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Original Investigation |

Factor V Leiden Homozygosity, Dyspnea, and Reduced Pulmonary Function FREE

Klaus Juul, MD; Anne Tybjærg-Hansen, MD, DMSc; Jann Mortensen, MD, DMSc; Peter Lange, MD, DMSc; Jørgen Vestbo, MD, DMSc; Børge G. Nordestgaard, MD, DMSc
[+] Author Affiliations

Author Affiliations: Department of Clinical Biochemistry, Herlev University Hospital, Herlev, Denmark (Drs Juul and Nordestgaard); Departments of Clinical Biochemistry (Dr Tybjærg-Hansen) and Clinical Physiology and Nuclear Medicine (Dr Mortensen), Rigshospitalet, Copenhagen, Denmark; Department of Respiratory Medicine, Hvidovre University Hospital, Hvidovre, Denmark (Dr Lange); North West Lung Center, Wythenshawe Hospital, Manchester, England (Dr Vestbo); and The Copenhagen City Heart Study, Bispebjerg University Hospital, Copenhagen (Drs Tybjærg-Hansen, Lange, and Nordestgaard).


Arch Intern Med. 2005;165(17):2032-2036. doi:10.1001/archinte.165.17.2032.
Text Size: A A A
Published online

Background  Factor V Leiden homozygosity predisposes patients to deep venous thrombosis and major pulmonary thromboembolism. Consequently, factor V Leiden homozygosity could, via unrecognized repeated minor pulmonary thromboemboli, cause chronic pulmonary disease. We tested the hypothesis that factor V Leiden homozygosity is associated with pulmonary symptoms and signs.

Methods  We studied a general population sample of 9253 individuals from the Copenhagen City Heart Study who were examined in 1991-1994. Of these, 6475 participants were also examined in 1976-1978 and/or 1981-1983. End points were dyspnea and lung function.

Results  Among 20 factor V Leiden homozygotes, a mean ± SD of 32% ± 11% had severe dyspnea compared with 6% ± 0.3% of 8534 noncarriers (χ2 test; P<.001). The corresponding adjusted odds ratio for severe dyspnea was 5.4 (95% confidence interval, 1.9-15.7). During follow-up, forced expiratory volume in 1 second and forced vital capacity were 5% to 10% lower in homozygotes vs noncarriers (analysis of variance; P = .003 and P = .03). The annual mean ± SD loss of forced expiratory volume in 1 second and forced vital capacity was 39 ± 8 mL/y and 35 ± 8 mL/y in homozygotes vs 21 ± 10 mL/y and 15 ± 10 mL/y in noncarriers (t test; P = .03 and P = .04), respectively. Factor V Leiden heterozygosity (n = 699) did not influence pulmonary symptoms and signs.

Conclusion  We demonstrate a previously unrecognized clinical presentation of factor V Leiden homozygosity with severe dyspnea and decreased pulmonary function.

Figures in this Article

Pulmonary thromboembolism secondary to deep venous thrombosis has a heterogeneous clinical presentation, and most cases are never clinically recognized.1 Repeated pulmonary thromboemboli are known to cause chronic pulmonary disease, the cardinal symptom of which is dyspnea. Whether hereditary thrombophilia, possibly via unrecognized repeated minor pulmonary thromboemboli, is also associated with chronic pulmonary symptoms and signs is currently unknown.

The most frequent and well-established hereditary prothrombotic risk factor is a single G-to-A substitution in the coagulation factor V gene in nucleotide position 1691 (factor V Leiden), which in the heterozygous and homozygous states is present in 8.0% and 0.2% of white individuals, respectively.2 This point mutation, which reduces coagulation factor V breakdown by activated protein C, increases the risk of deep venous thrombosis and pulmonary thromboembolism, particularly in the homozygous state.3 Consequently, factor V Leiden homozygosity could, via unrecognized repeated minor pulmonary thromboemboli, cause chronic pulmonary disease.

We tested the hypothesis that factor V Leiden homozygosity is associated with pulmonary symptoms and signs. To test this hypothesis, we genotyped 9253 individuals sampled from the Danish general population (The Copenhagen City Heart Study) and compared factor V Leiden homozygotes with noncarriers with respect to dyspnea and pulmonary function.

