|
|||||||||
|
|
|
|
|
|
|
|
|
|
|
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Department of Medical and Surgical Sciences,
Second Chair of Internal Medicine, University of Padua Medical School,
Italy.
In a prospective cohort study, we assessed the incidence of
spontaneous and risk period-related venous thromboembolism (VTE) in
asymptomatic family members of patients who experienced VTE and had the
factor V Leiden mutation. In all, 561 family members of 131 probands
were included, 313 of whom were carriers (299 heterozygous and 14 homozygous) and 248 of whom were noncarriers of the factor V Leiden
mutation. Average follow-up was 4 years (range, 4 months-6 years).
There were 1255 and 984 observation-years of follow-up in carriers and
noncarriers, respectively. Eight episodes of VTE occurred in
heterozygous carriers, resulting in an annual incidence of 0.67% (95%
confidence interval [CI], 0.29-1.33). Two events occurred in the
absence of associated risk factors, determining an annual incidence of
spontaneous VTE of 0.17% (95% CI, 0.02-0.6). Only one VTE (risk
period-related) occurred in noncarriers, with an annual incidence of
0.1% (95% CI, 0.003-0.56). Relative risk for VTE in heterozygous
carriers compared with noncarriers of the factor V Leiden mutation was
6.6 (95% CI, 1.1-39.8). Risk period-related VTE occurred with an
incidence of 18% and 5% per risk period in heterozygous
carriers and in noncarriers, respectively. Thus, the low rate of VTE in
asymptomatic family members carrying the mutation did not justify
continuous anticoagulant prophylaxis. Screening families of symptomatic
probands with the factor V Leiden mutation has the potential to
identify those asymptomatic carriers who might benefit from
thromboprophylaxis during risk periods.
(Blood. 2002;99:1938-1942) Factor V Leiden mutation (factor V Arg506 Benefits from an early identification of carriership status among
asymptomatic subjects in terms of appropriate prophylactic measures
should be balanced against the disadvantage of potential bleeding
complications secondary to preventive treatment and the inconvenience
of labeling otherwise healthy people as having a disease. Thus, valid
estimates of the absolute risk for spontaneous and risk period-related
VTE in asymptomatic family members who are carriers of the factor V
Leiden mutation are crucial for clinical decision making. According to
the results of 2 recent retrospective cohort studies involving a large
number of families with the factor V Leiden mutation,11,12
the overall annual incidence of VTE in carriers of this mutation was
found to be approximately 0.50% in persons older than 15 years of age.
This rate is approximately 5 times higher than that reported for the
general population.13
In this prospective follow-up study, we assessed the absolute risk for
spontaneous and risk period-related VTE in a wide number of
asymptomatic family members of probands who were carriers of factor V
Leiden and had experienced a thrombotic episode.
Identification of cohorts
All consenting family members of index patients older than 15 years
were eligible for this investigation. Detailed medical history was
obtained, with specific attention paid to the occurrence of prior VTE.
Patients with a history of previously documented VTE were excluded from
the study, as were those with active cancer. Eligible patients
underwent compression ultrasonography (CUS) of the legs, and subjects
with positive test results were also excluded. In the remaining
subjects, factor V Leiden determination was performed as indicated
elsewhere.12 According to laboratory results, subjects
were classified as carriers or noncarriers of the factor V mutation.
Patients in whom cancer developed during follow-up were removed from
the analysis. Recruitment into the study started in June 1994 and ended
in June 2000. Follow-up of recruited subjects was completed in October
2000. Informed consent was obtained from all study participants in
accordance with the Helsinki protocol.
