The incidence of recurrent venous thromboembolism in carriers of factor V Leiden is related to concomitant thrombophilic disorders

Abstract Background: Previous estimates of the rate of recurrent venous thromboembolism (VTE) during pregnancy in women with a history of VTE have vary between 0 and 13%. Therefore, the decision to administer or withhold heparin - especially in the antepartum period - has been discussed controversial. In a recent study by Brill-Edwards et al. (N Engl J Med2000;343:1439–44), no recurrences of VTE occurred in women (n=44) who had a previous episode of thrombosis that was associated with a temporary risk factor and who also had no evidence of thrombophilia. Based on these results, antepartum heparin prophylaxis is not routinely recommended in women without thrombophilia whose previous episode of thrombosis was associated with a temporary risk factor (ACCP guidelines 2004). The objective of our study was to evaluate the risk of recurrent pregnancy-associated thrombosis in women with a history of VTE. Materials and Methods: We retrospectively studied 198 women with at least one pregnancy (275 pregnancies in total) after a one previous episode of VTE. Sixty-three women (81 pregnancies) were excluded from the analysis because of antepartum heparin prophylaxis. Results: In the subgroup of women without heparin prophylaxis (n=135), 15 (7.7%) thromboembolic events occurred antepartum in 194 pregnancies. Further subgroup analysis, stratified for the nature of first VTE, gave the following number of antepartum VTE per number of pregnancies: 2 VTE/19 pregnancies (10.5%) in 14 women (first VTE: immobilization), 4 VTE/33 pregnancies (12.1%) in 24 women (first VTE: surgery), 5 VTE/69 pregnancies (7.2%) in 46 women (first VTE: oral contraception), 2 VTE/58 pregnancies (3.4%) in 40 women (first VTE: pregnancy), 2 VTE/15 pregnancies (13%) in 11 women (first VTE: idiopathic). Nine of the 15 women with VTE (7/13 women with first VTE triggered by temporary risk factor; 2/2 women with first idiopathic VTE) had a heterozygous factor V Leiden G1691A or prothrombin G20210A gene mutation. In the postpartum period, 16 VTE in 194 pregnancies occurred after live birth in the 135 women without heparin prophylaxis. Nine of these 16 women had a heterozygous FVL or prothrombin G20210A gene mutation. In Conclusion, the risk of recurrent antepartum VTE was similar in women with and without factor V Leiden G1691A or the prothrombin G20210A gene mutation and did not differ between women with first VTE triggered by a transient risk factor or an idiopathic first VTE. In addition to recommended postpartum heparin prophylaxis, our data support the need for a routine antepartum prophylaxis in women without thrombophilia whose previous episode of thrombosis was associated with a temporary risk factor.

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Influence of thrombophilia on risk of recurrent venous thromboembolism while on warfarin: results from a randomized trial

Blood ◽

10.1182/blood-2008-06-163279 ◽

2008 ◽

Vol 112 (12) ◽

pp. 4432-4436 ◽

Cited By ~ 71

Author(s):

Clive Kearon ◽

Jim A. Julian ◽

Michael J. Kovacs ◽

David R. Anderson ◽

Philip Wells ◽

...

Keyword(s):

Venous Thromboembolism ◽

Warfarin Therapy ◽

Factor V Leiden ◽

International Normalized Ratio ◽

Antiphospholipid Antibody ◽

Factor V ◽

Antithrombin Deficiency ◽

Recurrent Venous Thromboembolism ◽

Prothrombin Gene Mutation ◽

Recurrent Vte

Abstract We sought to determine whether thrombophilic defects increase recurrent venous thromboembolism (VTE) during warfarin therapy. Six hundred sixty-one patients with unprovoked VTE who were randomized to extended low-intensity (international normalized ratio [INR], 1.5-1.9) or conventional-intensity (INR, 2.0-3.0) anticoagulant therapy were tested for thrombophilia and followed for a mean of 2.3 years. One or more thrombophilic defects were present in 42% of patients. The overall rate of recurrent VTE was 0.9% per patient-year. Recurrent VTE was not increased in the presence of factor V Leiden (hazard ratio [HR], 0.7; 95% CI, 0.2-2.6); the 20210G>A prothrombin gene mutation (HR, 0); antithrombin deficiency (HR, 0); elevated factor VIII (HR, 0.7; 95% CI, 0.1-5.4); elevated factor XI (HR, 0.7; 95% CI, 0.1-5.0), or elevated homocysteine (HR, 0.7; 95% CI, 0.1-5.3), but showed a trend to an increase with an antiphospholipid antibody (HR, 2.9; 95% CI, 0.8-10.5). Compared with patients with no thrombophilic defects, the rate of recurrence was not increased in the presence of one (HR, 0.7; 95% CI, 0.2-2.3) or more than one (HR, 0.7; 95% CI, 0.2-3.4) defect. We conclude that single or multiple thrombophilic defects are not associated with a higher risk of recurrent VTE during warfarin therapy.

