The Risk of Recurrent Deep Venous Thrombosis among Heterozygous Carriers of Both Factor V Leiden and the G20210A Prothrombin Mutation

doi:10.1056/NEJM199909093411104

Volume 341:801-806		September 9, 1999		Number 11

The Risk of Recurrent Deep Venous Thrombosis among Heterozygous Carriers of Both Factor V Leiden and the G20210A Prothrombin Mutation

Valerio De Stefano, M.D., Ida Martinelli, M.D., Ph.D., Pier Mannuccio Mannucci, M.D., Katia Paciaroni, M.D., Patrizia Chiusolo, M.D., Ida Casorelli, M.D., Elena Rossi, M.D., and Giuseppe Leone, M.D.

Abstract

PDF

Letters

Add to Personal Archive

Add to Citation Manager

Notify a Friend

E-mail When Cited

PubMed Citation

ABSTRACT

Background Point mutations in the factor V gene (factor V Leiden)and the prothrombin gene (the substitution of A for G at position20210) are the most common causes of inherited thrombophilia.Whether or not factor V Leiden increases the risk of recurrentdeep venous thrombosis is controversial, and there is no informationon the risk of recurrence among carriers of both mutations.

Methods We studied a retrospective cohort of 624 patients whowere referred for a first episode of deep venous thrombosis.After excluding 212 patients with other inherited or acquiredcauses of thrombophilia, we compared 112 patients who were heterozygouscarriers of factor V Leiden with 17 patients who were heterozygousfor both factor V Leiden and the prothrombin mutation and 283patients who had neither mutation. The relative risk of recurrentdeep venous thrombosis was calculated with use of a proportional-hazardsmodel.

Results Patients who were heterozygous for factor V Leiden alonehad a risk of recurrent deep venous thrombosis that was similarto that among patients who had neither mutation (relative risk,1.1; 95 percent confidence interval, 0.7 to 1.6; P=0.76). Incontrast, patients who were heterozygous for both factor V Leidenand the prothrombin mutation had a higher risk of recurrentthrombosis than did carriers of factor V Leiden alone (relativerisk, 2.6; 95 percent confidence interval, 1.3 to 5.1; P=0.002).When the analysis was restricted to patients with spontaneousrecurrences (i.e., ones that occurred in the absence of transientrisk factors for venous thrombosis), the risk among carriersof both mutations, as compared with carriers of factor V Leidenalone, remained high (relative risk, 3.7; 95 percent confidenceinterval, 1.7 to 7.7; P<0.001), particularly if the firstevent had also been spontaneous (relative risk, 5.4; 95 percentconfidence interval, 2.0 to 14.1; P<0.001). In contrast,the risk of recurrence in the presence of transient risk factorswas similar among carriers of both mutations and carriers offactor V Leiden alone.

Conclusions The risk of recurrent deep venous thrombosis issimilar among carriers of factor V Leiden and patients withoutthis mutation. Carriers of both factor V Leiden and the G20210Aprothrombin mutation have an increased risk of recurrent deepvenous thrombosis after a first episode and are candidates forlifelong anticoagulation.

Inherited resistance to activated protein C is a thrombophiliccondition resulting from a mutant factor V (factor V Leiden).¹The mutation is relatively common among whites, with a frequencyof 5 percent in the general population of European ancestryand 11 to 21 percent among patients with venous thromboembolism.²The estimated risk of deep venous thrombosis is 7 times as highamong heterozygous carriers of the mutation as among personswithout the mutation, and 80 times as high among homozygotes.³There is disagreement whether factor V Leiden is associatedwith an increased risk of recurrent deep venous thrombosis.Several studies reported relative risks of recurrence rangingfrom 2.4 to 4.1 among patients with deep venous thrombosis whohad the mutation as compared with those who did not have themutation.⁴^,⁵ Other studies, however, failed to find an associationbetween factor V Leiden and recurrent deep venous thrombosis.⁶^,⁷^,⁸This issue is clinically important, because carriers of themutation should receive lifelong anticoagulant therapy if theirrisk of recurrent thrombosis is high.

Another thrombophilic mutation has been identified in the 3'untranslated region of the prothrombin gene (the substitutionof A for G at position 20210)⁹; the mutant allele is presentin 2 percent of the general population¹⁰ and increases the riskof deep venous thrombosis by a factor of 2.7 to 3.8.⁹^,¹¹^,¹²^,¹³The expected prevalence of both the factor V Leiden mutationand the prothrombin mutation in the general population is about1 per 1000; the prevalence has been estimated to be 1 to 5 percentamong patients with deep venous thrombosis.⁹^,¹¹^,¹²^,¹³^,¹⁴ Theprevalence of the 20210A allele among selected patients withfactor V Leiden and previous venous thromboembolism is 3 to27 percent.¹¹^,¹²^,¹³^,¹⁴^,¹⁵^,¹⁶ Because there is preliminary evidencethat carriers of the prothrombin 20210A allele who also haveother inherited thrombophilic conditions (deficiency of antithrombinIII, protein C, or protein S or the presence of factor V Leiden)are more prone to recurrent thrombotic episodes than personswith one thrombophilic condition,¹⁴^,¹⁷ we evaluated the riskof recurrent deep venous thrombosis among patients who wereheterozygous for factor V Leiden in the presence and the absenceof the prothrombin mutation as compared with patients with noknown causes of inherited thrombophilia.