Study design
Recruited subjects were asked to return to our institution for clinical evaluation every 6 months or earlier if clinical symptoms suggestive of deep vein thrombosis (DVT) or pulmonary embolism (PE) developed. At each visit they were interviewed, and special attention was paid to risk periods for thrombosis. Objective tests (CUS or phlebography in patients with suspected DVT, ventilation or perfusion lung scanning or spiral computed tomography followed by pulmonary angiography when needed in patients with suspected PE) were systematically used to diagnose or rule out a thromboembolic event in every symptomatic patient.14,15 All study subjects and their physicians received written information concerning the implications of the observed factor V Leiden mutation and advice to consider anticoagulant prophylaxis during risk periods. Our institutional review board approved the study protocol. Laboratory assay Blood samples were collected into plastic syringes containing 3.8% (wt/vol) sodium citrate in a ratio of 1:9 (vol/vol) anticoagulant to blood. Assays for antithrombin, protein C, and protein S and DNA analysis for the factor V Leiden mutation were performed as previously described.12,16 DNA analysis for prothrombin variant 20210A, tests for antiphospholipid antibodies, and determination of fasting plasma homocysteine levels were performed only in patients who became symptomatic for VTE during the follow-up. The methods used for these determinations have been described.17-19Outcomes The primary outcome was the occurrence of objectively documented VTE. This was defined as DVT of the leg or the arm, PE, or objectively documented venous thrombosis in other sites. A venous thromboembolic event was categorized as either spontaneous or secondary to a risk period. Spontaneous thromboembolism was defined as an event occurring without a predisposing risk period. Secondary VTE was defined as an event occurring during or within 3 months of a risk period.Statistical analysis The annual incidence of the first episode of spontaneous or risk period-related VTE, and its 95% confidence intervals (CIs) were calculated in the carrier and noncarrier groups and were expressed as number of events per 100 patient-years. Risk period-related VTE was related to the type of risk period and to anticoagulant prophylaxis administration. Relative risk for the development of total, spontaneous, and risk period-related VTE was calculated by dividing the incidence rate in carriers by the incidence rate in noncarrier family members. The 95% CIs and P values were calculated according to the normal approximation of the binomial distribution or by using the exact procedure as appropriate. Thrombosis-free survival in heterozygous carriers and in noncarriers was analyzed according to the Kaplan-Meier method. Both curves were compared using the log-rank test.
Study populations One hundred thirty-one unrelated patients with objectively documented VTE and factor V Leiden mutation served as index patients in this study. Mean age of index patients was 48 years (range, 16 to 93 years), and 35% of their first thrombotic events occurred spontaneously. From these 131 patients, 656 family members were identified as potentially eligible for participation in the study. Of these, 53 refused to participate. Of the remaining 603 subjects who were interviewed and underwent a baseline CUS, 42 were excluded because of the previous VTE (36) or the positive CUS (6). Thus 561 subjects were enrolled into the study; 313 (145 males) were found to be carriers of factor V Leiden (299 heterozygous, 14 homozygous) and 248 (125 males) noncarriers. Mean age of the subjects at the time of their inclusion in the study was 44 years (range, 15 to 95 years) in carriers and 43 years (range, 16 to 89 years) in noncarriers.Follow-up There were 1255 observation years in carriers (68 years in homozygous, 1187 in heterozygous) and 984 observation years in noncarriers of factor V Leiden. Average duration of observation was 4 years in each group (range, 4 months-6 years). At least 1 year of follow-up was available in 521 subjects. No subject died or was lost to follow-up.Incidence of venous thromboembolism Thromboembolic events during follow-up were recorded in 8 (2%) carriers of factor V Leiden, all of them belonging to the group of heterozygous subjects, accounting for an overall annual incidence of VTE of 0.67% (95% CI, 0.29-1.33). Two events were spontaneous (annual incidence of spontaneous VTE, 0.17%; 95% CI, 0.02-0.6), and the remaining 6 were risk period-related (Table 1). All events affected the proximal veins of either leg and were associated with symptomatic PE in one patient. Four events occurred in patients younger than 45, and the remaining occurred in patients older than 45 years. Observation-years of follow-up were similar in both age categories.
Of the patients in the noncarrier group in whom VTE symptoms developed, a 60-year-old woman was retrospectively excluded from the analysis because she was found to be a heterozygous carrier of the G20210A prothrombin variant. In addition, metastatic breast cancer developed 2 months after the thrombotic event. The only evaluable event in the noncarrier group was a proximal DVT arising in association with a triggering factor (Table 1). The annual incidence of VTE in this group was 0.1% (95% CI, 0.003-0.56). Relative risk for overall VTE in carriers of factor V Leiden compared with noncarriers was 6.6 (95% CI, 1.1-39.8). Thrombosis-free survival curves in carriers and noncarriers of factor V
Leiden are plotted in Figure 1 as a
function of the duration of follow-up. Among carriers, only those who
were heterozygous were considered for Kaplan-Meier analysis. The
difference between the curves appears to be statistically significant
(log-rank test: P = .047).
As shown in Table 2, 34 risk periods were
experienced by 32 heterozygous carriers of factor V Leiden, complicated
by thromboembolism in 6 patients and accounting for an incidence of
17.6% per risk period (95% CI, 8.3-33.5). Three pregnancies occurred
during follow-up in 2 homozygous women. They received low-dose low
molecular weight heparin (LMWH) during postpartum periods only
and remained asymptomatic. Among noncarriers, 21 risk periods were
experienced by 19 persons, complicated by VTE in 1 case, accounting for
an incidence of 4.8% per risk period (95% CI, 0.8-22.7).
