© 1999 American Heart Association, Inc.
Original Contributions |
Interaction Between the G20210A Mutation of the Prothrombin Gene and Oral Contraceptive Use in Deep Vein Thrombosis
From Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Department of Internal Medicine (I.M., P.B., S.A., P.M.M.), and Epidemiology Unit (E.T.), IRCCS Maggiore Hospital, University of Milan, Italy
Correspondence to Ida Martinelli, MD, PhD, Hemophilia and Thrombosis Center, IRCCS Maggiore Hospital, Via Pace 9, 20122 Milano, Italy. E-mail martin{at}polic.cilea.it
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Abstract |
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Abstract—Single-point mutations in the gene coding for prothrombin (factor II:A20210) or factor V (factor V:A1691) are associated with an increased risk of venous thromboembolism. The use of oral contraceptives is also a strong and independent risk factor for the disease, and the interaction between factor V:A1691 and oral contraceptives greatly increases the risk. No information is available about the interaction between oral contraceptives and mutant prothrombin. We investigated 148 women with a first, objectively confirmed episode of deep vein thrombosis and 277 healthy women as controls. Fourteen patients (9.4%) were carriers of factor II:A20210, 24 (16.2%) of factor V:A1691, and 4 (2.7%) of both defects. Among controls, the prevalence was 2.5% for either factor II:A20210 or factor V:A1691, and there was no carrier of both the mutations. The relative risk of thrombosis was 6-fold for factor II:A20210 and 9-fold for factor V:A1691. The most prevalent circumstantial risk factor in patients and the only one observed in controls was oral contraceptive use, which per se conferred a 6-fold increased risk of thrombosis. The risk increased to 16.3 and 20.0 when women with factor II:A20210 or factor V:A1691 who used oral contraceptives were compared with noncarriers and nonusers. These figures indicate a multiplicative interaction between the genetic risk factors and oral contraceptives. No difference in the type of oral contraceptives was observed between patients and controls, those of third generation being the most frequently used (73% and 80%). We conclude that carriers of the prothrombin mutation who use oral contraceptives have a markedly increased risk of deep vein thrombosis, much higher than the risk conferred by either factor alone.
Key Words: venous thrombosis • prothrombin mutation • factor V mutation • oral contraceptives
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Introduction |
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In the last few years the discovery of 2 point mutations, one in the factor V gene that is responsible for resistance to activated protein C (factor V:A1691)1 and the other in the 3'-untranslated region of the prothrombin gene (factor II:A20210),2 has broadened the spectrum of inherited thrombophilia. These mutations are common in the general population (on average, 2% to 3%), and their prevalence varies in different countries, factor V:A1691 being more frequent in Northern Europe and factor II:A20210 in the south.3 4 They are also the most common genetic defects associated with venous thrombosis, accounting, respectively, for 12% to 20%5 6 and 5% to 19%2 7 8 9 10 11 12 13 of patients selected with varying criteria. Carriers of factor V:A1691 or factor II:A20210 have a moderately increased risk of venous thrombosis, which has been estimated to be 3- to 7-fold for factor V:A16916 14 and 2- to 12-fold for factor II:A20210.2 7 8 9 10 11 12 13 An important factor in the evaluation of the relative risk of venous thrombosis in carriers of thrombophilic defects is the concomitant presence of circumstantial risk factors. It has been reported that oral contraceptive users who are carriers of factor V:A1691 have a 30-fold increased risk of deep vein thrombosis relative to noncarriers and nonusers.15 No information on the effect of the combination of factor II:A20210 and oral contraceptive use is available so far. Therefore, we performed a case-control study to evaluate the interaction between genetic thrombophilic defects and circumstantial risk factor for deep vein thrombosis in carriers of the mutation, with special emphasis on the use of oral contraceptives.
