Postepy Hig Med Dosw. (online), 2012; 66: 696-701
Original Article
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Is there an effect of folic acid supplementation on the coagulation factors and C-reactive protein concentrations in subjects with atherosclerosis risk factors?
Czy suplementacja kwasem foliowym ma wpływ na stężenia czynników krzepnięcia i białka C-reaktywnego u osób z czynnikami ryzyka miażdżycy?
Artur Mierzecki1  ABDEG, Karolina Kłoda1  DEF, Maria Jastrzębska2  D, Kornel Chełstowski2  C, Krystyna Honczarenko3  D, Małgorzata Kozłowska-Wojciechowska4  D, Marek Naruszewicz4  AG
1Independent Laboratory of Family Physician Education, Pomeranian Medical University in Szczecin, Poland
2Department of Laboratory Diagnostics and Molecular Medicine, Pomeranian Medical University in Szczecin, Poland
3Department of Neurology, Pomeranian Medical University in Szczecin, Poland
4Department of Pharmacognosy and Molecular Basis of Phytotherapy, Medical University of Warsaw, Poland
Corresponding author
Artur Mierzecki MD, PhD, Independent Laboratory of Family Physician Education, Pomeranian Medical University in Szczecin, ul. Rybacka 1, 70-204 Szczecin; e-mail: roklr@pum.edu.pl

Authors' Contribution:
A - Study Design, B - Data Collection, C - Statistical Analysis, D - Data Interpretation, E - Manuscript Preparation, F - Literature Search, G - Funds Collection

Source of support
The study was supported financially by the Pomeranian Medical University in Szczecin, Poland

Received:  2012.05.29
Accepted:  2012.07.29
Published:  2012.10.18

Streszczenie
Wprowadzenie: Kwas foliowy (FA) może opóźniać tworzenie się zmian miażdżycowych. W chorobach układu krążenia obserwuje się podwyższone poziomy czynnika von Willebranda (VWF) w osoczu, co zwiększa ryzyko zakrzepicy. Fibrynogen (Fb) jest dobrze udokumentowanym czynnikiem ryzy­ka chorób układu krążenia. Celem badania była analiza wpływu suplementacji FA na osoczowe stężenia Fb, VWF i białka C-reaktywnego (CRP) u osób z czynnikami ryzyka miażdżycy.
Materiał/Metody:
Do badania włączono 124 osoby rasy kaukaskiej (60 M, 64 K) z czynnikami ryzyka miażdży­cy - wywiadem rodzinnym przedwczesnego niedokrwiennego udaru mózgu, z nadciśnieniem tętniczym, dyslipidemią, nadwagą i otyłością, nikotynizmem i niewielką aktywnością fizycz­ną. Uczestnicy zostali poproszeni o przyjmowanie FA w niskiej dawce 0,4 mg/24 h przez trzy miesiące.
Wyniki:
Po suplementacji FA zaobserwowano istotną redukcję stężeń VWF u kobiet (76,6 vs 72,3%; p=0,028) i u mężczyzn (75,5 vs 66,9%; p=0,001). Wśród kobiet i mężczyzn z dyslipidemią stę­żenia VWF obniżyły się po suplementacji FA (odpowiednio 76,8 vs 69,6%; p=0,003 i 76,7 vs 67,8%; p=0,001). Wśród kobiet i mężczyzn z BMI >=25 kg/m2 stężenia VWF obniżyły się tylko u mężczyzn (77,6 vs 66,5%; p=0,001). U palących osobników płci męskiej i żeńskiej suplemen­tacja FA skutkowała obniżeniem stężeń VWF (odpowiednio 82,5 vs 74,4%; p=0,012 i 76,6 vs 69,5%; p=0,036).
Dyskusja:
Wyniki naszego badania wskazują, że suplementacja FA wpływa na stężenia VWF u osób z czyn­nikami ryzyka miażdżycy.
Słowa kluczowe: miażdzyca • czynniki krzepnięcia • CRP • fibrynogen • kwas foliowy • hemostaza • czynnik von Willebranda


