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Activation of coagulation during alimentary lipemia under real-life conditions
International Journal of Cardiology 114 (2007) 172 – 175 www.elsevier.com/locate/ijcard
Activation of coagulation during alimentary lipemia under real-life conditions Elif Elmas a,*, Thorsten Ka¨lsch a, Nenad Suvajac a, Hans Leweling b, Michael Neumaier c, Carl-Erik Dempfle a, Martin Borggrefe a a
I. Department of Medicine, University Hospital of Mannheim, Theodor-Kutzer-Ufer 1-3, D-68167, Mannheim, Germany b IV. Department of Medicine, University Hospital of Mannheim, Mannheim, Germany c Department of Clinical Chemistry, University Hospital of Mannheim, Mannheim, Germany Received 21 November 2005; accepted 8 January 2006 Available online 30 May 2006
Abstract High intake of saturated fat is a predictor of coronary heart disease mortality. The phenomenon of postprandial angina pectoris has been described many years ago. Although earlier studies have demonstrated postprandial activation of coagulation factors VII and XII, platelets and monocytes, conclusive evidence for intravascular fibrin formation after a fat-rich meal has not been reported yet. The present study included 33 healthy physicians (7 females, 26 males) with a mean age of 42 years (range 27 – 62 years), and 27 coronary heart disease patients (8 females, 19 males) with a mean age of 63 years (range 47 – 81 years). Of the coronary heart disease patients, 26/27 were treated with acetylsalicylic acid and 25/27 with lipid-lowering drugs simvastatin or atorvastatin. Blood samples were drawn 30 – 60 min before and 30 – 60 min after a dinner consisting of rye bread with liversausage and black pudding as hors d’oeuvre, lettuce with smoked bacon in a lard dressing, stuffed fried goose with red cabbage, potato dumplings and sweet chestnuts, and white and brown mousse au chocolat. Average intake per person was 3760kcal, with 125.9 g protein, 238.0 g fat and 268.9 g carbohydrate. We measured a significant postprandial increase in fibrinopeptide A (FpA) levels from 1.14 T 1.23Ag/l to 4.18 T 2.86 Ag/l ( p < 0.0001) in healthy probands, and 4.66 T 13.61Ag/l to 12.80 T 15.04 Ag/l ( p < 0.0001) in coronary heart disease patients. Triglycerides increased from 137.6 T 60.5 to 201.5 T 75.0mg/dl in healthy probands and from 211.9 T 94.6 to 273.6 T 122.5 mg/dl in coronary heart disease patients. Fat-rich meals may cause procoagulant episodes, which may promote vascular complications such as myocardial infarction, transient ischemia attacks in susceptible persons. D 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Postprandial coagulation activation; Triglycerides; Fibrinopeptide A; Coronary heart disease
1. Introduction A fat-rich diet is believed to have profound effects on the vascular system by induction of endothelial dysfunction and other changes leading to development of atherosclerosis. High intake of saturated fat is a predictor of coronary heart disease mortality and the phenomenon of postprandial angina pectoris has been described many years ago [1]. Although earlier studies have demonstrated postprandial activation of coagulation factors VII and XII [2 – 7], platelets * Corresponding author. Tel./fax: +49 6213832204, +49 6213833821. E-mail address: [email protected] (E. Elmas). 0167-5273/$ - see front matter D 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2006.01.011
and monocytes [8 –10], conclusive evidence for intravascular fibrin formation after a fat-rich meal has not been reported yet. Also, most studies on postprandial coagulation activation were performed after fasting and in the morning rather than under real-life conditions where fat-rich meals are predominantly consumed in the evening. In one study, probands received a serving of high-fat premium ice cream after 12h of fasting [6], which seems rather extraordinary as a breakfast. In many studies, probands were ordered to refrain from smoking and the consumption of alcohol or caffeine for 24h before as well as during the study. In addition, the test meal had to be consumed in a very limited period of time, such as 10 min. Our intention was to measure
E. Elmas et al. / International Journal of Cardiology 114 (2007) 172 – 175
parameters of coagulation activation after a fat-rich dinner under realistic conditions. The probands were healthy physicians (predominantly cardiologists), and patients with coronary heart disease. Alcoholic beverages, including red wine and white wine, were served, and smokers were allowed to consume their usual amount of cigarettes.
