF] M. H. A. Bos, M. Boltz, L. St. Pierre, P. P. Masci, J. de Jersey, M. F. Lavin, and R. M. 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A conotoxin from Conus textile with unusual posttranslational modifications reduces presynaptic Ca2+ influx PNAS, May 11, 1999; 96(10): 5758 - 5763. [Abstract] [Full Text] [PDF] A. V. Bendetowicz, R. J. Wise, and G. E. Gilbert Collagen-bound von Willebrand Factor Has Reduced Affinity for Factor VIII J. Biol. Chem., April 30, 1999; 274(18): 12300 - 12307. [Abstract] [Full Text] [PDF] E. L. G. Pryzdial, N. Lavigne, N. Dupuis, and G. E. Kessler Plasmin Converts Factor X from Coagulation Zymogen to Fibrinolysis Cofactor J. Biol. Chem., March 26, 1999; 274(13): 8500 - 8505. [Abstract] [Full Text] [PDF] X. He and A. R. Rezaie Identification and Characterization of the Sodium-binding Site of Activated Protein C J. Biol. Chem., February 19, 1999; 274(8): 4970 - 4976. [Abstract] [Full Text] [PDF] M. Kalafatis, F. Bernardi, P. Simioni, B. Lunghi, A. Girolami, and K. G. Mann Phenotype and Genotype Expression in Pseudohomozygous Factor VLEIDEN : The Need for Phenotype Analysis Arterioscler Thromb Vasc Biol, February 1, 1999; 19(2): 336 - 342. [Abstract] [Full Text] [PDF] P. J. Lenting, J. A. van Mourik, and K. Mertens The Life Cycle of Coagulation Factor VIII in View of Its Structure and Function Blood, December 1, 1998; 92(11): 3983 - 3996. [Full Text] [PDF] R. M. Camire, E. S. Pollak, K. Kaushansky, and P. B. Tracy Secretable Human Platelet-Derived Factor V Originates From the Plasma Pool Blood, November 1, 1998; 92(9): 3035 - 3041. [Abstract] [Full Text] [PDF] N. H. M. Senden, T. M. A. A. Jeunhomme, J. W. M. Heemskerk, R. Wagenvoord, C. van't Veer, H. C. Hemker, and W. A. Buurman Factor Xa Induces Cytokine Production and Expression of Adhesion Molecules by Human Umbilical Vein Endothelial Cells J. Immunol., October 15, 1998; 161(8): 4318 - 4324. [Abstract] [Full Text] [PDF] C. M. Mounier, T. M. Hackeng, F. Schaeffer, G. Faure, C. Bon, and J. H. Griffin Inhibition of Prothrombinase by Human Secretory Phospholipase A2 Involves Binding to Factor Xa J. Biol. Chem., September 11, 1998; 273(37): 23764 - 23772. [Abstract] [Full Text] [PDF] P. J. Fay and K. Koshibu The A2 Subunit of Factor VIIIa Modulates the Active Site of Factor IXa J. Biol. Chem., July 24, 1998; 273(30): 19049 - 19054. [Abstract] [Full Text] [PDF] A. R. Rezaie Rapid Activation of Protein C by Factor Xa and Thrombin in the Presence of Polyanionic Compounds Blood, June 15, 1998; 91(12): 4572 - 4580. [Abstract] [Full Text] [PDF] K. M. Cawthern, C. van `t Veer, J. B. Lock, M. E. DiLorenzo, R. F. Branda, and K. G. Mann Blood Coagulation in Hemophilia A and Hemophilia C Blood, June 15, 1998; 91(12): 4581 - 4592. [Abstract] [Full Text] [PDF] G. L. Long, D. Lu, R.