Factor V Leiden mutation

Abstract

Objective: To assess the risks and benefits of oral anticoagulant treatment extended beyond 3 months after a first episode of deep vein thrombosis in patients who carry factor V Leiden mutation. Such patients have over twice the risk of recurrence after the recommended treatment period, but more information is required before widespread genetic screening can be recommended. Design: A decision analysis Markov model (with data extracted form literature) representing the risks of developing symptomatic venous thromboembolism, the risks of major bleeding, and the efficacy of anticoagulant treatment. Subjects: A hypothetical cohort of 1000 carriers of factor V Leiden recovering from a first episode of deep vein thrombosis in the lower limbs. Main outcome measures: Risks and benefits of, firstly, stopping oral anticoagulation 3 months after first episode of thrombosis with reinitiation of treatment only after recurrent thrombosis and, secondly, extension of oral anticoagulation up to 1 to 5 years. Results: Despite consistent biases in favour of extended oral anticoagulation, analysis revealed that among factor V carriers the number of major haemorrhages induced by oral anticoagulants would exceed that of clinical pulmonary emboli prevented over the entire range of duration of anticoagulation (1 to 5 years). On the other hand, the number of recurrent deep vein thrombi prevented would exceed that of iatrogenic major bleedings. Conclusion: The lack of evidence of a net clinical benefit of prolonged oral anticoagulation, at least beyond 1 year, among patients recovering from acute deep vein thrombosis does not support the decision to promote widespread genetic screening programmes to detect the factor V mutation.

Introduction

A point mutation in which adenine is substituted for guanine at nucleotide 1691 in the gene coding for coagulation factor V results in the production of abnormal factor V (called factor V Leiden)[1] which is more resistant to inhibition by activated protein C[2] than the genuine factor V. This mutation is associated with a threefold[3] to sevenfold[4] increase in the risk of deep vein thrombosis. Because its prevalence is quite high in Western populations (about 5% in Europe with a maximum of 15% in southern Sweden), there is a large debate among specialists as to whether genetic screening is indicated.[5]

Before screening for any abnormality is advocated in more or less selected groups of symptomatic or asymptomatic patients, however, data should demonstrate that carriers of the mutation would benefit from the diagnosis. For example, women who carry the factor V Leiden mutation and use oral contraceptives have a more than 30-fold increased risk of thrombosis compared with women who are not carriers of the mutation and do not use oral contraceptives[6]; screening for the mutation, however, would deny effective contraception to a large number of women while preventing only a small number of deaths due to pulmonary emboli.[7] Similarly, the finding that factor V Leiden mutation is associated with a twofold risk of recurrent thrombosis,[8 9] a finding that has recently been challenged,[10] does not necessarily mean that patients who carry the mutation and present with acute deep vein thrombosis would benefit from more prolonged anticoagulation (some specialists advocate indefinite treatment) to prevent recurrent disease. This policy would imply the need for secondary screening programmes with factor V Leiden testing in all patients experiencing deep vein thrombosis. Ideally, the answer to that question should be derived from randomised trials comparing long term (but how long?) versus short term anticoagulation with adjusted dose oral anticoagulants in the secondary prevention of venous thromboembolism among patients heterozygous for factor V Leiden. Such trials with sufficiently large numbers of patients would be difficult to organise and their results would probably not be available for many months or even years. This prompted us to use a Markov decision analysis model explicitly considering the consequences of recurrent deep vein thrombosis and bleeding events and to quantify the risk-benefit trade offs for different durations of oral anticoagulant treatment in these patients at higher risk of recurrent thromboembolic events.

This kind of approach is particularly suited for assessing complex clinical issues by using the best available evidence from the literature. Moreover, sensitivity analyses allow one to establish how robust the results are by modifying the value of the critical variables. Finally, its conclusion may help investigators to select more carefully the clinical issues that have to be covered in clinical trials.

Methods

Decision tree

We considered this general example of the problem. A patient carrying the factor V Leiden mutation is recovering from deep vein thrombosis in the lower limb and is at increased risk of recurrent thromboembolism compared with a patient without the mutation. If the patient is given prolonged oral anticoagulants (beyond the usually recommended 3 month period) the risk of bleeding is increased, while that of recurrent deep vein thrombosis is decreased. Either kind of event can produce death, pulmonary embolism, or permanent morbidity. Should prolonged oral anticoagulation be given?

