The blood coagulation cascade is initiated when subendothelial tissue factor is exposed/expressed to the blood flow following either the damage or activation of the endothelium. This may occur as a consequence of the perforation of the vessel wall or activation of endothelium by chemicals, cytokines, or inflammatory processes [1-6]. Tissue factor binds to a serine protease, factor VIIa, already present in blood [7, 8] and forms the factor VIIa–tissue factor complex (extrinsic factor Xase), which activates the zymogens—factor IX and factor X [9-12]. The limited amounts of the serine protease factor Xa pro- duced generate picomolar concentrations of thrombin, which partially activates platelets and cleaves the proco- factors factor V and factor VIII generating the active cofactors—factor Va and factor VIIIa, respectively [13- 15]. Factor VIIIa forms the intrinsic factor Xase complex with the serine protease, factor IXa, on a membrane sur- face provided by platelets, microparticles, and endothe- lial and other cells [16-19] and activates factor X at a 50- 100-fold higher rate than the factor VIIa–tissue factor complex [12, 20, 21]. Factor Xa forms the prothrombinase complex with the cofactor, factor Va, on the membrane surface, which is the primary activator of prothrombin [22-24]. The thrombin produced further amplifies its own generation by activating factor XI [25] and completing activation of platelets and factors V and VIII [15, 26]. Thrombin also cleaves fibrinogen [27, 28] and factor XIII [29, 30] to form the insoluble cross-linked fibrin clot [31, 32]. The procoagulant processes are attenuated by a vari- ety of inhibitors, which inactivate either serine proteases or cofactors. One of the stoichiometric inhibitors, antithrombin III, appears to be the most quantitatively important. Antithrombin III is able to effectively neutral- ize all serine proteases produced during the blood coagu- lation process [33]. TFPI, another stoichiometric inhibitor of blood coagulation, which is present at rela- tively low concentrations in blood [34], is also an impor- tant regulator of the serine proteases. The principle tar- gets of TFPI are factor Xa and the factor VIIa–TF–fac- tor Xa complex [35-37]. The dynamic inhibitory system is generated when thrombin binds to its cofactor thrombo- modulin, which is constitutively present on the vascula- ture, and activates protein C to a serine protease activat- Biochemistry (Moscow), Vol. 67, No. 1, 2002, pp. 3-12. Translated from Biokhimiya, Vol. 67, No. 1, 2002, pp. 5-15. Original Russian Text Copyright © 2002 by Butenas, Mann. REVIEW 0006-2979/02/6701-0003$27.00 ©2002 MAIK “Nauka / Interperiodica” Abbreviations: TF) tissue factor; TFPI) tissue factor pathway inhibitor; CTI) corn trypsin inhibitor. * To whom correspondence should be addressed. Blood Coagulation S. Butenas and K. G. Mann* University of Vermont, Department of Biochemistry, Burlington, VT 05405-0068, USA; fax: 802-862-8229; E-mail: kmann@zoo.uvm.edu Received April 2, 2001 Revision received April 23, 2001 Abstract—The process of tissue factor initiated blood coagulation is discussed. Reactions of the blood coagulation cascade are propagated by complex enzymes containing a vitamin K-dependent serine protease and an accessory cofactor protein that are assembled on a membrane surface in a calcium-dependent manner. These complexes are 10 5 -10 9 -fold more efficient in pro- teolyses of their natural substrates than enzymes alone. Based upon data acquired using several in vitro models of blood coag- ulation, tissue factor initiated thrombin generation can be divided into two phases: an initiation phase and a propagation phase. The initiation phase is characterized by the generation of nanomolar amounts of thrombin, femto- to picomolar amounts of factors VIIa, IXa, Xa, and XIa, partial activation of platelets, and almost quantitative activation of procofactors, factors V and VIII. The duration of this phase is primarily influenced by concentrations of tissue factor and TFPI. The char- acteristic features of the propagation phase are: almost quantitative prothrombin activation at a high rate, completion of platelet activation, and solid clot formation. This phase is primarily regulated by antithrombin III and the protein C system. Thrombin generation during the propagation phase is remarkably suppressed in the absence of factor VIII and IX (hemophilia A and B, respectively) and at platelet counts <5% of mean plasma concentration. The majority of data accumulated in in vitro models and discussed in this review are in good agreement with the results of in vivo observations. Key words: blood coagulation, tissue factor, complex enzymes, thrombin generation, platelets, hemophilia, in vitro models