Methods

Patients

From November 1994 to December 1998, 624 consecutive unrelatedpatients who had had a first episode of deep venous thrombosisof the legs or had been given a diagnosis of recurrent venousthromboembolism in the hospital by their attending physicianswere referred to two specialized thrombosis centers (in Milanand Rome) for an assessment of the possible causes of thrombophilia.All patients were interviewed about their medical history byphysicians before undergoing any laboratory tests, so that thediagnosis of first or recurrent deep venous thrombosis was recordedwithout knowledge of the results of thrombophilia screening.The presence of known risk factors at the time of any episodeof deep venous thrombosis, such as oral-contraceptive use, pregnancyor recent childbirth, surgery, prolonged immobilization (bedrest for at least 10 days, or the need for a leg cast), andtrauma, was also recorded.

The diagnosis of a first episode of deep venous thrombosis wasconsidered valid if it had been based on objective methods suchas phlebography, ultrasonographic examination, or impedanceplethysmography. The diagnosis of contralateral recurrent deepvenous thrombosis also had to be objectively established, andrecurrences of pulmonary embolism were diagnosed on the basisof perfusion lung scanning or computed tomography. Episodesof ipsilateral deep venous thrombosis or pulmonary embolismthat occurred within three months after the first episode ofdeep venous thrombosis were considered to indicate progressionrather than recurrence. Episodes of ipsilateral deep venousthrombosis that occurred more than three months after the firstepisode of thrombosis were considered to indicate recurrenceif the results of the objective tests were worse than thoseobtained at the time of the initial episode or if a new courseof anticoagulant treatment was started.

After giving informed consent, all patients underwent screeningfor thrombophilia as previously described.¹⁸ DNA samples wereanalyzed for the presence of the prothrombin gene mutation accordingto the method of Poort et al.⁹

Of the 624 patients who were referred, 283 had neither mutationand 129 were heterozygous carriers of factor V Leiden, 17 ofwhom were also heterozygous for the G20210A prothrombin mutation.The remaining 212 patients were excluded from the study becauseof the presence of one or more of the following: deficiencyof antithrombin III, protein C, or protein S; homozygosity forfactor V Leiden; an isolated G20210A mutation or a G20210A mutationin combination with thrombophilic traits other than factor VLeiden; cancer or myeloproliferative diseases; autoimmune disorders(including primary antiphospholipid-antibody syndrome); treatmentwith an oral anticoagulant for more than six months after thefirst episode of deep venous thrombosis; or a diagnosis of recurrentsuperficial venous thrombosis without objective signs of deepvenous thrombosis.

Statistical Analysis

We used the chi-square test to estimate differences in prevalenceamong the three groups. We analyzed the interval from the firstepisode of deep venous thrombosis to a recurrence (uncensoredobservations) or to referral to the centers (censored observations)in order to estimate the probability of recurrent deep venousthrombosis as a function of time, according to the method ofKaplan and Meier.¹⁹ The probability of recurrent deep venousthrombosis was compared among the groups with use of the log-ranktest; the relative risk of recurrent deep venous thrombosisamong patients with one or both mutations as compared with thosewith neither mutation was estimated with use of a Cox proportional-hazardsmodel, with 95 percent confidence intervals.²⁰

Results

Characteristics of the Patients

The clinical characteristics of the patients are shown in Table 1.Seventeen carriers of the factor V Leiden mutation were alsocarriers of the G20210A prothrombin mutation; none of the patientswere homozygous for the prothrombin mutation. There were nosignificant differences among the group of patients with neithermutation, the group that was heterozygous for factor V Leidenalone, and the group that was heterozygous for both factor VLeiden and the prothrombin mutation with respect to sex distribution,age at the time of the first episode of deep venous thrombosis,age at referral, interval from the first episode of deep venousthrombosis to recurrence or referral, or rate of spontaneousfirst thrombotic events. With one exception, the prevalenceof known risk factors at the time of the first event did notdiffer among the groups; pregnancy and recent childbirth weremore common among the women who had one or both mutations thanamong those with neither mutation.

View this table:
[in this window]
[in a new window]
Table 1. Clinical Characteristics of the Patients with Deep Venous Thrombosis.

Risk of Recurrent Deep Venous Thrombosis

At the time of referral, the cumulative incidence of recurrentdeep venous thrombosis was 30 percent among carriers of factorV Leiden alone and patients with neither mutation. The cumulativeincidence was more than twice as high (65 percent) among the17 carriers of both factor V Leiden and the G20210A prothrombinmutation (P=0.005 and P=0.003, respectively, by the chi-squaretest) (Table 2).

View this table:
[in this window]
[in a new window]
Table 2. Relative Risk of Recurrent Deep Venous Thrombosis.

In general, patients with a first episode of deep venous thrombosisshould be advised not to take oral contraceptives and to startantithrombotic prophylaxis during situations that increase therisk of recurrence, such as surgery or pregnancy. Our patientsdid not always follow these recommendations; therefore, 39 of131 recurrences (30 percent) occurred among patients with aknown risk factor; however, the prevalence of recurrences thatwere associated with a known risk factor was similar in thethree groups: 10 percent among carriers of factor V Leiden alone,9 percent among patients with neither mutation, and 6 percentamong carriers of both factor V Leiden and the prothrombin mutation(P=0.87). When only spontaneous recurrences were considered,the cumulative incidence was still higher among patients withboth mutations (59 percent) than among those with factor V Leidenalone (21 percent, P<0.001) or those with neither mutation(21 percent, P<0.001) (Table 2).