PARTICIPANTS

The Copenhagen City Heart Study is a prospective cardiopulmonary study of 20- to 93-year-old Danes of both sexes sampled from the general population in 1976-1978 and reexamined in 1981-1983 and 1991-1994.48 Informed consent was obtained from all participants. The Ethics Committee of Copenhagen and Frederiksberg approved the study (study No. 100.2039/91).

MEASUREMENT OF OUTCOMES

At each examination, participants completed a questionnaire on risk factors for cardiopulmonary disease and details of dyspnea, the severity of which was graded according to a slightly modified version of the British Medical Research Council questionnaire’s breathlessness scale, grades II to IV. Light (grade II), moderate (grade III), and severe (grade IV) dyspnea grades were defined as confirmatory answers to the following questions, respectively: “Do you get shortness of breath when you walk at an ordinary pace on a level road alongside someone your age?” “Do you have to stop once in a while in order to catch your breath when walking at your own pace?” and “Do you get shortness of breath during morning toilette or when you get dressed?”9

At the 1976-1978 and 1981-1983 examinations, determinations of forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) were performed using an electronic spirometer (model N 403; Monaghan, Littleton, Colo), whereas at the 1991-1994 examination, a dry wedge spirometer was used (Vitalograph, Maidenhead, England). Each spirometry procedure was performed in triplicate, and results were accepted only if the variation between 2 of these was less than 5%. The highest measurements of FEV1 and FVC were used as absolute values (in milliliters) or as a percentage of predicted values (percent predicted). Algorithms for the calculation of the percent predicted FEV1 and FVC were made using multiple linear regression, with age and height as covariates in men and women separately in a subsample of never smokers.10 By using algorithms for each set of FEV1 and FVC measurements (from the 1976-1978, 1981-1983, and 1991-1994 examinations, respectively) to calculate the percent predicted FEV1 and FVC, systematic errors introduced by change of spirometer between examinations were accounted for. Despite this, the possibility still exists that the absolute level of FEV1 and FVC could have changed slightly from the 2 first examinations using the original electronic spirometer vs the last examination using the dry wedge spirometer, which potentially could have affected the measurement of change in FEV1 and FVC over time. However, because this is true for individuals with all 3 genotypes (factor V Leiden noncarriers, heterozygotes, and homozygotes), it is unlikely that change of spirometers between examinations would affect the observed differences between genotypes that span all 3 examinations. Therefore, we do not believe that the change of spirometer between examinations could have affected the conclusions of this article.

MEASUREMENTS OF PREDICTOR VARIABLES

Blood was drawn for DNA extraction at the 1991-1994 examination. All participants were genotyped for factor V Leiden as previously described.11 Exposure to occupational dust was defined as a confirmatory answer to the question, “Have you for long periods been exposed to occupational dust or welding fumes?” Diagnoses of deep venous thrombosis and pulmonary embolism were gathered from the Danish National Hospital Discharge Register and the Danish Register of Causes of Death until January 2000 (International Classification of Diseases, Eighth Revision [ICD-8], codes 450.99, 673.99, 451.00, 451.08, 451.09, 451.90, 451.92, and 671.01-671.09 and International Classification of Diseases, 10th Revision [ICD-10], codes I26.0, I26.9, I80.1, I80.2, I80.3, O22.3, O87.1, and O88.2).

STATISTICAL ANALYSES

Data were analyzed using the Stata statistical software package, version 8.0 (Stata Corp, College Station, Tex). We used the Pearson χ2 test, Mann-Whitney test, unconditional logistic regression, t test, 1-way analysis of variance (ANOVA), and repeated-measures ANOVA. Logistic regression analyses were performed with forced entry of covariates. Age, body mass index (square root transformation), FEV1, FVC, and FEV1/FVC were introduced as continuous covariates. Pack-years of cigarette smoking was categorized (0, <10, 10-20, and >20 pack-years) because linearity on the logit scale could not be achieved with this continuous covariate. Two-sided P≤.05 was considered statistically significant. Data are presented as mean ± SD.

Factor V Leiden genotype was not associated with any of the variables listed in Table 1. The genotype distribution did not differ from that predicted by the Hardy-Weinberg equilibrium (P = .17), and the frequency of factor V Leiden heterozygotes and homozygotes did not change as a function of age (Wald test; P = .78 and P = .85).