In 11 of 34 risk periods experienced by factor V Leiden carriers in which anticoagulant prophylaxis was given (low-dose LMWH in 8 cases, high-dose LMWH in 1, low-dose unfractionated heparin in 2), 1 VTE occurred after trauma and resulted in an incidence of 9.1% per risk period. Five VTE events occurred during the 23 risk periods in which no anticoagulant prophylaxis was given, with an incidence of 21.7% per risk period.
In full agreement with data from recent retrospective studies,11,12 the annual incidence of venous thromboembolic events occurring in asymptomatic carriers of factor V Leiden during a 6-year prospective follow-up was low. Spontaneous VTE occurred in carriers with an incidence of 0.17% patient-years as previously observed,20 whereas no spontaneous VTE occurred in the noncarriers. Accordingly, it should be expected that a spontaneous VTE event will occur during 1 year of follow-up for every 600 asymptomatic family members who are heterozygous carriers of the factor V Leiden mutation. This rate is considerably lower than that found in deficiencies of antithrombin, protein C, and protein S (approximately 0.8% patient-years).16 In addition, though limited observation-years are available, all 14 homozygous carriers of factor V Leiden remained asymptomatic during follow-up. Taken together, these observations indicate that factor V Leiden mutation is a mild risk factor for VTE. It is noteworthy, however, that in the current study the annual incidence of overall VTE in heterozygous carriers (0.67% patient-years) differed significantly from that found in family members with a normal genotype (0.1% patient-years); the latter is fully consistent with estimates available in the general population.13,21 However, because the risk for serious bleeding during the use of oral anticoagulants is much higher, ranging from 2% to 4% patient-years,22-24 there is likely no expected benefit from long-term anticoagulant prophylaxis in asymptomatic carriers of factor V Leiden. The question arises whether routinely screening family members of symptomatic carriers of a single identified factor V Leiden mutation is justified. In this prospective study, the risk for overall VTE was about 6.6 times higher in heterozygous carriers than in noncarriers, suggesting that family screening has the potential to identify a group of persons at higher risk for VTE. This increased risk is comparable to that found in a previous case-control study of consecutive patients with objectively documented VTE. 1 The increased risk for VTE found in heterozygous carriers during the follow-up is more pronounced during risk periods. Although the relatively small number of risk periods and the nonuniform approach concerning anticoagulant prophylaxis preclude definitive conclusions, it is interesting that the incidence of risk period-related VTE in carriers was 9.1% per risk period and 21.7% per risk period in the presence or the absence of anticoagulant prophylaxis, respectively. These figures are similar to those found in a recent prospective study with a similar study design addressing carriers of antithrombin, protein C, and protein S deficiencies,16 in whom the incidence of risk period-related VTE was 4.5% and 16.7% per risk period depending on whether prophylaxis was or was not given, respectively. Major trauma or surgery was complicated by VTE in 21% and 7.6% in carriers and noncarriers of factor V Leiden, respectively, suggesting that under these situations an increased risk for VTE indeed exists. Therefore, family members might take advantage of screening for factor V Leiden, assuming that the administration or optimization, or both, of prophylaxis has the potential to prevent, at least in part, these VTE events. This must be further addressed in proper studies. Pregnancy outcome may be influenced by the presence of factor V Leiden mutation, as reported in several studies.12,25,26 The postpartum period is considered a particularly high risk time for VTE in factor V Leiden carriers, and prophylaxis is usually given to women under these circumstances. In our cohort, almost 28% of postpartum periods were complicated by VTE in women who did not receive prophylaxis. No VTE events occurred in heterozygous or homozygous women who received prophylaxis during postpartum periods. This finding suggests a potential benefit from screening female family members of fertile age because of the possibility of preventing postpartum-related thrombosis in carriers of factor V Leiden with the use of prophylaxis. In carriers of factor V Leiden, no thromboembolism was observed during long-term hormonal therapy. This finding, which contrasts with most available information,27,28 might be accounted for by the low number of investigated risk periods, partly resulting from the tendency of young women who were conscious of their thrombophilic status or of thrombotic problems in their families to refrain from taking potentially dangerous drugs. In addition, even homozygous carriers of factor V Leiden mutation remain asymptomatic for VTE during long-term oral contraceptive treatment.29 Thus, additional studies are needed to establish whether women of fertile age who are