Review Diet and Blood Coagulation Factor VII–A Key Protein in Arterial

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 combination 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 physiologically 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 observation 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. are now available. It is essential that researchers are aware of the differences between these assays and that they select FVII and coronary heart disease carefully between them according to the aim of their study. Because of the assay differences, it is extremely important Based on the evidence presented so far, one would expect that all research publications within this area contain exact elevated plasma levels of FVII to be associated with an information about the methodology used for FVII measure- increased risk of arterial thrombosis. Till now, only two ment. prospective epidemiological studies have tried to demon- The classical FVII assay is based on the ability of a test strate that to be the case. The Northwick Park Heart Study plasma to correct the clotting time of FVII de®cient plasma (NPHS) comprised 1459 healthy middle-aged men who had and measures by de®nition FVII coagulant activity (FVIIc). their plasma FVIIc measured in non-fasting morning sam- It is a one-stage clotting assay in which diluted test plasma ples, and in that study FVIIc was indeed found to predict Diet and blood coagulation VII P Marckmann et al 77 total and fatal CHD cases within the ®rst 5 y of follow-up fat (62 En% from fat) and low-fat (13 En%) diets were (Meade et al, 1980, 1986a). With longer follow-up periods, followed for periods of 2±3 weeks by six volunteers, and FVIIc was only predicting fatal CHD (Meade et al, 1993; FVIIc was found to be 16% higher on the high-fat diet. The Ruddock & Meade, 1994). Meade and coworkers estimated authors suggested that the FVIIc effect was primarily due to that an increase in FVIIc of 1 s.d. (approximately 25%) will the dietary differences in fat content. The prescribed diets increase the 5 y risk of fatal CHD with 55% (Meade differed also in several other aspects (for example total et al, 1986a). The Prospective Cardiovascular MuÈnster energy, alcohol, and dietary ®ber contents), however. Later (PROCAM) study is based on the measurement of plasma observations have indicated that the independent effect of FVIIc in fasting blood samples of more than 2500 middle- the total fat content may be very limited and that complex aged men without prior history of myocardial infarction or dietary changes are required to obtain an effect on fasting stroke. In line with NPHS, the PROCAM study showed that FVIIc (Marckmann et al, 1992a, 1994). In our ®rst trial, the elevated FVIIc is associated with an increased risk of acute experimental low-fat high-®ber diets caused a signi®cant CHD events (fatal and non-fatal) as assessed after follow- 11±15% lowering of FVIIc compared with the moderately up periods of 6±8 y (Heinrich et al, 1994; Assmann et al, high-fat diets habitually eaten (Marckmann et al, 1990). 1996). The same study demonstrated that the effect on fasting Ecological studies have reported that FVIIc is higher in FVIIc was due to a change in the total FVII protein countries where CHD is more prevalent (Meade et al, concentration (FVIIag) with proportionate changes in 1986b; Iso et al, 1989). Also, CHD patients and individuals FVIIbt. Other studies con®rmed that diets corresponding at high risk of CHD had higher plasma levels of FVIIc, to current dietary recommendations, namely low in total fat FVIIa, or FVIIag than healthy controls in several case- content and high in ®ber, may lower healthy individuals' control studies (Hoffman et al, 1989; Suzuki et al, 1991; fasting FVIIc by 5±15% compared with the type of diet Burns et al, 1993; Kario et al, 1994; Moor et al, 1995). In eaten in most industrialized societies (Marckmann et al, other studies there were no differences between patients 1993a, 1994; Brace et al, 1994). Two larger studies of free- and controls, or even lower values among patients (Salo- living individuals were unable to con®rm the FVIIc low- maa et al, 1994; Lane et al, 1996). These inconcistencies ering effects seen in more strictly controlled dietary studies, are not easily understood, but methodologically differences however (Anderssen et al, 1995; Velthuis-te Wierik et al, between studies might contribute. Furthermore, CHD 1996). Their negative results might re¯ect an insuf®cient patients may have lowered their FVII levels by changes compliance with the dietary protocols which is supported in lifestyle after having been diagnosed in some of the by the absence of expected body weight and blood lipid studies. Within groups of patients with diagnosed athero- changes in the two studies. sclerosis or CHD, FVIIc is neither predicting future CHD Blood lipids, in particular LDL cholesterol concentra- risk nor associated with the number of diseased coronary tions, are strongly affected by the fatty acid composition of vessels (Cortellaro et al, 1992; ECAT Angina Pectoris the diet. Several trials have investigated whether fasting Study Group, 1993). FVII levels also are modi®ed by the dietary fat quality. The In conclusion, FVIIc was shown to be an independent issue is not fully resolved, but at present it may be predictor of acute CHD events in healthy males in two concluded thatÐwith few possible exceptionsÐthere is separate prospective studies. It remains to be investigated no effect of the dietary fatty acid composition. In one of whether FVIIa or FVIIag might be better predictors, and the earliest studies, strictly controlled diets rich in either whether FVII is also a risk factor among healthy females. monounsaturated (MUFA) or polyunsaturated fatty acids Apparently, FVII measurements can neither be used for (PUFA) were consumed in random order for periods of prediction of future acute CHD events nor assessment of 23 d by 38 young, healthy volunteers (Heinrich et al, the extent of coronary atherosclerosis within populations 1990). Plasma FVIIc was similar on the the two diets. with diagnosed CHD. We compared diets rich in either saturated fatty acids (SFA) or n-6 PUFA in two separate studies and concluded that the exchange of dietary fat had no effect on neither Dietary effects on FVII FVIIc, FVIIbt, nor FVIIag (Marckmann et al, 1990, FVIIs key position in the haemostatic system and CHD 1992b). Similar conclusions were reached in a study in pathogenesis makes it important to know whether FVII is which the intake of SFA and n-6 PUFA differed more in¯uenced by environmental factors. In that case, environ- markedly (Miller et al, 1991). In agreement herewith, one mental modi®cation of FVII function could contribute to study showed that dietary counseling aiming at decreasing prevention and treatment of CHD and other atherothrom- saturated and increasing polyunsaturated fat intake had no botic diseases. effect on FVIIc (Rankinen et al, 1994a). In a strongly designed study from New Zealand, 6±8 weeks on high fat Diet and fasting FVII diets enriched with either SFA (dairy and coconut pro- The ®rst dietary trial demonstrating an effect on FVII was a ducts), MUFA (olive and rapeseed oil), or n-6 PUFA single-armed intervention study in which eleven hyperli- (sun¯ower oil and margarine) resulted in similar FVIIc pemic men had their FVIIc assessed before and after a 1±5 levels, whereas expected differences in blood lipids were month period on a low energy, low-saturated fat diet seen (Foley et al, 1992). Two recent studies compared fats (Elkeles et al, 1980). An average plasma FVIIc decline of high in trans fatty acids with fats with a low content of trans 24% was observed. Others reported similar results when isomers and found no differences with respect to FVIIc non-insulin dependent diabetics or hypertriglyceridemic (Almendingen et al, 1996; Mutanen & Aro, 1997). Also, patients were treated with low-fat high-®ber diets for marine n-3 fatty acids seems to have no effect on FVII periods of 6±24 weeks (Simpson et al, 1982, 1983, Skar- levels (Schmidt et al, 1990, 1992; Marckmann et al, 1991, tlien et al, 1989, Jennings et al, 1991). In 1986, it was 1997a; ésterud et al, 1995; reviewed in: Marckmann, reported that FVIIc is also in¯uenced by diet in healthy 1995). Most previous trials thus agree that the dietary subjects (Miller et al, 1986). In this study, prescribed high- fatty acid composition has no effect on fasting FVII Diet and blood coagulation factor VII P Marckmann et al 78 It may be concluded that fasting FVIIc can be lowered 5±25% by a dietary change from a high-fat Western diet to a low-fat diet high in dietary ®ber (Table 1). A change of this magnitude may modify CHD risk markedly according to epidemiological studies. The available evidence suggests that the effect on FVIIc of a change from a high-fat to a low-fat high-®ber diet cannot be attributed to one single dietary component, in particular neither to fat quantity nor quality (Marckmann & Jespersen, 1996). Shea fat, an uncommon fat in Western countries, might have a unique ability to lower FVIIc which may be unrelated to its fatty acid composition. Finally, dietary supplementation with large amounts of oat bran might reduce FVIIc. The effect of shea fat and oat bran supplementation needs to be con®rmed, however. Dietary effects on fasting FVIIc seems primarily explained by changes in the plasma concentration of FVII protein concentration with proportionate changes in FVII zymogen and FVIIa.