Table Graphic Jump LocationTable 1. Characteristics of Participants*
DYSPNEA

Dyspnea was more frequent among homozygotes than among noncarriers (Table 2); 26% ± 10%, 20.0% ± 9.2%, and 32% ± 11% of homozygotes complained of light, moderate, or severe dyspnea compared with 11.3% ± 0.3%, 8.1% ± 0.3%, and 6.4% ± 0.3% of noncarriers (χ2 test; P = .04, P = .05, and P<.001, respectively). Unadjusted odds ratios (ORs) for light, moderate, and severe dyspnea in homozygotes relative to noncarriers were 2.8 (95% confidence interval [CI], 1.0-7.8), 2.8 (95% CI, 0.9-8.5), and6.7 (95% CI, 2.5-17.8), respectively. After adjustment for sex, age, smoking, exposure to occupational dust, and body mass index, the association between homozygosity and light and moderate dyspnea was attenuated; however, it remained significant for severe dyspnea with an OR of 5.4 (95% CI, 1.9-15.7). In a third logistic regression model, including additional adjustment for FEV1, FVC, and FEV1/FVC, an OR for severe dyspnea of 4.2 (95% CI, 1.3-13.7) was observed.

Table Graphic Jump LocationTable 2. Dyspnea by Factor V Leiden Genotype

With increasing age, the frequency of dyspnea (moderate and severe combined) increased in noncarriers (Wald test; P<.001), heterozygotes (P<.001), and homozygotes (P<.001). The increase with age was more pronounced among homozygotes than among noncarriers (P = .003), as shown in Figure 1. The prevalence of dyspnea among heterozygotes did not differ from that in noncarriers (Table 2 and Figure 1).

Place holder to copy figure label and caption
Figure 1.

Prevalence of dyspnea by age group. Error bars indicate SDs; lines, regression lines. The P value by Wald testing for equality of logistic regression coefficients for age was .73 for heterozygotes vs noncarriers and .003 for homozygotes vs noncarriers.

Graphic Jump Location
LUNG FUNCTION

During follow-up, FEV1 was consistently 5% to 10% lower among homozygotes than among noncarriers (repeated-measures ANOVA; P = .003), as shown in Figure 2. Likewise, FVC was consistently lower among homozygotes than among noncarriers (P = .03). Annual decline in FEV1 and FVC among homozygotes was 39 ± 8 mL/y and 35 ± 8 mL/y compared with 21 ± 10 mL/y and 15 ± 10 mL/y among noncarriers (t test; P = .03 and P = .04; Figure 3). No differences were observed between factor V Leiden heterozygotes and noncarriers on any of the spirometric measurements (Figure 2 and Figure 3).

Place holder to copy figure label and caption
Figure 2.

Forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) as percentage of predicted values by factor V Leiden genotype. Bars represent means ± SDs after adjustment for smoking. P values by repeated-measures analysis of variance adjusted for smoking were .99 (FEV1) and .42 (FVC) for heterozygotes vs noncarriers and .003 (FEV1) and .03 (FVC) for homozygotes vs noncarriers.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Annual change in forced expiratory volume in 1 second (FEV1) (A) and forced vital capacity (FVC) (B) by factor V Leiden genotype. Bars represent means ± SDs. P values by analysis of variance with identical adjustment are shown.

Graphic Jump Location
FACTOR V LEIDEN HOMOZYGOTES

Individual characteristics for the 20 factor V Leiden homozygotes at the 1991-1994 examination are presented in Table 3. Notably, pulmonary embolism had been diagnosed in only 1 of the 20 homozygotes and deep venous thrombosis in 3.

Table Graphic Jump LocationTable 3. Individual Characteristics of Factor V Leiden Homozygotes in 1991-1994

This study demonstrates for the first time, to our knowledge, that factor V Leiden homozygosity is associated with a 5-fold risk of severe dyspnea. Furthermore, homozygotes had lower FEV1 and FVC alongside an accelerated decrease in FEV1 and FVC. Factor V Leiden heterozygosity did not influence pulmonary symptoms and signs.

