Review Diet and Blood Coagulation Factor VII–A Key Protein in Arterial
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European Journal of Clinical Nutrition (1998) 52, 75±84 ß 1998 Stockton Press. All rights reserved 0954±3007/98 $12.00 Review Diet and blood coagulation factor VIIÐa key protein in arterial thrombosis P Marckmann1, E-M Bladbjerg2 and J Jespersen2 1Research Department of Human Nutrition, Royal Veterinary and Agricultural University, Frederiksberg, Denmark; and 2Institute for Thrombosis Research, South Jutland University Centre, Esbjerg, Denmark Descriptors: nutrition; coronary heart disease; haemostasis; tissue factor; blood coagulation factor VII Introduction has the ability to degrade ®brin and in¯uences the outcome by counteracting the prothrombotic processes. Accordingly, The haemostatic system is essential for the preservation of the thrombotic propensity is linked to the balance, namely life. The haemostatic system protects man from exsangui- the haemostatic balance, between thrombus promoters nation after wound injuries and also forms the basis for the (platelets and coagulation factors) on the one side, and numerous tissue repair processes that are believed to be the thrombus-resolving ®brinolytic system on the other constantly ongoing within the vascular bed as initially (Astrup, 1956, 1958; Jespersen, 1988; Jespersen et al, proposed by Tage Astrup more than four decades ago 1993; Marckmann, 1995; Marckmann & Jespersen, 1996). (Astrup, 1956). The haemostatic system contributes to It has been known for many years that the coagulation atherogenesis and controls intravascular thrombus forma- system can be activated in vitro by either the intrinsic (the tion, and thus plays an important role in the development of FXII-dependent route) or the extrinsic route (the Tissue coronary heart disease (CHD), notably acute ischaemic Factor (TF) pathway) (Davie et al, 1991). Formerly, the events (myocardial infarction, unstable angina pectoris, two activation pathways were considered functionally and sudden death), and ischaemic stroke (Fuster et al, separated, and both were considered physiologically impor- 1992a, 1992b; Falk & FernaÂndez-Ortiz, 1995). These tant. However, FVII de®ciency is, whereas FXII de®ciency diseases are dominant causes of death in industrialised is not, associated with increased bleeding tendency, indi- countries. Accordingly, it is of utmost interest to gain cating that the FVII-dependent TF pathway is the important insight into the haemostatic system and its possible modi- route in vivo. Other observations support that the TF path- ®cation by internal and external factors. Such knowledge way is the `prima ballerina' of the coagulation system, and could pave the way for rational prevention of cardio- and also suggest that factors that were traditionally considered cerebrovascular disease. The present review describes how purely intrinsic, notably FIX, act as ampli®ers of the TF diet affects one key protein of the haemostatic systemÐ pathway under most circumstances (Hemker, 1984; blood coagulation factor VII (FVII)Ðand also discusses the ésterud, 1990; Davie et al, 1991; Nemerson, 1992; Rapa- possible mechanisms underlying the dietary control of port & Rao, 1992, 1995) (Figure 1). The TF pathway may FVII. The impact of diet on FVII and other important be particularly important in arterial thrombosis because haemostatic factors has been discussed in several other atherosclerotic plaques have a high content of membrane- recent reviews to which interested readers are referred for bound TF which becomes exposed to the ¯owing blood additional reading (Marckmann & Jespersen, 1994, 1996; when plaques rupture (Ardissino et al, 1997). The ®rst step Marckmann, 1995; Mennen et al, 1996; Miller, 1996; of the TF pathway is the complex formation of TF and FVII Vorster et al, 1997; Yahia & Sanders, 1997). and this explains why FVII is crucial in haemostasis, in general, and in arterial thrombosis, in particular. In most FVIIÐits role in arterial thrombosis situations, FVII appears to be the essential humoral initiator and trigger of ®brin formation (Rapaport & Rao, 1995; Formation of an arterial thrombus involves the arterial Monroe et al, 1996). intima and the haemostatic system, namely platelets, blood coagulation factors, and the ®brinolytic system, and their complex interaction. The process is initiated by Native and activated FVII endothelial perturbation or disruption, primarily at sites of atherosclerotic plaques (Falk, 1991; Falk & FernaÂndez- FVII is produced by hepatocytes and is released into the Ortiz, 1995). The intimal perturbance causes activation of circulation in its native form, namely FVII zymogen. In this platelets and coagulation factors resulting in ®brin forma- form, it is a single-chained 406 amino acid residue glyco- tion and deposition on the location. The ®brinolytic system protein with a molecular mass of about 50 000 and a plasma half-life of 5±6 h. Vitamin K is cofactor for the post- translational carboxylation of glutamate residues of FVII Correspondence: Dr P Marckmann, Human Nutrition, Rolighedsvej 30, DK-1958 Frederiksberg