(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
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
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Abstract |
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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
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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.
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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.
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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.
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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%).
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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).
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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).
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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.
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Discussion |
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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).
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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
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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).
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Acknowledgments |
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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.
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References |
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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]
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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]
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R. H. Thomas Hypercoagulability Syndromes Arch Intern Med, November 12, 2001; 161(20): 2433 - 2439. [Abstract] [Full Text] [PDF]
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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]
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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]
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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]
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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]
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 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]
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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]
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 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]
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 U. Seligsohn and A. Lubetsky Genetic Susceptibility to Venous Thrombosis N. Engl. J. Med., April 19, 2001; 344(16): 1222 - 1231. [Full Text] [PDF]
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 B. M. Psaty, N. L. Smith, R. N. Lemaitre, H. L. Vos, S. R. Heckbert, A. Z. LaCroix, and F. R. Rosendaal Hormone Replacement Therapy, Prothrombotic Mutations, and the Risk of Incident Nonfatal Myocardial Infarction in Postmenopausal Women JAMA, February 21, 2001; 285(7): 906 - 913. [Abstract] [Full Text] [PDF]
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L. B. Goldstein, R. Adams, K. Becker, C. D. Furberg, P. B. Gorelick, G. Hademenos, M. Hill, G. Howard, V. J. Howard, B. Jacobs, et al. Primary Prevention of Ischemic Stroke : A Statement for Healthcare Professionals From the Stroke Council of the American Heart Association Circulation, January 2, 2001; 103(1): 163 - 182. [Full Text] [PDF]
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 J. S. Miles, J. P. Miletich, S. Z. Goldhaber, C. H. Hennekens, and P. M. Ridker G20210A mutation in the prothrombin gene and the risk of recurrent venous thromboembolism J. Am. Coll. Cardiol., January 1, 2001; 37(1): 215 - 218. [Abstract] [Full Text] [PDF]
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L. B. Goldstein, R. Adams, K. Becker, C. D. Furberg, P. B. Gorelick, G. Hademenos, M. Hill, G. Howard, V. J. Howard, B. Jacobs, et al. Primary Prevention of Ischemic Stroke : A Statement for Healthcare Professionals From the Stroke Council of the American Heart Association Stroke, January 1, 2001; 32(1): 280 - 299. [Full Text] [PDF]
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 T C F Sykes, C Fegan, and D Mosquera Thrombophilia, polymorphisms, and vascular disease Mol. Pathol., December 1, 2000; 53(6): 300 - 306. [Abstract] [Full Text]
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C. D. Bushnell and L. B. Goldstein Diagnostic Testing for Coagulopathies in Patients With Ischemic Stroke Stroke, December 1, 2000; 31(12): 3067 - 3078. [Abstract] [Full Text] [PDF]
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 P. Simioni, P. Prandoni, A. W. A. Lensing, D. Manfrin, D. Tormene, S. Gavasso, B. Girolami, C. Sardella, M. Prins, and A. Girolami Risk for subsequent venous thromboembolic complications in carriers of the prothrombin or the factor V gene mutation with a first episode of deep-vein thrombosis Blood, November 15, 2000; 96(10): 3329 - 3333. [Abstract] [Full Text] [PDF]
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 A. Hassan and H. S. Markus Genetics and ischaemic stroke Brain, September 1, 2000; 123(9): 1784 - 1812. [Abstract] [Full Text] [PDF]
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A. Girolami, P. Simioni, B. Girolami, and L. Scarano State-of-the-Art Review : G to A 20210 Prothrombin Polymorphism and Venous Thrombosis: Simple Association or Causal Relationship? Clinical and Applied Thrombosis/Hemostasis, July 1, 2000; 6(3): 135 - 138. [PDF]
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A. Nguyen State-of-the-Art Review : Review and Management of Patients With the Prothrombin G20210A Polymorphism Clinical and Applied Thrombosis/Hemostasis, April 1, 2000; 6(2): 94 - 99. [Abstract] [PDF]
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D. A. Lane and P. J. Grant Role of hemostatic gene polymorphisms in venous and arterial thrombotic disease Blood, March 1, 2000; 95(5): 1517 - 1532. [Full Text] [PDF]
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A. Girolami, P. Simioni, B. Girolami, and E. Zanon State-of-the-Art Review: Low Incidence of Venous Thrombosis in Homozygous Patients with NT 20210 G to a Prothrombin Polymorphism Clinical and Applied Thrombosis/Hemostasis, October 1, 1999; 5(4): 205 - 207. [PDF]
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 A. Irish Renal allograft thrombosis: can thrombophilia explain the inexplicable? Nephrol. Dial. Transplant., October 1, 1999; 14(10): 2297 - 2303. [Full Text] [PDF]
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