173
FpA, HISS Diagnostics, Freiburg, Germany; normal range: 0 –5 ng/ml) and prothrombin fragment F1 + 2 (Enzygnost F1 + 2 micro, Dade Behring; normal range: 0.4 –1.1 nmol/l) were performed by a microtiter plate ELISA.
3. Statistics 2. Subjects and methods The present study included 33 healthy physicians (7 females, 26 males) with a mean age of 42 years (range 27 – 62 years), and 27 coronary heart disease patients (8 females, 19 males) with a mean age of 63 years (range 47 –81 years). Of the coronary heart disease patients, 26/27 were treated with acetyl salicylic acid 100 mg/day, 25/27 received lipid lowering drugs, either simvastatin or atorvastatin, 2/27 were treated with phenprocoumon. Atrial fibrillation was present in 10/27 patients. After informed consent, blood samples were drawn 30 – 60 min before and 30 –60 min after a dinner consisting of rye bread with liversausage and black pudding as hors d’oeuvre, lettuce with smoked bacon in a lard dressing, stuffed fried goose with red cabbage, potato dumplings and sweet chestnuts, and white and brown mousse au chocolat. Average intake per person was 3760 kcal, with 125.9 g protein, 238.0 g fat and 268.9 g carbohydrate. Venous blood was drawn into 10-ml syringes containing 1 ml of 3.13% citrate solution for conventional coagulation analyses and coagulation inhibitors, and 5-ml syringes containing 0.5 mg of recombinant hirudin (Refludan, Aventis, Germany) in addition to the citrate solution for measurement of coagulation activation parameters. For measurement of cholesterol and triglycerides, blood was drawn into tubes for serum preparation. Coagulation assays included antithrombin (MDA Antithrombin), protein C (MDA Protein C), fibrinogen level (MDA Fibriquick), D-Dimer antigen (MDA D-Dimer), prothrombin time (MDA Simplastin) and activated partial thromboplastin time (MDA Platelin LS) using a MDA II coagulation analyzer (bioMe´rieux, Duncan, NC, USA). Measurements of thrombin-antithrombin-complexes (Enzygnost TAT micro, Dade Behring Marburg Germany; normal range: 1.0 –4.1 Ag/L), fibrinopeptide A (Novitec
The data were analyzed using JMP statistics software (SAS Institute, Heidelberg, Germany). A 2-tailed p-value of less than 0.05 was considered to indicate statistical significance. Numerical data were expressed as means T SD. Differences were calculated as the value obtained after the test meal minus the value obtained before food ingestion and were tested for significant differences using Wilcoxon/ Kruskal Wallis rank sum test with Chi square approximation.