C, Denmark. which is crucial for its ability to bind calcium ions and thus Received 7 July 1997; accepted 3 October 1997 for its function (Furie & Furie, 1992). Diet and blood coagulation factor VII P Marckmann et al 76 is mixed with human TF, CaCl2, and FVII de®cient plasma (Marbet & Duckert, 1992). The clotting time is recorded and FVIIc expressed relative to a log±log linear calibration curve based on a reference plasma. FVIIc re¯ects a combi- nation of the plasma concentrations of FVIIa and FVII zymogen, because FVII activation takes place in the test tube during assaying. The FVIIc measurement is dependent on the quality of the FVII de®cient plasma, and, in particular, on whether the TF used for the analysis is obtained from man or other species (Poggio et al, 1991). We consider human TF (brain or placenta) the physiologi- cally most relevant TF for FVIIc measurements in man, but rabbit TF may be an acceptable alternative. The concentration of FVIIa in plasma may be assessed by different methods (Kitchen et al, 1992). Initially, FVIIa was assessed in a one-stage clotting assay similar to that used for FVIIc, the only difference being that bovine TF Figure 1 A simpli®ed hypothetical outline of blood coagulation activa- replaced human TF. This principle was based on observa- tion in vivo. The interactions are dependent of phospholipids and are tions indicating that bovine TF has a selective af®nity for believed to take place on cell membrane surfaces. The dotted arrow FVIIa (Hemker et al, 1976; Poggio et al, 1991; Kitchen et represents the train of events leading from FXa downstream to ®brin al, 1992). The nomenclature is somewhat confusing, but we formation. Readers are referred to other reviews for details (Davie et al, 1991; Rapaport & Rao, 1992). Abbreviations: TF tissue factor; and others have used the term FVIIbt (bt for bovine TF) for F blood coagulation factor; a activated form. this measurement. A more speci®c assay for FVIIa was developed by Morrissey and coworkers (Morrissey et al, 1993; Morrissey, 1995). This assay is also a one-stage Native FVII protein can be converted to two-chained clotting assay, but uses a truncated, soluble, recombinant activated FVII (FVIIa) in vitro by thrombin, TF-FVIIa TF, which possesses cofactor function for FVIIa. The complex and activated forms of FIX, FX, and FXII. The truncated TF does not support autoactivation of FVII FVII activation is strongly facilitated by binding of FVII zymogen, however. Accordingly, FVII zymogen should zymogen to TF and is furthermore dependent on the not in¯uence this FVIIa measurement. Morrissey's presence of phospholipids, namely cell membranes (Rapa- FVIIa assay is now commercially available (Staclot1 port and Rao, 1992; Petersen et al, 1995). It is not known VII-rTF, Stago, AsnieÁres, France). A recent study com- with certainty by which mechanisms FVII activation takes pared it with the FVIIbt assay and concluded that the two place in vivo, but some observations indicate that circulat- methods were in good agreement (Kario et al, 1995). Most ing trace amounts of FVIIa or FIXa are the principal FVII recently, an ELISA assay based on FVIIa antibodies was activators. Subsequently, the newly formed TF-FVIIa will introduced (Philippou et al, 1997). According to this assay, attack its natural substrates, FIX and FX, resulting not only normal plasma FVIIa concentration is below 0.1 ng=mL in the propagation of the clotting cascade, but also in back- (less than 0.002 nmol=L), whereas Morrissey's functional activation of TF-bound unactivated FVII (Rapaport & Rao, assay estimates that it is about 3 ng=mL (0.06 nmol=L). 1995; Morrissey, 1995; Petersen et al, 1995) (Figure 1). This large difference could be explained by unexpected Under basal conditions, FVIIa circulates at concentrations FVII zymogen activation in the functional assay or the fact corresponding to approximately 1% of the concentration of that two different assay principles are used, but the question native FVII. Its estimated half-life is 2±3 h (Seligsohn et al, is unsettled. 1979). The total FVII protein concentration (zymogen and Tissue Factor Pathway Inhibitor (TFPI) is the only FVIIa) in plasma may be assessed by two methods, either known inhibitor of the TF-FVIIa complex. Following gen- directly in an ELISA assay using an antihuman FVII rabbit eration of FXa, TFPI ®rst binds to FXa thereby inhibiting polyclonal IgG as ®rst and second antibody, or indirectly by FXa. The TFPI-FXa complex subsequently binds to TF- a functional two-stage amidolytic micro-titre assay FVIIa forming an inactive quarternary complex. Readers (Coaset1 FVII, Chromogenix, MoÈlndal, Sweden). We are referred to other reviews for further details (Abildgaard recommend that FVII protein measurements are referred et al, 1993; Petersen et al, 1995). to as FVIIag (ag for antigen) when ELISA assays are used, and as FVIIam (am for amidolytic) when the amidolytic assay is used. The two methods should give comparable FVII assays results, except if the tested plasma contains FVII or FVIIa Various FVII assays describing different aspects of FVII that are functionally abnormal.