The observation of lower pulmonary function in homozygotes compared with noncarriers was unexpected because most patients with repeated pulmonary thromboemboli have normal spirometry results.12 To investigate if dyspnea among factor V Leiden homozygotes was related to the decreased ventilatory capacity, in addition to adjusting for age, sex, exposure to occupational dust, smoking, and body mass index, we adjusted for FEV1, FVC, and FEV1/FVC ratio. These adjustments, which resulted in merely trivial changes in the estimated OR for dyspnea, led us to believe that factor V Leiden causes dyspnea not only through reduced pulmonary function but also by some other mechanism. A possible explanation for the observed increased frequency of dyspnea among factor V Leiden homozygotes is that these individuals experience repeated peripheral venous thrombi that dislodge and result in small, clinically unrecognized pulmonary thromboemboli. An alternative explanation for the observed findings is confounding by some other unmeasured factor. However, for such a factor to confound our results, it must be associated with both dyspnea and factor V Leiden. We are not aware of such a factor. Thirty percent of factor V Leiden homozygotes had been exposed to occupational dust compared with 19% of noncarriers, a difference that was not significant. To confidently exclude that our conclusions were confounded by exposure to occupational dust, we repeated analyses after excluding individuals exposed to occupational dust; after this exclusion, FEV1 and FVC were still lower among homozygotes vs noncarriers (P = .004 and P = .03). Likewise, annual loss of FEV1 and FVC was lower among homozygotes than among noncarriers (P = .005 and P = .03), whereas the OR for severe dyspnea in factor V Leiden homozygotes vs noncarriers was 9.0 (95% CI, 2.6-30.5).

Previous studies1317 have suggested that factor V Leiden increases risk of deep venous thrombosis rather than pulmonary embolism. However, this apparent differential effect of factor V Leiden may not be real but could be a consequence of selection bias in studies of factor V Leiden and deep venous thrombosis.18 In accordance with this, we could not demonstrate a difference in the excess risk of deep venous thrombosis and pulmonary embolism in The Copenhagen City Heart Study, which constitutes the largest prospective cardiopulmonary study performed so far on unselected individuals.3 Finally, it should be recognized that previous studies on factor V Leiden and deep venous thrombosis or pulmonary embolism have investigated thromboembolic events that have been clinically detected. Therefore, even if factor V Leiden increases the risk of deep venous thrombosis more than that of pulmonary embolism, it does not contradict the findings of this study.

We cannot exclude the possibility that severe pulmonary disease may have prevented some individuals from participating in The Copenhagen City Heart Study. However, we believe that a potential selection bias would not differ by genotype and that in the present study, selection bias against factor V Leiden homozygotes is of limited significance because (1) the factor V Leiden genotype distribution in this study is similar to that observed in 4188 Danish newborns19 and (2) the relative genotype frequencies observed were not different from those predicted by the Hardy-Weinberg equilibrium.

In conclusion, we demonstrate a previously unrecognized clinical presentation of factor V Leiden homozygosity with severe dyspnea and decreased pulmonary function. The fact that approximately 0.2% of white populations are factor V Leiden homozygotes and that 30% to 40% of these individuals may have severe dyspnea makes this a potentially important observation.

Correspondence: Børge G. Nordestgaard, MD, DMSc, Department of Clinical Biochemistry, Herlev University Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark (brno@herlevhosp.kbhamt.dk).

Accepted for Publication: July 5, 2004.

Financial Disclosure: None.

Funding/Support: This study was supported by grants from The Danish Heart Foundation, Copenhagen; Chief Physician Johan Boserup and Lise Boserup’s Fund, Haslev, Denmark; Lykfeldt’s Fund, Hedehusene, Denmark; and Dagmar Marshall’s Fund, Wedelborg’s Fund, Lily Benthine Lund’s Fund, The Beckett Fund, and P. Carl Petersen’s Fund, Copenhagen.

Disclaimer: The sponsors of the study are public or nonprofit organizations that support science in general. They had no role in gathering, analyzing, or interpreting the data and had no right to approve or disapprove of the submitted paper. The work of the authors was independent of the funders of this study. All authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Acknowledgment: We thank laboratory technician Hanne Damm for technical support and the participants of The Copenhagen City Heart Study for their willingness to participate.