Meals and postprandial FVII Figure 2 Individual and median fasting FVIIc (%) of 12 young men after Zilversmit made the point that man is mostly non-fasting 16 d consumption of two strictly controlled diets served in random order. and that non-fasting biochemical events have a strong The two diets were identical except for their dietary ®ber content. The low- impact on human (patho)physiology, including atherogen- ®ber diet (LOW) contained 2.5 g=MJ, the oat-bran diet (OAT) 3.8 g ®ber=MJ. The difference was achieved by the incorporation of 10 g oat esis and thrombogenesis (Zilversmit, 1979). This prompted bran=MJ into the oat-bran diet (Marckmann & SandstroÈm, 1994). the initiation of numerous postprandial studies, amongst *P < 0.05. which some focused on FVII. Miller and coworkers were the ®rst to report an effect of diet composition on postprandial FVIIc (Miller et al, 1986). levels. Single exceptions are found. Shea fat rich in stearic They found that meals to which fat was added led to acid reduced FVIIc 15±20% as compared with fats high in markedly higher FVIIc levels in the afternoon than meals either palmitic acid (palm oil) or a combination of lauric added carbohydrates. Several later studies have con®rmed and myristic acid (palmkernel and high-oleic acid sun- that high-fat meals cause a postprandial increase in FVIIc ¯ower oil mixture) in one study (Tholstrup et al, 1994a). relative to isoenergetic low-fat meals (Marckmann et al, As underlined in the original article, this effect might have 1993b; Salomaa et al, 1993; Bladbjerg et al, 1994; Sanders been caused by non-glyceride components of shea fat, and et al, 1996; Larsen et al, 1997). These studies also showed this certainly seems to be the most likely explanation in the that the fat-induced FVIIc increase is caused by higher light of later reports (Almendingen et al, 1996; Mutanen & concentrations of FVIIa, whereas postprandial FVIIag pro- Aro, 1997). In another study, small FVIIc differences (2%) ®les are virtually similar for low- and high-fat meals. between fats rich in either palmitic (palm oil) or myristic Typical postprandial pro®les of FVIIc, FVIIa and FVIIag acid (synthetic fat) were found (Tholstrup et al, 1994b). after isoenergetic high- and lowfat meals are depicted in Finally, one study reported that a SFA-rich high-fat diet is Figure 3. The difference between diets is most apparent associated with higher FVIIc, FVIIag, and FVIIa levels during late afternoon and early evening. than a n-6 PUFA-rich high-fat diet (Mitropoulos et al, A few studies have elucidated the effect of different fats 1994). We would suggest that the low number of partici- and fatty acids on postprandial FVII levels. Diets high in pants (®ve) and limited dietary control of this study might either SFA or n-6 PUFA were similar with respect to have led to the con¯icting ®nding by chance. fasting and non-fasting FVIIc and FVIIag in the ®rst Few intervention trials investigated the independent report on this issue (Miller et al, 1991). Later studies also effect of other dietary components. The effect of increasing found that SFA and n-6 PUFA cause similar postprandial dietary ®ber from 2±4 g=MJ at a ®xed intake of carbohy- FVII pro®les (Salomaa et al, 1993; Freese & Mutanen, drate and fat by exchanging low-®ber with high-®ber foods 1995). Monounsaturated fats (rapeseed and olive oil) seem in a mixed diet had no effect in one unpublished study from to share the acute FVII activating effect with other common our department. However, dietary supplementation with fats (Freese & Mutanen, 1995; Sanders et al, 1996; Roche large amounts of oat bran (10 g=MJ) rich in soluble b- & Gibney, 1997; Larsen et al, 1997). As an exception, glucans caused a signi®cant decline in FVIIc in another triglycerides of medium chained fatty acids do not raise strictly controlled cross-over study of 12 young males postprandial FVIIc and FVIIa (Sanders et al, 1996). One (Figure 2) (Marckmann & SandstroÈm, 1994). Coffee and study compared the effect of stearic and myristic acid and caffeine seems to have no effect on FVIIc (Bak et al, 1990). found no signi®cant differences (Tholstrup et al, 1996). A

Table 1 Dietary changes leading to lowering of fasting FVII protein concentration (FVIIag) and proportionate decline in FVIIc and FVIIa

Exchanging high-fat diet with low-fat high-®ber diet: 5±25% reduction Exchanging habitual fat with shea fat: 15±20% reduction? Incorporating large amounts of oat bran into the diet: 5±10% reduction?

? Only shown in exploratory studies, needs con®rmation. Diet and blood coagulation VII P Marckmann et al 79 Diet and FVII in epidemiological studies Experimental studies provide the de®nitive proofs regarding diet and FVII, but epidemiological observations may support these ®ndings or suggest hitherto unknown relations. A series of cross-sectional studies investigated the relation between total dietary fat and FVIIc. These studies all share the problem of getting valid estimates of individual dietary intakes. Nevertheless, several trials suggested that total fat intake was positively associated with FVIIc (Miller et al, 1989; Connelly et al, 1993; VaÈisaÈnen et al, 1995). Others were unable to con®rm it, however (Ranki- nen et al, 1994b; Mutanen et al, 1995; Bijnen et al, 1996). Very recently, Mennen and coworkers published an out- standing epidemiological study on diet and FVIIc (Mennen et al, 1997). It was based on dietary assessments and FVIIc measurements of 3007 elderly individuals of both sexes. The dietary assessment methods (semiquantitative food- frequency questionnaire) was of high quality and allowed the estimation of other aspects of the diet than just total fat intake. Mennen and coworkers concluded that total and monounsaturated fat intakes were positively associated with FVIIc only in women, that saturated fat intake was positively associated with FVIIc in both sexes, that polyunsaturated fat intake was inversely associated with FVIIc in men only, and that the dietary ®ber content was strongly and inversely associated with FVIIc. The relation between dietary fatty acid composition as estimated from the plasma phospholipid fatty acid composition and FVIIc was studied in 2207 healthy middle-aged individuals (Folsom et al, 1994). A positive association between the saturated fatty acid content of phospholipids and FVIIc, and an inverse relationship between linoleic acid and FVIIc was observed. In a similar study, Girelli and coworkers found a positive association between plasma lipid contents of saturated fatty acids, notably stearic acid, and FVIIc (Girelli et al, 1996). Vegetarianism has been studied by two groups and they reached con¯icting conclusions (Haines et al, 1980; Pan et al, 1993). Finally, one study suggested that FVIIc is inversely associated with the intake of vitamin C as assessed from serum ascorbate concentrations (Khaw & Woodhouse, 1995). Overall, the epidemiological studies support the existence of a link from diet to FVIIc. Their ®ndings must be cautiously interpreted, however. Several of the observed associations might be explained by underlying covariance between speci®c nutrients and certain dietary patterns (for example those Figure 3 Typical diurnal variation in FVIIc, FVIIa, and FVIIag after with high saturated fat intake might be those eating high-fat consumption of low-fat (15±20% of energy from fat, broken line) and high-fat (40±60% of energy from fat) meals for breakfast, lunch, and diets with a low ®ber content). As stated earlier, the ®nal dinner. Fasting levels are set at 100 arbitrary units. Panel 1: FVII coagulant evidence comes from controlled dietary studies. activity (FVIIc). Panel 2: Activated FVII (FVIIa). Panel 3: FVII protein concentration (FVIIag). Possible mechanisms explaining dietary effects on FVII single study indicated that there was no acute in¯uence of Dietary modi®cation of fasting FVIIc may occur within 10± varying the ®ber content of meals from 2±4 g=MJ on 14 d after a dietary change due to changes in the plasma postprandial FVII levels (Marckmann et al, 1993b). concentration of FVII protein (FVIIag) with proportionate Contrary to what was concluded regarding the effect of a changes in FVII zymogen and FVIIa (Miller et al, 1986, dietary change on fasting FVIIc, the link between meal 1995; Marckmann et al, 1990, 1991, 1994; Bladbjerg et al, composition and postprandial FVII pro®les seems to be 1995). In contrast, FVIIa changes seems to explain the strongly in¯uenced by one single component, namely the entire acute and transient dietary effect on postprandial total fat content of the meal. Increasing the total fat content FVIIc in meal studies (Marckmann et al, 1993b; Salomaa et leads to more extensive postprandial FVII activation, irre- al, 1993; Bladbjerg et al, 1994; Silveira et al, 1994a; Miller spective of the type of fat used. Fats composed of medium et al, 1996a; Kapur et al, 1996). The mechanisms explain- chained fatty acids seems to be the only exception, which ing acute and longer term dietary effects on FVIIc may, may be related to the fact that medium chained fatty acids accordingly, differ. are not transported by chylomicrons but go directly to the Fasting plasma triglyceride concentrations correlate liver via the portal vein. positively with FVIIc and FVIIag in most studies (reviewed Diet and blood coagulation factor VII P Marckmann et al 80 in: Miller, 1993; Marckmann, 1995; Mennen et al, 1996) concentration suf®ciently high to allow micelle formation and treatment of hyperlipidaemia causes a reduction in seems unlikely due to the very high af®nity of albumin for FVIIc (Elkeles et al, 1980; Simpson et al, 1983). The unbound fatty acids (Bojesen & Bojesen, 1996). In addi- association between triglyceride-rich lipoproteins (TRLP) tion, recent trials showed that high-fat meals lead to FVII and FVIIc seems particularly strong (Mitropoulos et al, activation even in FXII-de®cient individuals (Miller et al, 1989a). Furthermore, FVIIag seems to co-vary with the 1996a; Silveira et al, 1996). The same studies underscored plasma concentration of other vitamin K-dependent coagu- that FIX is required for postprandial FVII activation which lation factors (Constantino et al, 1977; Burns et al, 1993; is in line with the current perception of the initiating steps Hoffman et al, 1994; Bladbjerg et al, 1995). These obser- in the activation of blood coagulation (cf. Figure 1). vations indicate that dietary modi®cation of FVIIag and Intravenous infusions of fat emulsions may lead to fasting FVIIc may be mediated through TRLP as part of a increased expression of TF activity by monocytes (Lattan- general effect on vitamin K dependent proteins. Two zio et al, 1984). This ®nding indicates that TRLP might different mechanisms explaining this link have been pro- in¯uence the availability of TF required for FVII activation posed. Firstly, elevated plasma concentrations of TRLP and offers an alternative hypothetical link from TRLP to might cause accentuated FVII activation leading to raised FVIIa. This possibility should be further investigated. prothrombin fragment 1 2 (F1 2) generation which might ®nally increase the hepatic synthesis of vitamin K dependent proteins. This hypothesis is based on a rabbit Non-dietary factors and FVII experiment in which intravenous injection of F1 2 frag- Plasma FVII levels are in¯uenced by several other factors ments was associated with a transient increase in the besides diet. It is not possible to discuss these other factors plasma concentrations of prothrombin and FX, both vita- in detail within the limits of the present review, but some min K-dependent proteins (Mitropoulos & Esnouf, 1990). points can be made. Plasma FVIIc increases with age The ®nding that accentuated FVII activation is not asso- (Brozovic et al, 1974; Balleisen et al, 1985; Folsom et al, ciated with increased F1 2 generation in healthy humans 1991). Body weight and body mass index are also posi- is in con¯ict with it, however. The other hypothesis is based tively associated with FVIIc (Balleisen et al, 1985; Folsom on experiments showing that FVII and FX adhere to TRLP et al, 1991), and FVIIc declines when obese individuals (chylomicrons and VLDL) which might make them less loose weight (Folsom et al, 1993). Smoking seems to have available for catabolic degradation, thus raising their no in¯uence (Balleisen et al, 1985; Folsom et al, 1991). plasma concentration (Sousa et al, 1988, 1989). This Pregnancy is associated with markedly elevated FVIIc hypothesis is challenged by the fact that patients with (Dalaker, 1986), whereas oral contraceptives and postme- lipoprotein lipase (LPL) de®ciency and massive hypertri- nopausal hormone replacement therapy seems to raise glyceridaemia have normal FVIIag levels (Mitropoulos et FVIIc more moderately (Folsom et al, 1991). Post- al, 1992). Both hypotheses are further challenged by the menopausal women have higher FVIIc levels than preme- fact that dietary changes in fasting triglycerides and FVIIc nopausal women of same age (Scarabin et al, 1996). There may be dissociated or even opposed (Schmidt et al, 1990, are only minor FVIIc differences between sexes in popula- 1992; Marckmann et al, 1993a, 1994). tion surveys (Brozovic et al, 1974; Balleisen et al, 1985). High-fat meals causing postprandial hypertriglyceride- However, previous dietary trials included mostly men and mia are associated with acute FVII activation. It is therefore an interaction between diet and gender with respect to tempting to suggest that TRLP or products of TRLP FVIIc cannot be excluded. Ethnic differences have been lipolysis are causally involved in postprandial FVII activa- reported, but they may be explained by differences in life- tion. The ®rst study in this ®eld reported that postprandial style and genetic constitution (Meade et al, 1986b; Iso et al, triglyceride peak concentrations correlated with FVIIc 1989). peaks 180 min later, indicating that postprandial FVII The FVII gene is located on chromosome 13 (Ott & activation is somehow controlled by the triglyceride con- Pfeiffer, 1984). Several mutations have been identi®ed, but centration (Miller et al, 1991). Several others tried to only the R353Q and promoter polymorphisms seem to be con®rm that postprandial triglycerides and FVIIa correlate, frequent and functionally important. The