Kaplan–Meier analysis showed that the likelihood of thrombosis-freesurvival after the first event was similar among carriers offactor V Leiden and patients with neither mutation (relativerisk of recurrence among the carriers, 1.1; P=0.76) (Table 2).Stratification of the risk of recurrence among patients whowere heterozygous for factor V Leiden alone as compared withthose with neither mutation according to whether the first eventwas spontaneous or due to known risk factors or to whether therecurrence was spontaneous or due to known risk factors didnot change the results substantially (Table 2). Analysis ofthe time-to-recurrence curves according to sex showed that thepresence of factor V Leiden did not significantly increase therisk of recurrent deep venous thrombosis among men (relativerisk, 1.1; 95 percent confidence interval, 0.6 to 1.9; P=0.77)or women (relative risk, 1.0; 95 percent confidence interval,0.5 to 1.7; P=0.89).

The overall risk of recurrent deep venous thrombosis among patientswho were heterozygous for both factor V Leiden and the G20210Aprothrombin mutation was 2.6 times as high as that among patientswho were heterozygous for factor V Leiden alone and 2.7 timesas high as that among patients with neither mutation (Table 2).The relative risk of spontaneous recurrent deep venous thrombosiswas 3.7 among patients with both mutations, as compared withpatients who were heterozygous for factor V Leiden alone (Table 2).Further stratification of the risk of recurrent thrombosisamong patients who were heterozygous for both mutations accordingto whether the first episode of thrombosis was spontaneous ordue to known risk factors produced statistical instability becauseof the small number of patients, as reflected by the wide 95percent confidence intervals. Yet the spontaneous occurrenceof an initial episode of thrombosis further increased the relativerisk, to 5.4, as compared with the patients who were heterozygousfor factor V Leiden alone (Table 2). The risk of recurrenceof a spontaneous episode of deep venous thrombosis was not increasedby the fact that the initial episode occurred in the presenceof known risk factors (Table 2).

Discussion

After a first episode of deep venous thrombosis, the risk ofrecurrence is higher among patients with a persistent risk factor(such as cancer or inherited thrombophilia) than among thosewith a transient risk factor (such as oral-contraceptive use,pregnancy or recent childbirth, surgery, or prolonged immobilization).²¹There is currently no general consensus on the optimal durationof treatment with oral anticoagulants after a first episodeof deep venous thrombosis in patients with inherited thrombophilia.Usually, long-term treatment is not recommended if the firstepisode occurred in association with known transient risk factors,whereas long-term treatment is considered appropriate when deepvenous thrombosis developed spontaneously.¹⁸^,²²^,²³ The decisionshould take into account the type and severity of the geneticdefect, the number of genetic defects, the site of the firstthrombotic event, and whether there is a family history of thromboembolicepisodes. The risk of recurrent thrombosis has to be weighedagainst the risk of major bleeding that is associated with long-termoral anticoagulation, which is estimated to range from 1.1 percentto 3.8 percent per patient-year.²⁴^,²⁵

The high prevalence of factor V Leiden among patients with deepvenous thrombosis prompted studies to determine the risk ofrecurrence associated with this mutation after a first episodeof deep venous thrombosis. An increase in the risk ranging from2.4 to 4.1 has been reported by some authors⁴^,⁵ but not by others.⁶^,⁷^,⁸Some of these studies suffered from limitations related to therelatively small number of patients who had the mutation⁴^,⁵^,⁶or to the short observation period.⁴^,⁶^,⁷ In addition, most ofthem were carried out before the identification of the G20210Aprothrombin mutation as a cause of inherited thrombophilia.Therefore, some discrepancies in the results may be due to thesimultaneous presence of this genetic defect in some carriersof factor V Leiden. This view is supported by the observationthat in small series of patients with venous thrombosis andinherited thrombophilia, patients who had the G20210A prothrombinmutation had a higher risk of recurrence than those with a singlethrombophilic trait.¹⁴^,¹⁷

To evaluate the risk of recurrent deep venous thrombosis amongpatients with factor V Leiden alone or in association with theG20210A prothrombin mutation, we carried out a retrospectivecohort study. None of the patients had other risk factors forthrombosis, such as deficiencies of naturally occurring coagulationinhibitors, cancer, or myeloproliferative or autoimmune diseases.Although hyperhomocysteinemia has been reported as an importantsynergistic risk factor for deep venous thrombosis in patientswith factor V Leiden,²⁶ we chose not to include it among theexclusion criteria, because the retrospective nature of ourstudy and the possible changes in the homocysteine levels asa result of changes in dietary habits during the observationperiod might have produced a misleading classification of thepatients.