We used the D Maker 7.1 (Pratt Medical Group, Boston, Massachussets) decision analysis program to create a model representing and measuring the consequences of either stopping oral anticoagulation after 3 months with reinitiation of treatment only after a clinical recurrent deep vein thrombosis has occurred (triggered oral anticoagulation) or extending oral anticoagulation for up to 1, 2, 3, 4, or 5 years. We used a Markov simulation to model repetitive clinical events beyond the control of patient arid physician.[11] In a Markov process patients move between various health states depending on the clinical events modelled in the decision tree and the probability of these events.

At the beginning of the Markov simulation patients are well and are in one of two states: taking oral anticoagulants or not taking oral anticoagulants. In either case, several groups of events are possible: recurrent deep vein thrombosis, pulmonary embolism, major bleeding events, or different combinations of those events. Patients on anticoagulant treatment incur risks related to anticoagulation but the risks of recurrent deep vein thrombosis with or without pulmonary embolism are diminished by the efficacy of the treatment. When treatment is discontinued patients again incur risks of recurrent thromboembolism, whereas the risks related to anticoagulation become zero. Patients not taking oral anticoagulants are at increased risk of recurrent deep vein thrombi and subsequent pulmonary emboli. The occurrence of those events will prompt treatment with oral anticoagulants. We calculated the average value (expected utility) of each strategy by tracking the number of recurrent deep vein thrombi and clinical pulmonary emboli prevented and the number of major bleeding events induced in the two strategies.

Assumptions

In formulating our model, we made severe assumptions. Firstly, for patients taking oral anticoagulants we considered only the risks of major haemorrhagic events (intracranial, retroperitoneal, or those that resulted in admission to hospital, transfusion, or death). Secondly, we assumed that the occurrence of a major haemorrhagic event would lead to the permanent discontinuation of treatment with anticoagulants, despite possible subsequent new thromboembolic events. Thirdly, in patients not receiving initial prolonged anticoagulation treatment, we assumed that any clinical recurrent thromboembolic event would lead to the initiation of indefinite anticoagulation treatment. Fourthly, we did not consider the inconvenience of taking anticoagulants in terms of determinations of international normalised ratio and the need to worry about bleeding, avoiding other drugs, and trauma. Fifthly, we ignored the potentially higher risk of bleeding in the period when treatment with anticoagulants is being initiated, thus we assumed the risk of bleeding to be relatively constant for the period being analysed. Finally, long term morbidity from recurrent deep vein thrombosis (the post-thrombotic syndrome) and from non-fatal pulmonary embolism (secondary pulmonary arterial hypertension) was not taken into consideration.

Parameters used in analysis

Risk of recurrent thromboembolism after proximal deep vein thrombosis -- In patients who are not carriers of factor V Leiden most recurrent thromboembolism occurs during the first 2 years after the initial event, with a cumulative recurrence rate of about 8% at 1 year and 15% at 2 years.[12-19] During the 3 subsequent years, recurrence seems less frequent with a rate of 1.7% a year. In factor V Leiden carriers the cumulative recurrence rate at 2 years is around 25%, whereas over the 3 following years it decreases around 15% (5% per year).[7-9] Thus, patients who carry the factor V Leiden mutation have more than twice the risk of recurrent deep vein thrombosis when compared with noncarriers.

Risk of symptomatic pulmonary embolism given recurrent deep vein thrombosis -- Symptomatic pulmonary emboli have been reported in 10% to 20% of patients with untreated proximal deep vein thrombosis.[20 21]. Among those events, 2% to 8% may be fatal.[22 23]

Efficacy of anticoagulant treatment -- The efficacy of chronic oral anticoagulant treatment in preventing recurrent deep vein thrombi and subsequent pulmonary emboli ranges between 70% and 90%.[24]

Risk of major haemorrhagic complications -- The incidence of bleeding in patients given oral anticoagulants because of deep vein thrombosis has been the subject of several reports.[25 26] Of note, it has been shown that among patients with deep vein thrombosis the risk of bleeding is higher compared with patients with other medical conditions (for instance, prosthetic heart valves, chronic atrial fibrillation).[25] Anticoagulation of moderate intensity is used because the risk of haemorrhage is clearly dependent on the intensity of anticoagulant treatment and a targeted international normalised ratio of 2-3 is now firmly established for venous thromboembolism. In a systematic review of prospective studies the rate of fatal or major haemorrhage was 4.8% (95% confidence interval 3.6% to 7.2%) per year.[26]