4. Results Most participants were able to complete their meal, including the desert consisting of a serving of mousse au chocolat decorated with cherries. Alcohol consumption was moderate and consisted mainly of red wine. No significant differences were seen between smokers and non-smokers concerning the laboratory results. Angina pectoris or other cardiovascular complications were not observed during the study period. Results of coagulation analyses and other laboratory assays are shown in Table 1. In the blood samples drawn from the healthy probands, we measured a significant postprandial increase in fibrinopeptide A (FpA) levels from 1.14 T 1.23 Ag/l to 4.18 T 2.86 Ag/l ( p < 0.0001), and an increase in thrombin –antithrombin complexes (TAT) from 1.93 T 0.43 to 2.25 T 0.83 Ag/l ( p = 0.0301) (Fig. 1). The correlation between FpA and TAT was r = 0.51. The coronary heart disease patients also displayed a significant postprandial increase in FpA levels from 4.66 T 13.61 Ag/l to 12.80 T 15.04 Ag/l ( p < 0.0001). The increase of TAT from 2.56 T 3.70Ag/l to 3.20 T 5.69 Ag/l was not statistically significant ( p = 0.2682). Prothrombin fragment F1 – 2 (PF1.2) levels remained unchanged in both groups, as did D-dimer levels in the healthy probands. Coronary heart disease patients displayed
Table 1 Results of laboratory analyses before and after test meal Healthy probands (n = 33)
Prothrombin fragment F1.2 [nmol/l] Thrombin – antithrombin complexes [Ag/l] Fibrinopeptide A [Ag/l] D-dimer antigen [mg/l] Cholesterol [mg/dl] Triglycerides [mg/dl]
Coronary heart disease patients (n = 27)
Before meal (mean T SD)
After meal (mean T SD)
p
Before meal (mean T SD)
After meal (mean T SD)
p
0.42 T 0.13 1.93 T 0.43 1.14 T 1.23 0.58 T 0.69 204.8 T 38.5 137.6 T 60.5
0.41 T 0.17 2.25 T 0.83 4.18 T 2.86 0.48 T 0.30 198.4 T 36.5 201.5 T 75.0
0.7301 0.0301 <0.0001 0.9326 0.4344 0.0008
0.89 T 0.51 2.56 T 3.70 4.66 T 13.61 0.33 T 0.35 231.2 T 42.1 211.9 T 94.6
0.94 T 0.69 3.20 T 5.69 12.80 T 15.04 0.44 T 0.38 227.8 T 42.3 273.6 T 122.5
0.7035 0.2682 <0.0001 0.0318 0.7293 0.0537
174
E. Elmas et al. / International Journal of Cardiology 114 (2007) 172 – 175
Fig. 1. Comparison of pre- and postprandial fibrinopeptide A (FpA) levels, and pre- and postprandial levels of thrombin – antithronbin complexes (TAT), F1.2 and D-dimer.
a slight postprandial increase in D-dimer levels from 0.33 T 0.35mg/l to 0.44 T 0.38 mg/l ( p = 0.0318). Whereas cholesterol levels did not change, triglyceride levels were significantly higher postprandially in both groups. Platelet count, prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, antithrombin and protein C remained unchanged (data not shown).
5. Discussion A high-fat meal results in postprandial hypertriglyceridemia, which promotes the production of atherogenic trigyleride-rich lipoproteins (TLRs). TLRs have been shown to initiate events resulting in factor VII activation [2,7]. Especially very low density lipoproteins (VLDL) support prothrombinase and other procoagulant enzymatic complexes [11,12]. Numerous studies have shown that Creactive protein (CRP) levels predict cardiovascular disease in apparently healthy individuals. CRP binds VLDL
[13,14]. Opsonization by CRP promotes the uptake of VLDL by macrophages [15,16], the formation of foam cells, and possibly the expression of procoagulant tissue factor [17]. In addition, the complex of CRP with VLDL has been shown to support coagulation activation more effectively than VLDL alone [18]. Coagulation activation induced by a fat-rich meal may therefore be more pronounced in individuals with elevated CRP levels. The present study is the first to show that even in apparently healthy persons, a fat-rich meal leads to intravascular formation of fibrin with release of fibrinopeptide A. Similar to the present study, ingestion of fat did not result in elevated levels of PF1.2 in earlier studies [7,19], which may be the result of the long plasma half life of PF1.2 obscuring acute effects of coagulation activation. Hunter et al. [20] found only a minor increase in FpA after test meals in healthy male volunteers, but compared with the present study, the test meals contained a considerably less fat. The present results indicate that FpA may be the most appropriate parameter for the detection of acute episodes of coagulation activation, although other activation products
E. Elmas et al. / International Journal of Cardiology 114 (2007) 172 – 175
with short plasma half life may be similarly useful. Coagulation activation parameters with long plasma halflife, such as TAT, prothrombin fragment F1.2, or D-dimer appear to be insufficiently sensitive for the detection of coagulation activation induced by a fat-rich meal or other acute stimuli. This is to our knowledge the first study to show postprandial coagulation activation in patients with coronary heart disease. This coagulation actuvation was present despite treatment with acetylsalicylic acid and lipid lowering drugs. Both simvastatin [21] and atorvastatin [22] reduce coagulation activation in patients with coronary artery disease [21] or hyperlipemia [22] . In the present study, postprandial FpA levels were approximately 5 times the preprandial values both in (untreated) healthy probands and in coronary heart disease patients treated with simvastatin or atorvastatin. Unfortunately we currently have no data on the extent of postprandial coagulation activation in coronary heart disease patients not treated with lipid lowering drugs. Fat-rich meals may cause procoagulant episodes, which may promote vascular complications such as myocardial infarction, transient ischemic attacks in susceptible persons.