R353Q poly- but their ®ndings have been inconsistent (Marckmann et al, morphism is located in exon 8 of the FVII gene. It is 1933b; Salomaa et al, 1993; Bladbjerg et al, 1994; Silveira caused by a single base change from guanine to adenine in et al, 1994a, 1994b, 1996; Kapur et al, 1996; Larsen et al, the codon for aminoacid residue 353 of native FVII protein, 1997). leading to the replacement of arginine (R) with glutamine In vitro studies indicate that lipolysis of TRLP promotes (Q). The Q allele frequency ranges from 0.03±0.29 in the activation of FXII to FXIIa (Mitropoulos & Esnouf, different populations. Heterozygous individuals (RQ) 1991; Mitropoulos et al, 1989b, 1992, 1993). Subse- have approximately 25% lower plasma levels of FVIIc, quently, FXIIa might cleave single-chain FVII to FVIIa, FVIIag, and FVIIa than RR individuals (Green et al, 1991; thus forming the link from postprandial plasma triglycer- Lane et al, 1992; Saha et al, 1994; Moor et al, 1995; ides to FVIIa. Mitropoulos and coworkers put special Bentzen et al, 1996; Bernardi et al, 1996). The promoter emphasis on the fatty acid composition of TRLP because polymorphism is caused by a 10 base pair insertion in the their studies showed that micelles of long-chained SFA promoter region. The frequency of the rare P10 allele is were far better FXII activators than unsaturated fatty acids similar to the Q allele of the R353Q polymorphism with (Mitropoulos & Esnouf, 1991). According to their hypoth- which its also shows strong allelic association. Similar to esis TRLP lipolysis leads to the formation of intravascular the Q allele, the P10 allele is associated with lower FVIIc, micelles of unbound albumin-free fatty acids that provide FVIIag, and FVIIa levels, and the P10 allele might be the the negatively charged surface necessary for FXII activa- stronger determinant of low FVII levels of the two tion. Although attractive, it is strongly contradicted by (Humphries et al, 1996; Bernardi et al, 1996). certain biochemical studies and human observations. Bio- The ®nding that the positive association between fasting chemically, the accumulation of unbound fatty acids at a plasma triglycerides and FVIIc is con®ned to the RR Diet and blood coagulation VII P Marckmann et al 81 genotype and weaker or absent among individuals carrying impact of dietary FVII modi®cation on thrombin generation the Q allele of the R353Q polymorphisms suggests an are highly warranted. The amazing ®ndings in trials where interaction between gene and environment (Lane et al, diet was used for secondary prevention of CHD could not 1992; Humphries et al, 1994). This possibility can be be explained by effects on traditional risk factors and might explored in dietary trials of individuals with different be related to dietary modi®cation of key components of the FVII genotypes. The ®rst studies indicate that RQ indivi- haemostatic system, not the least of FVII (Singh et al, duals respond in the same way as RR individuals to fatty 1992; de Lorgeril et al, 1994). Hopefully, future studies of meals, although at a lower level (Silveira et al, 1994b; this kind will include the measurement of FVII. Marckmann et al, 1997b). References Physiological impact of FVII Abildgaard U, Sandset PM & Lindahl AK (1993): Tissue factor pathway Plasma FVII de®ciency causes severe bleeding, and FVIIa inhibitor. In Blood Coagulation, ed. L Poller, pp 105±124. Edinburgh: infusions may correct increased bleeding tendency not only Churchill Livingstone. Almendingen K, Selje¯ot I, Sandstad B & Pedersen JI (1996): Effects of in cases of FVII de®ciency, but also in classical Hemophi- partially hydrogenated ®sh oil, partially hydrogenated soybean oil, and lia A and B (Mariani & Mazzucconi, 1983; Lusher, 1996; butter on hemostatic variables in men. Arterioscler. Thromb. Vasc. Biol. Bauer, 1996). These ®ndings demonstrate the importance 16, 375±380. of FVII in haemostasis. The impact of FVIIc in human Anderssen SA, Haaland A, Hjermann I, Urdal P, Gjesdal K & Holme I thrombogenesis was suggested by the ®nding of positive (1995): Oslo Diet and Exercise Study: A one-year randomized intervention trial. Effect on hemostatic variables and other coronary risk associations between FVIIc and prothrombin fragment factors. Nutr. Metab. Cardiovasc. Dis. 5, 189±200. 1 2 (F1 2) (Miller et al, 1996b; Gouin-Thibault et al, Ardissino D, Merlini PA, ArieÈns R, Coppola R, Bramucci E & Mannucci 1996), and by the rise in F1 2 that follows infusion of PM (1997): Tissue-factor antigen and activity in human coronary recombinant FVIIa in FVII-de®cient patients (Bauer et al, atherosclerotic plaques. Lancet 349, 769±771. Arnljots B, Ezban M & Hedner U (1997): Prevention of experimental 1996). More direct evidence comes from animal experi- arterial thrombosis by topical administration of active site-inactivated ments showing that inhibition of the TF pathway causes factor VIIa. J. Vasc. Surg. 25, 341±346. less ®brin formation and thrombogenesis following intimal Assmann G, Cullen P, Heinrich J & Schulte H (1996): Hemostatic injuries of the arteries (Speidel et al, 1996; Jang et al, 1995; variables in the prediction of coronary risk: Results of the 8 year Arnljots et al, 1997). follow-up of healthy men in the MuÈnster Heart Study (PROCAM). Isr. J. Med. Sci. 32, 364±370. An important question is whether dietary modi®cation Astrup T (1956): The biological signi®cance of ®brinolysis. Lancet, ii, of FVII affect in vivo thrombin generation and ®brin 565±568. formation or whether dietary FVII changes are counter- Astrup T (1958): The haemostatic balance. Thromb. Diath. Haemorrh. 2, balanced by some mechanism. This may be assessed by the 347±357. Bak AA, Vliet HHDM van & Grobbee DE (1990): Coffee, caffeine and measurement of split products of prothrombin and ®brino- hemostasis: Results from two randomized studies. Atherosclerosis 83, gen. The question has only been addressed in few studies. 249±255. One study reported that dietary lowering of fasting FVIIc Balleisen L, Bailey J, Epping P-H, Schulte H & Loo J van de (1985): and FVIIag was accompanied by a decrease in F1 2 Epidemiological study on factor VII, factor VIII and ®brinogen in an (Bladbjerg et al, 1995). This observation contrasts with industrial population: I. Baseline data on the relation to age, gender, body-weight, smoking, alcohol, pill-using and menopause. Thromb. those of two meal studies in which F1 2 levels were not Haemost. 