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(Circulation. 1999;99:999-1004.)
© 1999 American Heart Association, Inc.

Clinical Investigation and Reports

G20210A Mutation in Prothrombin Gene and Risk of Myocardial Infarction, Stroke, and Venous Thrombosis in a Large Cohort of US Men

Paul M. Ridker, MD; Charles H. Hennekens, MD; Joseph P. Miletich, MD, PhD

From the Divisions of Preventive Medicine (P.M.R., C.H.H.) and Cardiovascular Diseases (P.M.R.), Department of Medicine, Brigham and Women's Hospital, Boston, Mass; Department of Ambulatory Care and Prevention (C.H.H.), Harvard Medical School, Boston, Mass; Department of Epidemiology (C.H.H.), Harvard School of Public Health, Boston, Mass; and Laboratory Medicine Division (J.P.M.), Washington University School of Medicine, St Louis, Mo.

Correspondence to Dr Paul M. Ridker, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115. E-mail pmridker{at}bics.bwh.harvard.edu

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background—A single base pair mutation in the prothrombin gene has recently been identified that is associated with increased prothrombin levels. Whether this mutation increases the risks of arterial and venous thrombosis among healthy individuals is controversial.

Methods and Results—In a prospective cohort of 14 916 men, we determined the prevalence of the G20210A prothrombin gene variant in 833 men who subsequently developed myocardial infarction, stroke, or venous thrombosis (cases) and in 1774 age- and smoking status–matched men who remained free of thrombosis during a 10-year follow-up (control subjects). Gene sequencing was used to confirm mutation status in a subgroup of participants. Overall, carrier rates for the G20210A mutation were similar among case and control subjects; the relative risk of developing any thrombotic event in association with the 20210A allele was 1.05 (95% CI, 0.7 to 1.6; P=0.8). We observed no evidence of association between mutation and myocardial infarction (RR=0.8, P=0.4) or stroke (RR=1.1, P=0.8). For venous thrombosis, a modest nonsignificant increase in risk was observed (RR=1.7, P=0.08) that was smaller in magnitude than that associated with factor V Leiden (RR=3.0, P<0.001). Nine individuals carried both the prothrombin mutation and factor V Leiden (5 controls and 4 cases). One individual, a control subject, was homozygous for the prothrombin mutation.

Conclusions—In a large cohort of US men, the G20210A prothrombin gene variant was not associated with increased risk of myocardial infarction or stroke. For venous thrombosis, risk estimates associated with the G20210A mutation were smaller in magnitude than risk estimates associated with factor V Leiden.

Key Words: myocardial infarction • stroke • thrombosis • genetics • risk factors

	Introduction

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Over the past decade, it has been recognized that inherited abnormalities of coagulation are frequent among patients with a history of thrombophilia.¹ In particular, with the description of factor V Leiden as an inherited risk factor for both first and recurrent venous thrombosis,^{2 3 4 5 6 7 8 9} clinical interest in genetic causes of thrombosis has greatly increased. Most recently, Poort and colleagues¹⁰ have described a single-point mutation in the 3' untranslated region of the prothrombin gene (G-to-A transition at nucleotide position 20210) that appears to be associated with increased prothrombin levels. Moreover, these investigators and others have suggested that this mutation may be associated with increased risks of venous thrombosis, particularly among individuals with a family history of such events.^{10 11 12 13 14 15}

In the United States, the population frequency of the G20210A prothrombin mutation and its impact on the occurrence of venous thrombosis are uncertain. Moreover, although mutation in the prothrombin gene is hypothesized to confer a prothrombotic state, data relating this mutation to risks of myocardial infarction and stroke are sparse, and their interpretation has been controversial.^{16 17 18 19} We therefore evaluated in a large cohort of apparently healthy US men whether mutation in the prothrombin gene was associated with the future occurrence of thrombosis in the venous, arterial, and cerebral circulations.