Acknowledgement The study was supported by Pfizer, Karlsruhe, Germany.
References [1] Goldstein RE, Redwood DR, Rosing DR, Beiser GD, Epstein SE. Alterations in the circulatory response to exercise following a meal and their relationship to postprandial angina pectoris. Circulation 1971;44:90 – 100. [2] Larsen LF, Marckmann P, Bladbjerg EM, Ostergaard PB, Sidelmann J, Jespersen J. The link between high-fat meals and postprandial activation of blood coagulation factor VII possibly involves kallikrein. Scand J Clin Lab Invest 2000;60:45 – 54. [3] Miller GJ, Cooke CJ, Nanjee MN, et al. Factor VII activation, apolipoprotein A-I and reverse cholesterol transport: possible relevance for postprandial lipaemia. Thromb Haemost 2002;87:477 – 82. [4] Olsen AK, Bladbjerg EM, Hansen AK, Marckmann P. A high fat meal activates blood coagulation factor VII in rats. J Nutr 2002; 132:347 – 50. [5] Sanders TA, Miller GJ, de Grass T, Yahia N. Postprandial activation of coagulant factor VII by long-chain dietary fatty acids. Thromb Haemost 1996;76:369 – 71. [6] Kapur R, Hoffman CJ, Bhushan V, Haltin MB. Postprandial elevation of activated factor VII in young adults. Arterioscler Thromb Vasc Biol 1996;16:1327 – 32.
175
[7] Silveira A, Karpe F, Johnsson H, Bauer KA, Hamsten A. In vivo demonstration in humans that large postprandial triglyceride-rich lipoproteins activate coagulation factor VII through the intrinsic coagulation pathway. Arterioscler Thromb Vasc Biol 1996;16:1333 – 9. [8] Hyson DA, Paglieroni TG, Wun T, Rutledge JC. Postprandial lipemia is associated with platelet and monocyte activation and increased monocyte cytokine expression in normolipemic men. Clin Appl Thromb/Hemost 2002;8:147 – 55. [9] Fuhrman B, Brook JG, Aviram M. Increased platelet aggregation during alimentary hyperlipemia in normal and hypertriglyceridemic subjects. Ann Nutr Metab 1986;30:250 – 60. [10] Freese R, Mutanen M. Postprandial changes in platelet function and coagulation factors after high-fat meals with different fatty acid compositions. Eur J Clin Nutr 1995;49:658 – 64. [11] Moyer MP, Tracy RP, Tracy PB, van’t Veer C, Sparks CE, Mann KG. Plasma lipoproteins support prothrombinase and other procoagulant enzymatic complexes. Arterioscler Thromb Vasc Biol 1998; 18:458 – 65. [12] Rota S, McWilliam NA, Baglin TP, Byrne CD. Atherogenic lipoproteins support assembly of the prothrombinase complex and thrombin generation: modulation by oxidation and vitamin E. Blood 1998;91:508 – 15. [13] Cabana VG, Gewurz H, Siegel JN. Interaction of very low density lipoproteins (VLDL) with rabbit C-reactive protein. J Immunol 1982; 128:2342 – 8. [14] Rowe IF, Soutar AK, Trayner IM, Thompson GR, Pepys MB. Circulating human C-reactive protein binds very low density lipoproteins. Clin Exp Immunol 1984;58:237 – 44. [15] Zwaka TP, Hombach V, Torzewski J. C-reactive protein-mediated low density lipoprotein uptake by macrophages: implications for atherosclerosis. Circulation 2001;103:1194 – 7. [16] Fu T, Borensztajn J. Macrophage uptake of low-density lipoprotein bound to aggregated C-reactive protein: possible mechanism of foam-cell formation in atherosclerotic lesions. Biochem J 2002; 366:195 – 201. [17] Moons AH, Levi M, Peters RJ. Tissue factor and coronary artery disease. Cardiovasc Res 2002;53:313 – 25. [18] Toh CH, Samis J, Downey C, et al. Biphasic transmittance waveform in the APTT coagulation assay is due to the formation of a Ca(+)dependent complex of C-reactive protein with very-low-density lipoprotein and is a novel marker of impending disseminated intravascular coagulation. Blood 2002;100:2522 – 9. [19] Bladbjerg EM, Munster AM, Marckmann P, Keller N, Jespersen J. Dietary factor VII activation does not increase plasma concentrations of prothrombin fragment 1+2 in patients with stable angina pectoris and coronary