54, 475±479. affected by acute postprandial FVII activation (Silveira Bauer KA (1996): Treatment of factor VII de®ciency with recombinant et al, 1996; Kapur et al, 1996). All three studies included factor VIIa. Haemostasis 26, Suppl 1, 155±158. healthy volunteers with F1 2 concentrations very close to Bauer KA, Eichinger S, Mannucci PM & Rosenberg RD (1996): Deter- minants of coagulation activation in humans. Haemostasis 26, Suppl 1, the detection limit. Furthermore, it should be considered 72±75. that an increase in FVIIc, FVIIag, and=or FVIIa may rather Bentzen J, Bladbjerg EM, de Maat MPM & Marckmann P (1996): Plasma represent a state of increased `readiness' of the coagulation factor VII levels are determined by polymorphisms in the factor VII system than of increased thrombin formation. Major bursts gene. Fibrinolysis 10, Suppl 2, 17±18. of thrombin formation is dependent on local catastrophies Bernardi F, Marchetti G, Pinotti M, Arcieri P, Baroncini C, Papacchini M, Zepponi E, Ursicino N, Chiarotti F & Mariani G (1996): Factor VII of the arterial intima and massive TF exposure which are gene polymorphisms contribute about one third of the factor VII level unlikely to occur in healthy individuals. Therefore, we variation in plasma. Arterioscler. Thromb. Vasc. Biol. 16, 72±76. suggest that future studies investigate the consequences of Bijnen FCH, Feskens EJM, Giampaoli S, Menotti A, Fidanza F, Hornstra dietary modi®cation of FVII in individuals at high risk G, Caspersen CJ, Mosterd WL & Kromhout D (1996): Haemostatic parameters and lifestyle factors in elderly men in Italy and The of thrombosis, such as CHD patients with coronary Netherlands. Thromb. Haemost. 76, 411±416. atherosclerosis. Bladbjerg EM, Marckmann P, SandstroÈm B & Jespersen J (1994): Non- fasting factor VII coagulant activity (FVII:C) increased by high-fat diet. Thromb. Haemost. 71, 755±758. Conclusions and perspectives Bladbjerg EM, Tholstrup T, Marckmann P, SandstroÈm B & Jespersen J (1995): Dietary changes in fasting levels of factor VII The current understanding of the haemostatic system places coagulant activity (FVII:C) are accompanied by changes in factor VII FVII in a key position. In agreement herewith, epidemio- protein and other vitamin K-dependent proteins. Thromb. Haemost. 73, logic data indicate that raised plasma levels of FVIIc 239±242. promote coronary thrombosis. Dietary modi®cation of Bojesen E & Bojesen IN (1996): Albumin binding of long-chain fatty acids: Thermodynamics and kinetics. J. Phys. Chem. 100, 17981± FVIIc might thus have a role in the prevention of CHD. 17985. We want to emphasize that the impact of diet on FVIIc is Brace LD, Gittler-Buffa C, Miller GJ, Cole TG, Schmeisser D, Prewitt TE not tightly linked to its plasma lipid effects. This means that & Bowen PE (1994): Factor VII coagulant activity and cholesterol the speci®c link between diet and FVII needs to be taken changes in premenopausal women consuming a long-term cholesterol- into account when optimal diets for the prevention of CHD lowering diet. Arterioscler. Thromb. 14, 1284±1289. Brozovic M, Stirling Y, Harricks C, North WRS & Meade TW (1974): and other thrombotic diseases are discussed. Further studies Factor VII in an industrial population. Brit. J. Haematol. 28, 381± elaborating the impact of diet on FVII and, in particular, the 91. Diet and blood coagulation factor VII P Marckmann et al 82 Burns P, Hoffman CJ, Katz JP, Miller RH, Lawson WE & Hultin MB Heinrich J, Balleisen L, Schulte H, Assmann G & Loo J van de (1994): (1993): Vitamin K-dependent clotting factors are elevated in young Fibrinogen and factor VII in the prediction of coronary risk. Results adults who have close relatives with ischemic heart disease. J. Lab. from the PROCAM study in healthy men. Arterioscler. Thromb. 14, 54± Clin. Med. 122, 720±727. 59. Connelly JB, Roderick PJ, Cooper JA, Meade TW & Miller GJ (1993): Hemker HC (1984): Why do hemophiliacs bleed? Scand. J. Haematol. 33, Positive association between self-reported fatty food consumption and Suppl 40, 11±19. factor VII coagulant activity, a risk factor for coronary heart disease, in Hemker HC, Muller AD & Gonggrijp R (1976): The estimation of 4246 middle-aged men. Thromb. Haemost. 70, 250±252. activated human blood coagulation factor VII. J. Molecular Med. 1, Constantino M, Merskey C, Kudzma DJ & Zucker MB (1977): Increased 127±134. activity of vitamin K-dependent clotting factors in human hyperlipo- Hoffman CJ, Miller RH, Lawson WE & Hultin MB (1989): Elevation of proteinaemiaÐAssociation with cholesterol and triglyceride levels. factor VII activity and mass in young adults at risk of ischaemic heart Thromb. Haemost. 38, 465±474. disease. J. Am. Coll. Cardiol. 14, 941±946. Cortellaro M, Boschetti C, Cofransesco E, Zanussi C, Catalano M, de Hoffman CJ, Lawson E, Miller HR & Hultin MB (1994): Correlation of Gaetano G, Gabrielli L, Lombardi B, Specchia G, Tavazzi L, Tremoli E, vitamin K-dependent clotting factors with cholesterol and triglycerides della Volpe A, Polli E & the PLAT Study Group (1992): The PLAT in healthy young adults. Arterioscler. Thromb. 14, 1737±1740. Study: Hemostatic function in relation to atherothrombotic ischemic Humphries SE, Lane A, Green FR, Cooper J & Miller GJ (1994): Factor events in vascular disease patients. Principal results. Arterioscler. VII coagulant activity and antigen levels in healthy men are determined Thromb. 12, 1063±1070. by interaction between factor VII genotype and plasma triglyceride Dalaker K (1986): Clotting factor VII during pregnancy, delivery and concentration. Arterioscler. Thromb. 14, 193±198. puerperium. Br. J. Obstet. Gynaecol. 93, 17±21. Humphries S, Temple A, Lane A, Green F, Cooper J & Miller G (1996): Davie EW, Fujikawa K & Kisiel W (1991): The coagulation cascade: Low plasma levels of factor VIIc and antigen are more strongly Initiation, maintenance, and regulation. Biochemistry 30, 10363±10370. associated with the 10 base pair promoter (-323) insertion than the de Lorgeril M, Renaud S, Mamelle N, Salen P, Martin J-L, Monjaud I, glutamine 353 variant. Thromb. Haemost. 75, 567±572. Guidollet J, Touboul P & Delaye J (1994): Mediterranean alpha- Iso H, Folsom AR, Wu KK, Finch A, Munger RG, Sato S, Shimamoto T, linolenic acid-rich diet in secondary prevention of coronary heart Terao A & Komachi Y (1989): Hemostatic variables in Japanese and disease. Lancet 343, 1454±1459. Caucasian men. Plasma ®brinogen, factor VIIc, factor VIIIc, and von ECAT Angina Pectoris Study Group (1993): ECAT angina pectoris study: Willebrand factor and their relations to cardiovascular disease risk Baseline associations of haemostatic factors with extent of coronary factors. Am. J. Epidemiol. 130, 925±934. arteriosclerosis and other coronary risk factors in 3000 patients with Jang Y, Guzman LA, Lincoff AM, Gottsauner-Wolf M, Forudi F, Hart CE, angina pectoris undergoing coronary angiography. Eur. Heart J. 14, 8± Courtman DW, Ezban M, Ellis SG & Topol EJ (1995): In¯uence of 17. blockade at speci®c levels of the coagulation cascade on restenosis in a Elkeles RS, Chakrabarti R, Vickers M, Stirling Y & Meade TW (1980): rabbit atherosclerotic femoral artery injury model. Circulation 92, Effect of treatment of hyperlipidemia on haemostatic variables. BMJ 3041±305. 281, 973±974. Jennings AM, Ford I, Murdoch S, Greaves M, Preston FE & Ward Falk E (1991): Coronary thrombosis: Pathogenesis and clinical manifesta- JD (1991): The effects of diet and insulin therapy on coagulation tions. Am. J. Cardiol. 68, 28B±35B. factor VII, blood viscosity, and platelet release proteins in Falk E & FernaÂndez-Ortiz A (1995): Role of thrombosis in atherosclerosis diabetic patients with secondary sulphonylurea failure. Diabet. Med. and its complications. Am. J. Cardiol. 