	Methods

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We determined the presence of the G20210A mutation in the prothrombin gene in a nested case-control analysis within the Physicians' Health Study, a prospective cohort of 22 071 apparently healthy US male physicians aged 40 to 84 years at study entry who were followed over a period of 10 years for the occurrence of myocardial infarction, stroke, and venous thromboembolism.²⁰ As described elsewhere, Physicians' Health Study participants had no history of myocardial infarction, stroke, transient ischemic attack, or cancer at study entry and were randomly assigned to receive aspirin or beta-carotene as part of a randomized trial of these agents in the primary prevention of cardiovascular disease and cancer.²⁰ Reported cardiovascular endpoints occurring during study follow-up were confirmed through a detailed review of hospital records, death certificates, and autopsy reports. The diagnosis of myocardial infarction was confirmed with the presence of symptoms plus either increased cardiac enzyme changes indicative of infarction, with diagnostic changes on ECG, or with autopsy reports. The diagnosis of stroke was confirmed in the presence of a new focal neurologic deficit with signs and symptoms persisting for 24 hours; computed tomography scans were available in >95% of cases. The diagnosis of venous thrombosis was confirmed with a positive venography or ultrasound report, whereas the diagnosis of pulmonary embolism was confirmed with a positive angiogram or a ventilation-perfusion scan that showed 2 segmental defects.

At study entry, 14 916 participants provided a baseline blood sample sufficient for DNA analysis. Case subjects (patients) were defined as study participants who provided a baseline blood sample and subsequently had a first myocardial infarction, stroke, or venous thrombosis. For each patient, 2 or 3 control subjects were randomly selected from study participants who provided a baseline blood sample and remained free of reported cardiovascular disease during study follow-up. Control subjects were matched to patients by age (±1 year) and smoking status (past, current, never); using these criteria, we were able to analyze the G20210A prothrombin mutation among 833 patients who had had myocardial infarction, stroke, or venous thrombosis and among 1774 control subjects.

Each study participant had DNA samples that were obtained at study entry evaluated for the G20210A prothrombin mutation using the strategy and primers described by Poort et al.¹⁰ The amplification protocol included an initial denaturation at 94°C for 1 minute; 30 cycles of 40 seconds at 92°C, 40 seconds at 57°C, and 90 seconds at 72°C; and a final extension at 72°C for 5 minutes. An additional polymerase chain reaction (PCR) product, corresponding to nucleotides 19979 to 20246, was amplified from the DNA of an individual homozygous for the G20210A mutation and from 10 individuals heterozygous for the mutation and from 10 homozygous normal subjects. This amplification protocol consisted of initial denaturation at 94°C for 1 minute; 35 cycles of 30 seconds at 92°C, 30 seconds at 54°C, and 1 minute at 72°C; and a final extension at 72°C for 5 minutes. The forward and reverse primers were 5'-AACAACCGCTGGTATCAAATGG-3' and 5'-GAGCTGCCCATGAATAGCACTG-3', respectively. The sense primer was also used for Dye Terminator Cycle Sequencing as recommended by the manufacturer (PE Applied Biosystems).

Mean and proportion values for baseline characteristics were calculated for patients and control subjects, and differences were tested for significance using the Student's t test or the ² statistic. Genotype distributions and allele frequencies for the G20210A mutation were compared with use of ² analysis. Relative risks of thrombosis associated with the 20210A allele were computed with the use of logistic regression analysis; all risk estimates were adjusted for randomized treatment assignment to aspirin and beta-carotene. Prespecified analyses were performed for any thrombotic event and separately for myocardial infarction, stroke, and venous thrombosis. For study participants who had >1 end point, only the first event was counted. For venous thrombosis, we also computed relative risks for secondary events (those associated with cancer surgery or trauma) and for primary events. Subgroup analyses were further performed on the basis of age, smoking status, and the presence or absence of other cardiovascular risk factors. All probability values are 2-tailed and confidence intervals are computed at the 95% level.

	Results

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Table 1 displays baseline characteristics of the participants. As expected, the prevalence of diabetes, hypertension, obesity, and hyperlipidemia was higher among men who subsequently developed thrombotic events than among those who remained free of vascular disease during the 10-year follow-up period. Due to the matching, age and smoking status were virtually identical.

View this table: [in this window] [in a new window]   Table 1. Baseline Characteristics of 2607 Apparently Healthy Men Participating in the Physicians' Health Study, According to Development of Cardiovascular Disease During Follow-Up

Among the 1774 men who remained free of vascular disease, 1705 (96.1%) were homozygous for the 20210G allele, and 68 (3.8%) were heterozygous for both the 20210G and 20210A alleles. One control subject (0.06%) was homozygous for the 20210A allele (Table 2). Thus, the observed allele frequency for the 20210G allele among control participants was 98.0% (95% CI, 97.5% to 98.5%), and that of the 20210A allele was 2.0% (95% CI, 1.5% to 2.5%).