atherosclerosis. Arterioscler Thromb Vasc Biol 2000; 20:2494 – 9. [20] Hunter KA, Crosbie LC, Weir A, Miller GJ, Dutta-Roy AK. The effects of structurally defined triglycerides of differing fatty acid composition on postprandial haemostasis in young, healthy men. Atherosclerosis 1999;142:151 – 8. [21] Undas A, Brummel KE, Musial J, Mann KG, Szczeklik A. Simvastatin depresses blood clotting by inhibiting activation of prothrombin, factor V, and factor XIII and by enhancing factor Va inactivation. Circulation 2001;103:2248 – 53. [22] Nordoy A, Svensson B, Hansen JB. Atorvastatin and omega-3 fatty acids protect against activation of the coagulation system in patients with combined hyperlipemia. J Thromb Haemost 2003;1:690 – 7.
Activation of coagulation during alimentary lipemia under real-life conditions Elif Elmas a,*, Thorsten Ka¨lsch a, Nenad Suvajac a, Hans Leweling b, Michael Neumaier c, Carl-Erik Dempfle a, Martin Borggrefe a a
I. Department of Medicine, University Hospital of Mannheim, Theodor-Kutzer-Ufer 1-3, D-68167, Mannheim, Germany b IV. Department of Medicine, University Hospital of Mannheim, Mannheim, Germany c Department of Clinical Chemistry, University Hospital of Mannheim, Mannheim, Germany Received 21 November 2005; accepted 8 January 2006 Available online 30 May 2006
Abstract High intake of saturated fat is a predictor of coronary heart disease mortality. The phenomenon of postprandial angina pectoris has been described many years ago. Although earlier studies have demonstrated postprandial activation of coagulation factors VII and XII, platelets and monocytes, conclusive evidence for intravascular fibrin formation after a fat-rich meal has not been reported yet. The present study included 33 healthy physicians (7 females, 26 males) with a mean age of 42 years (range 27 – 62 years), and 27 coronary heart disease patients (8 females, 19 males) with a mean age of 63 years (range 47 – 81 years). Of the coronary heart disease patients, 26/27 were treated with acetylsalicylic acid and 25/27 with lipid-lowering drugs simvastatin or atorvastatin. Blood samples were drawn 30 – 60 min before and 30 – 60 min after a dinner consisting of rye bread with liversausage and black pudding as hors d’oeuvre, lettuce with smoked bacon in a lard dressing, stuffed fried goose with red cabbage, potato dumplings and sweet chestnuts, and white and brown mousse au chocolat. Average intake per person was 3760kcal, with 125.9 g protein, 238.0 g fat and 268.9 g carbohydrate. We measured a significant postprandial increase in fibrinopeptide A (FpA) levels from 1.14 T 1.23Ag/l to 4.18 T 2.86 Ag/l ( p < 0.0001) in healthy probands, and 4.66 T 13.61Ag/l to 12.80 T 15.04 Ag/l ( p < 0.0001) in coronary heart disease patients. Triglycerides increased from 137.6 T 60.5 to 201.5 T 75.0mg/dl in healthy probands and from 211.9 T 94.6 to 273.6 T 122.5 mg/dl in coronary heart disease patients. Fat-rich meals may cause procoagulant episodes, which may promote vascular complications such as myocardial infarction, transient ischemia attacks in susceptible persons. D 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Postprandial coagulation activation; Triglycerides; Fibrinopeptide A; Coronary heart disease
1. Introduction A fat-rich diet is believed to have profound effects on the vascular system by induction of endothelial dysfunction and other changes leading to development of atherosclerosis. High intake of saturated fat is a predictor of coronary heart disease mortality and the phenomenon of postprandial angina pectoris has been described many years ago [1]. Although earlier studies have demonstrated postprandial activation of coagulation factors VII and XII [2 – 7], platelets * Corresponding author. Tel./fax: +49 6213832204, +49 6213833821. E-mail address: [email protected] (E. Elmas). 0167-5273/$ - see front matter D 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2006.01.011