Moser  KMFedullo  PFLitteJohn  JKCrawford  R Frequent asymptomatic pulmonary embolism in patients with deep venous thrombosis. JAMA 1994;271223- 225
PubMed Link to Article
Rees  DCCox  MClegg  JB World distribution of factor V Leiden. Lancet 1995;3461133- 1134
PubMed Link to Article
Juul  KTybjaerg-Hansen  ASchnohr  PNordestgaard  BG Factor V Leiden and the risk for venous thromboembolism in the adult Danish population. Ann Intern Med 2004;140330- 337
PubMed Link to Article
Copenhagen City Heart Study Group, The Copenhagen City Heart Study: Østerbroundersøgelsen: a book of tables with data from the first examination (1976-78) and a five year follow-up (1981-1983). Scand J Soc Med Suppl 1989;411- 160
Juul  KTybjaerg-Hansen  ASteffensen  RKofoed  SJensen  GNordestgaard  BG Factor V Leiden: the Copenhagen City Heart Study and 2 meta-analyses. Blood 2002;1003- 10
PubMed Link to Article
Jensen  G Epidemiology of chest pain and angina pectoris. Acta Med Scand 1984;6821- 120
Lange  P Development and prognosis of chronic obstructive pulmonary disease with special reference to the role of tobacco smoking: an epidemiologic study. Dan Med Bull 1992;3930- 48
PubMed
Schnohr  PJensen  GLange  PScharling  HAppleyard  M The Copenhagen City Heart Study: tables with data from the third examination 1991-1994. Eur Heart J 2001;31- 83
Link to Article
Medical Research Council, Medical Research Council's committee on the etiology of chronic bronchitis: standardized questionnaires on respiratory symptoms. BMJ 1960;21665
Lange  PNyboe  JJensen  GSchnohr  PAppleyard  M Ventilatory function impairment and risk of cardiovascular death and of fatal or non-fatal myocardial infarction. Eur Respir J 1991;41080- 1087
PubMed
Simioni  PPrandoni  PLensing  AW  et al.  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;336399- 403
PubMed Link to Article
Braunwald  E Cor pulmonale. Fauci  ASBraunwald  EIsselbacher  KJ  et al. eds.Harrison's Principles of Internal Medicine. Vol 114th ed. New York, NY McGraw-Hill1998;1324- 1328
de Moerloose  PReber  GPerrier  APerneger  TBounameaux  H Prevalence of factor V Leiden and prothrombin G20210A mutations in unselected patients with venous thromboembolism. Br J Haematol 2000;110125- 129
PubMed Link to Article
Desmarais  Sde Moerloose  PReber  GMinazio  PPerrier  ABounameaux  H Resistance to activated protein C in an unselected population of patients with pulmonary embolism. Lancet 1996;3471374- 1375
PubMed Link to Article
Manten  BWestendorp  RGKoster  TReitsma  PHRosendaal  FR Risk factor profiles in patients with different clinical manifestations of venous thromboembolism: a focus on the factor V Leiden mutation. Thromb Haemost 1996;76510- 513
PubMed
Meyer  GEmmerich  JHelley  D  et al.  Factors V Leiden and II 20210A in patients with symptomatic pulmonary embolism and deep vein thrombosis. Am J Med 2001;11012- 15
PubMed Link to Article
Turkstra  FKaremaker  RKuijer  PMPrins  MHBuller  HR Is the prevalence of the factor V Leiden mutation in patients with pulmonary embolism and deep vein thrombosis really different? Thromb Haemost 1999;81345- 348
PubMed
Bounameaux  H Factor V Leiden paradox: risk of deep-vein thrombosis but not of pulmonary embolism. Lancet 2000;356182- 183
PubMed Link to Article
Larsen  TBLassen  JFBrandslund  IByriel  LPetersen  GBNorgaard-Pedersen  B The Arg506Gln mutation (FV Leiden) among a cohort of 4188 unselected Danish newborns. Thromb Res 1998;89211- 215
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Prevalence of dyspnea by age group. Error bars indicate SDs; lines, regression lines. The P value by Wald testing for equality of logistic regression coefficients for age was .73 for heterozygotes vs noncarriers and .003 for homozygotes vs noncarriers.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) as percentage of predicted values by factor V Leiden genotype. Bars represent means ± SDs after adjustment for smoking. P values by repeated-measures analysis of variance adjusted for smoking were .99 (FEV1) and .42 (FVC) for heterozygotes vs noncarriers and .003 (FEV1) and .03 (FVC) for homozygotes vs noncarriers.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Annual change in forced expiratory volume in 1 second (FEV1) (A) and forced vital capacity (FVC) (B) by factor V Leiden genotype. Bars represent means ± SDs. P values by analysis of variance with identical adjustment are shown.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Characteristics of Participants*
Table Graphic Jump LocationTable 2. Dyspnea by Factor V Leiden Genotype
Table Graphic Jump LocationTable 3. Individual Characteristics of Factor V Leiden Homozygotes in 1991-1994

