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�:ACQUIRED AND INHERITED THROMBOPHILIC FACTORS IN YOUNG PATIENTS WITH ACUTE CORONARY SYNDROME: A CASE-CONTROL STUDY.



Francesco Dragoni1, Felicita Andreotti2,  Flavia Chiarotti3, Antonio Chistolini1, Noemi Angelosanto1,  Patrizia Pignoloni1, Mariano Pellicano4, Pierpaolo Pellicori5, Carlo Gaudio4, Francesco Barilla�4, Concetta Torromeo4.

1)  Thrombosis Center, Department of �Biotecnologie Cellulari ed Ematologia�, University �Sapienza�, Rome, Italy.
2)  Department of  Cardiovascular Medicine, Catholic University, Rome, Italy.
3)  Department of �Biologia cellulare e Neuroscienze�, Istituto Superiore di Sanit�, Rome, Italy
4) Coronary Care Unit,  Department of �Cuore e Grossi vasi�, Attilio Reale, University 
� Sapienza�, Rome, Italy.
5)  Academic Cardiology, Hull and East Yorkshire NHS trust, Castle Hill Hospital, Hull ,UK.



 








Corresponding author:

Dragoni Francesco, MD
Thrombosis Center, Department of �Biotecnologie Cellulari ed Ematologia�, 
University "Sapienza", Via Benevento n. 6, 00161 � Rome, Italy 
Phone: +39-06-85795407
Fax: +39- 06-4403695
e-mail: dragonifrancesco@hotmail.it





ABSTRACT

The role of inherited or acquired thrombophilic conditions and their interaction with traditional cardiovascular risk factors in the development of premature acute coronary syndromes (ACS) have not been extensively investigated.
To evaluate the role of acquired and inherited thrombophilic factors and their interaction with classical risk factors in young patients with first acute coronary syndrome (<55 years), 58 patients   (51 men, mean 46.2 years, range 27-53)  underwent evaluation of antithrombin, protein C, free protein S, activated protein C resistance and homocysteine levels. The presence of lupus anticoagulant and anticardiolipin antibodies and the prevalences of F5 R506Q, F5 HR2 haplotype, F2 G20210A and homozygosis for the C677T thermolabile variant of methylenetetrahydrofolate reductase were also evaluated. The results were compared to those of 100 age-matched healthy controls . 
The stepwise logistic regression analysis selected F5 R506Q (OR= 6.84; 95%CI = 1.37-34.02), homocysteine levels (OR= 4.37; 95%CI = 1.54-12.45), hypertension (OR= 3.66; 95%CI = 1.31-10.25), hypercholesterolemia (OR= 6.31; 95%CI = 2.27-17.55), diabetes (OR= 10.04; 95%CI = 1.76-57.17) and smoking (OR= 11.00; 95%CI = 3.92-30.86) as significantly associated with premature ACS. The association between one or more thrombophilic polymorphisms and one or more classical cardiovascular risk factors markedly increased the risk of ACS (OR= 21.95; 95%CI = 6.28-76.80).
This study  suggests a significant role of F5 R506Q and homocysteine levels, in addition to hypertension, hypercholesterolemia, diabetes and smoking, in the development of ACS in young patients. The risk of premature disease was particularly high when thrombophilic conditions were associated with traditional cardiovascular risk factors.