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Methods |
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Patients
One hundred sixty-two unrelated women with a first, objectively documented episode of deep vein thrombosis of the lower extremities were consecutively referred to our thrombosis center to be investigated for thrombophilia from April 1995 to April 1998. For 148 of them (86%), DNA was available for testing and therefore they were included in this study. Their median age was 30 years (range, 6 to 71 years) at the time of thrombosis and 35 years (range, 6 to 75 years) at the time of blood sampling. Deep vein thrombosis involved a lower limb in 142 patients (96%), and it was bilateral in 6 patients (4%). All patients were apparently free from cancer or autoimmune disorders.
Controls
The control population consisted of 277 healthy women who were
friends or partners of the whole population of patients referred to our
thrombosis center in the same 3-year study period, with no genetic
relationship with them. Their median age at the time of blood sampling
was 46 years (range, 13 to 76 years). Previous thrombosis was excluded
using a structured questionnaire validated for the retrospective
diagnosis of venous thromboembolism.16
Information on oral contraceptive use at the time of thrombosis (for patients) or at the time of blood sampling (for controls) was recorded. Women were considered oral contraceptive users if they had taken the pill until 2 weeks or less before the thrombotic episode. One hundred twelve patients and 179 controls were of reproductive age (15 to 48 years); among them, 42 patients (64%) and 45 controls (25%) were oral contraceptive users. The type of oral contraceptive was also recorded, and the pills were classified into 3 categories, according with the dose of estrogen and the type of progestin: first generation (containing 50 µg or more of ethinyl-estradiol), second generation (30 µg of ethinyl-estradiol and levonorgestrel or norgestrel as progestin), and third generation (30 µg or less of ethinyl-estradiol and gestodene or desogestrel as progestin). In addition to oral contraceptive use, the presence of other circumstantial risk factors such as surgery, trauma, prolonged immobilization, pregnancy, or postpartum status was recorded in patients and controls.
Laboratory Tests
Blood samples were drawn into vacuum tubes containing 129
mmol/L sodium citrate as anticoagulant with a ratio of 9 parts blood
and 1 part citrate solution. DNA analysis for the G20210A
prothrombin and the G1691A factor V mutations were performed as
previously described by Poort et al17 and de Ronde and
Bertina.18 Because a screening for thrombophilia includes
also the search for deficiencies of the naturally occurring
inhibitors and the antiphospholipid syndrome, antithrombin,
protein C, and protein S plasma levels were measured, and the presence
of lupus anticoagulant and anticardiolipin antibodies was looked
for. Antithrombin heparin cofactor activity and protein C activity were
tested; if low results were obtained, antigen levels and functional
activity in the absence of heparin and by immunoelectrophoresis with or
without heparin19 for antithrombin, and antigen levels for
protein C, were measured. Protein S was assayed by total and free
antigen measurements.20 Protein C, protein S levels, and
lupus anticoagulant were not evaluated in 22 patients (15%) who
were on oral anticoagulant therapy at the time of blood sampling,
because measurements of vitamin K-dependent proteins are affected by
this treatment.
Statistical Analysis
Student's t test was used to compare the age at
thrombosis of patients with single or double thrombophilic defect. The
2 test was used to compare the observed
prevalence of the combined defect with the expected prevalence. Odds
ratios were considered as an approximation of the relative risks and
95% CI were calculated according to Woolf.21 Using a
logistic regression model, odds ratios were adjusted by age and the
presence of other thrombophilic defects. In the same model we evaluated
the interaction between oral contraceptive use and the presence of
either factor II:A20210 or factor V:A1691. With this analysis,
a relative risk close to 1.0 indicates a multiplicative
interaction.22 Prevalence of oral contraceptive use and
pregnancy or postpartum status was calculated on the number of women of
reproductive age. Because oral contraceptives and pregnancy or
postpartum condition mutually exclude each other, the prevalence and
thrombotic risk associated with oral contraceptives were calculated
excluding women who were pregnant or in the postpartum period at the
time of thrombosis, and the prevalence of pregnancy or postpartum
status excluding oral contraceptive users.