References

Moser  KMFedullo  PFLitteJohn  JKCrawford  R Frequent asymptomatic pulmonary embolism in patients with deep venous thrombosis. JAMA 1994;271223- 225
PubMed Link to Article
Rees  DCCox  MClegg  JB World distribution of factor V Leiden. Lancet 1995;3461133- 1134
PubMed Link to Article
Juul  KTybjaerg-Hansen  ASchnohr  PNordestgaard  BG Factor V Leiden and the risk for venous thromboembolism in the adult Danish population. Ann Intern Med 2004;140330- 337
PubMed Link to Article
Copenhagen City Heart Study Group, The Copenhagen City Heart Study: Østerbroundersøgelsen: a book of tables with data from the first examination (1976-78) and a five year follow-up (1981-1983). Scand J Soc Med Suppl 1989;411- 160
Juul  KTybjaerg-Hansen  ASteffensen  RKofoed  SJensen  GNordestgaard  BG Factor V Leiden: the Copenhagen City Heart Study and 2 meta-analyses. Blood 2002;1003- 10
PubMed Link to Article
Jensen  G Epidemiology of chest pain and angina pectoris. Acta Med Scand 1984;6821- 120
Lange  P Development and prognosis of chronic obstructive pulmonary disease with special reference to the role of tobacco smoking: an epidemiologic study. Dan Med Bull 1992;3930- 48
PubMed
Schnohr  PJensen  GLange  PScharling  HAppleyard  M The Copenhagen City Heart Study: tables with data from the third examination 1991-1994. Eur Heart J 2001;31- 83
Link to Article
Medical Research Council, Medical Research Council's committee on the etiology of chronic bronchitis: standardized questionnaires on respiratory symptoms. BMJ 1960;21665
Lange  PNyboe  JJensen  GSchnohr  PAppleyard  M Ventilatory function impairment and risk of cardiovascular death and of fatal or non-fatal myocardial infarction. Eur Respir J 1991;41080- 1087
PubMed
Simioni  PPrandoni  PLensing  AW  et al.  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;336399- 403
PubMed Link to Article
Braunwald  E Cor pulmonale. Fauci  ASBraunwald  EIsselbacher  KJ  et al. eds.Harrison's Principles of Internal Medicine. Vol 114th ed. New York, NY McGraw-Hill1998;1324- 1328
de Moerloose  PReber  GPerrier  APerneger  TBounameaux  H Prevalence of factor V Leiden and prothrombin G20210A mutations in unselected patients with venous thromboembolism. Br J Haematol 2000;110125- 129
PubMed Link to Article
Desmarais  Sde Moerloose  PReber  GMinazio  PPerrier  ABounameaux  H Resistance to activated protein C in an unselected population of patients with pulmonary embolism. Lancet 1996;3471374- 1375
PubMed Link to Article
Manten  BWestendorp  RGKoster  TReitsma  PHRosendaal  FR Risk factor profiles in patients with different clinical manifestations of venous thromboembolism: a focus on the factor V Leiden mutation. Thromb Haemost 1996;76510- 513
PubMed
Meyer  GEmmerich  JHelley  D  et al.  Factors V Leiden and II 20210A in patients with symptomatic pulmonary embolism and deep vein thrombosis. Am J Med 2001;11012- 15
PubMed Link to Article
Turkstra  FKaremaker  RKuijer  PMPrins  MHBuller  HR Is the prevalence of the factor V Leiden mutation in patients with pulmonary embolism and deep vein thrombosis really different? Thromb Haemost 1999;81345- 348
PubMed
Bounameaux  H Factor V Leiden paradox: risk of deep-vein thrombosis but not of pulmonary embolism. Lancet 2000;356182- 183
PubMed Link to Article
Larsen  TBLassen  JFBrandslund  IByriel  LPetersen  GBNorgaard-Pedersen  B The Arg506Gln mutation (FV Leiden) among a cohort of 4188 unselected Danish newborns. Thromb Res 1998;89211- 215
PubMed Link to Article

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