INTRODUCTION 
Thrombophilia can be defined as an increased tendency towards thrombosis through enhanced coagulation and/or platelet aggregability. It comprises several rare inherited abnormalities, associated with thrombosis at a young age. Acute coronary syndromes (ACS) have intravascular thrombogenesis as their main pathogenetic mechanism, the latter being influenced by a complex interplay involving multiple genetic and environment factors related to atherosclerosis, thrombosis and their interaction [1]. The classical cardiovascular risk factors such as diabetes, hypercholesterolemia, hypertension, obesity, family history and smoking have been well characterized, while the role of thrombophilic conditions in the development of ACS has been less well characterized [2].
Inherited deficiencies of factors associated with anticoagulation including antithrombin, protein C, and protein S were the first to be associated with increased thrombosis, in particular venous thrombosis. The discovery of activated protein C (APC) resistance and the subsequent F5 R506Q (FV G1691A) gene polymorphism responsible for 90% of cases has led to a much broader search for other prothrombotic gene polymorphisms [3]. The main clinical manifestation of variant factor V alleles is deep venous thrombosis [4,5,6]. The role of F5 R506Q in arterial thrombosis is less conclusive. A study of 560 men under 70 years of age with myocardial infarction revealed a small increased risk in carriers of F5 R506Q (OR = 1.4; 95%CI = 0.8-2.2) [7]. Moreover, an increased prevalence of F5 R506Q was found in patients with coronary artery disease [8,9].  Another longitudinal study based on more than 5000 men and women over 65 years of age with three-year follow up, found that F5 R506Q was not a significant predictor of myocardial infarction, angina, or stroke in 373 cases compared with 482 controls [10].  The F5 HR2 haplotype (A4070G) was discovered after an investigation to determine other causes of APC resistance and has a prevalence of 8�10% in Italian, Indian, and Somalian populations [11].  A French study performed in 200 patients demonstrated that it is associated with an increased risk of venous thrombosis (OR = 1.8; 95% CI = 1.1-2.8) [6,12] but no data have been reported on this haplotype in patients with arterial thrombosis. A single nucleotide change of glutamine to arginine was identified at position 20210 by Poort et al. in 1996 [13]. The presence of the abnormal gene is associated with increased circulating prothrombin levels. An initial study performed in 79 young women (18�44 years old) with myocardial infarction and 381 controls found an increased risk of myocardial infarction with this polymorphism (OR = 4.0; 95%CI = 1.1-15.1), especially in combination with other risk factors such as smoking [14].  
More recent meta-analyses have confirmed a small but significant role of this prothrombin variant for coronary artery disease [9], particularly for ACS before 55 years of age with limited extent of coronary atherosclerosis at angiography [15]. Frosst et al., in 1995, described a common C677T variant of the methylenetetrahydrofolate reductase (MTHFR) gene [16]. Increased levels of homocysteine have been linked with the TT homozygous genotype but have only been demonstrated when plasma folate values are low [17]. Of the many studies investigating a link between the MTHFR polymorphism and arterial thrombosis, particularly with regard to myocardial infarction, some studies have shown an association [18,19],  but most have failed to reveal a correlation [20,21]. Similarly, ischemic stroke has failed to be consistently linked with the MTHFR polymorphism, despite an association between the MTHFR variant and homocysteine concentrations [22,23].
It has been recently hypothesized that individual polymorphisms may have less or no independent effect on venous or arterial thrombosis, but may act in synergy with other genetic or established factors predisposing to cardiovascular disease [24,25].  However, the synergistic effect of prothrombotic polymorphisms and traditional cardiovascular risk factors on the risk of ACS in young patients has so far been only partially investigated. The aims of the present case-control study were to assess the role of the most common acquired and inherited thrombophilic factors (TF) in the pathogenesis of ACS in young patients, and to evaluate whether the association with traditional cardiovascular risk factors may have a significant impact on the development of the disease.