and monocytes [8 –10], conclusive evidence for intravascular fibrin formation after a fat-rich meal has not been reported yet. Also, most studies on postprandial coagulation activation were performed after fasting and in the morning rather than under real-life conditions where fat-rich meals are predominantly consumed in the evening. In one study, probands received a serving of high-fat premium ice cream after 12h of fasting [6], which seems rather extraordinary as a breakfast. In many studies, probands were ordered to refrain from smoking and the consumption of alcohol or caffeine for 24h before as well as during the study. In addition, the test meal had to be consumed in a very limited period of time, such as 10 min. Our intention was to measure
E. Elmas et al. / International Journal of Cardiology 114 (2007) 172 – 175
parameters of coagulation activation after a fat-rich dinner under realistic conditions. The probands were healthy physicians (predominantly cardiologists), and patients with coronary heart disease. Alcoholic beverages, including red wine and white wine, were served, and smokers were allowed to consume their usual amount of cigarettes.
173
FpA, HISS Diagnostics, Freiburg, Germany; normal range: 0 –5 ng/ml) and prothrombin fragment F1 + 2 (Enzygnost F1 + 2 micro, Dade Behring; normal range: 0.4 –1.1 nmol/l) were performed by a microtiter plate ELISA.
3. Statistics 2. Subjects and methods The present study included 33 healthy physicians (7 females, 26 males) with a mean age of 42 years (range 27 – 62 years), and 27 coronary heart disease patients (8 females, 19 males) with a mean age of 63 years (range 47 –81 years). Of the coronary heart disease patients, 26/27 were treated with acetyl salicylic acid 100 mg/day, 25/27 received lipid lowering drugs, either simvastatin or atorvastatin, 2/27 were treated with phenprocoumon. Atrial fibrillation was present in 10/27 patients. After informed consent, blood samples were drawn 30 – 60 min before and 30 –60 min after a dinner consisting of rye bread with liversausage and black pudding as hors d’oeuvre, lettuce with smoked bacon in a lard dressing, stuffed fried goose with red cabbage, potato dumplings and sweet chestnuts, and white and brown mousse au chocolat. Average intake per person was 3760 kcal, with 125.9 g protein, 238.0 g fat and 268.9 g carbohydrate. Venous blood was drawn into 10-ml syringes containing 1 ml of 3.13% citrate solution for conventional coagulation analyses and coagulation inhibitors, and 5-ml syringes containing 0.5 mg of recombinant hirudin (Refludan, Aventis, Germany) in addition to the citrate solution for measurement of coagulation activation parameters. For measurement of cholesterol and triglycerides, blood was drawn into tubes for serum preparation. Coagulation assays included antithrombin (MDA Antithrombin), protein C (MDA Protein C), fibrinogen level (MDA Fibriquick), D-Dimer antigen (MDA D-Dimer), prothrombin time (MDA Simplastin) and activated partial thromboplastin time (MDA Platelin LS) using a MDA II coagulation analyzer (bioMe´rieux, Duncan, NC, USA). Measurements of thrombin-antithrombin-complexes (Enzygnost TAT micro, Dade Behring Marburg Germany; normal range: 1.0 –4.1 Ag/L), fibrinopeptide A (Novitec
The data were analyzed using JMP statistics software (SAS Institute, Heidelberg, Germany). A 2-tailed p-value of less than 0.05 was considered to indicate statistical significance. Numerical data were expressed as means T SD. Differences were calculated as the value obtained after the test meal minus the value obtained before food ingestion and were tested for significant differences using Wilcoxon/ Kruskal Wallis rank sum test with Chi square approximation.