75, 5B±11B. 8, 346±353. Foley M, Ball M, Chisholm A, Duncan A, Spears G & Mann J (1992): Jespersen J (1988): Pathophysiology and clinical aspects of ®brinolysis Should mono- or poly-unsaturated fats replace saturated fat in the diet? and inhibition of coagulation. Experimental and clinical studies with Eur. J. Clin. Nutr. 46, 429±436. special reference to women on oral contraceptives and selected groups Folsom AR, Wu KK, Davis CE, Conlan MG, Sorlie PD & Szklo M (1991): of thrombosis prone patients (thesis). Dan. Med. Bull. 35, 1±33. Population correlates of plasma ®brinogen and factor VII, putative Jespersen J, Munkvad S & Gram J (1993): The ®brinolysis and coagulation cardiovascular risk factors. Atherosclerosis 91, 191±205. systems in ischaemic heart disease. Risk markers and their relation to Folsom AR, Qamhieh HT, Wing RR, Jeffery RW, Stinson VL, Kuller LH metabolic dysfunction of the arterial intima. Dan. Med. Bull. 40, 495± & Wu KK (1993): Impact of weight loss on plasminogen activator 502. inhibitor (PAI-1), factor VII, and other hemostatic factors in moderately Kapur R, Hoffman CJ, Bhushan V & Hultin MB (1996): Postprandial overweight adults. Arterioscler. Thromb. 13, 162±169. elevation of activated factor VII in young adults. Arterioscler. Thromb. Folsom AR, Ma J, Eckfeldt JH, Shahar E & Wu KK (1994): Plasma Vasc. Biol. 16, 1327±1332. phospholipid fatty acid composition and factor VII coagulant activity. Kario K, Miyata T, Sakata T, Matsuo T & Kato H (1994): Fluorogenic Atherosclerosis 111, 199±207. assay of activated factor VII. Plasma factor VIIa levels in relation to Freese R & Mutanen M (1995): Postprandial changes in platelet function arterial cardiovascular diseases in Japanese. Arterioscler. Thromb. 14, and coagulation factors after high-fat meals with different fatty acid 265±274. compositions. Eur. J. Clin. Nutr. 49, 658±664. Kario K, Matsuo T, Asada R, Sakata T, Kato H & Miyata T (1995): The Furie B & Furie BC (1992): Molecular and cellular biology of blood strong positive correlation between factor VII clotting activity using coagulation. N. Engl. J. Med. 326, 800±806. bovine thromboplastin and the activated factor VII level. Thromb. Fuster V, Badimon L, Badimon JJ & Chesebro JH (1992a): The pathogen- Haemost. 73, 429±434. esis of coronary artery disease and the acute coronary syndromes. N. Khaw K-T & Woodhouse P (1995): Interrelation of vitamin C, infection, Engl. J. Med. 326, 212±250. haemostatic factors, and cardiovascular disease. BMJ 310, 1559± Fuster V, Badimon L, Badimon JJ & Chesebro JH (1992b): The pathogen- 1563. esis of coronary artery disease and the acute coronary syndromes. N. Kitchen S, Malia RG & Preston FE (1992): A comparison of methods for Engl. J. Med. 326, 310±318. the measurement of activated factor VII. Thromb. Haemost. 68, 301± Girelli D, Olivieri O, Arigliano PL, Guarini P, Bassi A & Corrocher R 305. (1996): In¯uences of lipid and non-lipid nutritional parameters on factor Lane A, Cruickshank JK, Mitchell J, Henderson A, Humphries S & Green VII coagulant activity in normal subjects: The Nove Study. Eur. J. Clin. F (1992): Genetic and environmental determinants of factor VII Invest. 26, 199±204. coagulant activity in ethnic groups at differing risk of coronary heart Gouin-Thibault I, Dewar L, Craven S, Kulczycky M, Wun T-C & Ofosu disease. Atherosclerosis 94, 43±50. FA (1996): Probable regulation of factor VIIa-tissue factor and pro- Lane A, Green F, Scarabin PY, Nicaud V, Bara L, Humphries S, Evans A, thrombinase by factor Xa-TFPI and TFPI in vivo. Brit. J. Haematol. 95, Luc G, Cambou JP, Arveiler D & Cambien F (1996): Factor VII 738±746. Arg=Gln353 polymorphism determines factor VII coagulant activity Green F, Kelleher C, Wilkes H, Temple A, Meade T & Humphries S in patients with myocardial infarction (MI) and control subjects in (1991): A common genetic polymorphism associated with lower coa- Belfast and in France but is not a strong indicator of MI risk in the gulation factor VII levels in healthy individuals. Arterioscler. Thromb. ECTIM study. Atherosclerosis 119, 119±127. 11, 540±546. Larsen LF, Bladbjerg EM, Jespersen J & Marckmann P (1997): Effects of Haines AP, Chakrabarti R, Fisher D, Meade TW, North WRS & Stirling Y dietary fat quality and quantity on postprandial activation of blood (1980): Haemostatic variables in vegetarians and non-vegetarians. coagulation factor VII. Arterioscler Thromb. Vasc. Biol. (in press). Thromb. Res. 19, 139±148. Lattanzio A, Montemurro P, Pannarale O, Altomare DF, Palasciano N, de Heinrich J, Wahrburg U, Martin H & Assmann G (1990): The effect of Rinaldis P & Semeraro N (1984): Increased production of procoagulant diets, rich in mono- or polyunsaturated fatty acids, on lipid metabolism activity (tissue factor) by human peripheral blood monocytes after and haemostasis. Fibrinolysis 4, Suppl 2, 76±78. intralipid infusion. Clin. Nutr. 3, 177±181. Diet and blood coagulation VII P Marckmann et al 83 Lusher JM (1996): Recombinant factor VIIa (NovoSeven1 ) in the treat- Miller GJ (1996): Fat consumption and factor VII. In Nutrition, Genetics, ment of internal bleeding in patients with factor VIII and IX inhibitors. and Heart Disease, eds. GA Bray & DH Ryan, pp 15-28. Baton Rouge, Haemostasis 26, Suppl 1, 124±130. USA: Louisiana State University Press. Marbet GA & Duckert F (1992): Factor VII clotting activity. In ECAT Miller GJ, Martin JC, Webster J, Wilkes H, Miller NE, Wilkinson WH & Assay Procedures. A Manual of Laboratory Techniques, eds. J Jesper- Meade TW (1986): Association between dietary fat intake and plasma sen, RM Bertina & F Haverkate, pp 57±63. London: Kluwer Academic factor VII coagulant activityÐa predictor of cardiovascular mortality. Publishers. Atherosclerosis 60, 269±277. Marckmann P (1995): Diet, blood coagulation and ®brinolysis (thesis). Miller GJ, Cruickshank JK, Ellis LJ, Thompson RL, Wilkes HC, Stirling Dan. Med. Bull 42, 410±425. Y, Mitropoulos KA, Allison JV, Fox TE & Walker AO (1989): Fat Marckmann P & Jespersen J (1994): Introduction to diet and endogenous consumption and factor VII coagulant activity in middle-aged men. An ®brinolysis. Fibrinolysis 8, Suppl 2, 37±40. association between a dietary and thrombogenic coronary risk factor. Marckmann P & Jespersen J (1996): Low-fat=high-®ber diets and coagu- Atherosclerosis 78, 19±24. lation=®brinolysis. In Nutrition, Genetics, and Heart Disease, eds. GA Miller GJ, Martin JC, Mitropoulos KA, Reeves BEA, Thompson RL, Bray & DH Ryan, pp 50±61. Baton Rouge, USA: Louisiana State Meade TW, Cooper JA & Cruickshank JK (1991): Plasma factor VII is University Press. activated by postprandial triglyceridaemia, irrespective of dietary fat Marckmann P & SandstroÈm B (1994): Oat bran supplementation: effects composition. Atherosclerosis 86, 163±171. on blood lipids and markers of thrombotic risk. In Leiden Fibrinolysis Miller GJ, Stirling Y, Howarth DJ, Cooper JC, Green FR, Lane A & Workshop 5. Intervention in Fibrinolysis, eds. C Kluft, Verheijen JH, Humphries SE (1995): Dietary fat intake and plasma factor VII antigen Kortmann C, p 7. Leiden, Holland: Leiden Fibrinolysis Workshop concentration. Thromb. Haemost. 