MATERIALS AND METHODS
General design
We conducted a prospective population-based case-control study in young Italian subjects with ACS. Data collection was achieved via personal interview, review of medical records, and analysis of blood samples. Cases and controls underwent assessment of the whole set of factors. 
Patients 
The study was conducted between December 2007 and December 2009 in the Coronary Care Unit, Department of �Cuore e Grossi vasi�, Attilio Reale, University �Sapienza�, Rome, Italy. Eligibility criteria for patients were European origin, residence in Italy, age  not exceeding 54 years and a diagnosis of first acute coronary syndrome. The criteria for a diagnosis of acute myocardial infarction were derived from the Cardiovascular Health Study [26] and were defined by evidence of symptoms, elevated enzymes, and electrocardiographic changes. Unstable angina was defined as class IIIB of Braunwald's classification [27]. 
Control subjects 
The control group was consecutively selected (up to 50 males and 50 females) among the patients� personal assistants, doctors or medical attendants, visiting the Cardiological or Hematological Departments of the �Sapienza� University during the same study period. Eligibility criteria were  a comparable age and good health status with no prior history of coronary heart disease or cerebrovascular disease.
Risk factor assessment
Systemic hypertension, diabetes mellitus, and hypercholesterolemia were considered present if drugs for these conditions had been prescribed before admission or if these conditions were diagnosed during the hospital stay. The respective criteria for diagnosis were: blood pressure >140/90 mmHg on more than one occasion, fasting glycaemia >126 mg/dL on at least two occasions, and a total serum cholesterol concentration >240 mg/dL. Smokers were defined as subjects who smoked more than 10 cigarettes per day at the time of admission. A family history of myocardial infarction was defined as at least one first degree relative with a fatal or non-fatal myocardial infarction before the age of 60 years. Clinical information of patients and controls is in Table 1.
Determination of acquired and inherited thrombophilic factors
In patients, the evaluation of inherited and acquired thrombophilic factors was performed at least six months after the diagnosis of ACS. Antithrombin (AT) and protein C (PC) activities were evaluated by commercially available kits (Dade-Behring, Marburg, Germany) (Normal ranges expressed as mean � 2SD were 75-135% and 72-135%, respectively). Free and total protein S (PS) were determined by an ELISA method following the manufacturer's instruction (Assera-Plate, Stago, Asni�res, France) (normal ranges expressed as mean � 2SD were 64-155% and 62-136%, respectively). Resistance to activated protein C was evaluated by a commercially available test (Dade-Behring Diagnostic, Milan, Italy) based on the method described by Dahlback et al. [28]. Normalised sensitivity ratio was considered normal if above 0.85. Homocysteine levels were measured using a Microparticle Enzyme Immunoassay (MEIA) method with IMx (Abbott Diagnostic, Germany; normal limit <15 (mol/L).
Venous blood for the evaluation of antiphospholipid antibodies (APA) was collected by venipuncture with a 21-gauge butterfly infusion set into a plastic syringe containing 106 mM/L of sodium citrate (blood/citrate ratio 9:1). Platelet-poor plasma (PPP) was obtained by centrifugation at 2,000 g for 20 minutes. Plasma was subsequently centrifuged for an additional 10 minutes at a higher speed (> 2,500 g) according to the updated guidelines for lupus anticoagulant detection [29]. After double centrifugation, the platelet count in all samples (measured using the H3-Bayer system, Bayer Diagnostics, Milan, Italy) was less than 10,000/(L and the samples were therefore considered suitable for the evaluation of coagulation parameters. PPP was then divided into small aliquots (500 (L) and immediately frozen at -80�C until use. The presence of lupus anticoagulant (LA) was evaluated by Kaolin Clotting Time (KCT) and diluted Russell�s viper venom time (dRVVT). The KCT was performed according to the method of Exner et al. [30]  using a 2% kaolin suspension. Mixing studies, aimed at documenting the inhibitory activity