Thrombophilia Screening?

Leading authority and former co-Chair of the American College of Chest Physicians Conference on Antithrombotic Therapy (ACCP) questions the value of thrombophilia screening for most situations

Lori B. Hornsby, PharmD, BCPS^*
December, 2008

A recent review by Dalen concludes that thrombophilia screening may not be useful for those with a previous thromboembolic event (unless antiphospholipid antibody syndrome is present) or those considering combined oral contraceptive (COC) therapy (unless there is a family history of clotting problems).¹ While it is difficult to disagree with the conclusions of his thoughtful analysis, questions remain that will likely cause continued controversy in this area.

Various thrombophilias ("hypercoagulable states") are well established risk factors for initial thromboembolic events, but the value such information provides when deciding on primary or secondary prevention remains controversial.^2-9 In all situations, the benefits of continued anticoagulation must be weighed against the risk of hemorrhage and the burden of monitoring with continued treatment.^10-13 With the exception of antiphospholipid syndrome, however, the presence of a thrombophilia does not influence the most recent recommendations by ACCP which do not advocate the use of thrombophilias when determining treatment duration.¹⁴

In the critique by Dalen, screening for the purpose of primary prevention is advocated only for women considering COC therapy if they have a family history of thrombosis.¹ Similarly, an earlier analysis also concluded that the clinical utility of such routine screening would be cost prohibitive.¹⁵

The value of screening patients for thrombophilias for secondary prevention after an initial idiopathic event also is questioned based on the following: 1) screening all patients with a first time idiopathic event would be costly considering the large portion (>50%) of initial events found to be idiopathic, 2) the association between thrombophilias and idiopathic events is questionable, and 3) the risk of recurrence does not appear appreciably different in the presence or absence of most thrombophilias. Dalen cites several trials demonstrating a similar prevalence of thrombophilias in those with provoked and idiopathic events. He also highlights three clinical trials and one meta-analysis suggesting the risk of recurrence is not significantly increased in patients with underlying thrombophilias (excluding antiphospholipid syndrome).^16-19 Two trials failed to find an increased risk of recurrence with factor V Leiden, prothrombin mutation, or anticoagulant deficiencies (Protein C-, S-, and AT deficiency).^16,17 A third, reporting no difference in thrombosis recurrence with factor V Leiden alone, did find an increased risk in patients with mutations for both factor V Leiden and prothrombin (RR=2.6, 95% CI, 1.3-5.1).¹⁸ The meta analysis reported a significant, but small, increased risk for both factor V Leiden (RR=1.4, 95% CI, 1.1-1.8) and the prothrombin mutation (1.7, 95% CI, 1.3-2.3).¹⁹ Although a small, but significant, increased risk of recurrence was found with elevated fibrinogen levels (RR=1.7, 95% CI, 1.1-2.8), there was no association between hyperhomocysteinemia, elevated factors VIII, IX, and XI and increased recurrence.¹⁶ In contrast, another trial did report a higher increased risk of recurrence in patients with elevated factor VIII levels above the 90th percentile (RR=6.6, 95%CI, 2.4-18.4).²⁰

Dalen concludes the risk of VTE recurrence is not significantly increased by the presence of most thrombophilias and therefore does not warrant routine screening for the purpose of guiding duration of anticoagulation therapy. He excludes antiphospholipid syndrome which has been shown to increase the risk of recurrence (RR=2.5), warranting lifelong therapy. He acknowledges the increased risk of recurrence found in patients with multiple thrombophilias but suggests screening all patients with idiopathic events to find these few individuals would not be warranted. He points out the risk of recurrence is greatest for those with initial idiopathic episodes as compared to provoked, regardless of thrombophilia status.

Dalen suggests the duration of anticoagulation treatment be based on whether or not the event was idiopathic or provoked, associated with cancer, antiphospholipid syndrome, or is a second event. His recommendation for duration of treatment is 3 months for initial provoked events, indefinite treatment for VTE associated with cancer, second episodes, and in those with antiphospholipid syndrome, and 1 year for all other initial idiopathic events.

