High prevalence of thrombophilia among young patients with myocardial infarction and few conventional risk factors

International Journal of Cardiology 98 (2005) 421 – 424 www.elsevier.com/locate/ijcard

High prevalence of thrombophilia among young patients with myocardial $ infarction and few conventional risk factors Amit Segev a,*, Martin H. Ellis b, Fani Segev a, Ziva Friedman c, Tamar Reshef d, John D. Sparkes, Jana Tetro a,1, Hana Pauzner a, Daniel David a a

Department of Cardiology, Meir General Hospital, Kfar-Saba, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel b Hematology Unit, Meir General Hospital, Kfar-Saba, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel c Coagulation Laboratory, Meir General Hospital, Kfar-Saba, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel d Clinical Immunology Laboratory, Meir General Hospital, Kfar-Saba, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel Received 2 July 2003; received in revised form 15 October 2003; accepted 25 October 2003 Available online 16 April 2004

Abstract Background: Thrombophilia refers to series of acquired and inherited conditions that confer a tendency to thrombus formation. The exact relationship between thrombophilia and MI is not well established. Objectives: To determine the prevalence of thrombophilia in young patients with their first MI and few conventional risk factors. Methods: We evaluated the baseline characteristics and the thrombophilia profile, including anti-cardiolipin antibodies, activated protein C resistance (APCR) with the factor V Leiden mutation, prothrombin G20210A mutation, protein C, protein S, and antithrombin-III levels, among 85 consecutive patients ( < 50 year old) who were admitted to CCU with their first MI. Patients were divided into two groups: group A—patients with V 1 risk factor and group B—patients with z 2 risk factors. Results: 92% were male and 55% with anterior wall MI. Overall, the risk factor profile was: smoking in 60%, hyperlipidemia in 42%, positive family history in 29%, hypertension in 18%, diabetes mellitus in 13%, and obesity in 8%. Forty-seven percent of patients had V 1 risk factor (n = 40, group A) and 53% had z 2 risk factors (n = 45, group B). The prevalence of the prothrombin mutation was 15% in group A compared to 7% in group B ( p = 0.12). APCR secondary to a heterozygous genotype of factor V Leiden mutation was found in 20% in group A compared to 2% in group B ( p < 0.01). Anti-cardiolipin antibodies were found in 16% in group A compared to 22% in group B ( p = ns). Finally, we have found that the likelihood of identifying at least one thrombophilia marker was 50% in group A compared to 29% in group B ( p = 0.046). Conclusions: The likelihood to detect at least one thrombophilia marker in young patients with MI and few conventional risk factors is significantly high. Thrombophilia may contribute to the development of MI in this specific group of young patients. D 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Myocardial infarction; Thrombophilia; Young patients; Risk factors

1. Introduction Acute myocardial infarction (MI) is caused by a total occlusion of an epicardial coronary artery secondary to an atherosclerotic plaque complicated by thrombus formation, a process called atherothrombosis. Thrombophilia refers to a

$ This work was presented as an abstract at the American Heart Association 76th Scientific Sessions, Orlando, FL. * Corresponding author. Division of Cardiology, St. Michael’s Hospital, 30 Bond Street, Toronto, Ontario, Canada M5B 1W8. Tel.: +1416-864-5913; fax: +1-416-864-5978. E-mail address: [email protected] (A. Segev). 1 The study is dedicated to the memory of Dr. Jana Tetro.

0167-5273/$ - see front matter D 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2003.10.057

series of acquired and inherited conditions that are present in the plasma and confer a tendency to thrombus formation. Established causes of thrombophilia include protein S, protein C and anti-thrombin III deficiencies; prothrombin (factor II) G20210A mutation; activated protein C resistance (APCR) mainly due to the factor V Leiden mutation; high titers of anti-cardiolipin antibodies (the so-called anti-phospholipid syndrome); and hyperhomocysteinemia [1]. The role of thrombophilia in the pathogenesis of myocardial infarction is controversial. APCR is present in about 4 –5% of the general population, and in more than 10% of patients with venous thrombosis [2]. The etiological role of APCR in arterial thrombosis is controversial. Both Ridker et al. [2] and Redondo et al. [3] showed that APCR was not

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Table 1 Baseline characteristics Characteristics

Number (%) (total, n = 85)

Male gender Anterior myocardial infarction Current smoking Hyperlipidemiaa Family history of CAD Treated hypertension Treated diabetes mellitus Obesity (BMI z 30) No risk factors