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Results |
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Among the 277 controls, 7 (2.5%) were carriers of factor II:A20210 and 7 (2.5%) of factor V:A1691, none of them being homozygote or carrier of both the defects. Fourteen patients (9.4%) were heterozygous carriers of factor II:A20210 and 24 (16.2%) (2 homozygotes and 22 heterozygotes), were carriers of factor V:A1691. There was no homozygous carrier of factor II:A20210. Four patients (2.7%) were heterozygous carriers of both the mutations. This 2.7% prevalence was higher than the 0.06% prevalence expected by multiplying the frequencies of the single mutations in the control group. The median age at thrombosis was 30 years (range, 18 to 63 years) for carriers of factor II:A20210, 29 years (range, 15 to 57 years) for carriers of factor V:A1691, and 30 years (range, 18 to 39 years) for double carriers (differences not statistically significant). Sixteen patients (10.8%) and 3 controls (1%) had other thrombophilic defects. Among patients, 2 had antithrombin deficiency, 5 protein C deficiency, 2 protein S deficiency, and 7 lupus anticoagulant. Two controls had antithrombin deficiency and 1 had protein S deficiency.
Table 1
shows the relative risk of
deep vein thrombosis for carriers of the prothrombin or factor V
mutations. After adjustment for the presence of other thrombophilic
conditions, the odds ratio for factor II:A20210 was 5.7 (95% CI, 2.2
to 14.6) and that for factor V:A1691 was 9.7 (95% CI, 3.9 to 23.8).
Excluding from the analysis the 2 homozygous carriers of factor
V:A1691, the risk associated with this mutation did not substantially
change (odds ratio, 9.1 [95% CI, 3.6 to 23.1]). As none of the
controls was a carrier of the combined defect, the risk of thrombosis
for double carriers could not be calculated.
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Table 2 shows that the distribution
of circumstantial risk factors predisposing to deep vein thrombosis was
roughly similar in carriers of factor II:A20210 and factor V:A1691 and
in those with the combined defect, with oral contraceptive use being
the most frequent. The effect of oral contraceptives in determining
thrombosis and their interaction with genetic thrombophilic defects
were analyzed in more details in 313 women of reproductive
age, 179 controls and 134 patients. Among controls, 6 (3.4%) had
factor II:A20210 and 5 (2.8%) had factor V:A1691. Among patients, 12
(9.0%) had factor II:A20210, 21 (15.7%) had factor V:A1691, and 4
(3.0%) had the combined defect. In these women, the adjusted odds
ratio was 4.6 (95% CI, 1.7 to 12.7) for the prothrombin mutation and
6.0 (95% CI, 2.0 to 17.4) for the factor V mutation. After exclusion
of 19 patients who were pregnant or in the postpartum period at the
time of thrombosis, the prevalence of oral contraceptive users was 64%
(74/115) among patients and 25% (45/179) among controls, and the risk
conferred by oral contraceptives was 5.6 (95% CI, 3.3 to 9.6). To
compare the type of oral contraceptives used by patients at the time of
thrombosis with that used by controls at the time of blood sampling, we
limited the analysis to patients who had thrombosis in the
3-year study period, because the prescription of oral contraceptives
may have changed over time. Fifteen of the 74 patients (20%) on oral
contraceptives were therefore excluded because they had thrombosis
before 1995. Both in patients and controls the most frequently used
oral contraceptives were those of third generation, accounting,
respectively, for 73% (43/59) and 80% (36/45).
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Table 3 shows the risk of thrombosis
according to the use of oral contraceptives and the presence of the
mutations. Three women with both factor II:A20210 and factor V:A1691
were excluded from the analysis. The risk for women who used
oral contraceptives and were carriers of a mutation was 16.3 (95% CI,
3.4 to 79.1) for the prothrombin and 20.0 (95% CI, 4.2 to 94.3) for
factor V mutation, in comparison with nonusers and noncarriers.