Why would disorders known to increase the occurrence of initial thromboembolic events not also increase the incidence of recurrent events? One consideration is differences in VTE risks in the reference populations. When assessing the risk of an initial event in those with thrombophilias, the general population, with a low absolute risk of thrombosis, serves as the reference population. In contrast, when assessing recurrence rates, patients with previous events, who are known to carry a higher risk for thrombosis, are the reference population.²¹ It becomes more difficult to demonstrate thrombophilia status as an independent risk factor when comparing recurrence rates within a group at an increased risk. Also, the potential effect of any unidentified thrombophilias should be considered. It seems reasonable to question if thrombus formation could be truly idiopathic, but rather signify some predisposition for thrombus formation in patients with unprovoked events. This could explain not only the similar event rates but also the significant rate of recurrence after an idiopathic event in general.

The individual studies reviewed by Dalen also had limitations that should be considered. The Christiansen trial, reporting similar rates of recurrence in those with anticoagulant deficiencies as compared to those without, informed patients of their anticoagulant deficiency status and allowed continuation of anticoagulation treatment (n=57) at varying times during the study.¹⁶ Although the authors state they "repeated the analysis while excluding all such periods," the effects of continued therapy on the risk of recurrence still may be a factor. The Christiansen trial also utilized mailed questionnaires for patient follow-up, contacting patients by telephone only when they reported an occurrence or if they failed to respond. Additionally they did not appear to account for all causes of death which may have underestimated the incidence of fatal pulmonary embolism (PE). Their inclusion criteria allowed for a heterogeneous mix of patients. Both idiopathic and provoked events as well as thrombosis of the upper extremities were included. The initial event was idiopathic in only 55% of enrolled patients and there was an overall low prevalence of protein C, protein S, and antithrombin deficiencies (5%). Although they did assess the effect of thrombophilias specifically in the idiopathic group, the low prevalence of anticoagulant deficiencies combined with an assessment of a smaller portion of patients, would further decrease the power needed to find a potential difference in this population

In the Baglin trial the initial event was idiopathic in only 44% of patients.¹⁷ Patients with thrombosis in the distal lower extremities as well as upper extremities were included. Again, the lower recurrence rates with provoked as well as distal events may make it more difficult to predict the true effect of thrombophilias on the recurrence of idiopathic events in a proximal vein.

DeStefano who demonstrated an increased risk for recurrence in those with multiple thrombophilias allowed for the inclusion of patients with recurrent events, potentially skewing the results towards finding an increased risk.¹⁸ Patients with anticoagulant deficiencies and those homozygous for Factor V Leiden where excluded, so the results of this trial cannot be extrapolated to these thrombophilias. Additional trials not included in the Dalen review also excluded patients with Protein C and S, and antithrombin deficiencies leaving the true recurrence rate of these less common thrombophilias difficult, if not impossible, to determine .^22-24

There are other trials not mentioned in the Dalen review reporting conflicting results.^24-27 In general those demonstrating an increased risk with thrombophilias had longer durations of follow-up as compared to those that failed to show a difference.^{17, 22, 23} Prandoni reported an increased risk with anticoagulant deficiencies (HR 1.44) during 8 years of follow-up.²⁵ Simioni reported a significant risk with both factor V Leiden (HR 2.4) and prothrombin mutation (HR 2.4) over a similar duration of follow-up.²⁷ Miles reported an increased risk in males with a prothrombin mutation (RR of 4.9).²⁶ Although Lindermarker did not find a difference in those heterozygous for factor V Leiden, he did find an increased risk in homozygous individuals (OR 4.8).²⁴ These trials were not without flaws. One included patients with malignancies and did not account for factor V Leiden or prothrombin status, both of which could potentially increase the risk of recurrence.²⁵ Another allowed for the diagnosis of recurrent VTE to be made on clinical suspicion, rather than objective confirmation.²⁴ In general, there were similar issues related to inclusion/exclusion criteria, as mentioned in the studies cited by Dalen.^{16, 17, 22, 23, 28}

The risk of recurrence with underlying thrombophilias is unclear. Knowing that not all patients with a first idiopathic episode experience a recurrence and not all patients with thrombophilias experience a first event, the risk of thrombosis in general is unquestionably multifactorial. Large prospective trials of sufficient duration in patients with idiopathic proximal DVT and PE are needed to resolve this issue. In the meantime data suggesting all patients with idiopathic events may benefit from long-term therapy, questions the clinical utility of thrombophilia screening.¹⁴