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Prothrombin Fragment F1+2 Is not Predictive for Recurrent Venous Thromboembolism

Thrombosis and Haemostasis ◽

10.1055/s-0038-1656062 ◽

1997 ◽

Vol 77 (05) ◽

pp. 0829-0833 ◽

Cited By ~ 19

Author(s):

P A Kyrle ◽

S Eichinger ◽

I Pabinger ◽

A Stümpflen ◽

M Hirschl ◽

...

Keyword(s):

Venous Thromboembolism ◽

Venous Thrombosis ◽

Protein C ◽

Oral Anticoagulants ◽

Factor V Leiden ◽

Factor V ◽

Recurrent Thrombosis ◽

Prothrombin Fragment ◽

Recurrent Venous Thromboembolism ◽

History Of

SummaryIt would be important to estimate in advance the risk of recurrent thrombosis. Deficiencies of antithrombin, protein C or protein S, or resistance to activated protein C are associated with a biochemically detectable prethrombotic state. It is thus far unknown whether in patients with a history of thromboembolism but without a defined clotting abnormality a heightened coagulation activation is detectable.We investigated the value of prothrombin fragment Fl+2 (FI+2) as a predictor of recurrent venous thromboembolism. Furthermore, we compared the Fl+2 levels of thrombosis patients without a defined clotting defect to those of Factor V Leiden patients with a history of venous thrombosis and to those of healthy controls. 180 patients without a defined clotting abnormality and 73 patients with Factor V Leiden were prospectively followed after discontinuation of oral anticoagulants for venous thrombosis and Fl+2 was measured at regular intervals.Recurrent venous thromboembolism occurred in 23 (9%) of the 253 patients. Before or at several time points after oral anticoagulants, no significant difference in Fl+2 levels was found in patients with and without recurrent thrombosis. Fl+2 levels at 3 weeks and prior to recurrence were not significantly different in both patient groups. Over a one-year observation period, Fl+2 levels of both patients with and without Factor V Leiden were higher than those of the controls. No difference in Fl+2 was seen between patients with and without Factor V Leiden.We conclude that monitoring of Fl+2 is not suitable for identification of individuals at risk of recurrent venous thrombosis. Permanent hemostatic system activation is detectable both in patients with a defined abnormality of the clotting system and in patients in whom a particular defect has not (yet) been identified.

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Factors That Predict The Risk Of Recurrent Venous Thromboembolism (VTE) In Patients With VTE And Factor V Leiden (FVL)

10.1164/ajrccm-conference.2010.181.1_meetingabstracts.a1932 ◽

2010 ◽

Author(s):

Francis Couturaud ◽

Elise Noel-Savina ◽

Nicolas Paleiron ◽

Gilles Quere ◽

Dominique Mottier ◽

...

Keyword(s):

Venous Thromboembolism ◽

Factor V Leiden ◽

Factor V ◽

Recurrent Venous Thromboembolism

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Long-term, low-dose warfarin among venous thrombosis patients with and without factor V Leiden mutation: rationale and design for the Prevention of Recurrent Venous Thromboembolism (PREVENT) trial

Vascular Medicine ◽

10.1177/1358836x9800300114 ◽

1998 ◽

Vol 3 (1) ◽

pp. 67-73 ◽

Cited By ~ 21

Author(s):

Paul M Ridker ◽

Keyword(s):

Venous Thromboembolism ◽

Venous Thrombosis ◽

Low Dose ◽

Factor V Leiden ◽

Factor V ◽

Factor V Leiden Mutation ◽

Dose Warfarin ◽

Recurrent Venous Thromboembolism ◽

Prevent Trial

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Risk of recurrent venous thromboembolism in patients with the factor V Leiden (FVR506Q) mutation: effect of warfarin and prediction by precipitating factors

British Journal of Haematology ◽

10.1046/j.1365-2141.1998.00632.x ◽

1998 ◽

Vol 100 (4) ◽

pp. 764-768 ◽

Cited By ~ 35

Author(s):

Caroline Baglin ◽

Karen Brown ◽

Roger Luddington ◽

Trevor Baglin ◽

Keyword(s):

Venous Thromboembolism ◽

Factor V Leiden ◽

Factor V ◽

Precipitating Factors ◽

Recurrent Venous Thromboembolism

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Prediction of Recurrent Venous Thromboembolism by Endogenous Thrombin Potential and D-Dimer