View this table: [in this window] [in a new window]   Table 2. Distribution and Allele Frequency of G20210A Polymorphism Among 2607 Apparently Healthy Men Participating in the Physicians' Health Study, According to Development of Cardiovascular Disease During Follow-Up

As also shown in Table 2, the genotype distribution (95.9 GG, 4.1 GA, and 0.0 AA) and allele frequency (98.0 G and 2.0 A) of the prothrombin mutation among study participants who subsequently developed vascular events were virtually identical to those of the control group (P=0.8). The relative risk of developing any thrombotic event associated with carriage of the 20210A allele was 1.05 (95% CI, 0.7 to 1.6; P=0.8) (Table 3).

View this table: [in this window] [in a new window]   Table 3. Crude and Adjusted RR of Myocardial Infarction, Stroke, or Venous Thrombosis Associated With Carriage of 20210A Allele

No evidence of association was observed between the prothrombin mutation and myocardial infarction (relative risk [RR]=0.8; 95% CI, 0.4 to 1.4) or stroke (RR=1.1; 95% CI, 0.6 to 2.1). The relative risk for any arterial event associated with mutation was 0.9 (95% CI, 0.6 to 1.5; P=0.8). There was no significant evidence of any modification of this lack of effect in subgroup analyses stratified by age, smoking status, and other cardiovascular risk factors or in analyses limited to strokes considered to be thromboembolic (Table 4). To evaluate the possibility that randomized aspirin use (325 mg PO QD) might have modulated the effect of the prothrombin mutation on risks of myocardial infarction, we performed an additional stratified analysis for events that occurred before the unblinding of the aspirin component of the Physician's Health Study. In these analyses, we found no evidence of association between the G20210A mutation and risks of myocardial infarction among those randomly assigned to receive aspirin (RR=0.8, P=0.6) or placebo (RR=0.7, P=0.4).

View this table: [in this window] [in a new window]   Table 4. RR and 95% CI of Arterial or Venous Thrombosis in Carriers of 20210A Allele According to Age, Smoking, and Risk Factor Status

Among patients with venous thrombosis, the frequency of the 20210A allele was 3.2% compared with 2.0% among control subjects, such that the relative risk of any venous thromboembolic event associated with the prothrombin mutation was 1.7 (95% CI, 0.9 to 3.1; P=0.08) (Table 3). There appeared to be no evidence of effect modification based on whether the venous thrombotic events were associated with cancer, surgery, or trauma. Specifically, the relative risk of primary venous thromboembolism (n=99) associated with the presence of the prothrombin mutation was 1.9 (95% CI, 0.8 to 4.2; P=0.1), whereas the relative risk of secondary venous thromboembolism (n=115) was 1.6 (95% CI, 0.7 to 3.6; P=0.2). We found no evidence of effect modification by age, smoking status, or other risk factors (Table 4). By contrast, the relative risks of venous thrombosis in this cohort associated with factor V Leiden were 3.0 for any venous thrombosis (P<0.001) and 4.5 for primary venous thrombosis (P<0.001).^{7 8}

Of the 2607 individuals screened in the present analysis, 9 were identified who carried both the prothrombin mutation and factor V Leiden: 5 were control subjects and 4 were patients (1 myocardial infarction and 3 venous thromboses). One individual, a control subject, was found to be homozygous for the prothrombin mutation.

Gene sequencing was performed on 10 study participants determined with use of the PCR to be homozygous normal subjects, 10 determined to be heterozygous carriers, and 1 determined to be a homozygous carrier for the prothrombin mutation. In each case, gene sequencing confirmed PCR-based mutation status.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Prothrombin (factor II) is a precursor of thrombin and plays a critical role in fibrin formation; thus, the recent demonstration that a single-point mutation in the prothrombin gene is associated with increased prothrombin levels¹⁰ has generated considerable clinical interest, and it has been suggested that this polymorphism may lead to increased risks of both arterial and venous thrombosis.^{10 11 12 13 14 15 16 17 18 19}

We performed a large-scale, prospective, nested case-control study of the G20210A prothrombin mutation in an otherwise healthy population of US men who were followed over a 10-year period for the occurrence of myocardial infarction, stroke, or venous thrombosis. With regard to arterial thrombosis, we found no evidence of association between the 20210A allele and risks of either myocardial infarction or stroke, nor any evidence of effect modification by known cardiovascular risk factors or by randomized aspirin assignment. Thus, as was previously described in this cohort for factor V Leiden,⁷ there appears to be no increase in the risk of coronary or cerebral occlusion in association with the prothrombin mutation. With regard to venous thrombosis, the presence of the 20210A allele in this cohort was associated with a modest nonsignificant increase in risk (RR=1.7l; 95% CI, 0.9 to 3.1; P=0.08).