Results

By using the data defined in the table we measured the consequences of different durations of oral anticoagulation treatment after a first episode of deep vein thrombosis for a hypothetical cohorts of 1000 carriers and non-carriers of factor V Leiden. The figure depicts the clinical benefit of pursuing anticoagulation treatment beyond the usually recommended 3 month period versus anticoagulation triggered by clinically overt recurrent deep vein thrombi. To avoid overlooking a benefit favouring prolonged prophylactic anticoagulation, we deliberately biased this analysis. Thus, we used the extreme ranges of clinical data (see table) that would consistently favour the clinical benefits provided by anticoagulants: high rate of clinical pulmonary emboli (20%), maximum efficacy of anticoagulants (90%), and low risk of bleeding (3.6% per year). Despite this favourable set of clinical data representing the best case scenario favouring prolonged anticoagulation, our analysis suggests that among factor V carriers the number of major haemorrhages induced by anticoagulants exceeds the number of clinical pulmonary emboli prevented over the entire range of duration of anticoagulation. Practically, the results of this intentionally biased analysis obviate the need for multiple sensitivity analyses, whose results would in any setting (that is, increased bleeding risk, lower efficacy of anticoagulation) reinforce our results. In other words, if the use of the most optimistic clinical data favouring prolonged anticoagulation does not result in a clear therapeutic benefit (more pulmonary emboli prevented compared with the number of major bleedings induced), any other scenario (with less optimistic data) will invariably lead to the conclusion that the risks of prolonged anticoagulation overwhelm its benefits. Finally, we measured the "threshold" rate of major haemorrhages below which the number of clinical pulmonary emboli prevented would exceed the number of bleedings induced, thus favouring prolonged oral anticoagulation. This analysis revealed that it is only when the risk of bleeding is below 2.5% per year (0.2% per month) that prolonged anticoagulation becomes the preferred strategy.

Summary of data extracted from literature and used in analysis. Figures are cumulative risk of recurrent deep vein thrombosis after first episode (percentages)

Conclusions

In conclusion, even if the most favourable set of assumptions is used, our model suggests that the benefits of prolonged oral anticoagulant treatment in factor V Leiden carriers after a first episode of deep vein thrombosis are usually overwhelmed by its risks. Specifically, for all different durations of prophylactic treatment (1 to 5 years) tested, our model demonstrates that the risks of major haemorrhage exceed the number of clinical pulmonary emboli that could be prevented. Prolonged anticoagulation treatment would be beneficial only if one assumes that one episode of recurrent deep vein thrombosis prevented equals one major bleeding event. Consequently, this lack of clinical evidence showing a net benefit of prolonged anticoagulation should question the decision to promote genetic screening programmes to detect the factor V mutation in all patients recovering from acute idiopathic deep vein thrombosis. This questioning is even more necessary as three studies suggested recently that the risk of pulmonary embolism in carriers of the factor V Leiden mutation might be less than the risk of deep vein thrombosis,[28-30] a fact which should further decrease the utility of prolonging anticoagulant treatment and, consequently, the benefit of screening. On the other hand, two recent reports point to the fact that factor V Leiden might be a significant risk factor for recurrent deep vein thrombosis only after the age of 50 years,[10 31] which would restrict our conclusions to this category of patients, at least in men. Lastly, our conclusion is confined to screening for the factor V Leiden mutation in an unselected population of patients with a first episode of deep vein thrombosis and does not imply that extensive thrombophilia screening (including factor V Leiden, protein C, protein S, antithrombin, prothrombin 3' polymorphism, lupus anticoagulant, anticardiolipin antibodies, plasminogen) should not be performed in a young patient presenting with a thromboembolic event or in the presence of recurrent episodes of idiopathic deep vein thrombosis or if there is a strong familial history of thrombophilia.

[1] Bertina RM, Koeleman BPC, Koster T, Rosendaal FR, Dirven RJ, de Ronde H, et al. Mutation in blood coagulation factor V associated with resistance, to activated protein C. Nature 1994;369:64-7.