Patients who had only factor V Leiden had a risk of recurrentdeep venous thrombosis that was nearly identical to that amongpatients with neither mutation, irrespective of the outcomeanalyzed (any type of recurrence, spontaneous recurrence, orspontaneous recurrence after either a spontaneous first episodeor an episode due to known risk factors). The presence of bothfactor V Leiden and the G20210A prothrombin mutation increasedthe risk of recurrent deep venous thrombosis by a factor of2.6 and the risk of a spontaneous recurrence by a factor of3.7, as compared with the risk among patients who were heterozygousfor factor V Leiden alone. The relative risk of recurrent deepvenous thrombosis among carriers of both mutations, as comparedwith carriers of factor V Leiden alone, was not significantlyincreased when the first episode occurred in the presence ofa known risk factor.

We do not know whether the increased risk of recurrence amongheterozygous carriers of factor V Leiden and the G20210A prothrombinmutation is due to an interaction between the two mutationsor simply to the presence of the mutant prothrombin gene. Thelatter possibility is not supported by the results of two recentprospective studies, which failed to find an increased riskof recurrent deep venous thrombosis in association with theG20210A prothrombin mutation.⁸^,²⁷

Although we studied a selected group of patients, our resultscan be applied to the majority of patients with factor V Leiden(with or without the G20210A prothrombin mutation) and a previousepisode of deep venous thrombosis. In our initial retrospectivecohort of 624 consecutive patients, the prevalence of heterozygosityfor factor V Leiden was 21 percent, in close agreement withprevious data obtained in consecutive patients with deep venousthrombosis.² In our cohort, a large fraction of first eventswas associated with oral-contraceptive use or pregnancy or recentchildbirth, yet when the analysis was restricted to male patientsor to patients who had had a spontaneous first episode of deepvenous thrombosis, there was a low risk of recurrence associatedwith the presence of factor V Leiden alone, as compared withthe absence of both mutations.

The retrospective nature of our study and the use of recurrenceof deep venous thrombosis as the primary outcome may have ledto bias. The diagnosis of a first episode of deep venous thrombosisor recurrence was made by the attending hospital physiciansbefore the patients were referred to the thrombosis centers,and each episode was validated by the staff members of the centersbefore laboratory screening was conducted, so that the interviewerswere unaware of the genotype of the patients. Moreover, theperiod after referral to the centers was not considered, becausepatients with a diagnosis of inherited thrombophilia were likelyto be observed carefully for the onset of recurrent deep venousthrombosis, whereas patients with no identified cause of thrombosisin many cases had no further contact with the centers. Thus,it is unlikely that the rate of recurrence was overestimatedin patients with mutations causing thrombophilia. A number ofrecurrences may have been missed because of the retrospectiveevaluation of medical records and because episodes were countedas recurrent only in the presence of objective documentation.However, there is no reason to think that the pattern of underestimationshould have differed among the three groups.

From a practical point of view, our findings suggest that heterozygouscarriers of factor V Leiden with no additional thrombophilictraits should not receive lifelong anticoagulation after a firstepisode of deep venous thrombosis and that they should be treatedlike patients with no known mutations. This suggestion is alsosupported by a recent study of the optimal duration of anticoagulanttreatment after a spontaneous first episode of deep venous thrombosis.²⁵That study failed to find an association between factor V Leidenand recurrent thromboembolism. Our results also support theuse of thorough screening for thrombophilia in patients withdeep venous thrombosis, because a finding of heterozygosityfor both factor V Leiden and the G20210A prothrombin mutationshould prompt lifelong treatment with oral anticoagulants. Sucha recommendation appears to apply in particular to patientsin whom the first episode of deep venous thrombosis occurredin the absence of transient risk factors. Prospective cohortstudies are needed to confirm our findings.

Source Information

From the Department of Hematology, Catholic University, Rome (V.D., K.P., P.C., I.C., E.R., G.L.), and the Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Maggiore, University of Milan, Milan (I.M., P.M.M.) — both in Italy.

Address reprint requests to Dr. De Stefano at the Istituto Semeiotica Medica, Università Cattolica, Largo Gemelli 8, 00168 Rome, Italy.