These figures are multiplicative of the separate relative risks, and
can also be calculated by multiplying the risk owing to oral
contraceptive use in the absence of either mutation (odds ratio, 4.6)
by that owing to the mutations in the absence of oral contraceptive use
(odds ratios, 2.7 and 2.4) (Table 3). In the logistic regression
model the relative risk for the interaction between factor II:A20210 or
factor V:A1691 and oral contraceptives was 1.1 (95% CI, 0.1 to 10.2)
and 1.6 (95% CI, 0.2 to 18.0), indicating the multiplicative effect of
the 2 risk factors.
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Discussion |
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In this case-control study performed in women with a first episode of deep vein thrombosis, we confirm that the 2 most common genetic thrombophilic defects, ie, factor V:A1691 and factor II:A20210, are strongly associated with an increased risk for the disease. We also found that this risk increased markedly when oral contraceptive use was associated with carriership of either factor V or prothrombin mutation. Although the risk conferred by the presence of both the defects could not be estimated because of the absence of double carriers among controls, we found that the 2.7% prevalence of the combined defect observed in patients was 35 times higher than that expected, indicating a strong tendency to thrombosis in these patients.23 24 25 26
Oral contraceptive use is associated with a 4-fold increased risk
of venous thrombosis, independent of the presence of other genetic or
acquired risk factors.27 It has been reported that women
with factor V mutation who use oral contraceptives have an increased
risk of deep vein thrombosis (30-fold) in comparison with noncarriers
and nonusers.15 We found a similar effect of oral
contraceptives in carriers of the mutant prothrombin. This finding
extends preliminary results recently obtained by us in a small, highly
selected group of women with deep vein thrombosis.28 In
this series of patients consecutively referred to us for a screening of
thrombophilia, we observed that the majority of women had developed
deep vein thrombosis in the presence of a circumstantial risk factor,
such as oral contraceptive use or pregnancy or postpartum status. Women
of reproductive age had a risk of thrombosis associated with the
use of oral contraceptives that was quite similar to the risk
associated with the presence of mutant prothrombin (odds ratios, 5.6
and 4.6, respectively). The risk of thrombosis for carriers of the
mutation who used oral contraceptives was 16-fold, indicating a
multiplicative interaction of the 2 risk factors. Obviously, this
estimate has to be considered approximate, because it is affected by
the small number of women (only 2 among controls) with both risk
factors. It is likely that the same limitation has affected the
estimates of the risks in carriers of either prothrombin or factor V
mutation who did not use the pill (Table 3
). However, the
magnitude of the risk in carriers of the prothrombin mutation who used
oral contraceptives was 65% higher than the additive effect of the 2
single risks, suggesting a strong interaction, although larger studies
are needed to obtain a more reliable estimate of the risk. From a
biochemical point of view, it has been reported that mutant
prothrombin2 and oral contraceptives29 are
independently associated with elevated plasma levels of prothrombin. A
hypothesis that should be evaluated is whether the presence of both
risk factors leads to particularly high plasma levels of
prothrombin.
Another aim of this study was to look at the type of oral contraceptives, as those of third generation, which contain 30 µg or less of ethinyl-estradiol and gestodene or desogestrel as progestin, have been claimed to be associated with a 2-fold increased risk of venous thromboembolism relative to the older second-generation preparations, containing levonorgestrel as progestin.27 We found no association between thrombosis and the type of oral contraceptives, those of third generation being the most frequently used both among patients and controls (73% and 80%, respectively). The high prevalence of third-generation pills in the control population is in contrast to that reported by investigators from other countries,30 but is in agreement with the global pill consumption in the Italian general population.
