CLINICAL UTILITY

Question 26. What is the natural history of the disorder?

The following paragraphs describe major complications that can occur after a first episode of deep venous thrombosis, including death from a pulmonary embolism, the post-thrombotic syndrome, recurrent episodes of thrombosis, and side effects of treatment, such as major hemorrhage. 

Pulmonary embolism
The International Cooperative Pulmonary Embolism Registry (Goldhaber et al., 1999) found an overall three-month mortality of 17.4 percent for all patients with pulmonary embolism, with 45 percent of deaths ascribed directly to the embolic event.  Simmoneau et al. (1997) and the Columbus (1997) investigators found lower rates of 1.0 percent and 2.2 percent, respectively.  However, neither article included individuals with massive pulmonary embolism requiring thrombolytic treatment.

It is now believed that the prevalence of the factor V Leiden mutation is higher in patients with uncomplicated deep venous thrombosis (i.e., without pulmonary embolism) than in patients with pulmonary embolism (with or without deep venous thrombosis) (Manten et al 1996; Martinelli et al., 1997).  Bounameaux (2000) performed a meta-analysis that included the studies described above and came to the same conclusion as that reached in the separate studies.  Several possible explanations are described for the difference in prevalence of the factor V Leiden mutation between patients with pulmonary embolism and patients with uncomplicated deep venous thrombosis.  One explanation might be that all patients with pulmonary embolism are consecutive (unselected), while the patients with deep venous thrombosis come from specialized centers.  However, this difference in prevalence was confirmed by several studies, making this explanation unlikely.  Possibly, the clot in patients with factor V Leiden is more stable and more adherent to the vessel wall, thus leading less often to pulmonary embolism.  In vitro observations show that, in factor V Leiden carriers, the thrombus occurs less often in the iliofemoral vein.  Also, the thrombus is smaller in patients with factor V Leiden.

Margaglione et al. (2000) found that the frequency of the prothrombin 20210A mutation was the same among individuals with uncomplicated deep venous thrombosis and those with deep venous thrombosis and pulmonary embolism, whereas the frequency was lower for patients with pulmonary embolism only.

Post-thrombotic syndrome
The post-thrombotic syndrome occurs as a result of venous hypertension due to outflow obstruction and damage to the venous valves.  Clinical characteristics are leg pain, skin changes and swelling.  Leg ulcers are one of the most serious complications of post-thrombotic syndrome.  Prandoni et al. (1996) found a cumulative incidence of the post-thrombotic syndrome of 22.8 percent after two years, 28 percent after five years, and 29.1 percent after eight years.  Brandjes et al. (1996) found that, in patients with a first episode of proximal deep venous thrombosis, the cumulative incidence of mild-to-moderate post-thrombotic syndrome is about 50 percent, and of severe post-thrombotic syndrome 23 percent.  The post-thrombotic syndrome is more likely to occur after recurrent episodes of deep venous thrombosis and can have great impact on quality of life.  A study by Maessen-Visch et al. (1999) showed a significantly increased prevalence of the factor V Leiden mutation (23 percent) in patients with venous leg ulcers compared to a control group (7.5 percent).  Ninety-one percent of the patients with the factor V Leiden mutation had a history of venous thromboembolism compared with 48 percent of the controls, suggesting that patients with venous thromboembolism and the factor V Leiden mutation have an increased risk of developing leg ulcers.

Recurrence risk
As shown in Question 21, few studies are available on the incidence of recurrence within five years after the first thrombosis.  Rates vary around 20 percent for recurrent venous thrombosis within 10 years after the first event. 

Bleeding risk
The risk of major bleeding due to anticoagulant treatment is 1-2.7 percent per year, of which one in five cases is fatal (Van der Meer et al., 1993; Palareti et al., 1996).  The risk of bleeding complications rises significantly with age and the achieved International Normalized Ratio (Hirsh et al.,2002).

1. Bounameaux H.  2000.  Factor V Leiden paradox: risk of deep-vein thrombosis but not pulmonary embolism.  Lancet  356:182-183.
   
2. Brandjes DPM, Büller HR, Heijboer H, Huisman MV, de Rijk M, Jagt H, et al.  1997.  Randomized trial of effect of compression stockings in patients with symptomatic proximal-vein thrombosis.  Lancet  349:759-762.
3. Goldhaber SZ, Visani L, De Rosa M.  1999.  Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER).  Lancet  353:1686-1689.
4. Hirsh J, Lee AYY.  2002.  How we diagnose and treat deep vein thrombosis.  Blood  99:3102-3110.
   
