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J Am Coll Cardiol, 2000; 36:717-722
© 2000 by the American College of Cardiology Foundation
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CLINICAL STUDY

Prevalence of factor v leiden and prothrombin variant g20210a in patients age <50 years with no significant stenoses at angiography three to four weeks after myocardial infarction

Neil S. Van de Water, PhD* {dagger}, John K. French, MB, PhD, FESC* {dagger}, Mayanna Lund, MB{ddagger}, Thomas A. Hyde, MB{ddagger}, Harvey D. White, MB, DSc, FACC{ddagger} and Peter J. Browett, MB{ddagger}

* Department of Molecular Medicine, University of Auckland, Auckland Hospital, Auckland, New Zealand
{dagger} Hematology Department, Auckland Hospital, Auckland, New Zealand
{ddagger} Cardiology Department, Green Lane Hospital, Auckland, New Zealand

Manuscript received November 17, 1999; revised manuscript received March 1, 2000, accepted April 13, 2000.

Reprint requests and correspondence: Dr. John French, Cardiology Department, Green Lane Hospital, Private Bag 92 189, Auckland 1030, New Zealand
johnf{at}ahsl.co.nz


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES

We sought to determine the frequencies of factor V Leiden and prothrombin variant G20210A in patients age <50 years with no significant coronary stenoses three to four weeks after myocardial infarction (MI).

BACKGROUND

Factor V Leiden and prothrombin variant G20210A occur frequently in patients with venous thromboembolism. However, the contribution of these mutations to the development of MI requires clarification.

METHODS

The frequencies of factor V Leiden and prothrombin variant G20210A were determined in 41 patients age <50 years who had "normal" or "near normal" coronary arteries (no stenosis >50%) at angiography three to four weeks after MI (the study group) and compared with those in 114 patients who had at least one angiographic stenosis >50% after MI (the control group). Patients age ≥50 years with, or without, stenoses were also studied.

RESULTS

The frequency of factor V Leiden was 14.6% in patients age <50 years in the study group compared with 3.6% in patients in the control group (odds ratio [OR] 4.7 [95% confidence interval (CI) 1.3–17.7], p = 0.02). The frequency of the prothrombin variant G20210A was 7.3% in the study group compared with 1.8% in the control group (OR 4.4 [95% CI 0.7–27.5], p = 0.12). One or both mutations were present in 8 of the 41 patients (19.5%) age <50 years in the study group compared with 6 of the 114 patients (5.5%) in the control group (OR 4.4 [95% CI 1.4–13.5], p = 0.01). In all 271 patients (irrespective of age) with normal arteries, the frequency of factor V Leiden was 11.7% (7/60) compared with 4.3% (9/211) in patients with at least one >50% stenosis (OR 2.9 [95% CI 1.1–8.3], p = 0.04), and the frequency of prothrombin variant G20210A was 6.7% (4/60) compared with 1.4% (3/211) (OR 4.9 [95% CI 1.1–22.8], p = 0.04), respectively.

CONCLUSIONS

The frequencies of factor V Leiden and/or prothrombin variant G20210A are increased in patients age <50 years with normal or near normal coronary arteries after MI.

Abbreviations and Acronyms
  CI = confidence interval
  MI = myocardial infarction
  OR = odds ratio
  PCR = polymerase chain reaction

The contribution of genetic and functional alterations in factors of the coagulation and fibrinolytic pathways (that is, hemostatic risk factors) to the development of arterial thrombosis requires clarification. In several studies, fibrinogen levels have been identified as an indicator of risk for the future development of stroke and myocardial infarction (MI) (1–5). Inherited abnormalities of plasminogen activator inhibitor-1, von Willebrand factor, factor V and prothrombin have also been implicated in the pathogenesis of MI (6–10).

Factor V Leiden, which results in activated protein C resistance, has been identified as a risk factor for venous thromboembolism, occurring in 20% to 30% of patients with this condition (11,12). Factor V Leiden occurs in 4% to 6% of individuals in most Caucasian populations including New Zealand (13,14). The prothrombin variant G20210A, a genetic variation in the 3'-untranslated region of the prothrombin gene, is associated with elevated plasma prothrombin and thrombin levels, thus increasing the risk of thrombotic events (15). This has a frequency of 1.7% (95% confidence interval [CI] 1.3–2.2) in populations of northern European descent (16).