-L. Xie, and M. Kalafatis Human Protein S Cleavage and Inactivation by Coagulation Factor Xa J. Biol. Chem., May 8, 1998; 273(19): 11521 - 11526. [Abstract] [Full Text] [PDF] A. Betz and S. Krishnaswamy Regions Remote from the Site of Cleavage Determine Macromolecular Substrate Recognition by the Prothrombinase Complex J. Biol. Chem., April 24, 1998; 273(17): 10709 - 10718. [Abstract] [Full Text] [PDF] R. M. Camire, M. Kalafatis, P. Simioni, A. Girolami, and P. B. Tracy Platelet-Derived Factor Va/VaLeiden Cofactor Activities Are Sustained on the Surface of Activated Platelets Despite the Presence of Activated Protein C Blood, April 15, 1998; 91(8): 2818 - 2829. [Abstract] [Full Text] [PDF] M. Kalafatis Identification and Partial Characterization of Factor Va Heavy Chain Kinase from Human Platelets J. Biol. Chem., April 3, 1998; 273(14): 8459 - 8466. [Abstract] [Full Text] [PDF] M. P. Moyer, R. P. Tracy, P. B. Tracy, C. v.'t Veer, C. E. Sparks, and K. G. Mann Plasma Lipoproteins Support Prothrombinase and Other Procoagulant Enzymatic Complexes Arterioscler Thromb Vasc Biol, March 1, 1998; 18(3): 458 - 465. [Abstract] [Full Text] [PDF] R. J. Baugh, G. J. Broze Jr., and S. Krishnaswamy Regulation of Extrinsic Pathway Factor Xa Formation by Tissue Factor Pathway Inhibitor J. Biol. Chem., February 20, 1998; 273(8): 4378 - 4386. [Abstract] [Full Text] [PDF] O. D. Christophe, P. J. Lenting, J. A. Kolkman, G. G. Brownlee, and K. Mertens Blood Coagulation Factor IX Residues Glu78 and Arg94 Provide a Link between Both Epidermal Growth Factor-like Domains That Is Crucial in the Interaction with Factor VIII Light Chain J. Biol. Chem., January 2, 1998; 273(1): 222 - 227. [Abstract] [Full Text] [PDF] E. Bevers, P. Comfurius, D. Dekkers, M. Harmsma, and R. Zwaal Review : Regulatory mechanisms of transmembrane phospholipid distributions and pathophysiological implications of transbilayer lipid scrambling Lupus, January 1, 1998; 7(2_suppl): S126 - S131. [Abstract] [PDF] A. Z. Dudek, C. A. Pennell, T. D. Decker, T. A. Young, N. S. Key, and A. Slungaard Platelet Factor 4 Binds to Glycanated Forms of Thrombomodulin and to Protein C. A POTENTIAL MECHANISM FOR ENHANCING GENERATION OF ACTIVATED PROTEIN C J. Biol. Chem., December 12, 1997; 272(50): 31785 - 31792. [Abstract] [Full Text] [PDF] M. R. Sutherland, C. M. Raynor, H. Leenknegt, J. F. Wright, and E. L. G. Pryzdial Coagulation initiated on herpesviruses PNAS, December 9, 1997; 94(25): 13510 - 13514. [Abstract] [Full Text] [PDF] M. F. Hockin, M. Kalafatis, M. Shatos, and K. G. Mann Protein C Activation and Factor Va Inactivation on Human Umbilical Vein Endothelial Cells Arterioscler Thromb Vasc Biol, November 1, 1997; 17(11): 2765 - 2775. [Abstract] [Full Text] A. Mathur, D. Zhong, A. K. Sabharwal, K. J. Smith, and S. P. Bajaj Interaction of Factor IXa with Factor VIIIa. EFFECTS OF PROTEASE DOMAIN Ca2+ BINDING SITE, PROTEOLYSIS IN THE AUTOLYSIS LOOP, PHOSPHOLIPID, AND FACTOR X J. Biol. Chem., September 12, 1997; 272(37): 23418 - 23426. [Abstract] [Full Text] [PDF] A. K. Sabharwal, K. Padmanabhan, A. Tulinsky, A. Mathur, J. Gorka, and S. P. Bajaj Interaction of Calcium with Native and Decarboxylated Human Factor X.. EFFECT OF PROTEOLYSIS IN THE AUTOLYSIS LOOP ON CATALYTIC EFFICIENCY AND FACTOR Va BINDING J. Biol. Chem., August 29, 1997; 272(35): 22037 - 22045. [Abstract] [Full Text] [PDF] J. D. Kulman, J. E. Harris, B. A. Haldeman, and E. W. Davie Primary structure and tissue distribution of two novel proline-rich gamma -carboxyglutamic acid proteins PNAS, August 19, 1997; 94(17): 9058 - 9062. [Abstract] [Full Text] [PDF]

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