References

Bertina RM, Koeleman BPC, Koster T, et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994;369:64-67. [CrossRef][Medline]
De Stefano V, Chiusolo P, Paciaroni K, Leone G. Epidemiology of factor V Leiden: clinical implications. Semin Thromb Hemost 1998;24:367-379. [Medline]
Rosendaal FR, Koster T, Vandenbroucke JP, Reitsma PH. High risk of thrombosis in patients homozygous for factor V Leiden. Blood 1995;85:1504-1508. [Free Full Text]
Ridker PM, Miletich JP, Stampfer MJ, Goldhaber SZ, Lindpaintner K, Hennekens CH. Factor V Leiden and risks of recurrent idiopathic venous thromboembolism. Circulation 1995;92:2800-2802. [Free Full Text]
Simioni P, Prandoni P, Lensing AWA, 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;336:399-403. [Free Full Text]
Rintelen C, Pabinger I, Knobl P, Lechner K, Mannhalter C. Probability of recurrence of thrombosis in patients with and without factor V Leiden. Thromb Haemost 1996;75:229-232. [Medline]
Eichinger S, Pabinger I, Stumpflen A, et al. The risk of recurrent venous thromboembolism in patients with and without factor V Leiden. Thromb Haemost 1997;77:624-628. [Medline]
Lindmarker P, Schulman S, Sten-Linder M, et al. The risk of recurrent venous thromboembolism in carriers and non-carriers of the G1691A allele in the coagulation factor V gene and the G20210A allele in the prothrombin gene. Thromb Haemost 1999;81:684-689. [Medline]
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. [Free Full Text]
Rosendaal FR, Doggen CJM, Zivelin A, et al. Geographic distribution of the 20210 G to A prothrombin variant. Thromb Haemost 1998;79:706-708. [Medline]
Hillarp A, Zoller B, Svensson PJ, Dahlback B. The 20210 A allele of the prothrombin gene is a common risk factor among Swedish outpatients with verified deep venous thrombosis. Thromb Haemost 1997;78:990-992. [Medline]
Leroyer C, Mercier B, Oger E, et al. Prevalence of the 20210 A allele of the prothrombin gene in venous thromboembolism patients. Thromb Haemost 1998;80:49-51. [Medline]
Margaglione M, Brancaccio V, Giuliani N, et al. Increased risk for venous thrombosis in carriers of the prothrombin G $->$ A²⁰²¹⁰ gene variant. Ann Intern Med 1998;129:89-93. [Free Full Text]
De Stefano V, Chiusolo P, Paciaroni K, et al. Prevalence of the factor II G20210A mutation in symptomatic patients with inherited thrombophilia. Thromb Haemost 1998;80:342-343. [Medline]
Ehrenforth S, Ludwig G, Klinke S, Krause M, Scharrer I, Nowak-Gottl 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. [Free Full Text]
Zoller B, Svensson PJ, Dahlback B, Hillarp A. The A20210 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. [Free Full Text]
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]
De Stefano V, Finazzi G, Mannucci PM. Inherited thrombophilia: pathogenesis, clinical syndromes, and management. Blood 1996;87:3531-3544. [Free Full Text]
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457-81.
Simon R. Confidence intervals for reporting results of clinical trials. Ann Intern Med 1986;105:429-435.
Prandoni P, Lensing AWA, Cogo A, et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med 1996;125:1-7. [Free Full Text]
Lane DA, Mannucci PM, Bauer KA, et al. Inherited thrombophilia. Thromb Haemost 1996;76:824-834. [Erratum, Thromb Haemost 1997;77:1047.] [Medline]
Guidelines on oral anticoagulation: third edition. Br J Haematol 1998;101:374-387. [CrossRef][Medline]
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]
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. [Free Full Text]
Ridker PM, Hennekens CH, Selhub J, Miletich JP, Malinow MR, Stampfer MJ. Interrelation of hyperhomocyst(e)inemia, factor V Leiden, and risk of future venous thromboembolism. Circulation 1997;95:1777-1782. [Free Full Text]
Eichinger S, Minar E, Hirschl M, et al. The risk of early recurrent venous thromboembolism after oral anticoagulant therapy in patients with the G20210A transition in the prothrombin gene. Thromb Haemost 1999;81:14-17. [Medline]


	Abstract
	PDF


	Letters


	Add to Personal Archive
	Add to Citation Manager
	Notify a Friend
	E-mail When Cited


	PubMed Citation

Related Letters:

The Risk of Recurrent Deep Venous Thrombosis
van der Heijden J. F., Kraaijenhagen R. A., Büller H. R., De Stefano V., Martinelli I., Leone G., Mannucci P. M.
Extract | Full Text
N Engl J Med 2000; 342:214-215, Jan 20, 2000. Correspondence

This article has been cited by other articles:

Lijfering, W. M., Brouwer, J.-L. P., Veeger, N. J. G. M., Bank, I., Coppens, M., Middeldorp, S., Hamulyak, K., Prins, M. H., Buller, H. R., van der Meer, J. (2009). Selective testing for thrombophilia in patients with first venous thrombosis: results from a retrospective family cohort study on absolute thrombotic risk for currently known thrombophilic defects in 2479 relatives. Blood 113: 5314-5322 [Abstract] [Full Text]
Zhu, T., Martinez, I., Emmerich, J. (2009). Venous Thromboembolism: Risk Factors for Recurrence. Arterioscler. Thromb. Vasc. Bio. 29: 298-310 [Abstract] [Full Text]
Ferguson, J. L., Hennion, D. R. (2008). Portal Vein Thrombosis: An Unexpected Finding in a 28-Year-Old Male With Abdominal Pain. J Am Board Fam Med 21: 237-243 [Abstract] [Full Text]
Goldenberg, N. A. (2008). Thrombophilia States and Markers of Coagulation Activation in the Prediction of Pediatric Venous Thromboembolic Outcomes: A Comparative Analysis with Respect to Adult Evidence. ASH Education Book 2008: 236-244 [Abstract] [Full Text]
Prandoni, P., Noventa, F., Ghirarduzzi, A., Pengo, V., Bernardi, E., Pesavento, R., Iotti, M., Tormene, D., Simioni, P., Pagnan, A. (2007). The risk of recurrent venous thromboembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism. A prospective cohort study in 1,626 patients. haematol 92: 199-205 [Abstract] [Full Text]
Zheng, X., Li, W., Gu, J.-M., Qu, D., Ferrell, G. L., Esmon, N. L., Esmon, C. T. (2007). Effects of membrane and soluble EPCR on the hemostatic balance and endotoxemia in mice. Blood 109: 1003-1009 [Abstract] [Full Text]
Scarvelis, D., Wells, P. S. (2006). Diagnosis and treatment of deep-vein thrombosis.. CMAJ 175: 1087-1092 [Abstract] [Full Text]
Ho, W. K., Hankey, G. J., Quinlan, D. J., Eikelboom, J. W. (2006). Risk of recurrent venous thromboembolism in patients with common thrombophilia: a systematic review.. Arch Intern Med 166: 729-736 [Abstract] [Full Text]
Vossen, C. Y., Walker, I. D., Svensson, P., Souto, J. C., Scharrer, I., Preston, F. E., Palareti, G., Pabinger, I., van der Meer, F. J.M., Makris, M., Fontcuberta, J., Conard, J., Rosendaal, F. R. (2005). Recurrence Rate After a First Venous Thrombosis in Patients With Familial Thrombophilia. Arterioscler. Thromb. Vasc. Bio. 25: 1992-1997 [Abstract] [Full Text]
Davis, C. L., Delmonico, F. L. (2005). Living-Donor Kidney Transplantation: A Review of the Current Practices for the Live Donor. J. Am. Soc. Nephrol. 16: 2098-2110 [Abstract] [Full Text]
Christiansen, S. C., Cannegieter, S. C., Koster, T., Vandenbroucke, J. P., Rosendaal, F. R. (2005). Thrombophilia, Clinical Factors, and Recurrent Venous Thrombotic Events. JAMA 293: 2352-2361 [Abstract] [Full Text]
Nojima, J., Kuratsune, H., Suehisa, E., Iwatani, Y., Kanakura, Y. (2005). Acquired Activated Protein C Resistance Associated with IgG Antibodies against {beta}2-Glycoprotein I and Prothrombin as a Strong Risk Factor for Venous Thromboembolism. Clin. Chem. 51: 545-552 [Abstract] [Full Text]
Bank, I., Libourel, E. J., Middeldorp, S., van Pampus, E. C. M., Koopman, M. M. W., Hamulyak, K., Prins, M. H., van der Meer, J., Buller, H. R. (2004). 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 164: 1932-1937 [Abstract] [Full Text]
Buller, H. R., Agnelli, G., Hull, R. D., Hyers, T. M., Prins, M. H., Raskob, G. E. (2004). Antithrombotic Therapy for Venous Thromboembolic Disease: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 126: 401S-428S [Abstract] [Full Text]
Kearon, C. (2004). Long-Term Management of Patients After Venous Thromboembolism. Circulation 110: I-10-I-18 [Abstract] [Full Text]
Eichinger, S., Schonauer, V., Weltermann, A., Minar, E., Bialonczyk, C., Hirschl, M., Schneider, B., Quehenberger, P., Kyrle, P. A. (2004). Thrombin-activatable fibrinolysis inhibitor and the risk for recurrent venous thromboembolism. Blood 103: 3773-3776 [Abstract] [Full Text]
Humphries, S. E., Ridker, P. M., Talmud, P. J. (2004). Genetic Testing for Cardiovascular Disease Susceptibility: A Useful Clinical Management Tool or Possible Misinformation?. Arterioscler. Thromb. Vasc. Bio. 24: 628-636 [Abstract] [Full Text]
Caprini, J. A., Glase, C. J., Anderson, C. B., Hathaway, K. (2004). Laboratory Markers in the Diagnosis of Venous Thromboembolism. Circulation 109: I-4-I-8 [Abstract] [Full Text]
von Ahsen, N., Oellerich, M. (2004). The intronic prothrombin 19911A>G polymorphism influences splicing efficiency and modulates effects of the 20210G>A polymorphism on mRNA amount and expression in a stable reporter gene assay system. Blood 103: 586-593 [Abstract] [Full Text]
McBane, R. D. II (2003). Genetically Determined Procoagulant States and Heparin Use. SEMIN CARDIOTHORAC VASC ANESTH 7: 427-442 [Abstract]
