(Chest. 2003;124:4S-10S.)
© 2003
American College of Chest Physicians
Thrombin Formation*
Kenneth G. Mann, PhD
* From the Department of Biochemistry, University of Vermont College of Medicine, Burlington, VT.
Correspondence to: Kenneth G. Mann, PhD, Department of Biochemistry, 89 Beaumont Ave, Given Building, Room C401 University of Vermont College of Medicine, Burlington, VT 05405; e-mail: Kenneth.Mann{at}uvm.edu
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Abstract
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The generation of the enzyme thrombin from its precursor prothrombin is the central event of the blood coagulation process, which is essential to hemostasis and the culprit in thrombosis. Thrombin is produced by a complex series of proteolytic events that are initiated when cryptic tissue factor interacts with plasma factor VIIa to initiate the complex series of events leading to the formation of the blood coagulation enzyme complexes that lead to the efficient generation of the enzyme. During these processes, thrombin contributes to both the generation of the catalysts involved in its ultimate production and to the catalysts that lead to attenuation of its production. Thrombin-catalyzed events both enhance and diminish the process of thrombin generation, which is down-regulated by stoichiometric and dynamic inhibitory processes. The combinations of intensities of activation and inhibition processes provide tight regulation of the hemostatic process, establishing reaction thresholds, essentially leading to an "on/off" switch. This review provides a brief summary of the evolution of knowledge with respect to present-day concepts of thrombin generation via the tissue factor pathway and its regulation.
Key Words: antithrombin III • tissue factor • tissue factor pathway inhibitor • vitamin K-dependent proteins, enzymes, complexes
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Introduction
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Not infrequently, medical students and physicians become exasperated with the apparently overwhelming complexity of the coagulation system. However, the thrombin-generating system is probably less complex than many other biological processes. The complexity of the hemostatic process occurs because our knowledge of the inventory of components essential to this process has been advantaged by two factors: parents recognize and report unusual bleeding, and blood is a conveniently available tissue. As a consequence, current knowledge of the thrombin-producing process is the result of 150 years of clinical and laboratory observation, which has produced a substantial inventory of molecular species.
Each complex catalyst (Fig 1
) that has been observed to participate in the generation of thrombin is composed of a serine protease interacting with a receptor/cofactor protein, both of which are anchored to a discreet surface. In most cases, the surface is the membrane of an activatable cell. At the turn of the last century, the thrombin-producing pathway included only the elements of the extrinsic pathway, which forms when tissue factor and factor VIIa combine to form the extrinsic factor X-activating complex, and factor Va-factor Xa assemble on a membrane surface to form prothrombinase, the prothrombin-activating complex.1
The observation that blood placed in an artificial container clots without the addition of tissue juices led to the formulation of the intrinsic pathway of coagulation, which begins with surface activation of factor XII and proceeds, with the accessory components prekallekrein and high-molecular-weight kininogen, to activate factor XI to factor XIa.2
3
Factor XIa activates factor IX to factor IXa, which with factor VIIIa forms the intrinsic factor X activator, which is defective in hemophilia A (factor VIII deficiency) and hemophilia B (factor IX deficiency). Factor Xa produced by this complex contributes the serine protease component of the prothrombinase complex to form the common generator of thrombin. The fundamental appeal of the intrinsic pathway was that it explained the pathology of hemophilia A and hemophilia B, which without question incurs significant pathologic risk and requires replacement therapy. In contrast, individuals lacking those elements of the intrinsic pathway prior to the activation of factor XI display laboratory, but not clinical, pathology associated with hemorrhage. The inclusion of factor VIII and factor IX in a tissue factor-initiated reaction was permitted by the observation of Osterud and Rapaport,4
who showed that factor IX can be activated to factor IXa by factor VIIa-tissue factor.
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Figure 1.. A representative map of the various catalysts required to generate the enzymes of the hemostatic system. The outline of the "contact catalyst" of the intrinsic pathway is dashed because of its uncertain contributions to the hemostatic process. The contribution of the contact catalyst to thrombosis is unresolved. The various points at which thrombin catalyzes its own generation by conversion of zymogens and procofactors to the active species required for catalyst formation are illustrated. HMW = high molecular weight; PC = protein C; TAFI = thrombin activated fibrinolysis inhibitor.
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The Vitamin K-Dependent Catalysts
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The combination of laboratory data with established clinical pathology has led to the conclusion that the physiologically relevant hemostatic mechanism is primarily composed of three procoagulant vitamin K-dependent enzyme complexes (which utilize the proteases factor IXa, factor Xa, and factor VIIa) and one anticoagulant vitamin K-dependent complex (see the article by Dr. Esmon in this supplement) [Fig 2
].5
Each complex involves a vitamin K-dependent serine protease and a cofactor protein with the protein-protein complex assembled on a phospholipid membrane surface provided by an activated or damaged cell.