5. Low-molecular-weight heparin in the treatment of patients with venous thromboembolism.  The Columbus Investigators.  1997.  N Engl J Med  337:657-662.
   
6. Maessen-Visch MB, Hamulyak K, Tazelaar DJ, et al. The prevalence of factor V Leiden mutation in patients with leg ulcers and venous insufficiency. Arch Dermatol 1999;135:41-44.
   
7. Manten B, Westendorp RGJ, Koster T, Reitsma PH, Rosendaal FR.  1996.  Risk factor profiles in patients with different clinical manifestations of venous thromboembolism: a focus on the factor V Leiden mutation.  Thromb Haemost  76:510-513.
   
8. Margaglione M, Brancaccio V, De Lucia D, Martinelli I, Ciampa A, Grandone E, Di Minno G.  2000.  Inherited thrombophilic risk factors and venous thromboembolism: distinct role in peripheral deep venous thrombosis and pulmonary embolism.  Chest  118:1405-1411.
   
9. Martinelli I, Cattaneo M, Panzeri D, Mannucci PM.  1997.  Low prevalence of factor V:Q506 in 41 patients with isolated pulmonary embolism.  Thromb Haemost  77:440-443.
   
10. Palareti G, Leali N, Coccheri S, Poggi M, Manotti C, D’Angeloa A, et al.  1996.  Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT).  Italian Study on Complications of Oral Anticoagulant Therapy.  Lancet  348:423-428.
    
11. Prandoni P, Lensing A, Cogo A, Cuppini S, Villalta S, Carta M, et al.  1996.  The long-term clinical course of acute deep venous thrombosis.  Ann Intern Med  125:1-7.
    
12. van der Meer FJM, Rosendaal FR, Vandenbroucke JP, Briet E.  1993.  Bleeding complications in anticoagulant therapy.  An analysis of risk factors.  Arch Intern Med  153:1557-1562.
    
13. Simonneau G, Sors H, Charbonnier B, Page Y, Laaban JP, Azarian R, et al.  1997.  A comparison of low molecular-weight heparin with unfractionated heparin for acute pulmonary embolism.  The THESEE Study Group.  Tinzaparine ou Heparine Standard: Evaluations dans l’Embolie Pulmonaire.  N Engl J Med  337:663-669.

CLINICAL UTILITY

Question 27: What is the impact of a positive (or negative) test on patient care?

There are no conclusive studies addressing the question of the optimal duration of anticoagulation among homozygous individuals with the factor V Leiden mutation or among individuals either homozygous or heterozygous for the prothrombin 20210A mutation.  Sarasin et al. (1998) developed a decision analysis model to determine the risks and benefits of stopping oral anticoagulation after three months, with re-initiation only after recurrent thrombosis, versus extending oral anticoagulation up to one to five years.  The hypothetical cohort consisted of 1,000 carriers of factor V Leiden recovering from a first episode of deep vein thrombosis in the lower limbs.  Even with using a best case scenario favoring prolonged anticoagulation (at least beyond one year), their analysis suggests that, among factor V Leiden carriers, the number of major hemorrhages induced by anticoagulants exceeds the number of clinical pulmonary emboli prevented over the entire range of duration of anticoagulation.  However, the number of recurrent deep vein thrombi prevented by prolonged treatment widely exceeds the number of iatrogenic induced hemorrhages.

A few studies provide reliable estimates on the risk of recurrent episodes of venous thrombosis in different treatment settings.  They concluded that six weeks of oral anticoagulation is sufficient in isolated calf deep vein thrombosis (Pinede et al., 2001), and that four weeks (Levine et al., 1995), six weeks (Schulman et al., 1995) and three months (Pinede et al., 2001) of treatment is sufficient for patients with temporary risk factors.  Patients with persisting risk factors may require six months of treatment (Schulman et al., 1995), or at least more than three months of treatment (Levine et al., 1995; Kearon et al., 1999).