[2] Dahlback B. Inherited thrombophilia: resistance to activated protein C as a pathogenic factor of venous thromboembolism. Blood 1995;85:607-14.

[3] Ridker PM, Hennekens CH, Lindpainter 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 thromboembolism in apparently healthy men. N Engl J Med 1995;332:912-7.

[4] Koster T, Rosendaal FR, 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;342:1503-6.

[5] Koepke JA. Testing for hereditary hypercoagulability. Activated protein C resistance (editorial). Am J Clin Path 1996;106:161-2.

[6] Vandenbroucke JP, Koster T, Briet T, Reitsma PH, Bertina RM, Rosendaal FR. Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation. Incet 1994;344:1453-7.

[7] Vandenbroucke JP, van der Meer FJM, Helmerhorst FM, Rosendaal FR. Factor V Leiden: should we screen oral contraceptive users and pregnant women? BMJ 1996;313:1127-30.

[8] Ridker PM, Miletich JP, Stampfer MJ, Goldhaber SZ, Lindpainter K, Hennenkens CH. Factor V Leiden and risk, of recurrent idiopathic venous thromboembolism. Circulation 1995;92:2800-2.

[9] Simioni P, Prandoni P, Lensing AWA, Scudeller A, Sardella C, Prins MH, et al. The risk of recurrent venous thromboembolism in patients with an [Arg.sup.506] [right arrow] Gln mutation in the gene factor V (factor V Leiden). N Engl J Med 1997;336:399-403.

[10] Eichinger S, Pabinger I, Stumpflen A, Hirschl M, Bialonczk C, Schneider B, et al. The risk of recurrent venous thromboembolism in patients with and without factor V Leiden. Thromb Haemost 1997;4:624-8.

[11] Sonnenberg FA, Beck JR. Markov models in medical decision making: a practical guide. Med Decis Making 1993;13:322-8.

[12] Research Committee of the British Thoracic Society. Optimum duration of anticoagulation for deep-vein thrombosis and pulmonary embolism. Lancet 1992;340:873-6.

[13] Schulman S, Rhedin AS, Lindmarker P, Carlsson A, Lators G, Nicol P, et al. A comparison of six weeks with six months or oral anticoagulation after a first episode of venous thromboembolism: duration of anticoagulation trial study group. N Engl J Med 1995;332:1661-5.

[14] Levine MN, Hirsh J, Gent M, Turpie AGG, Weitz J, Ginsberg J, et al. 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 1995;74:606-11.

[15] Schulman S, Lockner D, Juhlin-Dannfelt A. The duration of oral anticoagulation after deep vein thrombosis. Acta Med Scand 1985;217:547-52.

[16] Holmgren KAJ, Andersson G, Fagrell B, Johnson H, Ljunbeg B, Nilsson E, et al. One- month versus six-month therapy with oral anticoagulants after symptomatic deep vein thrombosis. Acta Med Scand 1985;218: 279-84.

[17] Beyth RJ, Cohen AM, Landefeld CS. Long-term outcomes of deep-vein thrombosis. Arch Intern Med 1995;218:279-84.

[18] Prandoni P, Lensing AWA, Buller HR, Carta M, Cogo A, Vigo, M, et al. Comparison of subcutaneous low-molecular-weight heparin with intravenous standard heparin in proximal deep-vein thrombosis. Lancet 1992;339:441-5.

[19] Koopman MWM, Prandoni P, Piovella F, Ockelford PA, Brandjes DP, van de Meer J, et al. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. N Engl J Med 1996;334:682-7.

[20] Monreal M, Ruiz J, Olazabal A, Arias A, Roca J. Deep venous thrombosis and the risk of pulmonary embolism: a systematic study. Chest 1992;102:677-81.

[21] Ginsberg JS. Management of venous thromboembolism. N Engl J Med 1996;335:1816-28.

[22] Carson JL, Kelley MA, Duff A, Palevitch M. The clinical course of pulmonary embolism. N Engl J Med 1992;326:1240-5.

[23] Paraskos JA, Adelstein SJ, Smith RE, Rickman FD, Grossman W, Dexter L, et al. Late prognosis of acute pulmonary embolism. N Engl J Med 1973;289:55-8.