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Figure 2.. The vitamin K-dependent complexes and their substrates. Blood clotting is initiated when factor VIIa binds to exposed/expressed tissue factor. The factor VIIa tissue factor complex (extrinsic factor Xase) initiates coagulation by activating factor X and factor IX. The factor IXaß-factor VIIIa (intrinsic factor Xase) complex will activate factor X to factor Xa 50 times more efficiently than the factor VIIa-tissue factor complex. Factor Xa from either source forms a complex with factor Va, prothrombinase, which converts prothrombin (factor II) to thrombin (factor IIa). Thrombin also initiates an anticoagulant pathway by binding to thrombomodulin and catalyzing protein C activation. Tissue factor and thrombomodulin are cell membrane proteins that extend a 20- to 35-amino-acid residue "tails" into the cell cytoplasm. Used with permission (The Dynamics of Hemostasis, Haematologic Technology, K.G. Mann, PhD, 2002).
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The same hemostatic process required for preventing blood from leaking from the vasculature can also be life threatening when responsible for an intravascular occlusion. Thus, nature has elected a highly regulated, multiconstituent activity presentation system that provides formidable catalytic power, which will lead to a regionally limited, vigorous arrest of hemorrhage. All the plasma proteins involved in the process require proteolytic activation to participate in the thrombin-generating process. In addition, platelet adhesion and activation (see the article by Dr. Brass in this supplement) are required to provide the membrane-binding sites explicitly at the site of vascular damage.6
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The Inhibitors
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Of equal importance to the processes are the stoichiometric and dynamic inhibitory systems, which block and down-regulate the presentation of thrombin. Under normal circumstances, the sum of these inhibitory functions is far in excess of the potential procoagulant response. These inhibitory processes illustrated in Figure 3
act in synergy, providing activation thresholds for which a sufficient stimulating level of tissue factor must be achieved prior to significant thrombin generation.6
7
Antithrombin III (AT-III) and tissue factor pathway inhibitor (TFPI) are the principal stoichiometric inhibitors, while the thrombin thrombomodulin-protein C system is dynamic in its function.
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Dynamics
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The key initiating event in the generation of thrombin depends on the interaction of normally cryptic, membrane-bound tissue factor with plasma factor VIIa. The latter is preexistent in blood at approximately 1 to 2% of the total factor VII concentration (10 nmol/L).8
While the source and presentation of active tissue factor is controversial,9
10
the damage or cytokine-related presentation of the active tissue factor trigger for the process is essential. Plasma factor VIIa appears to possess all the appropriate catalytic machinery to display the active site of an effective serine protease; however, it does not express proteolytic activity unless it is bound to tissue factor. Thus, naked factor VIIa at natural biological concentrations has no significant activity toward either factor IX or factor X prior to its binding to tissue factor.11
The defective active site also allows factor VIIa to escape inhibition by the high concentration of AT-III present in blood. The factor VIIa-tissue factor protein-protein interaction switches on the active site of factor VIIa by increasing the catalytic rate constant of the enzyme and increases the rate of factor X activation by four orders of magnitude.12
This latter increase is the result of the aforementioned improvement in catalytic efficiency and the membrane binding of the macromolecular substrates factor IX and factor X.
The factor VIIa-tissue factor (extrinsic factor Xase) complex (Fig 2)
catalyzes the activation of both factor IX and factor X, the latter initially being the more efficient substrate. Thus, the initial product formed by the extrinsic factor Xase is factor Xa. The factor IX zymogen is a competitive substrate with factor X and requires two peptide-bond cleavages (at arginines 145 and 180) for activity. While both of these cleavages are catalyzed by factor VIIa-tissue factor, factor Xa, bound to a membrane, can provide one of the two required cleavages (arginine 145) to produce the intermediate factor IX
. Thus, this feedback cleavage by membrane-bound factor Xa enhances the rate of generation of factor IXa, which is completed with the second bond cleavage (arginine 180) by factor VIIa-tissue factor.13
The initial factor Xa produced when bound to membrane activates small (nanomoles per liter) amounts of prothrombin to thrombin, albeit rather inefficiently; this initial thrombin is essential to the acceleration of the process by serving as the activator for platelets (see the article by Dr. Brass in this supplement), factor V, and factor VIII14
(Fig 1)
[see the article by Dr. Di Cera in this supplement]. Once factor VIIIa is formed, the factor IXa generated by factor VIIa-tissue factor combines with factor VIIIa on the activated platelet membrane to form the "intrinsic factor Xase" (Fig 2)
, which becomes the major activator of factor X. The factor IXa-factor VIIIa complex is 105- to 106-fold more active than factor IXa alone as a factor X activator and approximately 50 times more efficient than factor VIIa-tissue factor in catalyzing factor X activation; thus, the bulk of factor Xa is ultimately produced by factor IXa-factor VIIIa.15
As reaction time progresses, factor Xa generation by the more active intrinsic factor Xase complex exceeds that of the extrinsic factor Xase. As a consequence, most (> 90%) of factor Xa is ultimately produced by the factor VIIIa-factor IXa complex in the tissue factor-initiated hemostatic processes (Fig 4
). In the absence of factor VIII or factor IX, the intrinsic factor Xase cannot be assembled; thus, no amplification of the factor Xa generation occurs. This is the principal defect observed in hemophilia A and hemophilia B.16
Factor Xa combines with factor Va on the activated platelet membrane surface, and this factor Va-factor Xa "prothrombinase" catalyst (Fig 2
, Fig 4
) converts prothrombin to thrombin. Prothrombinase is 300,000-fold more active than factor Xa alone in catalyzing prothrombin activation.