The frequencies of factor V Leiden and the prothrombin variant G20210A have not been consistently shown to be increased among patients with previous MI or stroke (9,10,17). However, increased frequencies of factor V Leiden and prothrombin variant G20210A in younger women with MI have been shown by one group (18,19).

After MI, the prevalence of "normal" or "near normal" coronary angiography varies between 1% and 12%, and various etiological factors have been implicated, including coronary spasm, coronary embolism and cocaine use (20). In a previous small series, almost all of the patients without significant stenoses on coronary angiography after MI were males aged <50 years and frequent cigarette smokers (20). Inherited hemostatic risk factors may have more influence on the development of MI in patients with "normal" coronary angiograms than in patients with more severe stenoses before MI in whom there is shear stress-induced platelet activation.

To determine whether particular inherited hemostatic risk factors may have contributed to the development of MI in patients without significant coronary stenoses at angiography three to four weeks after MI, we assessed the frequencies of factor V Leiden and prothrombin variant G20210A, particularly in patients age <50 years.


   Methods
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 Abstract
 Methods
Results
 Discussion
 References
 
Patient population.   Patients being followed-up after six randomized controlled trials of different therapies for acute MI (21–26) and patients screened for cohort studies (27,28) were approached to enter this study. Local ethics committee approval and individual written informed consent were obtained. Details of angiography performed three to four weeks after MI (including myocardial score) and clinical follow-up were as previously described (26,29). All consenting survivors of MI who were age <50 years and had "normal" or "near normal" coronary angiograms (no coronary stenosis >20% and >50%, respectively) formed the study group, and patients age <50 years selected at random from the above studies, with at least one stenosis >50%, formed the control group. The frequency of mutations/polymorphism in patients aged ≥50 years with, or without, stenoses >50% after MI was also determined. In this New Zealand study, 81% of patients were of European origin (of whom >90% were of northern European origin) (30), 16% were Polynesian, and 3% were Asian.

Patient samples.   Ten milliliters of venous blood was collected into a tube containing sodium citrate. DNA was prepared by either the proteinase K/phenol or DNAzol (Life Technologies, Gaithersburg, Maryland) extraction methods.

Mutational analysis.   Single base changes for factor V Leiden and prothrombin variant G20210A were detected by polymerase chain reaction (PCR) amplification followed by restriction enzyme digestion of the PCR product for factor V Leiden, as previously described by Bertina et al. (12), and Hind III restriction enzyme cleavage of a 169 bp PCR product for prothrombin variant 20210A, using a modified method of Poort et al. (15).

Statistical analysis.   Baseline characteristics are expressed as means ± standard deviations or percentages. Continuous variables were compared by a one-way analysis of variance. Chi-square tests or, where appropriate, Fisher exact tests, were used to compare discrete variables. Odds ratios (OR), with 95% CIs and p values, were obtained using logistic regression.


   Results
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 Results
Discussion
 References
 
A total of 41 patients age <50 years with "normal" or "near normal" coronary arteries were identified on coronary angiography at a median of 23 days (interquartile range 19–27) after MI (study group); 12 of these patients had no coronary stenosis >20%. The control group consisted of 114 patients age <50 years with at least one stenosis >50%. Patients age ≥50 years with "normal" or "near normal" coronary angiograms (n = 19) and patients with at least one stenosis >50% (n = 97) after MI were also studied. The characteristics of these patient groups, which were defined by age and angiographic coronary disease severity at the time of angiography, were similar except for smoking (Table 1).


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  		Table 1 Patient Characteristics

 
Frequency of factor V leiden.   The frequency of factor V Leiden was 14.6% (6/41) in patients age <50 years with "normal" or "near normal" angiograms (without hemodynamically significant stenosis) compared with 3.6% (4/114) in patients with at least one stenosis >50% (OR 4.7 [95% CI 1.3–17.7], p = 0.02) (Fig. 1). Of the 12 patients age <50 years with no coronary stenosis >20%, 16.6% (2/12) had factor V Leiden.



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  		Figure 1 Frequencies of factor V Leiden (A) and prothrombin variant G20210A (B) compared in the study group (patients <50 years with no stenosis) and the control group (patients <50 years with ≥1 stenosis).

 
When the frequency of factor V Leiden in all patients without significant stenoses (irrespective of age) was compared with that in all patients with at least one stenosis >50%, there was an increased frequency (11.7% [8/60] vs. 4.3% [9/211], OR 2.9 [95% CI 1.1–8.3], p = 0.04) (Fig. 2).