4. Results Most participants were able to complete their meal, including the desert consisting of a serving of mousse au chocolat decorated with cherries. Alcohol consumption was moderate and consisted mainly of red wine. No significant differences were seen between smokers and non-smokers concerning the laboratory results. Angina pectoris or other cardiovascular complications were not observed during the study period. Results of coagulation analyses and other laboratory assays are shown in Table 1. In the blood samples drawn from the healthy probands, we measured a significant postprandial increase in fibrinopeptide A (FpA) levels from 1.14 T 1.23 Ag/l to 4.18 T 2.86 Ag/l ( p < 0.0001), and an increase in thrombin –antithrombin complexes (TAT) from 1.93 T 0.43 to 2.25 T 0.83 Ag/l ( p = 0.0301) (Fig. 1). The correlation between FpA and TAT was r = 0.51. The coronary heart disease patients also displayed a significant postprandial increase in FpA levels from 4.66 T 13.61 Ag/l to 12.80 T 15.04 Ag/l ( p < 0.0001). The increase of TAT from 2.56 T 3.70Ag/l to 3.20 T 5.69 Ag/l was not statistically significant ( p = 0.2682). Prothrombin fragment F1 – 2 (PF1.2) levels remained unchanged in both groups, as did D-dimer levels in the healthy probands. Coronary heart disease patients displayed
Table 1 Results of laboratory analyses before and after test meal Healthy probands (n = 33)
Prothrombin fragment F1.2 [nmol/l] Thrombin – antithrombin complexes [Ag/l] Fibrinopeptide A [Ag/l] D-dimer antigen [mg/l] Cholesterol [mg/dl] Triglycerides [mg/dl]
Coronary heart disease patients (n = 27)
Before meal (mean T SD)
After meal (mean T SD)
p
Before meal (mean T SD)
After meal (mean T SD)
p
0.42 T 0.13 1.93 T 0.43 1.14 T 1.23 0.58 T 0.69 204.8 T 38.5 137.6 T 60.5
0.41 T 0.17 2.25 T 0.83 4.18 T 2.86 0.48 T 0.30 198.4 T 36.5 201.5 T 75.0
0.7301 0.0301 <0.0001 0.9326 0.4344 0.0008
0.89 T 0.51 2.56 T 3.70 4.66 T 13.61 0.33 T 0.35 231.2 T 42.1 211.9 T 94.6
0.94 T 0.69 3.20 T 5.69 12.80 T 15.04 0.44 T 0.38 227.8 T 42.3 273.6 T 122.5
0.7035 0.2682 <0.0001 0.0318 0.7293 0.0537
174
E. Elmas et al. / International Journal of Cardiology 114 (2007) 172 – 175
Fig. 1. Comparison of pre- and postprandial fibrinopeptide A (FpA) levels, and pre- and postprandial levels of thrombin – antithronbin complexes (TAT), F1.2 and D-dimer.
a slight postprandial increase in D-dimer levels from 0.33 T 0.35mg/l to 0.44 T 0.38 mg/l ( p = 0.0318). Whereas cholesterol levels did not change, triglyceride levels were significantly higher postprandially in both groups. Platelet count, prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, antithrombin and protein C remained unchanged (data not shown).