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Figure 4.. Top: The factor Xa generated by the factor VIIa-tissue factor complex activates a small amount of thrombin, which activates factor V and factor VCIII, leading to the presentation of the intrinsic factor Xase (factor IXa-factor VIIIa) and prothrombinase (factor Xa-factor Va). At this point in the reaction, factor IXa generation is cooperatively catalyzed by membrane-bound factor Xa and by factor VIIa-tissue factor. The thick arrow representing factor Xa generation by the intrinsic factor Xase illustrates the more efficient Xa generation by this catalyst. Bottom: TFPI interacts with the factor VIIa-tissue factor-factor Xa product complex to block the tissue factor-initiated activation of both factor IX and factor X, leaving the factor IXaß-factor VIIIa complex as the only viable catalyst for factor X activation. Used with permission (The Dynamics of Hemostasis, Haematologic Technologies; K.G. Mann, PhD, 2002).
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The coagulation system is under extraordinarily tight regulation by both stoichiometric and dynamic inhibition systems (Fig 3)
. The tissue factor concentration threshold for reaction initiation is steep, and the ultimate amount of thrombin produced is largely regulated by the concentrations of plasma procoagulants, the stoichiometric inhibitors, and the constituents of the dynamic inhibition processes.
The principal influence of TFPI is to block the factor VIIa-tissue factor-factor Xa product complex (Fig 4)
, thus effectively neutralizing the extrinsic factor Xase and eliminating the generation of this catalyst of both factor Xa and factor IXa (Fig 4)
.17
TFPI function eliminates the essential initial production of factor Xa by the intrinsic factor Xase; however, the high-affinity TFPI is present at low abundance (approximately 2.5 nmol/L) in blood and can only delay the hemostatic reaction. The lower-affinity stoichiometric inhibitor AT-III is normally present in plasma at over twice the concentration (3.2 µmol/L) of any potential target coagulation enzyme generated by the tissue factor pathway. AT-III is an effective neutralizer of all the procoagulant serine proteases (Fig 3)
.18
The targets of AT-III are primarily the uncomplexed enzyme products of these reactions, including thrombin.
To initiate the dynamic protein C system, the product enzyme thrombin binds to constitutively present vascular thrombomodulin and activates the protein C to its activated species (activated protein C [APC]) [see the article by Dr. Esmon in this supplement].19
APC competitively binds with both factor VIIIa and factor Va, interfering with the formation of the prothrombinase and the intrinsic Xase, initially by competition with factor Xa and factor IXa and ultimately by cleaving the cofactor factor Va and factor VIIIa to eliminate these complexes (see the article by Dr. Esmon in this supplement).20
Thus, the combinations of TFPI and the protein C system and TFPI and AT-III cooperate to produce steep tissue factor concentration thresholds, acting like a digital "switch," allowing or blocking significant thrombin formation. The delay incurred by TFPI and the slower inhibitions by AT-III and the APC system control the level of tissue factor required to overcome the reaction threshold. TFPI can be released from the vasculature by the action of heparin,21
while thrombomodulin is constitutively present on the vascular endothelium. The relative concentrations of these two important regulators throughout the vascular system are not known.
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Initiation and Propagation
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Regardless of the analytical system chosen, the display of thrombin generation following tissue factor initiation of the hemostatic reaction is approximately the same.14
This behavior is illustrated in Figure 5
, which illustrates the generation of thrombin as a function of time in whole blood. Shortly following the addition of tissue factor, tiny amounts of thrombin are produced in an interval, which we define operationally as the initiation phase of the reaction. Subsequently, the major bolus (> 96%) of thrombin is produced during a propagation phase.