of prolonged KCT samples, were performed by adding normal PPP in a proportion of 1:1 and 1:4 in all KCT prolonged samples. Failure to observe the correction of clotting time after incubation was considered consistent with the presence of the circulating inhibitor. LA confirmatory studies were performed by adding (1:5 v/v) natural phospholipids (Pathromtin SL, Istituto Behring, Scoppitto, Italy) to positive samples. Only samples with a prolonged KCT not corrected by mixing procedures and characterized by a correction after the addition of natural phospholipids were considered positive for LA. The normal range (mean � 2SD) of the KCT ratio was 0.74-1.30. The dRVVT was carried out according to the method of Thiagarajian et al. [31]  using a commercial kit (Instrumentation Laboratory Diagnostics, Milan, Italy) and following the manufacturer�s instructions. The normal range (mean ratio � 2SD) of dRVVT was 0.85 - 1.25. IgM and IgG anticardiolipin antibodies (ACA) were performed using an ELISA method [32] , with a commercial kit (Chromogenix, Molndal, Sweden), according to the manufacturer's instruction. Results were expressed as GPL units/mL and MPL units/mL (U/mL) according to Harris et al. [33]. Values exceeding 13 GPL U/mL and 11 MPL U/mL were considered above the normal limit. According to the International Consensus Statement on the updated classification criteria for definite APA syndrome, the positivity of APA was defined as the presence of LA or ACA in serum or plasma present in medium or high titer [34]. Therefore, the IgG and IgM isotypes were categorized as positive > 23 GPL U/mL or > 11 MPL U/ml, respectively. The normal ranges (mean � 2SD) of the evaluated parameters were derived from 80 healthy subjects (Male = 40, Female = 40, mean age 41.2 years, range 28-56). 
Genomic DNA was isolated from peripheral blood collected in EDTA, using the InstaGene Genomic DNA kit (Bio-Rad Laboratories, Hercules, CA). Detection of F5 R506Q was carried out by polymerase chain reaction following the method of Bertina et al. [35]. The presence of a point mutation in exon 10 at position 1691 was detectable by the loss of a cleavage site for Mnl 1 and the relative altered restriction fragment length polymorphism pattern. F 2 G20210A was determined by the presence of a HindIII restriction site in the PCR fragment according to the method described by Poort et al. [36]. The presence of C677T mutation in the gene of the MTHFR, which converts an alanine to a valine residue, was analysed by allele-specific digestion with Hinfl (New England Biolabs, Inc, Beverly, Mass) and separation on 3% agarose gel. The procedure was performed according to the method described by Froost et al. [37]. The presence of F5 HR2 haplotype was evaluated using a commercial kit (Nuclear Laser medicine, Milan, Italy).
Statistical analysis
Quantitative variables are presented as means ( SD and ranges, while categorical variables are presented as absolute and percent frequencies. Chi-square test and Fisher�s exact probability test and the calculation of the Odds ratios (OR) with the 95% confidence intervals (95%CI) were computed to compare differences between patients and controls as for sex, smoking habit, hypertension, hypercholesterolemia, acquired and inherited prothrombotic factors. Patients were also classified based on the presence of at least one cardiovascular risk factor (CRF) among smoke, diabetes, hypertension and hypercholesterolemia, combined with at least one inherited thrombophilic factor (TF) among F5 R506Q, F 2 G20210A, F5 HR2 haplotype and thermolabile variant C677T of MTHFR. Four classes were identified for CRF/TF variable: neither CRF nor TF (no/no), CRF only (yes/no), TF only (no/yes), CRF and TF (yes/yes). A logistic regression analysis with stepwise backward selection of variables was performed to assess the factors significantly associated with the outcome under study (ACS yes vs no), considering such factors separately or in combination. Finally, a logistic regression was performed to estimate the ORs with the 95%CIs, taking into account all potential factors and/or confounders. For all statistical tests a significance level of p < 0.05 was used. Statistical analyses were performed by STATA Software (Release 8.0) [38].                  