Our findings of a strong interaction between oral contraceptive use and genetic defects raise the question whether or not screening for the prothrombin and factor V mutations should be recommended before prescribing oral contraceptives. It has already been stated that screening for mutant factor V is not cost-effective,31 because the absolute risk of venous thromboembolism is approximately 0.5/10 000 per year for women aged <45 years. This negative consideration can now be extended also to the mutant prothrombin, because to prevent one episode of deep vein thrombosis, oral contraceptives should be withheld from approximately 800 carriers of the mutations. Furthermore, 14 000 women should be tested to identify 800 carriers, which indicates that at present indiscriminate screening for both the mutations is not worthwhile. Currently, we recommend withholding oral contraceptives from carriers who have experienced thrombosis while taking the pill, considering alternative methods of contraception in those who have had thrombosis in the absence of the pill, and carefully evaluating each woman for the presence of other risk factors, such as a positive family history of thrombosis, that may contraindicate use of the pill.32
Received July 21, 1998; accepted September 7, 1998.
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References |
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|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Bertina RM, Koeleman RPC, 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]
2.
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.
3. Rees DC, Cox M, Clegg JB. Word distribution of factor V Leiden. Lancet. 1995;346:1133–1134.[Medline] [Order article via Infotrieve]
4. Rosendaal FR, Doggen CJM, Zivelin A, Arruda VR, Aiach M, Siscovick DS, Hillarp A, Watzke HH, Bernardi F, Cumming AM, Preston FE, Reitsma PH. Geographic distribution of the 20210 G to A prothrombin variant. Thromb Haemost. 1998;79:706–708.[Medline] [Order article via Infotrieve]
5. Bertina RM, Koeleman BP, 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: Leiden thrombophilia study. Nature. 1994;369:64–67.
6.
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
thromboembolism in apparently healthy men. N Engl J
Med. 1995;332:912–917.
7. Cattaneo M, Chantarangkul V, Taioli E, Hermida Santos J, Tagliabue L. The G20210A mutation of the prothrombin gene in patients with previous first episode of deep-vein thrombosis: prevalence and association with factor V G1691A, methylene tetrahydrofolate reductase C677T and plasma prothrombin levels. Thromb Res.. 1999;93:1–8.[Medline] [Order article via Infotrieve]
8.
Rajesh KK, Mills LA, Spitzer SG, Hultin MB. A
prothrombin gene mutation is significantly associated with venous
thrombosis. Arterioscler Thromb Vasc Biol. 1997;17:2875–2879.
9. Hillarp A, Zöller B, Svensson PJ, Dählback 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]
10. 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]
11. Arruda VR, Annichino-Bizzacchi JM, Gonçalves 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]
12. Cumming AM, Keeney S, Salden A, Bhavnani M, Shwe KH, Hay CRM. The prothrombin gene G20210A variant: prevalence in a UK anticoagulant clinic population. Br J Haematol. 1997;98:353–355.[Medline] [Order article via Infotrieve]
13. Margaglione M, D'Andrea G, d'Addedda M, Giuliani N, Cappucci G, Iannacone L, Vecchione G, Grandone E, Brancaccio V, Di Minno G. The methylenetetrahydrofolate reductase TT677 genotype is associated with venous thrombosis independently of the coexistence of the FV Leiden and the prothrombin A20210 mutation. Thromb Haemost. 1998;79:907–911.[Medline] [Order article via Infotrieve]
14. Koster T, Rosendaal FR, de Ronde H, Briët E, Vandenbroucke 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]
15. Vandenbroucke JP, Koster T, Briët E, Reitsma PH, Bertina RM, Rosendaal FR. Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation. Lancet. 1994;344:1453–1457.[Medline] [Order article via Infotrieve]
16.
Frezzato M, Tosetto A, Rodeghiero F. Validated
questionnaire for the identification of previous personal or familial
venous thromboembolism. Am J Epidemiol. 1996;143:1257–1265.