considering the use of oral contraceptives or who intend to become pregnant might benefit from the routine screening of this mutation. Costs of such an approach might be affordable because of the selection of persons to be screened (asymptomatic women in fertile age who are family members of a symptomatic [VTE] carrier of a single identified factor V Leiden mutation), which undoubtedly would reduce the high cost-benefit ratio of unselected population screening. We believe that our results provide a valid estimate of the annual frequency of thromboembolic events in asymptomatic carriers of a single identified heterozygous factor V Leiden mutation. All identified subjects were prospectively followed up at the study center. All episodes of clinically suspected DVT or PE were investigated with properly validated objective tests. Moreover, confounding factors were minimized by the exclusion from our cohort of patients who had a history of thromboembolism and other known thrombophilic conditions. Although our conclusions stem from a moderate-sized sample of patients followed-up for an average of 6 years, it is unlikely that a different estimate of the risk for spontaneous venous thromboembolism will be obtained by a prolongation of the follow-up period. Finally, because of the limited number of homozygous carriers of the factor V Leiden mutation included in this study, no conclusion regarding the risk for VTE can be drawn for this condition. In conclusion, asymptomatic persons who are daily identified in coagulation laboratories through the screening of families with factor V Leiden exhibit a low risk for venous thromboembolism. Systematic screening for this abnormality in family members of symptomatic patients with a single identified factor V Leiden mutation has the potential to identify those persons who might benefit from prophylaxis for VTE in high-risk situations. However, accurate evaluation of the cost-benefit ratio of screening selected family members should be performed in properly designed studies before this is recommended as a routine approach.
We thank Sonia Luni and Mariangela Fadin for excellent technical assistance.
Submitted July 27, 2001; accepted October 29, 2001.
Supported in part by a grant from Regione del Veneto, Ricerca Sanitaria Finalizzata no. 783/01/97 (P.S.).
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Paolo Simioni, Department of Medical and Surgical Sciences, Via Ospedale, 105 35128-Padua, Italy; e-mail: paolo.simioni{at}unipd.it.
1. Koster T, Rosendaal F, de Ronde H, Briet E, Vandenbroucke JP, Bertina RM. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden thrombophilia study. Lancet. 1993;342:1503-1506[CrossRef][Medline] [Order article via Infotrieve].
2.
Svensson PJ, Dahlback B.
Resistance to activated protein C as a basis for venous thrombosis.
N Engl J Med.
1994;330:517-522
3.
Simioni P, Prandoni P, Lensing AWA, et al.
The risk of recurrent venous thromboembolism in patients with an Arg 506Gln mutation in the gene for factor V Leiden (factor V Leiden).
N Engl J Med.
1997;336:399-403
4.
Rosendaal FR, Koster T, Vandenbroucke JP, Reitsma PH.
High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance).
Blood.
1995;85:1504-1508
5.
Price DT, Ridker PM.
Factor V Leiden mutation and the risks for thromboembolic disease: a clinical perspective.
Ann Intern Med.
1997;127:895-903
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 thrombosis in apparently healthy men.
N Engl J Med.
1995;332:912-917
7.
Koeleman BP, Reitsma PH, Allaart CF, Allaart CF, Bertina RM.
Activated protein C resistance as an additional risk factor for thrombosis in protein C deficient families.
Blood.
1994;84:1031-1035 8. Tosetto A, Rodeghiero F, Martinelli I, et al. Additional genetic risk factors for venous thromboembolism in carriers of the factor V Leiden mutation. Br J Haematol. 1998;103:871-876[CrossRef][Medline] [Order article via Infotrieve].
9.
Ridker PM, Hennekens CH, Selhub J, Miletich JP, Malinow MR, Stampfer MJ.
Interrelation of hyperhomocystinemia, factor V Leiden, and risk of future venous thromboembolism.
Circulation.
1997;95:1777-1782 10. Makris M, Preston FE, Beauchamp NJ, et al. 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].
11.
Middeldorp S, Henkens CMA, Koopman MMW, et al.
The incidence of venous thromboembolism in family members of patients with factor V Leiden mutation and venous thrombosis.
Ann Intern Med.
1998;128:15-20 12. Simioni P, Sanson BJ, Prandoni P, et al. Incidence of venous thromboembolism in families with inherited thrombophilia. Thromb Haemost. 1999;81:198-202[Medline] [Order article via Infotrieve]. 13. Nordstrom M, Lindblad B, Bergqvist D, Kjellstrom T. A prospective study of the incidence of deep-vein thrombosis within a defined urban population. J Intern Med. 1992;232:155-160[Medline] [Order article via Infotrieve]. 14. Cogo A, Lensing AWA, Wells PS, Prandoni P, Büller HR. Non-invasive diagnostic tests for the diagnosis of clinically suspected deep-vein thrombosis. Haemostasis. 1995;25:27-39[Medline] [Order article via Infotrieve]. 15. Kearon C, Hirsh J. The diagnosis of pulmonary embolism. Haemostasis. 1995;25:72-87[Medline] [Order article via Infotrieve].