RESULTS
Two-hundred-ten patients were hospitalized for a first acute coronary syndrome during the study period. Among them, 58 patients (51 men, age between 27 and 53 years) fulfilled the eligibility criteria and thus were enrolled. Thirty-two patients had ST-elevation acute myocardial infarction (STEMI), 20 acute myocardial infarction without ST- elevation (NSTEMI) and 6 had unstable angina. Inherited and acquired thrombophilic factors were also evaluated in one hundred healthy subjects residing in Italy comparable for age (Male = 50, Female = 50, mean age = 44.6 years, SD = 5.0, range = 29-55). The clinical information and the prevalence of classical cardiovascular risk factors for ACS among cases and controls are shown in Table 1. All patients and all normal controls were of European origin. As expected, the classical cardiovascular risk factors for acute coronary syndrome were more common in the patients than in the normal controls.
Antithrombin (Mean = 104.8%, SD = 10.8), PC (Mean =119.07%, SD = 19.5) and free PS (Mean = 97.7%, SD =15.2) were normal in all cases. F5 R506Q was found in 7 out of 58 (12.07%) patients and in 2 out of 100 (2%) normal controls (OR= 6.73; 95%CI = 1.35-33.56). F5 HR2 haplotype was found in 7 out of 58 (12.07%) patients and in 8 out of 100 (8%) normal controls (OR= 1.58; 95%CI = 0.54-4.60). F 2 G20210A was found in 1 out of 58 (1.72%) cases and in 2 out of 100 (2%) normal controls (OR = 0.86; 95%CI = 0.08-9.69). The presence of the C677T variant in the gene of the MTHFR was found in 12 out of 58 (20.69%) patients and in 13 out of 100 (13%) normal controls (OR= 1.75; 95%CI = 0.74-4.13). The positivity of APA was revealed in 3 out of 58 (5.17%) cases and in 1 out of 100 (1%) normal controls (OR= 5.40; 95%CI = 0.55-53.17). Pathological levels of homocysteine were found in 18 out of 58 (31.03%) cases and in 12 out of 100 (12%) normal controls (OR= 3.30; 95%CI = 1.45-7.50). Hypertension was present in 26 out of 58 (44.83%) cases and in 14 out of 100 (14%) normal controls (OR= 4.99; 95%CI = 2.32-10.74), hypercholesterolemia in 32 out of 58 (55.17%) cases and in 12 out of 100 (12%) normal controls (OR= 9.03; 95%CI = 4.08-19.98). Diabetes mellitus was found in 8 out of 58 (13.79%) cases and in 2 out of 100 (2%) normal controls (OR= 7.84; 95%CI = 1.60-38.31). Current smokers were 45 out of 58 (77.59%) cases and 25 out of 100 (25%) normal controls (OR= 10.38; 95%CI = 4.83-22.32). 
Stepwise logistic regression selected F5 R506Q, homocysteine levels, hypertension, hypercholesterolemia, diabetes and smoking as factors significantly associated to the diagnosis of ACS (Table 2). The effect of the association among one or more traditional cardiovascular risk factors and one or more evaluated polymorphisms on the odds of ACS was assessed by logistic regression. Table 3 shows the crude ORs with the corresponding 95%CIs estimated for each combination of factors. As can be seen, the presence of one or more cardiovascular risk factors increased the risk of ACS nine fold, while the combination of one or more cardiovascular risk factors with one or more evaluated thrombophilic polymorphisms increased the risk even further, more than 20 fold. Logistic regression performed adjusting for sex and age gave similar results as for ORs and CIs (CRF: OR = 8.84, 95%CI = 2.69-29.03; CRF+TF: OR = 19.48, 95%CI = 5.16-73.50).