The prevalence of prothrombin mutation among control subjects in our study was 3.9%, a rate higher than that reported in several prior studies (Table 5). As has been observed for factor V Leiden,^{21 22} it is possible that there are different rates of the prothrombin mutation in different populations. It is also possible, however, that previously reported mutation rates based on smaller samples may have underestimated the prevalence of the 20210A allele. For example, in 1 study from the United States that involved 381 control subjects, a mutation rate of 1.6% was reported, indicating that only 6 heterozygotes were identified.¹⁶ Similarly, investigators in the Netherlands have reported allele frequencies that vary by >2-fold despite sampling from similar population groups.^{10 17 18} In our study, we investigated the presence of the prothrombin mutation in a total of 1774 control subjects, a sample size substantially greater than that reported in any prior analysis; as a result, our estimate of the control prevalence for the G20210A mutation has quite narrow 95% CIs (Table 5).

View this table: [in this window] [in a new window]   Table 5. Sample Size, Number of 20210A Carriers Identified and Carrier Frequencies for Prothrombin Mutation in Control Groups From Several Published Studies

It is interesting to compare and contrast our findings for the prothrombin mutation in this cohort to those for the factor V Leiden mutation, particularly with regard to venous thrombosis.^{7 8} Specifically, although the prevalence of factor V Leiden among control subjects in our study population (5.0%) is only modestly greater than that of the prothrombin mutation (3.9%), the clinical impact of factor V Leiden appears to be greater. As demonstrated in the Figure, compared with normal individuals or with those with the prothrombin mutation, those with factor V Leiden had substantially greater risks of developing any venous thrombosis as well as thrombotic events considered to be idiopathic. Moreover, in contrast to estimates for the prothrombin mutation, the risks of venous thrombosis associated with the factor V Leiden mutation were highly statistically significant (all P<0.001). Thus, at least for these data, any potential risk of venous thrombosis attributable to the prothrombin mutation appears to be small in comparison with that associated with factor V Leiden.²³

View larger version (20K): [in this window] [in a new window]   Figure 1. Relative risks of developing future venous thromboembolism (VTE) among participants in the Physicians' Health Study according to presence or absence of prothrombin or factor V Leiden mutations. Data are shown for any VTE and for events not associated with cancer, surgery, or trauma (idiopathic VTE).

In summary, these prospective data for a large cohort of US men show no evidence of association between the prothrombin mutation and risks of myocardial infarction or stroke. For venous thrombosis, we observed a modest increase in risk associated with the G20210A mutation (RR=1.7, P=0.08) that was smaller in magnitude than that associated with factor V Leiden (RR=3.0, P<0.001).

	Acknowledgments

 
This work was supported by grants from the National Heart, Lung, and Blood Institute and by an Established Investigator Award from the American Heart Association (Dr Ridker).

Received July 23, 1998; revision received November 3, 1998; accepted November 18, 1998.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Miletich JP, Prescott SM, White R, Majerus PW, Bovill EG. Inherited predisposition to thrombosis. Cell. 1993;72:477–480.[Medline] [Order article via Infotrieve]
   
2. Bertina RM, Koeleman BPC, Koster T, Rosendaal FR, Dirven RJ, de Ronde H, van der Velden PA, Reitsma PH. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature. 1994;369:64–67.[Medline] [Order article via Infotrieve]
   
3. Dahlback B, Carlsson M, Svensson PJ. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C. Proc Natl Acad Sci U S A. 1993;90:1004–1008.[Abstract/Free Full Text]
   
4. Zoller B, Dahlback B. Linkage between inherited resistance to activated protein C and factor V gene mutation in venous thrombosis. Lancet. 1994;343:1536–1538.[Medline] [Order article via Infotrieve]
   
5. Svensson PJ, Dahlback B. Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med. 1994;330:517–522.[Abstract/Free Full Text]
   
6. Koster T, Rosendaal FR, de Ronde H, Briet E, Vandenbrouke JP, Bertina RM. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study. Lancet. 1993;342:1503–1506.[Medline] [Order article via Infotrieve]
   