Summary
Introduction: Folic acid (FA) may delay the formation of atherosclerotic lesions. Increased plasma levels of von Willebrand factor (VWF) are observed in cardiovascular disease, which leads to higher risk of thrombosis. Fibrinogen (Fb) is a well-documented risk factor of cardiovascular disease. The aim of this study was to analyze the effect of FA supplementation on the Fb, VWF and C-reactive protein (CRP) plasma concentrations in subjects with atherosclerosis risk factors.
Material/Methods: The study enrolled 124 Caucasian individuals (60 M, 64 F) with atherosclerosis risk factors - family history of premature ischaemic stroke, arterial hypertension, dyslipidaemia, overweight and obesity, cigarette smoking and low physical activity. The participants were asked to take FA in the low dose of 0.4 mg/24 h for three months.
Results: After FA supplementation a significant reduction of the VWF concentrations in females (76.6 vs 72.3%; p=0.028) and in males (75.5 vs 66.9%; p=0.001) was observed. Among women and men with dyslipidaemia concentrations of VWF decreased after FA supplementation (76.8% vs 69.6%; p=0.003 and 76.7% vs 67.8%; p=0.001 respectively). Among females and males with BMI >=25 kg/m2 concentrations of VWF decreased only in men (77.6% vs 66.5%; p=0.001). In fema­le and male smokers supplementation of FA decreased VWF concentrations (82.5% vs 74.4%; p=0.012 and 76.6% vs 69.5%; p=0.036 respectively).
Discussion: The results of our study suggest that there is an effect of FA supplementation on VWF concen­trations in subjects with atherosclerosis risk factors.
Key words: atherosclerosis • coagulation factors • CRP • fibrinogen • folic acid • haemostasis • von Willebrand factor




Introduction
Numerous reports confirm preventive effects of folic acid (FA) on developmental birth defects, Alzheimer's disease, megaloblastic anaemia and depressive disorders [18,21]. There is no consensus among researchers on the preventive effect of FA on cardiovascular disease. It has been shown that, through lowering of homocysteine (Hcy) concentra­tions in the blood, FA may delay the formation of athero­sclerotic lesions [1]. The report by Brown et al. indicates that even a slight FA deficiency promotes atherosclerosis formation in arterial endothelium [54]. However, large-sca­le clinical trials have shown that a preventive use of FA in individuals with established cardiovascular disease or with history of myocardial infarction was not associated with a lower risk of new cardiovascular events [2,3,4,17,28].
Increased concentration of fibrinogen (Fb) promotes hy­percoagulability and incidents of thrombosis, leading to myocardial infarction, stroke or critical limb ischaemia. It is classified as an acute-phase protein; therefore Fb levels may also be elevated in inflammation [27]. Fibrinogen is a well-documented risk factor of cardiovascular disease [13]. However, results of studies on the association of FA with coagulation factors are ambiguous. Liem et al. re­ported lack of association of FA supplementation with Fb concentration [15]. Nevertheless, other reports indicate a beneficial anticoagulative effect of FA through decreasing concentration of Fb and increasing concentrations of pla­sminogen and antithrombin III [23]. Von Willebrand fac­tor (VWF) has a crucial role in blood coagulation [26]. Increased plasma levels of VWF are observed in cardio­vascular, neoplastic and connective tissue diseases, proba­bly because of endothelium dysfunction, which leads to an increased risk of thrombosis [16]. The ARIC study confir­med that VWF is a risk factor of ischaemic stroke [15]. It was found that FA supplementation decreases VWF con­centrations [23]. C-reactive protein (CRP) levels rise in re­sponse to inflammation. Some research suggest that indi­viduals with elevated basal concentrations of CRP are at an increased risk of diabetes and cardiovascular disease [8,19]. Therefore CRP is not only an inflammation mar­ker, but is also considered as a risk indicator for cardiova­scular disease [7].
The aim of this study was to analyse the effect of folic acid supplementation on fibrinogen, von Willebrand factor and C-reactive protein plasma concentrations.
Material and Methods