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  		Figure 2 Frequencies of factor V Leiden (A) and prothrombin variant G20210A (B) compared in patients of all ages with no stenosis and those with ≥1 stenosis.

 
Interaction of factor V leiden with other risk factors.   The frequencies and ORs of major cardiovascular risk factors in the study group compared with the control group are shown in Table 2. Comparison of the study group patients with those who had at least one <50% stenosis after MI revealed no differences in any major cardiovascular risk factor. When the study group patients were analyzed for an association between factor V Leiden and other risk factors, there was a trend towards an increased incidence of hypertension in the patients with factor V Leiden (OR 5.83 [95% CI 0.95–36], p = 0.058) (Table 2).


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  		Table 2 Interaction of Factor V Leiden With Other Risk Factors

 
Prothrombin variant G20210A.   The frequency of prothrombin variant G20210A was 7.3% (3/41) in patients age <50 years with no significant coronary disease and 1.8% (2/114) in those with coronary artery stenoses (OR 4.4 [95% CI 0.7–27.5], p = 0.12) (Fig. 1). When patients of all ages with no significant stenosis were considered together, the frequency of this mutation was 6.7% (4/60) compared with 1.4% (3/211) in patients with coronary artery stenoses (OR 4.9 [95% CI 1.1–22.8], p = 0.04) (Fig. 2).

Factor V leiden and prothrombin variant G20210A.   Among patients age <50 years with no significant coronary stenosis (the study group), the frequency of either or both of these mutations was 19.5% (8/41) versus 5.5% (6/114) in the control group (OR 4.4 [CI 1.4–13.5], p = 0.01).

The interaction of factor V Leiden or prothrombin variant G20210A with major cardiovascular risk factors was considered. Within the study group, no major cardiovascular risk factors were more prevalent in patients with either mutation than in those without mutations although there was a trend towards an increased incidence of hypertension in patients with factor V Leiden or prothrombin variant G20210A (OR 4.13, p = 0.12).


   Discussion
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References
 
Factor V Leiden is more common in individuals with venous thromboembolism, emphasizing the important role of activated protein C resistance in venous thrombosis (11). An increased frequency of factor V Leiden has not previously been reported in studies of unselected patients surviving acute MI (31) and has not been found to be associated with the severity of coronary artery disease (32).

In this study we postulated that in circumstances of "normal" or "near normal" coronary arteries (little or no coronary stenosis) and, thus, relatively low shear stress, an increased procoagulant tendency mediated by factor V Leiden or prothrombin variant G20210A may contribute to the development of MI, perhaps in conjunction with other factors, particularly smoking. This study was designed to examine the hypothesis that there may be an increased frequency of factor V Leiden among individuals age <50 years with no angiographic stenosis three to four weeks after MI (compared with patients <50 years with ≥1 stenosis >50%), and it was found that the OR for the increased frequency of factor V Leiden in these patients was 4.7 (14.6% vs. 3.6%, p = 0.02). There was a trend towards an increase in the frequency of prothrombin variant G20210A (from 1.8% to 7.3%, p = 0.12). The frequency of either or both of these inherited thrombophilias was 19.5% (8/41) in the study group compared with 5.5% in the control group (OR 4.4 [CI 1.4–13.5], p = 0.01).

In a study of 22 young patients with MI and normal coronary arteries, there was a trend towards an increased incidence of factor V Leiden compared with young patients with angiographic coronary artery disease after MI or age-matched controls (9.1% vs. 3.8%, p = NS) (33). A preliminary report of an enlarged cohort from the same group documented a 14% frequency of factor V Leiden in patients age <50 years with "normal" coronary arteries (34), which is similar to our frequency of 14.6%.

Two other studies have identified an increased frequency of factor V Leiden in selected subgroups of survivors of MI (18,35). The reported frequency of factor V Leiden was 9.5% in female survivors of first MI age 18 to 44 years from western Washington state compared with 4.1% in age-matched controls without MI (OR 2.4 [95% CI 1.0–5.9]), and the OR for factor V Leiden was higher when combined with at least one other risk factor (18). Smoking was the main risk factor interacting with factor V Leiden and leading to increased risk although an interaction with treated hypertension was not reported separately (18). Neither factor V Leiden nor prothrombin variant G20210A has been shown to be independently increased in patients age <70 with first MI although these mutations were increased in frequency in conjunction with one of the major cardiovascular risk factors (smoking, hypertension, dyslipidemia and diabetes) or obesity (35). However, these studies did not examine factor V Leiden with respect to the severity of angiographic coronary artery disease.