Frazee, L. A, Chomo, D. L (2003). Duration of Anticoagulant Therapy After Initial Idiopathic Venous Thromboembolism. The Annals of Pharmacotherapy 37: 1489-1496 [Abstract] [Full Text]
Heit, J. A. (2003). The Potential Role of Direct Thrombin Inhibitors in the Prevention and Treatment of Venous Thromboembolism. Chest 124 : 40S-48S [Abstract] [Full Text]
Eichinger, S., Minar, E., Bialonczyk, C., Hirschl, M., Quehenberger, P., Schneider, B., Weltermann, A., Wagner, O., Kyrle, P. A. (2003). D-Dimer Levels and Risk of Recurrent Venous Thromboembolism. JAMA 290: 1071-1074 [Abstract] [Full Text]
Schulman, S. (2003). Care of Patients Receiving Long-Term Anticoagulant Therapy. NEJM 349: 675-683 [Full Text]
Palareti, G., Legnani, C., Cosmi, B., Valdre, L., Lunghi, B., Bernardi, F., Coccheri, S. (2003). Predictive Value of D-Dimer Test for Recurrent Venous Thromboembolism After Anticoagulation Withdrawal in Subjects With a Previous Idiopathic Event and in Carriers of Congenital Thrombophilia. Circulation 108: 313-318 [Abstract] [Full Text]
Anderson, F. A. Jr., Spencer, F. A. (2003). Risk Factors for Venous Thromboembolism. Circulation 107: I-9-16 [Abstract] [Full Text]
Erali, M., Schmidt, B., Lyon, E., Wittwer, C. (2003). Evaluation of Electronic Microarrays for Genotyping Factor V, Factor II, and MTHFR. Clin. Chem. 49: 732-739 [Abstract] [Full Text]
Ridker, P. M, Goldhaber, S. Z., Danielson, E., Rosenberg, Y., Eby, C. S., Deitcher, S. R., Cushman, M., Moll, S., Kessler, C. M., Elliott, C. G., Paulson, R., Wong, T., Bauer, K. A., Schwartz, B. A., Miletich, J. P., Bounameaux, H., Glynn, R. J., the PREVENT Investigators, (2003). Long-Term, Low-Intensity Warfarin Therapy for the Prevention of Recurrent Venous Thromboembolism. NEJM 348: 1425-1434 [Abstract] [Full Text]
Eckman, M. H., Erban, J. K., Singh, S. K., Kao, G. S. (2003). Screening for the Risk for Bleeding or Thrombosis. ANN INTERN MED 138: W-15-W-24 [Abstract] [Full Text]
Deitcher, S. R, Gomes, M. P. (2003). Hypercoagulable state testing and malignancy screening following venous thromboembolic events. Vasc Med 8: 33-46 [Abstract]
Crowther, M. A., Kelton, J. G. (2003). Congenital Thrombophilic States Associated with Venous Thrombosis: A Qualitative Overview and Proposed Classification System. ANN INTERN MED 138: 128-134 [Abstract] [Full Text]
Schafer, A. I., Levine, M. N., Konkle, B. A., Kearon, C. (2003). Thrombotic Disorders: Diagnosis and Treatment. ASH Education Book 2003: 520-539 [Abstract] [Full Text]
Eichinger, S., Weltermann, A., Mannhalter, C., Minar, E., Bialonczyk, C., Hirschl, M., Schonauer, V., Lechner, K., Kyrle, P. A. (2002). The Risk of Recurrent Venous Thromboembolism in Heterozygous Carriers of Factor V Leiden and a First Spontaneous Venous Thromboembolism. Arch Intern Med 162: 2357-2360 [Abstract] [Full Text]
Evans, J. G., Lee-Tataseo, C. (2002). Determination of the Factor V Leiden Single-Nucleotide Polymorphism in a Commercial Clinical Laboratory by Use of NanoChip Microelectronic Array Technology. Clin. Chem. 48: 1406-1411 [Abstract] [Full Text]
Burke, W., Atkins, D., Gwinn, M., Guttmacher, A., Haddow, J., Lau, J., Palomaki, G., Press, N., Richards, C. S., Wideroff, L., Wiesner, G. L. (2002). Genetic Test Evaluation: Information Needs of Clinicians, Policy Makers, and the Public. Am J Epidemiol 156: 311-318 [Abstract] [Full Text]
Joffe, H. V, Goldhaber, S. Z (2002). Laboratory thrombophilias and venous thromboembolism. Vasc Med 7: 93-102 [Abstract]
Eckman, M. H., Singh, S. K., Erban, J. K., Kao, G. (2002). Testing for Factor V Leiden in Patients with Pulmonary or Venous Thromboembolism: A Cost-Effectiveness Analysis. Med Decis Making 22: 108-124 [Abstract]
Rosendaal, F.R., Helmerhorst, F.M., Vandenbroucke, J.P. (2002). Female Hormones and Thrombosis. Arterioscler. Thromb. Vasc. Bio. 22: 201-210 [Abstract] [Full Text]
Bauer, K. A., Rosendaal, F. R., Heit, J. A. (2002). Hypercoagulability: Too Many Tests, Too Much Conflicting Data. ASH Education Book 2002: 353-368 [Abstract] [Full Text]
Herrington, D. M., Klein, K. P. (2001). Genome and Hormones: Gender Differences in Physiology: Invited Review: Pharmacogenetics of estrogen replacement therapy. J. Appl. Physiol. 91: 2776-2784 [Abstract] [Full Text]
Thomas, R. H. (2001). Hypercoagulability Syndromes. Arch Intern Med 161: 2433-2439 [Abstract] [Full Text]
Bauer, K. A. (2001). The Thrombophilias: Well-Defined Risk Factors with Uncertain Therapeutic Implications. ANN INTERN MED 135: 367-373 [Abstract] [Full Text]