The study enrolled 124 adult Caucasian individuals (60 males aged 20-39 and 64 females aged 19-39) with athe­rosclerosis risk factors. A standard interview on the envi­ronmental risk factors for atherosclerosis was performed and revealed the presence of family history of premature ischaemic stroke, arterial hypertension, dyslipidaemia, overweight and obesity, cigarette smoking and low phy­sical activity among study participants. The inclusion criteria for the study group were: age >=18 years, patien­t's informed consent granted, absence of concurrent in­flammation, no hypolipidaemic or metabolism-modula­ting agents, no administration of B-group vitamins or vitamin preparations within 6 months before the study (use of hypotensive agents and oral contraceptives did not constitute exclusion criteria), young age of parents at the moment of ischaemic stroke (fathers younger than 55 years, mothers younger than 65 years) confirmed by means of computed tomography or magnetic resonance. The study involved an initial assessment through medi­cal history taking, physical examination and blood ana­lysis. Next, the participants were asked to take FA in the low dose of 0.4 mg/24 h for three months [24,29], after which a follow-up examination was performed, again through medical history taking, physical examination and blood analysis. Initially, FA supplementation was offered to 147 subjects, 23 of whom (15.6%) were exc­luded in the course of the study due to non-complian­ce (irregular taking of FA, stopping taking it altogether, or not reporting for the follow-up examination at the end of the treatment period). The study was approved by the Bioethics Committee of the Pomeranian Medical University in Szczecin, Poland.
Fasting blood for biochemistry was collected. The folic acid level was determined by an Abbott test kit (Abbott Laboratories, Chicago, Illinois, USA) using the ion cap­ture method on an IMX immunochemical analyser (by Abbott). Total homocysteine (Hcy) was determined by high performance liquid chromatography (HPLC) using test kits from Bio-Rad, on a Hewlett-Packard analyser with a fluorescence detector. Fibrinogen level was de­termined by the Clauss method on a Hemolab analyser, using bioMérieux test kits. The von Willebrand factor was measured by means of a miniVidas analyser (bio­Mérieux) and enzyme-linked immunosorbent assay. High-sensitivity C-reactive protein (hsCRP) was measu­red by the immunonephelometric method using a Dade- Behring BN-100 analyser (Dade Behring Holding GmbH, Liederbach, Germany).
Statistical analysis was performed using the STATISTICA StatSoft Polska v.9.0 package (StatSoft Inc., Tulsa, Oklahoma, USA) and the examined parameters were first evaluated for normal distribution (Shapiro-Wilk test). The significance of statistical differences was assessed with the chi-square test, chi-square test with Yates correction or Fisher's exact test. The paired Student t test was used for the comparison of mean values of measured parameters. The two-way analysis of variance (ANOVA) with statisti­cal significance in the post hoc test (NIR) was carried out. The CRP values were subjected to logarithmic transforma­tion. The significance level was set at p<=0.05.
Results
Table 1 shows the characteristics of examined patients. Low physical activity was adopted according to the Drygas de­finition [9]. Tables 2 and 3 show that low-dose FA supple­mentation resulted in statistically significant elevation of FA levels in studied females (6.3 vs 12.5 ng/dL; p=0.001) and males (6.4 vs 11.4 ng/dL; p=0.001) and concomitantly, a decrease in Hcy levels (10.6 vs 8.3 µmol/L; p=0.001 and 11.5 vs 9.3; p=0.001 respectively). There were no signifi­cant differences in Fb concentrations before and after FA supplementation in both genders. A significant reduction in mean concentration for VWF in females (76.6 vs 72.3%; p=0.028) and in males (75.5 vs 66.9%; p=0.001) was ob­served. There were no significant differences in CRP con­centrations before and after FA supplementation in both genders. Tables 4 and 5 show that evaluation of FA sup­plementation in women (n=43) and men (n=46) with dys­lipidaemia revealed a significant decrease in VWF concen­trations (76.8% vs 69.6%; p=0.003 and 76.7% vs 67.8%; p=0.001 respectively). Among females (n=19) and males (n=29) with BMI>=25 kg/m2 the concentrations of VWF decreased after FA supplementation only in men (77.6% vs 66.5%; p=0.001). In female (n=24) and male smokers (n=21) supplementation of FA resulted in decrease of VWF concentrations (82.5% vs 74.4%; p=0.012 and 76.6% vs 69.5%; p=0.036 respectively).
Table 1. Subjects' characteristics