17. Poort SR, Bertina RM, Vos HL. Rapid detection of the prothrombin 20210 A variation by allele specific PCR. Thromb Haemost. 1997;78:1157–1158.[Medline] [Order article via Infotrieve]
18. de Ronde H, Bertina RM. Laboratory diagnosis of APC-resistance: a critical evaluation of the test and the development of diagnostic criteria. Thromb Haemost. 1994;72:880–886.[Medline] [Order article via Infotrieve]
19. Sas G, Pepper DS, Cash JD. Plasma and serum antithrombin III: differentiation by crossed immunoelectrophoresis. Thromb Res. 1975;6:87–91.[Medline] [Order article via Infotrieve]
20.
Comp PC, Doray D, Patton D, Esmon CT. An abnormal
plasma distribution of protein S occurs in functional protein S
deficiency. Blood. 1986;67:504–508.
21. Woolf B. On estimating the relation between blood group and disease. Ann Hum Gen. 1995;19:251–253.
22. Rothman KJ, Greenland S. Modern Epidemiology. 2nd ed. Philadelphia: Lippincot-Raven; 1998.
23.
Alhenc-Gelas M, Le Cam-Duchez V, Emmerich J, Frebourg
T, Fiessinger JN, Borg JY, Aiach M. The A20210 allele of the
prothrombin gene is not frequently associated with the factor V Arg 506
to Gln mutation in thrombophilic families. Blood. 1997;90:1711.
24.
Howard TE, Marusa M, Boisza J, Young A, Sequeira J,
Channell C, Guy C, Benson E, Duncan A. The prothrombin gene
3'-untranslated region mutation is frequently associated with factor V
Leiden in thrombophilic patients and shows ethnic-specific variation in
allele frequency. Blood. 1998;91:1092–1093.
25.
Ehrenforth S, Ludwig G, Klinke S, Krause M, Scharrer I,
Nowak-Göttl U. The prothrombin 20210 A allele is frequently
coinherited in young carriers of the factor V Arg 506 to Gln mutation
with venous thrombophilia. Blood. 1998;91:2209–2210.
26.
Zöller B, Svensson PJ, Dahlbäck B, Hillarp
A. The A 20210 allele of the prothrombin gene is frequently
associated with the factor V Arg 506 to Gln mutation but not with
protein S deficiency in thrombophilic families. Blood. 1998;91:2210–2211.
27. Helmerhorst FM, Bloemenkamp KWM, Rosendaal FR, Vandenbroucke JP. Oral contraceptives and thrombotic disease: risk of venous thromboembolism. Thromb Haemost. 1997;78:327–333.[Medline] [Order article via Infotrieve]
28.
Martinelli I, Sacchi E, Landi G, Taioli E, Duca F,
Mannucci PM. High risk of cerebral-vein thrombosis in carriers of a
prothrombin-gene mutation and in users of oral contraceptives.
N Engl J Med. 1998;338:1793–1797.
29. Kluft C, Lansink M. Effect of oral contraceptives on hemostatic variables. Thromb Haemost. 1997;78:315–326.[Medline] [Order article via Infotrieve]
30. de Bruijn SFTM, Stam J, Vandenbroucke JP, for the CVST study group. Increased risk of cerebral venous sinus thrombosis with third-generation oral contraceptives: Central Venous Sinus Thrombosis Study Group. Lancet. 1998;351:1404.[Medline] [Order article via Infotrieve]
31.
Vandenbroucke JP, van der Meer FJM, Helmerhorst FM,
Rosendaal FR. Factor V Leiden. should we screen oral contraceptive
users and pregnant women? BMJ. 1996;313:1127–1130.