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Figure 5.. Top: Thrombin generation during tissue factor-initiated whole-blood experiments. The total thrombin formed is plotted as a function of time for sequential samples of human blood at 37°C inhibited only with respect to contact pathway activation and activated by the addition of 5 pmol/L tissue factor and 10 nmol/L phospholipid. The data (± SEM) are presented for 35 individual experiments (healthy adults) with an average clot time (C.T.) of 4.7 ± 0.2 min. The operationally defined initiation and propagation phases correspond respectively to the slow and fast kinetic expressions of thrombin formation. Reproduced with permission.14
Bottom: Thrombin generation and the points of initial detection of products from substrates during the initiation phase for the experiments presented in Figure 5
, top. Thrombin concentration is plotted on the vertical axis on an exponential scale vs time. Initial product detection includes platelet activation, factor V cofactor activation, fibrinopeptides, and other products. The inception of the "propagation phase" corresponds to the point at which there is a transition from slow to rapid thrombin generation. Reproduced with permission.14
FPA = fibrinopeptide A; FPB = fibrinopeptide B.
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During early events associated with the initiation phase (Fig 5) , thrombin activates the products required to provide the catalysts (Fig 2)
, which generate most of the thrombin produced during the propagation phase of the reaction. Under normal circumstances, the rate-limiting component of prothrombinase complex formation and the ultimate generation of thrombin activity is the concentration of factor Xa.22
The activations of platelets (see the article by Dr. Brass in this supplement) and factor V interactions occur rapidly to produce surplus factor Va and platelet membrane-binding sites (Fig 5
, bottom). However, under conditions of congenital deficiency, thrombocytopenia, platelet pathology, or antiplatelet pharmacologic intervention, the tissue factor-initiated reaction can become sensitive to factor V or platelets.23
The presentation of a clot, or clotting time depends on the generation of only 10 to 20 nmol/L of thrombin (Fig 5
, bottom). Thus, at high tissue factor concentrations, the robust generation of factor Xa by factor VIIa-tissue factor completely masks the contribution of the factor VIIIa-factor IXa complex in clot end point assays. This is the case for the standard prothrombin time assay in which the concentrations of thromboplastin (tissue factor and phospholipid) are chosen to produce a clot time of 11 to 15 s corresponding to a tissue factor concentration of > 20 nmol/L. In Figure 5
, a concentration of 5 pmol/L tissue factor was used, producing a clotting time of approximately 5 min. In hemophilia A and B, at the latter tissue factor concentrations the clotting time is prolonged; however, the major defect is associated with the absence of a propagation phase.24
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Accessory Processes
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In humans, the zymogen factor XI, which is present in plasma and platelets, has been variably associated with hemorrhagic pathology.25
Factor XI is a substrate for thrombin (Fig 1)
, and has been invoked in the so-called "revised pathway of coagulation," serving as another contributor to factor IX activation.26
Studies of blood from individuals with XI deficiency illustrate the importance of the feedback activation of factor XI, but only at the lowest tissue factor concentrations.24
At moderate concentrations of tissue factor (5 to 10 pmol/L), which produce clotting times in the range of 3 to 5 min, factor XI has little or no effect on thrombin generation or other procoagulant parameters. The variability of pathology with factor XI deficiency is most likely a reflection of the nature and extent of the vascular lesion in deficient individuals. While factor XII, prekallekrein, and high-molecular-weight kininogen do not appear to be fundamental to the process of hemostasis, the contribution of the contact pathway elements to thrombosis remains an open question and requires further experimentation to resolve this issue.
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Summary
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Technical advances in genetics, protein chemistry, bioinformatics, physical biochemistry, and cell biology provide us with an impressive array of tools and information with respect to normal pathologic processes leading to hemorrhagic or thrombotic disease. The challenge for the 21st century will be to merge mechanism-based, quantitative data with epidemiologic studies and subjective clinical experience associated with the tendency to bleed or thrombose, and with the therapeutic management of individuals with thrombotic or hemorrhagic disease. Our knowledge of the biology of coagulation is incomplete without considerations of pathology, rheology, vascular biology, and clinical medicine. We need to integrate mechanistic data with the vast amount of clinical experience regarding the management of individuals with thrombotic and hemorrhagic disease to develop algorithms that can combine the art of clinical management with the quantitative science available to define the phenotype vis á vis the outcome of a challenge or the efficacy of an intervention. Ultimately, we must tailor diagnosis and pharmacologic intervention to the individual.
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Footnotes
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Supported by grants HL 46703, HL 34575, and HL 07594 from the National Institutes of Health-National Heart, Lung and Blood Institute.
Abbreviations: APC = activated protein C; AT-III = antithrombin III; FPA = fibrinopeptide A; FPB = fibrinopeptide B; TFPI =tissue factor pathway inhibitor; TF = tissue factor
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Abstract
Introduction