73, 890 (letter). (abstract). Miller GJ, Martin JC, Mitropoulos KA, Esnouf MP, Cooper JA, Morrissey Marckmann P, SandstroÈm B & Jespersen J (1990): Effects of total fat JH, Howarth DJ & Tuddenham EGD (1996a): Activation of factor VII content and fatty acid composition in diet on factor VII coagulant during alimentary lipemia occurs in healthy adults and patients with activity and blood lipids. Atherosclerosis 80, 227±233. congenital factor XII or factor XI de®ciency, but not in patients with Marckmann P, Jespersen J, Leth T & SandstroÈm B (1991): Effect of ®sh factor IX de®ciency. Blood 87, 4187±4196. diet versus meat diet on blood lipids, coagulation and ®brinolysis in Miller GJ, Bauer KA, Barzegar S, Cooper JA & Rosenberg RD (1996b): healthy young men. J. Intern. Med. 229, 317±323. Increased activation of the haemostatic system in men at high risk of Marckmann P, SandstroÈm B & Jespersen J (1992a): Fasting fatal coronary heart disease. Thromb. Haemost. 75, 767±771. blood coagulation and ®brinolysis of young healthy adults Mitropoulos KA & Esnouf MP (1990): The prothrombin activation peptide unchanged by reduction in dietary fat content. Arterioscler. Thromb. regulates synthesis of the vitamin K-dependent proteins in the rabbit. 12, 201±205. Thromb. Res. 57, 541±549. Marckmann P, SandstroÈm B & Jespersen J (1992b): Dietary n-3 and n-6 Mitropoulos KA & Esnouf MP (1991): The autoactivation of factor XII in polyunsaturated fatty acids affect the ®brinolytic system differently. In the presence of long-chain saturated fatty acids ± a comparison with the Essential Fatty Acids and Eicosanoids, eds. A Sinclair & RE Gibson, pp potency of sulphatides and dextran sulphate. Thromb. Haemost. 66, 325±329. Champaign: American Oil Chemists' Society. 446±452. Marckmann P, SandstroÈm B & Jespersen J (1993a): Favorable long-term Mitropoulos KA, Miller GJ, Reeves BEA, Wilkes HC & Cruickshank JK effect of a low-fat=high-®ber diet on human blood coagulation and (1989a): Factor VII coagulant activity is strongly associated with the ®brinolysis. Arterioscler. Thromb. 13, 505±511. plasma concentration of large lipoprotein particles in middle-aged men. Marckmann P, SandstroÈm B & Jespersen J (1993b): Dietary effects on Atherosclerosis 756, 203±208. circadian ¯uctuation in human blood coagulation factor VII and Mitropoulos KA, Martin JC, Reeves BEA & Esnouf MP (1989b): The ®brinolysis. Atherosclerosis 101, 225±234. activation of the contact phase of coagulation by physiologic surfaces in Marckmann P, SandstroÈm B & Jespersen J (1994): Low-fat high-®ber diet plasma: The effect of large negatively charged liposomal vesicles. favorably affects several independent risk markers of ischemic heart Blood 73, 1525±1533. disease. Observations on blood lipids, coagulation, and ®brinolysis from Mitropoulos KA, Miller GJ, Watts GF & Durrington PN (1992): Lipolysis a trial of middle-aged Danes. Am. J. Clin. Nutr. 59, 935±939. of triglyceride-rich lipoproteins activates coagulant factor XII: A study Marckmann P, Bladbjerg EM & Jespersen J (1997a): Dietary ®sh oil (4 g in familial lipoprotein-lipase de®ciency. Atherosclerosis 95, 119±125. daily) and cardiovascular risk markers in healthy men. Arterioscler. Mitropoulos KA, Reeves BEA & Miller GJ (1993): The activation of Thromb. Vasc. Biol. (in press). factor VII in citrated plasma by charged long-chain saturated fatty acids Marckmann P, Larsen LF, Bentzen J, Maat Md, Bladbjerg EM & Jespersen at the interface of large triglyceride-rich lipoproteins. Blood Coagul. J (1997b): Genetic in¯uence on factor VII activation following Fibrinolysis 4, 943±951. high-saturated fat meals. Thromb. Haemost. Suppl June 1997, 413 Mitropoulos KA, Miller GJ, Martin JC, Reeves BEA & Cooper J (1994): (abstract). Dietary fat induces changes in factor VII coagulant activity through Mariani G & Mazzucconi MG (1983): Factor VII congenital de®ciency. effects on plasma free stearic acid concentration. Arterioscler. Thromb. Clinical picture and classi®cation of the variants. Haemostasis 13, 169± 14, 214±222. 177. Monroe DM, Hoffman M & Roberts HR (1996): Transmission of a Meade TW, Chakrabarti R, Haines AP, North WRS, Stirling Y & procoagulant signal from tissue factor-bearing cells to platelets. Blood Thompson SG (1980): Haemostatic function and cardiovascular Coagul. Fibinolysis 7, 459±464. death: Early results of prospective study. Lancet i, 1051±1053. Moor E, Silveira A, van't Hooft F, Suontaka AM, Eriksson P, BlombaÈck M Meade TW, Brozovic M, Chakrabarti R, Haines AP, Imeson JD, Mellows & Hamsten A (1995): Coagulation factor VII mass and activity in S, Miller GJ, North WRS, Stirling Y & Thompson SG (1986a): young men with myocardial infarction at a young age. Role of plasma Haemostatic function and ischaemic heart disease: Principal results of lipoproteins and factor VII genotype. Arterioscler. Thromb. Vasc. Biol. the Northwich Park Heart Study. Lancet ii, 533±537. 15, 655±664. Meade TW, Stirling Y, Thompson SG, Vickers MV, Woolf L, Ajdukie- Morrissey JH (1995): Tissue factor modulation of factor VIIa activity: Use wicz AB, Stewart G, Davidson JF, Walker ID, Douglas AS, Richardson in measuring trace levels of factor VIIa in plasma. Thromb. Haemost. IM, Weir RD, Aromaa A, Impivaara O, Maatela J & Hladovec J 74, 185±188. (1986b): An international and interregional comparison of haemostatic Morrissey JH, Macik BG, Neuenschwander PF & Comp PC (1993): variables in the study of ischaemic heart disease. Int. J. Epidemiol. 15, Quantitation of activated factor VII levels in plasma using a tissue 331±336. factor mutant selectively de®cient in promoting factor VII activation. Meade TW, Ruddock V, Stirling Y, Chakrabarti R & Miller GJ (1993): Blood 81, 734±744. Fibrinolytic activity, clotting factors, and long-term incidence of Mutanen M & Aro A (1997): Coagulation and ®brinolysis factors in ischaemic heart disease in the Northwith Park Heart Study. Lancet healthy subjects consuming high stearic or trans fatty acid diets. 342, 1076±1079. Thromb. Haemost. 77, 99±104. Mennen LI, Schouten EG, Grobbee DE & Kluft C (1996): Coagulation Mutanen M, Krusius T, RaÈsaÈnen L, Freese R, Vahtera E & Viikari factor VII, dietary fat and blood lipids: A review. Thromb. Haemost. 76, JSA (1995): Habitual diet, platelet function, ®brinogen and factor 492±499. VII coagulant activity in young Finns. J. Intern. Med. 237, 577± Mennen LI, Wittman CM, Breeijen JH den, Schouten EG, Jong PTVM de, 583. Hofman A & Grobbee DE (1997): The association of dietary fat and Nemerson Y (1992): The tissue factor pathway of blood coagulation. Sem. ®ber with coagulation factor VII in the elderly: The Rotterdam Study. Hematol. 29, 170±176. Am. J. Clin. Nutr. 65, 732±736. Ott R & Pfeiffer RA (1984): Evidence that activities of coagulation factors Miller GJ (1993): Hyperlipidaemia and hypercoagulability. Prog. Lipid VII and X are linked to chromosome 13 (q34). Hum. Hered. 34, 123± Res. 32, 61±69. 