32. Briët E, van der Meer FJM, Rosendaal FR, Houwing-Duistermatt JJ, van Houvwelingen JC. The family history and inherited thrombophilia. Br J Haematol. 1994;87:348–352.[Medline] [Order article via Infotrieve]
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A. Girolami, L. Spiezia, F. Vianello, B. Girolami, and F. Fabris Changes in Prescription Patterns of Oral Contraceptives in a Northern Italian Province: Relation With Venous Thromboembolism Clinical and Applied Thrombosis/Hemostasis, April 1, 2003; 9(2): 125 - 130. [Abstract] [PDF]
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 J. L. Anderson, J. F. Carlquist, B. D. Home, and J. B. Muhlestein Cardiovascular Pharmacogenomics: Current Status, Future Prospects Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2003; 8(1): 71 - 83. [Abstract] [PDF]
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S. R Deitcher and M. P. Gomes Hypercoagulable state testing and malignancy screening following venous thromboembolic events Vascular Medicine, February 1, 2003; 8(1): 33 - 46. [Abstract] [PDF]
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 C. Legnani, G. Palareti, G. Guazzaloca, B. Cosmi, B. Lunghi, F. Bernardi, and S. Coccheri Venous thromboembolism in young women. Role of thrombophilic mutations and oral contraceptive use Eur. Heart J., June 2, 2002; 23(12): 984 - 990. [Abstract] [Full Text] [PDF]
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A. Girolami, L. Spiezia, B. Girolami, and F. Vianello Tentative Guidelines and Practical Suggestions to Avoid Venous Thromboembolism During Oral Contraceptive Therapy Clinical and Applied Thrombosis/Hemostasis, April 1, 2002; 8(2): 97 - 102. [Abstract] [PDF]
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A. Girolami, L. Spiezia, F. Rossi, and E. Zanon Oral Contraceptives and Venous Thromboembolism: Which Are the Safest Preparations Available? Clinical and Applied Thrombosis/Hemostasis, April 1, 2002; 8(2): 157 - 162. [Abstract] [PDF]
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 F.R. Rosendaal, F.M. Helmerhorst, and J.P. Vandenbroucke Female Hormones and Thrombosis Arterioscler Thromb Vasc Biol, February 1, 2002; 22(2): 201 - 210. [Abstract] [Full Text] [PDF]
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J. Aznar and Y. Mira Prothrombotic Activity of Oral Contraceptives in Patients with Congenital Thrombophilia Clinical and Applied Thrombosis/Hemostasis, January 1, 2002; 8(1): 91 - 92. [PDF]
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 A. Tripodi and P. M. Mannucci Laboratory Investigation of Thrombophilia Clin. Chem., September 1, 2001; 47(9): 1597 - 1606. [Abstract] [Full Text] [PDF]
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 J. M Kemmeren, A. Algra, and D. E Grobbee Third generation oral contraceptives and risk of venous thrombosis: meta-analysis BMJ, July 21, 2001; 323(7305): 131 - 131. [Abstract] [Full Text] [PDF]
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 J. P. Vandenbroucke, J. Rosing, K. W.M. Bloemenkamp, S. Middeldorp, F. M. Helmerhorst, B. N. Bouma, and F. R. Rosendaal Oral Contraceptives and the Risk of Venous Thrombosis N. Engl. J. Med., May 17, 2001; 344(20): 1527 - 1535. [Full Text] [PDF]
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 L. D. Botto and M. J. Khoury Commentary: Facing the Challenge of Gene-Environment Interaction: The Two-by-Four Table and Beyond Am. J. Epidemiol., May 15, 2001; 153(10): 1016 - 1020. [Abstract] [Full Text] [PDF]
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B. Cosmi, C. Legnani, F. Bernardi, S. Coccheri, and G. Palareti Value of family history in identifying women at risk of venous thromboembolism during oral contraception: observational study BMJ, April 28, 2001; 322(7293): 1024 - 1025. [Full Text]
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B. G. Macik, J. H. Rand, and B. A. Konkle Thrombophilia: What's a Practitioner to Do? Hematology, January 1, 2001; 2001(1): 322 - 338. [Abstract] [Full Text] [PDF]
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Y. Mira, J. Aznar, A. Estelles, A. Vaya, P. Villa, and F. Ferrando State-of-the-Art Review : Congenital and Acquired Thrombotic Risk Factors in Women Using Oral Contraceptives: Clinical Aspects Clinical and Applied Thrombosis/Hemostasis, July 1, 2000; 6(3): 162 - 168. [Abstract] [PDF]
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