The reasons why patients with normal or near normal coronary arteries have clinical events are unclear, as subclinical thrombosis often occurs at sites of plaque fissuring or rupture (36,37), but differences in various hemostatic risk factors may be a contributory factor.

In contrast with earlier reports (20,35), we did not find an increased frequency of smoking in young patients with normal coronary arteries compared with those with angiographic stenoses although all patients age <50 years were more likely than older patients to have been smokers at the time of MI.

Prothrombin, the precursor of thrombin, potentiates coagulation, and prothrombin variant G20210A leads to elevated levels of prothrombin, thereby increasing the risk of venous thrombosis (15). We found a trend towards an increased frequency (7.3%) of prothrombin variant G20210A in young patients without angiographic coronary stenoses compared with 1.8% in patients with ≥1 coronary stenoses and the general population. Furthermore, one or both of these inherited thrombophilias occurred in 19.5% of young patients with no hemodynamically significant stenoses after MI.

The U.S. Physicians’ Health Study reported no association between factor V Leiden and MI (9). This study predominantly included individuals with a lower frequency of major risk factors for MI than in other studies (17). The U.S. Physicians’ Health Study also reported a lack of association between prothrombin variant G20210A and MI but did report a higher frequency (3.9%) of prothrombin variant G20210A although ethnicity was not reported (17). This frequency is higher than the figure of 1.7% (95% CI 1.3–2.2) derived from several published papers in the analyses of Rosendaal and colleagues (16) of 2,756 individuals of northern European descent.

Study limitations.   A limitation of coronary angiography is that it is a "lumenogram," which does not consistently demonstrate the increase in vessel diameter occurring in the early stages of atherosclerosis (38). In this study we categorized patients as having "normal" or "near normal" coronary arteriograms according to the absence of stenoses >50% at three to four weeks after MI, and it must be noted that angiographically "normal" coronary arteries are found in 1% to 12% of all patients after MI (20). Angioscopy and intracoronary ultrasound are more sensitive methods of demonstrating the early stages of coronary atherosclerosis and, particularly, plaque rupture.

To recruit our prespecified group of patients aged <50 years with no coronary angiographic stenosis >50%, we obtained samples for the study group from all consenting patients from our series (21–28), and patients in the control group were randomly selected from these series. Unappreciated selection bias could have occurred although, as in-hospital coronary angiography was performed in only 10% of patients after MI in Auckland, New Zealand in 1993 (39), consecutive patients undergoing angiography would have been highly selected.

Another potential limitation of this work was the reliability of the estimate of the frequencies of factor V Leiden and prothrombin variant G20210A due to the relatively small number of patients with angiographically "normal" coronary arteries. While both our prespecified subgroup of patients age <50 and all patients (irrespective of age) with "normal" coronary angiograms after MI had higher frequencies of factor V Leiden (14.6% and 11.7%) and prothrombin variant G20210A (7.3% and 6.7%), respectively, this observation needs to be confirmed prospectively in a larger patient cohort. However, the frequency estimates of factor V Leiden and prothrombin variant G20210A reported here in the control group of post-MI patients with >50% angiographic coronary stenosis (3.6% and 1.8%, respectively) are consistent with those derived from populations of predominantly northern European descent (4% to 6% and 1.7% [95% CI 1.3–2.2], respectively) (15,16).

Conclusions.   We conclude that the frequencies of factor V Leiden or prothrombin variant G20210A are increased in patients age <50 years who suffer MI but have no significant coronary stenoses at angiography. Whether such patients with inherited thrombophilias should receive specific therapies is unknown.


   Acknowledgments
 
We gratefully acknowledge the assistance of Loretta Bush and Alison Randall in obtaining blood samples, Stephanie Kaye and Janine Lander for technical assistance, Drs. Toby Whitlock and Samuel Manda for statistical advice and Edie Scadden for secretarial support.


   Footnotes
 
This study was supported, in part, by grants from the Health Research Council of New Zealand and the Auckland Medical Research Foundation.


   References
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 Abstract
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 References
 

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