Table 2. The effect of three-month diet supplementation with folic acid on Fb, VWF and CRP concentrations in females (n=64)

Table 3. The effect of three-month diet supplementation with folic acid on Fb, VWF and CRP concentration in males (n=60)

Table 4. The effect of three-month supplementation with folic acid on VWF, Fb and CRP concentrations depending on dyslipidaemia (n=43), BMI >=25 kg/m2 (n=19) and smoking (n=24) in females

Table 5. The effect of three-month supplementation with folic acid on VWF, Fb and CRP concentrations depending on dyslipidaemia (n=46), BMI >=25 kg/m2 (n=29) and smoking (n=21) in males

Discussion
The effect of low-dose FA supplementation (0.4 mg/24 h) on fibrinogen, von Willebrand factor and CRP concentra­tions was evaluated in this study. FA supplementation re­sulted in a significant decrease of VWF concentrations in analyzed individuals. Moreover, the decrease of VWF con­centrations was especially marked in smoking or dyslipida­emic women and in smoking or dyslipidaemic or overwe­ight and obese men. FA supplementation had no effect on Fb and CRP concentrations in the studied group.
Fibrinogen induces reversible aggregation of erythrocy­tes, reduces the fluidity of blood and affects clot forma­tion through thrombocyte aggregation [6,13,27]. Fb also binds to leukocytes due to their surface receptors and acts as a ligand for ICAM-1 (intercellular adhesion molecu­le-1) located on the thrombocytes and endothelium. This interaction leads to adhesion of platelets and leukocytes to the endothelial cells and plays a significant role in athe­rothrombosis [12]. A meta-analysis of prospective clini­cal trials regarding the effect of Fb on the cardiovascular incidents revealed that Fb concentrations were correlated with risk of death as a result of coronary heart disease, stro­ke (both ischaemic and haemorrhagic) or other vascular causes [10]. We found no correlation between FA supple­mentation and Fb concentrations. Liem et al. also reported a lack of impact of FA (0.5 mg/24 h) supplementation on Fb concentrations [15]. The authors stated that low-dose folic acid supplementation in regard to cardiovascular risk should be treated with caution. However, two reports in­dicate a beneficial effect of FA supplementation. Oral ad­ministration of FA (10 mg/24 h) decreased Fb and VWF concentrations and increased plasminogen and antithrom­bin III concentrations in studied subjects [23]. The second report showed a decrease of Fb concentrations and an in­crease of antithrombin concentrations after FA supple­mentation (dose of 5.0 or 10.0 mg/24 h) in patients with hyperhomocysteinaemia [22]. Mangoni et al. observed an anti-thrombotic effect of FA [20]. CRP along with Fb is a marker of an inflammatory response and is classified as an acute-phase protein. The role of CRP is binding to pho­sphocholine on microbes and damaged cells and enhan­cing phagocytosis by macrophages [31]. Therefore CRP takes part in the clearance of necrotic and apoptotic cells [25]. There are some reports on the association between FA supplementation and inflammatory markers. As in our study, some research carried out by other authors showed no effect of FA supplementation on CRP concentrations in analysed subjects [15,20,31].
Von Willebrand factor is a multimeric blood glycoprotein, produced by endothelial cells, subendothelial connective tissue and partly by megakaryocytes [26]. It is involved in primary haemostasis as an adhesive protein through bin­ding platelets to the collagen and secondary haemostasis due to forming a complex with factor VIII, protecting it against proteolysis [26]. VWF is considered to be a mar­ker of endothelial dysfunction in vascular disorders [16]. The ARIC study analysed VWF as an ischaemic stroke risk factor through comparison of the highest and the lowest quartile of VWF concentrations in analysed subjects. The relative risk of an ischaemic stroke, after amendments to the conventional risk factors, was 1.71 (without regarding CRP) and 1.21 (after correction for CRP) [11]. We obse­rved a significant decrease of VWF concentrations among studied subjects. Our observations confirm the results ob­tained by Mayer et al., who achieved a 6.8% reduction in VWF concentrations among individuals with high cardio­vascular risk, after FA supplementation in the dose of 10 mg/24 h [23]. However, it should be noted that we achie­ved a similar reduction in VWF concentrations using a 25 times lower dose of FA than Mayer et al. Moreover, we observed a significant reduction of VWF serum concen­trations especially in subjects with dyslipidaemia, obese males and cigarette smoking individuals. The decrease of VWF levels was demonstrated probably because low do­ses of FA improve vascular endothelium function, which is involved in the synthesis, storage and release of VWF. When endothelial cells are damaged, the VWF release is increased. Therefore VWF levels are useful as an atherosc­lerosis/thrombosis indicator. Endothelial damage is secon­dary to arterial hypertension, hyperlipidaemia, smoking, diabetes or metabolic disorders and results in activation of the coagulation cascade [26]. Hcy, levels of which are increased in those diseases, is linked to oxidation and en­dothelial injury. Administration of FA improves endothe­lial cell function through Hcy levels lowering and oxida­tive stress reduction [23]. Nevertheless, not all authors have obtained similar results. Mangoni et al., Vermuelen et al. and Klerk et al., applying doses of 5.0 mg/24 h or 0.8 mg/24 h, observed no correlation between FA supple­mentation and VWF concentrations [14,20,30]. Reported differences are associated with studied subjects and me­thods of FA supplementation. Mangoni et al. analysed a group which consisted of 100% smokers, while 36.3% of our group were smokers. Vermeuelen et al. supplemented not only FA, but also vitamin B6. Klerk applied FA du­ring a 1-year period, but in our study the supplementation lasted for 12 weeks because of earlier reported observa­tions that FA supplementation effects are noticeable from the 4th week of oral intake [24,29].
The results of our study suggest that there is an effect of folic acid supplementation on von Willebrand factor con­centrations in subjects with atherosclerosis risk factors. However, to confirm this observation further studies are needed.
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The authors have no potential conflicts of interest to declare.