Mira, Y., Todoli, J., Alonso, R., Mico, M. L., Vaya, A., Ferrando, F., Estelles, A., Villa, P., Aznar, J. (2001). Factor V Leiden and Prothrombin G20210A in Relation to Arterial and/or Vein Rethrombosis: Two Cases. CLIN APPL THROMB HEMOST 7: 234-237 [Abstract]
Marchetti, M., Quaglini, S., Barosi, G. (2001). Cost-effectiveness of screening and extended anticoagulation for carriers of both factor V Leiden and prothrombin G20210A. QJM 94: 365-372 [Abstract] [Full Text]
CHAK, M, WALLACE, G R, GRAHAM, E M, STANFORD, M R (2001). Thrombophilia: genetic polymorphisms and their association with retinal vascular occlusive disease. Br J Ophthalmol 85: 883-886 [Full Text]
Federman, D. G., Kirsner, R. S. (2001). An Update on Hypercoagulable Disorders. Arch Intern Med 161: 1051-1056 [Abstract] [Full Text]
Seligsohn, U., Lubetsky, A. (2001). Genetic Susceptibility to Venous Thrombosis. NEJM 344: 1222-1231 [Full Text]
Nowak-Gottl, U., Junker, R., Kreuz, W., von Eckardstein, A., Kosch, A., Nohe, N., Schobess, R., Ehrenforth, S. (2001). Risk of recurrent venous thrombosis in children with combined prothrombotic risk factors. Blood 97: 858-862 [Abstract] [Full Text]
Vaya, A., Todoli, J., Ricart, J., Estelles, A., Mira, Y., Villa, P., Calabuig, J. R., Aznar, J. (2001). Upper Extremity Deep Vein Thrombosis in a Young Patient Double Heterozygous for Factor V Leiden and Prothrombin G20210A Mutation. CLIN APPL THROMB HEMOST 7: 72-74 [Abstract]
Miles, J. S., Miletich, J. P., Goldhaber, S. Z., Hennekens, C. H., Ridker, P. M. (2001). G20210A mutation in the prothrombin gene and the risk of recurrent venous thromboembolism. J Am Coll Cardiol 37: 215-218 [Abstract] [Full Text]
Cui, J., Eitzman, D. T., Westrick, R. J., Christie, P. D., Xu, Z. J., Yang, A. Y., Purkayastha, A. A., Yang, T. L., Metz, A. L., Gallagher, K. P., Tyson, J. A., Rosenberg, R. D., Ginsburg, D. (2000). Spontaneous thrombosis in mice carrying the factor V Leiden mutation. Blood 96: 4222-4226 [Abstract] [Full Text]
Douketis, J. D., Foster, G. A., Crowther, M. A., Prins, M. H., Ginsberg, J. S. (2000). Clinical Risk Factors and Timing of Recurrent Venous Thromboembolism During the Initial 3 Months of Anticoagulant Therapy. Arch Intern Med 160: 3431-3436 [Abstract] [Full Text]
Sykes, T C F, Fegan, C, Mosquera, D (2000). Thrombophilia, polymorphisms, and vascular disease. Mol. Pathol. 53: 300-306 [Abstract] [Full Text]
Simioni, P., Prandoni, P., Lensing, A. W. A., Manfrin, D., Tormene, D., Gavasso, S., Girolami, B., Sardella, C., Prins, M., Girolami, A. (2000). 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 96: 3329-3333 [Abstract] [Full Text]
Solymoss, S. (2000). Risk factors for thromboembolism: pathophysiology and detection. CMAJ 163: 991-994 [Full Text]
Kyrle, P. A., Minar, E., Hirschl, M., Bialonczyk, C., Stain, M., Schneider, B., Weltermann, A., Speiser, W., Lechner, K., Eichinger, S. (2000). High Plasma Levels of Factor VIII and the Risk of Recurrent Venous Thromboembolism. NEJM 343: 457-462 [Abstract] [Full Text]
Castoldi, E., Simioni, P., Kalafatis, M., Lunghi, B., Tormene, D., Girelli, D., Girolami, A., Bernardi, F. (2000). Combinations of 4 mutations (FV R506Q, FV H1299R, FV Y1702C, PT 20210G/A) affecting the prothrombinase complex in a thrombophilic family. Blood 96: 1443-1448 [Abstract] [Full Text]
Madonna, P., De Stefano, V., Coppola, A., Albisinni, R., Cerbone, A. M. (2000). G20210A PRTH Gene Mutation and Other Trombophilic Polymorphisms in Patients With Cerebral Vein Thrombosis. Stroke 31 : 1785-1790 [Full Text]
Nguyen, A. (2000). State-of-the-Art Review : Review and Management of Patients With the Prothrombin G20210A Polymorphism. CLIN APPL THROMB HEMOST 6: 94-99 [Abstract]
Lane, D. A., Grant, P. J. (2000). Role of hemostatic gene polymorphisms in venous and arterial thrombotic disease. Blood 95: 1517-1532 [Full Text]
van der Heijden, J. F., Kraaijenhagen, R. A., Buller, H. R., De Stefano, V., Martinelli, I., Leone, G., Mannucci, P. M. (2000). The Risk of Recurrent Deep Venous Thrombosis. NEJM 342: 214-215 [Full Text]
Topol, E. J., McCarthy, J., Gabriel, S., Moliterno, D. J., Rogers, W. J., Newby, L. K., Freedman, M., Metivier, J., Cannata, R., O'Donnell, C. J., Kottke-Marchant, K., Murugesan, G., Plow, E. F., Stenina, O., Daley, G. Q. (2001). Single Nucleotide Polymorphisms in Multiple Novel Thrombospondin Genes May Be Associated With Familial Premature Myocardial Infarction. Circulation 104: 2641-2644 [Abstract] [Full Text]
Eitzman, D. T., Westrick, R. J., Bi, X., Manning, S. L., Wilkinson, J. E., Broze, G. J., Ginsburg, D. (2002). Lethal Perinatal Thrombosis in Mice Resulting From the Interaction of Tissue Factor Pathway Inhibitor Deficiency and Factor V Leiden. Circulation 105: 2139-2142 [Abstract] [Full Text]

Comments and questions? Please contact us.