Clinical Chemistry ◽

10.1373/clinchem.2008.112243 ◽

2008 ◽

Vol 54 (12) ◽

pp. 2042-2048 ◽

Cited By ~ 82

Author(s):

Sabine Eichinger ◽

Gregor Hron ◽

Marietta Kollars ◽

Paul A Kyrle

Keyword(s):

Venous Thromboembolism ◽

Thrombin Generation ◽

Factor V Leiden ◽

Study Endpoint ◽

Factor V ◽

Risk Of Recurrence ◽

Endogenous Thrombin Potential ◽

Increased Risk ◽

Recurrent Venous Thromboembolism ◽

D Dimer

Abstract Background: Increased thrombin generation is associated with an increased risk of recurrent venous thromboembolism. We investigated the relation between endogenous thrombin potential (ETP) and risk of recurrent venous thromboembolism and evaluated whether prediction of recurrence can be improved by a combined analysis of ETP and D-dimer. Methods: We followed 861 patients with first spontaneous venous thromboembolism and determined ETP and D-dimer after discontinuation of anticoagulation. Patients with natural inhibitor deficiency, lupus anticoagulant, or cancer were excluded. The study endpoint was symptomatic recurrent venous thromboembolism. Results: One hundred thirty patients (15.1%) had recurrence. High ETP (≥100%) conferred a 1.6-fold increased risk of recurrence (95% CI 1.1–2.3) after adjustment for age, sex, factor V Leiden, factor II G20210A, and duration of anticoagulation. After adjustment for D-dimer, risk of recurrence remained significantly higher among patients with high ETP [hazard ratio 1.6 (95% CI 1.01–2.4)]. After adjustment for ETP, high D-dimer (≥0.5 mg/L) conferred a 1.8-fold (95% CI 1.1–2.8) increased risk of recurrence. Compared with patients with low ETP and low D-dimer, risk of recurrence was 2.8-fold (95% CI 1.5–5.3) higher among patients with both high ETP and high D-dimer after adjustment for potential confounders. Conclusions: ETP and D-dimer are independent predictors of recurrent venous thromboembolism. Assessing risk of recurrence can be optimized by combining these indicators of thrombin generation.

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Coexistence of Factor V Leiden and Factor II A20210 Mutations and Recurrent Venous Thromboembolism

Thrombosis and Haemostasis ◽

10.1055/s-0037-1614882 ◽

1999 ◽

Vol 82 (12) ◽

pp. 1583-1587 ◽

Cited By ~ 71

Author(s):

Giovanna D’Andrea ◽

Donatella Colaizzo ◽

Giuseppe Cappucci ◽

Annamaria del Popolo ◽

Vincenzo Brancaccio ◽

...

Keyword(s):

Venous Thromboembolism ◽

Antiphospholipid Antibodies ◽

Gene Mutations ◽

Factor V Leiden ◽

Factor V ◽

Factor Ii ◽

Recurrent Venous Thromboembolism ◽

Fv Leiden ◽

Gene Defects ◽

Work Up

SummaryPatients carrying the FV Leiden or the FII A20210 mutation have a high risk of venous thromboembolism. Among 542 patients with a documented diagnosis of deep venous thrombosis in one leg consecutively referred for a thrombophilic work-up, we have retrospectively assessed the rate of objectively documented previous recurrence in carriers of both FV Leiden and FII A20210 mutations. Eighty-two patients had experienced 115 episodes of recurrent venous thromboembolism. The rate of recurrent venous thromboembolism was 29.2% among subjects with and 14.5% in those without deficiencies of natural anticoagulant proteins (p = 0.055), and 24.6% among patients with and 14.0% in those without antiphospholipid antibodies (p = 0.036). The frequency of having a recurrent thromboembolism was 16.2%, 20.0%, and 36.4% among carriers of FV Leiden, FII A20210 mutation, or both gene defects, respectively, and 12.8% in subjects carrying neither mutation (p for trend = 0.004). When adjusted for age, sex, and thrombophilic risk factors, the rate was higher among patients with than in those without deficiencies of natural anticoagulant proteins (OR: 3.0; 95% CI: 1.2-7.5), aPL 2.5 (95% CI: 1.3-4.9), or both FV Leiden and FII A20210 gene mutations (OR 4.8; 95% CI: 1.9-12.2).The rate of previous recurrent venous thromboembolism was significantly higher in subjects carrying both FV Leiden and FII 20210 mutations and was comparable to that observed in subjects with deficiencies of natural anticoagulant proteins or antiphospholipid antibodies.

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