DISCUSSION
Acute coronary syndrome is a less frequent event in young compared to older patients. Although several traditional risk factors such as hypercholesterolemia, hypertension, diabetes and smoking have been well characterized [2],  the role of inherited and acquired thrombophilic factors has been less well evaluated in these patients. Many studies provide conflicting data concerning the clinical importance of gene polymorphisms in the pathogenesis of arterial disease and myocardial infarction [7,10,14] . The complex pathogenesis of thrombosis means that a single gene defect probably determines only a small effect; moreover, the impact of a given polymorphism will depend on gene�environment interactions that may be specific for a given cohort of patients. We designed our study to evaluate the role of inherited and acquired prothrombotic factors in a group of relatively young patients with ACS and to estimate their interaction with the well established classical cardiovascular risk factors.
The main clinical manifestation of the F5 R506Q is deep venous thrombosis [4], while its role in arterial thrombosis has been only partially investigated. A study of 560 men under 70 years of age (mean age 56.2 years) with myocardial infarction, born in the Netherlands and living in the Leiden region, revealed a small increase in risk in carriers of F5 R506Q and F2 G20210A [7]. On the other hand, a case-control study of 112 young males, living in Asia, Africa, Europe and America, with first acute myocardial infarction found a similar prevalence of heterozygote for FV G1691A in cases and controls [24].  In our study of young patients with a mean age of 46.1 years residing in Italy, we found an association between the presence of F5 R506Q and the risk to develop ACS. The difference prevalence of F5 R506Q reported in these studies could be due to the different study samples and to the variable frequency of inherited thrombophilic variants such as F5 R506Q in different populations. In fact, the F5 R506Q was not found in any of 1600 chromosomes of indigenous populations from Africa, Southeast Asia, Australasia and America, while a high prevalence was found among Europeans [39]. Our study is in agreement with a previous one that evaluated young women (mean age 39.6 years) residing in contiguous counties of western Washington state, in which a significant risk of F5 R506Q for acute myocardial infarction was documented [25]. Similarly, we investigated a selected group of Caucasian patients, from a geographical area in which the prevalence of F5 R506Q is higher than in other countries. Inherited prothrombotic factors may have a more important effect in young compared to older patients because atherosclerosis has had less time to progress [8,15]; indeed, in young patients with acute myocardial infarction, atherosclerosis is not always evident at angiography[15]. Recently, F5 R506Q was associated with an increased risk of myocardial infarction in a large cohort of 1880 young Italian patients [40].
Mild hyperhomocysteinemia, whose blood levels are influenced by nutritional factors and daily vitamins intake, is an independent predictor of peripheral, coronary and cerebral vascular disease [22,41,42].  Homozygosity for the thermolabile variant C677T of the MTHFR gene seems to play an important role in determining high homocysteine levels especially in the presence of folate deficiency [17]. In our study, multivariate analysis selected pathological levels of homocysteine as a significant predictor of ACS in young patients. Our study additionally confirmed a significant role of classical cardiovascular risk factors, such as smoking, hypertension, hypercholesterolemia and diabetes mellitus, in the pathogenesis of ACS. 
In previous studies, the interaction of prothrombotic polymorphisms with the traditional cardiovascular risk factors, especially smoking, seems to determine a significant rise in the risk of arterial thrombosis [43].  In one study, when the presence of one or more of the three prothrombotic polymorphisms was analyzed, only a mildly increased risk of acute myocardial infarction was observed;  but when the presence of one or more of the prothrombotic polymorphism was evaluated in combination with the major cardiovascular risk factors, the estimated risk increased nine fold with hypertension, hypercholesterolemia, or diabetes and almost 18-fold with current smoking. Moreover, the estimated risk increased 25-fold when adjustment for atherogenic metabolic risk factors was undertaken [24]. These results are in accordance with the studies of Rosendaal et al in which a similar synergism was found in a group of young women with myocardial infarction [25].
The lupus anticoagulant has been indicated as a major risk factor for arterial thrombotic events (myocardial infarction and ischemic stroke) in young women and the association of lupus anticoagulant with traditional cardiovascular risk factors increased the risk even further [44].  In our study, when the presence of one or more prothrombotic polymorphisms was analyzed separately, no effect on the risk of ACS was observed. This observation is in agreement with the results of Inbal et al., who observed only a mildly increased risk due to the presence of one or more prothrombotic polymorphisms in patients with acute myocardial infarction [24]. On the contrary, when the presence of one or more prothrombotic polymorphisms was analyzed in association with one or more cardiovascular risk factors, we found an up to 22-fold increase in the estimated risk of developing ACS, suggesting that the association between one or more prothrombotic polymorphisms and the major cardiovascular risk factors plays a synergistic role in the pathogenesis of ACS. A limitation of the present study is the low number of patients and control subjects, resulting in relatively large confidence intervals for the estimated ORs. However, the analysis of the combination of CRF and TF yielded a lower boundary of the Odds Ratio�s Confidence Interval far from unity, supporting a role of specific gene-environment interactions on the risk of developing ACS.  It is interesting to note that, while the presence of inherited thrombophilic factors is a congenital condition, the effect of cardiovascular risk factors such as hypertension, hypercholesterolemia, diabetes and smoking in the pathogenesis of ACS may be significantly modified by a pharmacological intervention and by a healthy lifestyle. In fact, a 12-week unsupervised walking program  exhibits a pronounced hearth rate recovery amelioration,  attenuates endothelial damage, reduces homocysteine levels  and induces a concomitant improvement in perceived quality of life in patients with chronic heart failure [45]. Moreover, a correct lifestyle, in young subjects with no prior history of coronary heart disease who have genetic thrombophilic factors,   could  play a role in reducing the risk of  ACS. 
In conclusion, this study found a significant role of F5 R506Q, homocysteine levels and classical cardiovascular risk factor in the development of ACS in young patients. Moreover, the association between inherited thrombophilic factors and traditional cardiovascular risk factors seems to increase the risk even further. Further studies on a larger number of patients and controls may be necessary to assess more specifically the role of gene�environment interactions in arterial thrombosis.