7. Ridker PM, Hennekens CH, Lindpaintner K, Stampfer MJ, Eisenberg PR, Miletich JP. Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men. N Engl J Med. 1995;332:912–917.[Abstract/Free Full Text]
   
8. Ridker PM, Miletich J, Goldhaber SZ, Stampfer MJ, Lindpaintner K, Hennekens CH. Factor V Leiden and risks of recurrent idiopathic venous thromboembolism. Circulation. 1995;92:2800–2802.[Abstract/Free Full Text]
   
9. Simioni P, Prandoni P, Lensing AW, Scudeller A, Sardella C, Prins MH. The risk of recurrent venous thromboembolism in patients with an Arg506-Gln mutation in the gene for factor V (factor V Leiden). N Engl J Med. 1997;336:399–403.[Abstract/Free Full Text]
   
10. Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3'-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood. 1996;88:3698–3703.[Abstract/Free Full Text]
    
11. Makris M, Preston FE, Beauchamp NJ, Cooper PC, Daly ME, Hampton KK, Bayliss P, Peake IR, Miller GJ. Co-inheritance of the 20210A allele of the prothrombin gene increases the risk of thrombosis in subjects with familial thrombophilia. Thromb Haemost. 1997;78:1426–1429.[Medline] [Order article via Infotrieve]
    
12. Arruda VR, Annichino-Bizzacchi JM, Goncalves MS, Costa FF. Prevalence of the prothrombin gene variant (nt20210A) in venous thrombosis and arterial disease. Thromb Haemost. 1997;78:1430–1433.[Medline] [Order article via Infotrieve]
    
13. Hillarp A, Zoller B, Svensson PJ, Dahlback B. The 20210 A allele of the prothrombin gene is a common risk factor among Swedish outpatients with verified deep venous thrombosis. Thromb Haemost. 1997;78:990–992.[Medline] [Order article via Infotrieve]
    
14. Cumming AM, Keeney S, Salden A, Bhavnani M, Shwe KH, Hay CR. The prothrombin gene G20210A variant: prevalence in a UK anticoagulant clinic population. Br J Haematol. 1997;98:353–355.[Medline] [Order article via Infotrieve]
    
15. Brown K, Luddington R, Williamson D, Baker P, Baglin T. Risk of venous thromboembolism associated with a G to A transition at position 20210 in the 3'-untranslated region of the prothrombin gene. Br J Haematol. 1997;98:907–909.[Medline] [Order article via Infotrieve]
    
16. Rosendaal FR, Siscovick DS, Schwartz SM, Psaty BM, Raghunathan TE, Vos HL. A common prothrombin variant (20210 G to A) increases the risk of myocardial infarction in young women. Blood. 1997;5:1747–1750.
    
17. Franco RF, Trip MD, ten Cate H, Prins MH, Kastelein JJP, Reitsma PH. The prevalence of the 20210 G-A mutation in the 3'-untranslated region of the prothrombin gene in patients with premature coronary artery disease. Thromb Haemost. 1997;78:769. Abstract.
    
18. Doggen CJM, Manger Cats V, Bertina RM, Rosendaal FR. Interaction of coagulation defects and cardiovascular risk factors: increased risk of myocardial infarction associated with factor V Leiden or prothrombin 20210A. Circulation. 1998;97:1037–1041.[Abstract/Free Full Text]
    
19. Longstreth WT, Rosendaal FR, Siscovick DS, Vos HL, Schwartz SM, Psaty BM, Raghunathan TE, Koepsell TD, Reitsma PH. Risk of stroke in young women and two prothrombotic mutation: factor V Leiden and prothrombin gene variant (G20210A). Stroke. 1998;29:577–580.[Abstract/Free Full Text]
    
20. Steering Committee of the Physicians' Health Study Research Group. Final report of the aspirin component of the ongoing Physicians' Health Study. N Engl J Med. 1989;321:129–135.[Abstract]
    
21. Rees DC, Cox M, Clegg JB. World distribution of factor V Leiden. Lancet. 1995;346:1133–1134.[Medline] [Order article via Infotrieve]
    
22. Ridker PM, Miletich JP, Hennekens CH, Buring JE. Ethnic distribution of factor V Leiden in 4047 men and women: implications for venous thromboembolism screening. JAMA. 1997;277:1305–1307.[Abstract]
    
23. Price DT, Ridker PM. Factor V Leiden mutation and the risks for thromboembolic disease: a clinical perspective. Ann Intern Med. 1997;127:895–903.[Abstract/Free Full Text]
    