[24] Claggett GP, Anderson FA, Heit J, Levine MN, Wheeler HB. Prevention of venous thromboembolism: Fourth American College of Chest Physicians consensus conference on antithrombotic therapy. Chest 1995;108(suppl):312-34s.

[25] Levine M, Raskob GE, Landefeld CS, Hirsh J. Hemorrhagic complication of anticoagulant treatment: Fourth American College of Chest Physicians consensus conference on antithrombotic therapy. Chest 1995;108(suppl):276-90s.

[26] Bounameaux H, de Moerloose P, Sarasin FP. Optimal duration of oral anticoagulant therapy following deep vein thrombosis of lower limbs. Blood Coagul Fibrinolysis 1996;7:507-14.

[27] Landefeld CS, Beyth RJ. Anticoagulant-related bleeding: clinical epidemiology, prediction, and prevention. Am J Med 1993;95:1710-1.

[28] Desmarais S, De Moeloose P, Reber G, Minazio P, Perrier A, Bounameaux H. Resistance to activated protein C in an unselected population of patients with pulmonary embolism. Lancet 1996;347:1374-5.

[29] Manten B, Rudi G, Westendorp J, Koster J, Reitsma PH, Rosendaal FR. Risk factors profiles in patients with different clinical manifestations of venous thromboembolism: a focus on the factor V Leiden mutation. Thromb Haemost 1996;76:510-3.

[30] Martinelli I, Cattaneo M, Panzeri D, Mannucci PM. Low prevalence of factor V: [Q.sup.506] in 41 patients with isolated pulmonary embolism. Thromb Haemost 1997;77:440-3.

[31] Ridker PM, Glynn RJ, Miletich JP, Goldhaber SZ, Stampfer NJ, Hennekens CH. Age-specific incidence rates of venous thromboembolism among heterozygous carriers of factor V Leiden mutation. Ann Intern Med 199;126:528-31.

A memorable patient

Deja vu

It was a dark winter afternoon in January 1981. The friendly Dublin porter at the top of the formidable entrance steps to the Mater Hospital pointed to the corridor where the membership examination was being held. The old high ceilinged wards were dim, and the lights outside brightened the gloom. The long case was behind the screens in the corner of the ward and my well rehearsed approach of history taking followed by examination started. He was an active lively 13 year old, more streetwise for his years than me, with a broad Dublin brogue which his rapid delivery made it almost impossible to follow. Communication was a major problem, and his attention was swiftly slipping.

Unable to obtain any history my anxiety and despair quickly rose. The only interest he had in matters medical was my stethoscope, which in desperation I gave to him and proceeded anxiously to start the examination with his pulse, conscious that the allotted time was ticking by. Following a short period of fruitless examination, I retrieved the stethoscope after a struggle and realised that part of the struggle was due to his difficulty releasing it, and the presence of myotonus was revealed. The diagnosis now became clearer, and the examiners were satisfied that a proper history and examination had taken place.

Ten years later as a membership examiner I arrived in the same hospital to see the minor cases before the examination started. The harassed registrar showed the examiners the minor cases, but apologised that the one with dystrophia myotonica had failed to arrive. At that moment a young man sauntered into the ward with his can of coke and paper folded at the racing page. A relieved registrar told us that the final short case had arrived. Slowly the sense of strange familiarity, accompanied by a distinct sense of unease and deja vu, was confirmed by his broad, still almost unintelligible diction. Thanking him for his help with the examination, I asked if he had attended before and he replied, "Oh yes Doc, for a brave number of years."

It was a unique but unsettling experience to examine on a case that I had previously been examined on.

Key messages

* Patients who carry the factor V Leiden mutation have a more than twice the risk of recurrence after a first episode of deep vein thrombosis

* Before screening for the abnormality is advocated in all patients recovering from acute deep vein thrombosis, it should be determined whether carriers of the mutation would benefit from the diagnosis

* The risks (major haemorrhage) of extended oral anticoagulation beyond the usually recommended 3 month period would exceed its benefits, in terms of clinical pulmonary emboli prevented

* The decision to promote widespread screening programmes to detect factor V mutation should be questioned in the absence of clinical benefit provided by extended use of oral anticoagulants

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