Acknowledgements 
We would like to thank Mr. Michael Redante, 6015 Lower Mountain Rd., New Hope, PA, USA, for the revision of the English form of this manuscript.
 
 





 




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Table 1 

Clinical Information on Patients with Acute Coronary Syndrome and Normal Controls

 	ACS Patients (n. = 58) 	Normal Controls (n. = 100)
------------------------------------------------------------------------------------------------------------------------ 
	 N. 	% 	N. 	% 	P( INCLUDEPICTURE "http://bloodjournal.hematologylibrary.org/math/12pt/normal/chi.gif" \* MERGEFORMATINET � test) 
------------------------------------------------------------------------------------------------------------------------ 
Smoking 	45	77.6	25	25.0	<0.0001


Hypertension 	26	44.8	14	14.0	<0.0001


Diabetes mellitus 	8	13.8	2	2.0	0.0094


Hypercholesterolemia 	32 	55.2	12	12.0	<0.0001

------------------------------------------------------------------------------------------------------------------------ 

Table 2

Results of stepwise logistic regression analysis of inherited thrombophilic and acquired cardiovascular risk factors for acute coronary syndrome

Factors 	Odds Ratio 	      SE* 	       95%CI�
--------------------------------------------------------------------------------------------------------
F5 R506Q 	6.84 	                5.60 	               1.37 - 	34.02 
Homocysteine 	4.37 	                2.33 	               1.54 - 	12.45 
Hypertension 	3.66 	                1.92 	               1.31 - 	10.25 
Hypercholesterolemia 	6.31 	                3.29 	               2.27 - 	17.55 
Diabetes mellitus 	10.04 	                8.91 	               1.76 - 	57.17 
Smoke 	11.00 	                5.79 	               3.92 - 	30.86 
--------------------------------------------------------------------------------------------------------
*SE = Standard Error
�CI = Confidence Interval


Table 3
Results of stepwise logistic regression analysis of cardiovascular risk factors and risk of ACS with and without the simultaneous presence of the evaluated prothrombotic polymorphisms.
Cardiovascular risk factors (CRF)Inherited risk factors (IRF)PatientsControlsOR*95%CINoNo442  1NoYes1130.810.08-7.88YesNo30349.262.97-28.88YesYes231121.956.28-76.80* All odds ratios are relative to the reference group, i.e. the group of patients who had neither CRF nor IRF. Age- and sex-adjusted logistic regression led to similar results (for both ORs and 95%CIs). CRF = Cardiovascular Risk factors, IRF= Inherited Thrombophilic Factors


 










PAGE  20


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