We find a mean incidence of recurrent venous thrombosis in factor V Leiden carriers of 4.8 percent per year in five studies, with three finding no significant increase over patients without the mutation.  The mean incidence of recurrent venous thrombosis in prothrombin 20210A carriers per year is 4.1 percent with two out of the four eligible studies showing no significant difference in the recurrence risk between patients with and without the prothrombin 20210A mutation (Table 4, Questions 18 and 19).  In one of the studies with a significant difference found, individuals with the factor V Leiden mutation were not excluded from the calculation (Miles et al., 2001).  Thus, from the results in this report, we can conclude that the risk of a recurrent venous thrombosis is not different among individuals who carry either the factor V Leiden or the prothrombin mutation, as opposed to individuals without these mutations.  This implies that the outcome of these genetic tests (i.e. either a positive or a negative test) should not influence patient care.  However, other studies are needed to confirm this.

Impact of a negative test
A negative test result could lead to under-treatment and an increased prevalence of recurrent thrombotic episodes among individuals who are found not to have one of the mutations after an initial episode of venous thrombosis.

Recommendations regardless the outcome of a screening or diagnostic test
Brandjes et al. (1997) studied the effect of elastic stockings on the risk of developing post-thrombotic syndrome after a first episode of venous thrombosis in a randomized trial.  Patients with proximal vein thrombosis were randomized in a group with (n=96) and a group without elastic stockings (n=98).  Wearing elastic stockings for at least two years after the first thrombotic event reduced the risk of post thrombotic syndrome by 50 percent.  Venous ulceration was observed in four patients, one in the group wearing elastic stockings and three in the group without elastic stockings.  In this study, none of the patients was tested for the factor V Leiden mutation.  No difference in the rate of recurrent venous thrombosis was observed between the group wearing elastic stockings and the group that did not wear elastic stockings.

References

1. Brandjes DP, Büller HR, Heijboer H, Huisman MV, de Rijk M, Jagt H, et al.  1997.  Randomised trial of effect of compression stockings in patients with symptomatic proximal-vein thrombosis.  Lancet  349:759-762.
   
2. Kearon C, Gent M, Hirsh J, Weitz J, Kovacs JM, Anderson DR, et al.  1999.  A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism.  N Engl J Med  340:901-917.
   
3. Levine MN, Hirsch J, Gent M, Turpie GA, Weitz J, Ginsberg J, et al.  1995.  Optimal duration of oral anticoagulant therapy: a randomized trial comparing four weeks with three months of warfarin in patients with proximal deep vein thrombosis.  Thromb Haemost  74:606-611.
   
4. Miles JS, Miletich JP, Goldhaber SZ, Hennekens CH, Ridker PM.  2001.  G20210A mutation in the prothrombin gene and the risk of recurrent venous thrombosis.  J Am Coll Cardiol  37:215-218.
   
5. Pinede L, Ninet J, Duhaut P, Chabaud S, Demolombe-Rague S, Durieu I, et al.  2001.  Comparison of 3 and 6 months of oral anticoagulant therapy after a first episode of proximal deep vein thrombosis or pulmonary embolism and comparison of 6 and 12 weeks of therapy after isolated calf deep vein thrombosis.  Circulation  103:2453-2460.
   
6. Sarasin FP, Bounameaux H.  1998.  Decision analysis model of prolonged oral anticoagulant treatment in factor V Leiden carriers with first episode of deep vein thrombosis.  BMJ  316:95-99.
   
7. Schulman S, Rhedin A, Lindmarker P, Carlsson A, Larfars G, Nicol P, et al.  1995.  A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism.  Duration of Anticoagulation Trial Study Group.  N Engl J Med  332:1661-1665.

CLINICAL UTILITY

Question 28: If applicable, are diagnostic tests available?

No diagnostic tests are available.

CLINICAL UTILITY

Question 29: Is there an effective remedy, acceptable action or other measurable benefit?

In patients receiving anticoagulant therapy, the likelihood of a recurrent episode of venous thrombosis is reduced, if the international normalized ratio (INR) is in the therapeutic range, although patients with advanced malignancy or anti-phospholipid antibody syndrome are at increased risk for recurrence despite having a therapeutic INR value (Hirsh et al., 2002).  However, as the risk of bleeding in general during therapy is high, lifelong treatment with anticoagulants is not generally recommended after a first episode of venous thrombosis.

References

1. Hirsh J, Lee AYY.  2002.  How we diagnose and treat deep vein thrombosis.  Blood  99:3102-3110.