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				F. Burzotta, K. Paciaroni, V. De Stefano, P. Chiusolo, A. Manzoli, I. Casorelli, A.M. Leone, E. Rossi, G. Leone, A. Maseri, et al. Increased prevalence of the G20210A prothrombin gene variant in acute coronary syndromes without metabolic or acquired risk factors or with limited extent of disease Eur. Heart J., January 1, 2002; 23(1): 26 - 30. [Abstract] [Full Text] [PDF]

				P. Madonna, V. de Stefano, A. Coppola, F. Cirillo, A. M. Cerbone, G. Orefice, and G. Di Minno Hyperhomocysteinemia and Other Inherited Prothrombotic Conditions in Young Adults With a History of Ischemic Stroke Stroke, January 1, 2002; 33(1): 51 - 56. [Abstract] [Full Text] [PDF]

				S. M. Boekholdt, N. R. Bijsterveld, A. H.M. Moons, M. Levi, H. R. Buller, and R. J.G. Peters Genetic Variation in Coagulation and Fibrinolytic Proteins and Their Relation With Acute Myocardial Infarction: A Systematic Review Circulation, December 18, 2001; 104(25): 3063 - 3068. [Abstract] [Full Text] [PDF]

				R. H. Thomas Hypercoagulability Syndromes Arch Intern Med, November 12, 2001; 161(20): 2433 - 2439. [Abstract] [Full Text] [PDF]

				S. Lopaciuk, K. Bykowska, H. Kwiecinski, A. Mickielewicz, A. Czlcankawska, T. Mendel, A. Kuczynska-Zardzewialy, D. Szelagowska, J. Windyga, W. Schroder, et al. Factor V Leiden, Prothrombin Gene G20210A Variant, and Methylenetetrahydrofolate Reductase C677T Genotype in Young Adults With Ischemic Stroke Clinical and Applied Thrombosis/Hemostasis, October 1, 2001; 7(4): 346 - 350. [Abstract] [PDF]

				G. J. Hankey, J. W. Eikelboom, F. M. van Bockxmeer, E. Lofthouse, N. Staples, and R. I. Baker Inherited Thrombophilia in Ischemic Stroke and Its Pathogenic Subtypes Stroke, August 1, 2001; 32(8): 1793 - 1799. [Abstract] [Full Text] [PDF]

				C. Russo, D. Girelli, O. Olivieri, P. Guarini, F. Manzato, F. Pizzolo, B. Zaia, A. Mazzucco, and R. Corrocher G20210A Prothrombin Gene Polymorphism and Prothrombin Activity in Subjects With or Without Angiographically Documented Coronary Artery Disease Circulation, May 22, 2001; 103(20): 2436 - 2440. [Abstract] [Full Text] [PDF]

				P. M. Spooner, C. Albert, E. J. Benjamin, R. Boineau, R. C. Elston, A. L. George Jr, X. Jouven, L. H. Kuller, J. W. MacCluer, E. Marban, et al. Sudden Cardiac Death, Genes, and Arrhythmogenesis : Consideration of New Population and Mechanistic Approaches From a National Heart, Lung, and Blood Institute Workshop, Part II Circulation, May 22, 2001; 103(20): 2447 - 2452. [Abstract] [Full Text] [PDF]

				M. S. Williams and P. F. Bray Genetics of Arterial Prothrombotic Risk States Experimental Biology and Medicine, May 1, 2001; 226(5): 409 - 419. [Abstract] [Full Text]

				P. W. Kamphuisen, J. C. J. Eikenboom, and R. M. Bertina Elevated Factor VIII Levels and the Risk of Thrombosis Arterioscler. Thromb. Vasc. Biol., May 1, 2001; 21(5): 731 - 738. [Full Text] [PDF]

				G.J. Hademenos, M.J. Alberts, I. Awad, M. Mayberg, T. Shephard, A. Jagoda, R.E. Latchaw, H.W. Todd, K. Viste, R. Starke, et al. Advances in the genetics of cerebrovascular disease and stroke Neurology, April 24, 2001; 56(8): 997 - 1008. [Abstract] [Full Text] [PDF]

				U. Seligsohn and A. Lubetsky Genetic Susceptibility to Venous Thrombosis N. Engl. J. Med., April 19, 2001; 344(16): 1222 - 1231. [Full Text] [PDF]