78 47 51 36 25 15 11 7 9

a

(92) (55) (60) (42) (29) (18) (13) (8) (10)

Defined as LDL cholesterol >160 mg/dl prior to admission.

associated with increased relative risk for MI. Small studies have shown that the prothrombin G20210A mutation may serve as a risk factor for the development of MI generally [4], and specifically among young women [5]. However, in a cohort of US men, the prothrombin G20210A mutation was not associated with increased risk of MI or stroke [6]. The prevalence of anticardiolipin antibodies in the general population is reported to be between 1% and 9% [7,8]. Anticardiolipin antibodies were shown to be an independent risk factor for MI and recurrent events [9,10]. In the present study, we evaluated the yield of thrombophilia screening among young patients with MI and examined the relationship between the presence of thrombophilia and patients’ traditional risk factor profile.

tion mutation G20210A in the prothrombin gene, PCR was performed on genomic DNA followed by a primer extension incorporating a single biotynilated nucleotide at the mutation site [11]. Detection of the mutation was then determined by ELISA visually or colorimetrically (Prontok, Savyon Diagnostics, Israel). Resistance to APC was initially assayed by chromogenic assay using factor V deficient plasma according to the manufacturer’s instructions (Chromogenix, Sweden). We first tested the samples for APCR ratio (PTT on patient’s plasma with APC/PTT on patient’s plasma without APC, a ratio of < 2 is considered abnormal). In patients with APCR, the factor V Leiden mutation was detected by using a commercially available kit, as for the prothrombin G20210A mutation (Prontok, Savyon Diagnostics) [12]. 2.3. Statistical analysis Differences between groups A and B were analyzed by the statistical method based on chi-square and Fisher’s exact test. In order to assess whether each risk factor was an independent predictor for the presence of thrombophilia marker, a multivariate regression analysis was performed adjusting for each risk factor independently (SAS software, version 8.02). P < 0.05 was considered a significant difference.

3. Results 2. Methods 2.1. Patients Eighty-five consecutive patients under the age of 50 hospitalized in the cardiac intensive care unit with their first acute ST-elevation MI between January 2001 and December 2001 were studied. Patients were treated by primary percutaneous coronary intervention (PCI), fibrinolysis or conservatively in the case of late presentation to hospital. Blood samples for thrombophilia markers were drawn at the fourth and fifth hospital day while patients were not on unfractionated heparin, low molecular weight heparin, or warfarin. Baseline demographic data regarding known traditional risk factors for coronary artery disease were collected in all patients. Patients were divided into two groups: group A consisted of 40 patients with V 1 traditional risk factor and group B consisted of 45 patients with z 2 risk factors. 2.2. Measurement of thrombophilia markers Anticardiolipin antibodies were detected using a quantitative ELISA sensitive to cardiolipin and h2 glycoprotein1, for both IgG and IgM isotypes (BL Diagnostika, Czech Republic). Results were expressed as GPL units for IgG (positive >10 GPL) and MPL units for IgM (positive >7 MPL). For the direct identification of the nucleotide transi-

Eighty-five consecutive patients (group A = 40, group B = 45) with acute ST-elevation MI admitted to the CCU were studied. All patients were under the age of 50 (mean 44 F 5). Baseline characteristics of the study patients are summarized in Table 1. Ninety-two percent were males. There was a high prevalence of current smoking (60%), hyperlipidemia (42%) and family history of premature coronary artery disease (29%). Angiographic data were available in 83 patients (98%). The majority of patients (75 patients, 90%) had one-vessel disease, 6 patients (7%) had two-vessel disease, and 2 patients (3%) had three-vessel Table 2 Prevalence of thrombophilia markers All, n = 85 Prothrombin G20210A mutation APCR Anti-cardiolipin antibodies PS, PC or AT deficiencies

Group A, n = 40

Group B, n = 45

9 (10.6)

6 (15)

3 (6.7)

9 (10.6) 16 (18.8)

8 (20) 6 (15)

1 (2.2) 10 (22.2)

2 (2.3)

1 (2.5)

1 (2.2)

p value 0.12

< 0.01 NS NS

Values are numbers (%). Group A—patients with V 1 risk factor; group B—patients with z 2 risk factors. NS = nonsignificant.