126. Diet and blood coagulation factor VII P Marckmann et al 84 Pan W-H, Chin C-J, Sheu C-T & Lee M-H (1993): Hemostatic factors and Silveira A, Karpe F, Johnsson H, Bauer KA & Hamsten A (1996): In blood lipids in young Buddhist vegetarians and omnivores. Am. J. Clin. vivo demonstration in humans that large postprandial triglyceride- Nutr. 58, 354±359. rich lipoproteins activate coagulation factor VII through the intrinsic Petersen LC, Valentin S & Hedner U (1995): Regulation of the extrinsic coagulation pathway. Arterioscler. Thromb. Vasc. Biol. 16, 1333± pathway system in health and disease: The role of factor VIIa and tissue 1339. factor pathway inhibitor. Thromb. Res. 79, 1±47. Simpson HCR, Mann JI, Chakrabarti R, Imeson JD, Stirling Y, Tozer M, Philippou H, Adami A, Amersey RA, Stubbs PJ & Lane DA (1997): A Woolf L & Meade TW (1982): Effect of high-®bre diet on haemostatic novel speci®c immunoassay for plasma two-chain factor VIIa: Investi- variables in diabetes. BMJ 284, 1608. gation of FVIIa levels in normal individuals and in patients with acute Simpson HCR, Mann JI, Meade TW, Chakrabarti R, Stirling Y & Woolf L coronary syndromes. Blood 89, 767±775. (1983): Hypertriglyceridaemia and hypercoagulability. Lancet i, 786± Poggio M, Tripodi A, Mariani G & Mannucci PM (1991): Factor VII 789. clotting assay: In¯uence of different thromboplastins and factor VII- Singh RB, Rastogi SS, Verma R, Laxmi B, Singh R, Ghosh S & Niaz MA de®cient plasmas. Thromb. Haemost. 65, 160±164. (1992): Randomised controlled trial of cardioprotective diet in patients Rankinen T, Rauramaa R, VaÈisaÈnen S, Halonen P & PenttilaÈ IM (1994a): with recent acute myocardial infarction: Results of one year follow up. Blood coagulation and ®brinolytic factors are unchanged by aerobic BMJ 304, 1015±1019. exercise or fat modi®ed diet. Fibrinolysis 8, 48±53. Skartlien AH, Lyberg-Beckmann S, Holme I, Hjermann I & Prydz H Rankinen T, Rauramaa R, VaÈisaÈnen S, PenttilaÈ IM & Uusitupa M (1994b): (1989): Effect of alteration in triglyceride levels on factor VII-phos- Relation of habitual diet and cardiorespiratory ®tness to blood coagula- pholipid complexes in plasma. Arteriosclerosis 9, 798±801. tion and ®brinolytic factors. Thromb. Haemost. 71, 180±183. Sousa JC de, Soria C, Ayrault-Jarrier M, Pastier D, Bruckert E, Amiral J, Rapaport SI & Rao LVM (1992): Initiation and regulation of tissue factor- Bereziat G & Caen JP (1988): Association between coagulation factor dependent blood coagulation. Arterioscler. Thromb. 12, 1111±1121. VII and X with triglyceride rich lipoproteins. J. Clin. Pathol. 41, 940± Rapaport SI & Rao LVM (1995): The tissue factor pathway: How it has 944. become a `Prima Ballerina'. Thromb. Haemost. 74, 7±17. Sousa JC de, Bruckert E, Giral P, Soria C, Chapman J, Truffert J, Dairou F, Roche HM & Gibney MJ (1997): Postprandial coagulation factor VII De Gennes JL & Caen JP (1989): Coagulation factor VII and plasma activity: The effect of monounsaturated fatty acids. Br. J. Nutr. 77, 537± triglycerides. Decreased catabolism as a possible mechanism of factor 549. VII hyperactivity. Haemostasis 19, 125±130. Ruddock V & Meade TW (1994): Factor VII activity and ischaemic heart Speidel CM, Thornton JD, Meng YY, Eisenberg PR, Edgington TS & disease: Fatal and non-fatal events. QJM 87, 403±406. Abendschein DR (1996): Procoagulant activity on injured arteries and Saha N, Liu Y, Heng CK, Hong S, Low PS & Tay JSH (1994): Association associated thrombi is mediated primarily by the complex of tissue factor of factor VII genotype with plasma factor VII activity and antigen levels and factor VIIa. Coron. Artery Dis. 7, 57±62. in healthy Indian adults and interaction with triglycerides. Arterioscler. Suzuki T, Yamauchi K, Matsushita T, Furumichi T, Furui H, Tsuzuki J & Thromb. 14, 1923±1927. Saito H (1991): Elevation of factor VII activity and mass in coronary Salomaa V, Rasi V, Pekkanen J, Jauhiainen M, Vahtera E, Pietinen P, artery disease of varying severity. Clin. Cardiol. 14, 731±736. Korhonen H, Kuulusmaa K & Ehnholm C (1993): The effects of Tholstrup T, Marckmann P, Jespersen J & SandstroÈm B (1994a): A fat saturated fat and n-6 polyunsaturated fat on postprandial lipemia and high in stearic acid favorably affects blood lipids and factor VII hemostatic activity. Atherosclerosis 103, 1±11. coagulant activity in comparison to fats high in palmitic acid and Salomaa V, Rasi V, Pekkanen J, Vahtera E, Jauhiainen M, Vartiainen E, high in myristic and lauric acid. Am. J. Clin. Nutr. 59, 371±377. MyllylaÈ G & Ehnholm C (1994): Haemostatic factors and prevalent Tholstrup T, Marckmann P, Jespersen J, Vessby B, Jart A & SandstroÈm B coronary heart disease; the FINRISK haemostasis study. Eur. Heart J. (1994b): Effect on blood lipids, coagulation, and ®brinolysis of a fat 15, 1293±1299. high in myristic acid and a fat high in palmitic acid. Am. J. Clin. Nutr. Sanders TAB, Miller GJ, Grassi T de & Yahia N (1996): Postprandial 60, 919±925. activation of coagulant factor VII by long-chain dietary fatty acids. Tholstrup T, Andreasen K & SandstroÈm B (1996): Acute effect of high-fat Thromb. Haemost. 76, 369±371. meals rich in either stearic or myristic acid on hemostatic factors in Scarabin PY, Vissac AM, Kirzin JM, Bourgeat P, Amiral J, Agher R & healthy young men. Am. J. Clin. Nutr. 64, 168±176. Guize L (1996): Population correlates of coagulation factor VII. VaÈisaÈnen S, Rankinen T, PenttilaÈ I & Rauramaa R (1995): Factor VII Importance of age, sex, and menopausal status as determinants of coagulant activity in relation to serum lipoproteins and dietary fat in activated factor VII. Arterioscler. Thromb. Vasc. Biol. 16, 1170±1176. middle-aged men. Thromb. Haemost. 73, 435±438. Schmidt EB, Varming K, Ernst E, Madsen P & Dyerberg J (1990): Dose- Velthuis-te Wierik EJM, Kluft C, van den Berg H & Weststrate JA (1996): response studies on the effect of n-3 polyunsaturated fatty acids on Consumption of reduced-fat products, haemostatic parameters and oral lipids and haemostasis. Thromb. Haemost. 63, 1±5. glucose tolerance test. Fibrinolysis 10, 159±166. Schmidt EB, Lervang H-H, Varming K, Madsen P & Dyerberg J (1992): Vorster HH, Cummings JH & Veldman FJ (1997): Diet and haemostasis: Long-term supplementation with n-3 fatty acids, I: effect on blood Time for nutrition science to get more involved. Br. J. Nutr. 77, 671± lipids, haemostasis and blood pressure. Scand. J. Clin. Lab. Invest. 52, 684. 221±228. Yahia N & Sanders TAB (1997): The in¯uence of dietary fat on Seligsohn U, Kasper CK, ùsterud B & Rapaport SI (1979): Activated postprandial lipaemia and factor VII coagulant activity in human factor VII: Presence in FIX concentrates and persistence in the circula- subjects. Proc. Nutr. Soc. 56, 489±496. tion after infusion. Blood 53, 828±837. Zilversmit DB (1979): Atherogenesis: A postprandial phenomenon. Cir- Silveira A, Karpe F, BlombaÈck M, Steiner G, Walldius G & Hamsten A culation 60, 473±485. (1994a): Activation of coagulation factor VII during alimentary lipemia. ésterud B (1990): Factor VII and haemostasis. Blood Coagul. Fibrinolysis Arterioscler. Thromb. 14, 60±69. 1, 175±182. Silveira A, Green F, Karpe F, BlombaÈck M, Humphries S & Hamsten A ésterud B, Elvevoll E, Barstad H, Brox J, Halvorsen H, Lia K, Olsen JO, (1994b): Elevated levels of factor VII activity in the postprandial state: Olsen RL, Sissener C, Rekdal ù & Vognild E (1995): Effect of marine Effect of the factor VII arg-gln polymorphism. Thromb. Haemost. 72, oils supplementation on coagulation and cellular activation in whole 734±739. blood. Lipids 30, 1111±1118.