5. Discussion A high-fat meal results in postprandial hypertriglyceridemia, which promotes the production of atherogenic trigyleride-rich lipoproteins (TLRs). TLRs have been shown to initiate events resulting in factor VII activation [2,7]. Especially very low density lipoproteins (VLDL) support prothrombinase and other procoagulant enzymatic complexes [11,12]. Numerous studies have shown that Creactive protein (CRP) levels predict cardiovascular disease in apparently healthy individuals. CRP binds VLDL
[13,14]. Opsonization by CRP promotes the uptake of VLDL by macrophages [15,16], the formation of foam cells, and possibly the expression of procoagulant tissue factor [17]. In addition, the complex of CRP with VLDL has been shown to support coagulation activation more effectively than VLDL alone [18]. Coagulation activation induced by a fat-rich meal may therefore be more pronounced in individuals with elevated CRP levels. The present study is the first to show that even in apparently healthy persons, a fat-rich meal leads to intravascular formation of fibrin with release of fibrinopeptide A. Similar to the present study, ingestion of fat did not result in elevated levels of PF1.2 in earlier studies [7,19], which may be the result of the long plasma half life of PF1.2 obscuring acute effects of coagulation activation. Hunter et al. [20] found only a minor increase in FpA after test meals in healthy male volunteers, but compared with the present study, the test meals contained a considerably less fat. The present results indicate that FpA may be the most appropriate parameter for the detection of acute episodes of coagulation activation, although other activation products
E. Elmas et al. / International Journal of Cardiology 114 (2007) 172 – 175
with short plasma half life may be similarly useful. Coagulation activation parameters with long plasma halflife, such as TAT, prothrombin fragment F1.2, or D-dimer appear to be insufficiently sensitive for the detection of coagulation activation induced by a fat-rich meal or other acute stimuli. This is to our knowledge the first study to show postprandial coagulation activation in patients with coronary heart disease. This coagulation actuvation was present despite treatment with acetylsalicylic acid and lipid lowering drugs. Both simvastatin [21] and atorvastatin [22] reduce coagulation activation in patients with coronary artery disease [21] or hyperlipemia [22] . In the present study, postprandial FpA levels were approximately 5 times the preprandial values both in (untreated) healthy probands and in coronary heart disease patients treated with simvastatin or atorvastatin. Unfortunately we currently have no data on the extent of postprandial coagulation activation in coronary heart disease patients not treated with lipid lowering drugs. Fat-rich meals may cause procoagulant episodes, which may promote vascular complications such as myocardial infarction, transient ischemic attacks in susceptible persons.
Acknowledgement The study was supported by Pfizer, Karlsruhe, Germany.
References [1] Goldstein RE, Redwood DR, Rosing DR, Beiser GD, Epstein SE. Alterations in the circulatory response to exercise following a meal and their relationship to postprandial angina pectoris. Circulation 1971;44:90 – 100. [2] Larsen LF, Marckmann P, Bladbjerg EM, Ostergaard PB, Sidelmann J, Jespersen J. The link between high-fat meals and postprandial activation of blood coagulation factor VII possibly involves kallikrein. Scand J Clin Lab Invest 2000;60:45 – 54. [3] Miller GJ, Cooke CJ, Nanjee MN, et al. Factor VII activation, apolipoprotein A-I and reverse cholesterol transport: possible relevance for postprandial lipaemia. Thromb Haemost 2002;87:477 – 82. [4] Olsen AK, Bladbjerg EM, Hansen AK, Marckmann P. A high fat meal activates blood coagulation factor VII in rats. J Nutr 2002; 132:347 – 50. [5] Sanders TA, Miller GJ, de Grass T, Yahia N. Postprandial activation of coagulant factor VII by long-chain dietary fatty acids. Thromb Haemost 1996;76:369 – 71. [6] Kapur R, Hoffman CJ, Bhushan V, Haltin MB. Postprandial elevation of activated factor VII in young adults. Arterioscler Thromb Vasc Biol 1996;16:1327 – 32.
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