16.
Sanson BJ, Simioni P, Tormene D, et al.
The incidence of venous thromboembolism in asymptomatic carriers of a deficiency of antithrombin, protein C, or protein S: a prospective cohort study.
Blood.
1999;94:3702-3706 17. Simioni P, Tormene D, Manfrin D, et al. Prothrombin antigen levels in symptomatic and asymptomatic carriers of the 20210A prothrombin variant. Br J Haematol. 1998;103:1045-1050[CrossRef][Medline] [Order article via Infotrieve]. 18. Simioni P, Prandoni P, Burlina A, et al. Hyperhomocystinemia and deep-vein thrombosis: a case-control study. Thromb Haemost. 1996;76:883-886[Medline] [Order article via Infotrieve]. 19. Zanon E, Saracino MA, Simioni P, et al. Prevalence of antiphospholipid antibodies and lupus anticoagulant in juvenile patients with objectively documented deep vein thrombosis. Clin Appl Thromb Hemost. 1996;2:69-73
20.
Simioni P, Prandoni P, Girolami A.
Low rate of venous thromboembolism in asymptomatic relatives of probands with factor V Leiden [abstract].
Ann Intern Med.
1999;130:538 21. Hansson PO, Werlin L, Tibblin G, Eriksson H. Deep vein thrombosis and pulmonary embolism in the general population. Arch Intern Med. 1997;157:1665-1670[Abstract].
22.
Schulman S, Granqvist S, Holmstrom M, et al.
The duration of oral anticoagulant therapy after a second episode of venous thromboembolism.
N Engl J Med.
1997;336:393-398 23. Palareti G, Leali N, Coccheri S, et al. Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT). Lancet. 1996;348:423-428[CrossRef][Medline] [Order article via Infotrieve].
24.
Kearon C, Gent M, Hirsh J, et al.
A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism.
N Engl J Med.
1999;340:901-907
25.
Gerhardt A, Scharf RE, Beckmann MW, et al.
Prothrombin and factor V mutations in women with a history of thrombosis during pregnancy and the puerperium.
N Engl J Med.
2000;342:374-380 26. McColl MD, Walker ID, Greer IA. The role of inherited thrombophilia in venous thromboembolism associated with pregnancy. Br J Obstet Gynaecol. 1999;106:756-766[Medline] [Order article via Infotrieve]. 27. Vandenbroucke JP, Koster T, Briet 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[CrossRef][Medline] [Order article via Infotrieve].
28.
Vandenbroucke JP, van den Meer FJ, Helmerhorst FM, Rosendaal FR.
Factor V Leiden: should we screen oral contraceptive users and pregnant women?
Br Med J.
1996;313:1127-1130 29. Girolami A, Simioni P, Girolami B, Radossi P. Homozygous patients with APC-resistance may remain paucisymptomatic or asymptomatic during oral contraception. Blood Coagul Fibrinol. 1996;7:590-594[Medline] [Order article via Infotrieve].
© 2002 by The American Society of Hematology.
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
|
 |
|
  A. K. Wittkowsky Anticoagulation in Hypercoagulable Conditions: Special Considerations in the Treatment and Prevention of Venous Thromboembolism Journal of Pharmacy Practice, October 1, 2004; 17(5): 308 - 316. [Abstract] [PDF]
|
|
|
|
 |
|
 I. Bank, E. J. Libourel, S. Middeldorp, E. C. M. van Pampus, M. M. W. Koopman, K. Hamulyak, M. H. Prins, J. van der Meer, and H. R. Buller Prothrombin 20210A Mutation: A Mild Risk Factor for Venous Thromboembolism but Not for Arterial Thrombotic Disease and Pregnancy-Related Complications in a Family Study Arch Intern Med, September 27, 2004; 164(17): 1932 - 1937. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Tormene, P. Simioni, P. Prandoni, F. Franz, P. Zerbinati, G. Tognin, and A. Girolami The incidence of venous thromboembolism in thrombophilic children: a prospective cohort study Blood, September 18, 2002; 100(7): 2403 - 2405. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|||||||||
 |
 |
 |
 |
 |
 |
 |
 |
||||
| |||||||||||
Top
Abstract
Introduction
Gln) is
the most common genetic defect associated with an increased risk for
venous thromboembolism (VTE).