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Fig. 1. The presence of at least one thrombophilia marker in relation to conventional risk factors. *p = 0.046.

disease. We found no relation between the extent of coronary artery disease and thrombophilia. In the overall group of patients, there was a high prevalence of APCR, which in all cases was due to a homozygous type of the factor V Leiden mutation (11%). Prothrombin mutation was detected in 11% and the presence of high titers anticardiolipin antibodies in 19% compared to much lower prevalence among healthy individuals [2,6 – 8]. Patients with none or only one conventional risk factor for coronary artery disease (group A) had 10-fold higher incidence of the factor V Leiden mutation than patients with more than one conventional risk factor (group B) (20% vs. 2%, p < 0.01) and 2fold higher incidence of the prothrombin G20210A mutation (15% vs. 7%, p = 0.12) (Table 2). There was no significant difference in the prevalence of anticardiolipin antibodies between groups A and B. Protein S, protein C and antithrombin III deficiencies were found in only two patients (2%), one in each group. Lastly, and most importantly, to determine the yield of screening young patients for thrombophilia in relation to their traditional risk factors, we calculated the chance of detecting at least one positive marker of thrombophilia (factor V Leiden mutation or prothrombin G20210A mutation or anticardiolipin antibodies). At least one thrombophilia marker was present in 50% of patients in group A compared to 29% in group B ( p = 0.046) (Fig. 1). After multivariate regression analysis adjusting for each risk factor independently, no specific risk factor was found to predict the presence of thrombophilia in our cohort of patients.

4. Discussion Our study demonstrates that thrombophilia as manifested by the presence of the factor V Leiden and the prothrombin G20210A mutations is increased in young patients with a few traditional risk factors for atherosclerosis. Furthermore, we showed that in young patients with V 1 traditional risk factor, the likelihood of detecting at least one thrombophilia marker is 50%. The factor V Leiden and prothrombin mutations have been causally related to venous thrombosis [2]. However,

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their relation to arterial thrombosis and atherosclerosis is controversial. In an older population ( < 70 year old), the risk of MI for carriers of factor V Leiden mutation was increased by 40% while the presence of the prothrombin G20210A mutation increased the risk of MI by 50% [4]. However, other studies have failed to establish a definitive role of inherited thrombophilia in arterial vascular events (MI and stroke) [2,3,6]. In a subgroup of patients with MI and near normal coronary arteries, Van de Water et al. [13] found increased prevalence of factor V Leiden and prothrombin G20210A mutations. In young women ( < 44 year old), Rosendaal et al. [5] found that the presence of the prothrombin mutation was associated with 4-fold increase in the risk of MI, especially when another major cardiovascular risk factor was also present, such as smoking (43-fold). These data suggest that inherited thrombophilia may have a synergistic effect with the other cardiovascular risk factors. Furthermore, Inbal et al. [14] demonstrated that the combination of prothrombotic and ApoE4 polymorphysms with current smoking was associated with 25-fold increase of the risk of developing myocardial infarction among male patients aged less than 52 years. In contrast to inherited thrombophilia, the role of anticardiolipin antibodies in the pathophysiology of arterial vascular thrombotic events is very well established [9,10,14]. There is no data to clarify the yield of screening for thrombophilia among MI survivors less than 50 years of age, particularly in relation to their traditional risk factors. First, we have shown that overall this patient population has a higher prevalence of both factor V Leiden and prothrombin mutations compared to published prevalence in the normal population. Furthermore, we found that among patients with a few traditional risk factors for atherosclerosis, there is a very high likelihood of identifying at least one thrombophilia marker (50%). This finding may suggest that thrombophilia may have a role in the development of acute thrombotic coronary events, such as MI, in young patients without multiple traditional risk factors. The therapeutic consequences of the presence of thrombophilia in patients with MI remain controversial. In patients with MI and high titers of anticardiolipin antibodies (an established antiphospholipid syndrome), treatment with long-term anticoagulation has been recommended [15]. However, to date, no clinical trials have assessed the beneficial effects of anticoagulation among patients with inherited thrombophilia and arterial vascular events, such as MI. Limitations of our study are its relatively small number of patients and the lack of a healthy control group. However, the main objective of this work is to show the relationship between thrombophilia and traditional risk factors and to establish the yield of screening for thrombophilia in young patients with myocardial infarction in relation to risk factors. In conclusion, we have shown high prevalence of inherited thrombophilia among young patients with their first MI, particularly in the absence of traditional risk factors

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for atherosclerosis. Further studies on thrombophilia involving larger numbers of MI patients without significant traditional risk factors are warranted.

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