At this time it may be prudent to inform patients of the potential risk for recurrence and the risks/benefits associated with long term anticoagulation treatment after an initial idiopathic episode, rather than routinely screening for thrombophilias. Those who chose to discontinue treatment or those in whom the hemorrhagic risk is felt to outweigh the benefits of continued treatment, should be educated on the signs and symptoms of VTE and given instructions for seeking medical attention. They should also be informed of avoidance of known risk factors and the need for appropriate prophylaxis in situations exposing them to increased risk. Screening for anticardiolipin antibodies and lupus anticoagulant would be warranted in the presence of clinical signs suggesting antiphospholipid syndrome.²⁹

^*Lori B. Hornsby, PharmD, BCPS is Assistant Clinical Professor, Department of Pharmacy Practice at Auburn University Harrison School of Pharmacy in Auburn, AL. Additionally, she is Ambulatory Clinical Pharmacist at Columbus Regional Healthcare System in Columbus, GA.

References

1. Dalen J. Should patients with venous thromboembolism be screened for thrombophilia? American Journal of Medicine 2008; 121:458-63.
   
   
2. Griffin J, Evatt B, Zimmerman T, Kleiss A. Deficiency of protein C in congenital thrombotic disease. J Clin Invest 1981;68:1370-73.
   
   
3. Brouwer J, Veeger N, Kluin-Nelemans H, van der Meer J. The pathogenesis of venous thromboembolism: evidence for multiple interrelated causes. Ann Intern Med 2006;145:807-15.
   
   
4. Koster T, Rosendaal F, Briet E, van der Meer J, et al. Protein C deficiency in a controlled series of unselected outpatients: an infrequent but clear risk factor for venous thrombosis (Leiden Thrombophilia Study). Blood 1995;85:2756-61.
   
   
5. Poort S, Rosendaal F, Reitsma P, Bertina R. 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.
   
   
6. Gezer S. Antiphospholipid syndrome. Dis Mon 2003;49:696-741.
   
   
7. Ray J. Meta-analysis of hyperhomocysteinemia as a risk factor for venous thromboembolic disease. Arch Intern Med 1998;158:2101-06.
   
   
8. Crowther M, Kelton J. Congenital thrombophilic states associated with venous thrombosis: a qualitative overview and proposed classification system. Ann Intern Med 2003;138:128-34.
   
   
9. Bauer K. The thrombophilias: well-defined risk factors with uncertain therapeutic implications. Ann Intern Med 2001;135:367-73.
   
   
10. Lagerstedt CI, Olsson CG, Fagher BO, et al. Need for long-term anticoagulant treatment in symptomatic calf-vein thrombosis. Lancet 1985; 515-18.
    
    
11. Hull R, Delmore T, Genton E, et al. Warfarin sodium versus low-dose heparin in the long-term treatment of venous thrombosis. The N Engl J Med 1979; 301:855-58.
    
    
12. Levine MN, Hirsh J, Gent M, 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.
    
    
13. Optimum duration of anticoagulation for deep-vein thrombosis and pulmonary embolism. Lancet 1992;340:873-76.
    
    
14. Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob G E, Comerota AJ. Antithrombotic therapy for venous thromboembolic disease. American College of chest Physicians Evidence-Based Practice Guidelines (8th edition). CHEST 2008; 133:454S-545S.
    
    
15. Vandenbroucke J, van der Meer F, Helmerhorst F, Rosendaal F. Factor V Leiden: should we screen oral contraceptive users and pregnant women? BMJ 1996; 313:1127-30.
    
    
16. Christiansen S, Cannegieter, S, Koster T, Vandenbroucke J, Rosendaal F. Thrombophilia, clinical factors, and recurrent thromboembolic events. JAMA 2005;293:2352-61.
    
    
17. Baglin T, Luddington R, Brown K, Baglin C. Incidence of recurrent venous thromboembolism in relation to clinical and thrombophilic risk factors: prospective cohort study. Lancet 2003;362:523-26.
    
    
18. DeStefano V, Martinelli I, Mannucci P, Paciaroni K, et al. The risk of recurrent deep venous thrombosis among heterozygous carriers of both factor V Leiden and the G20210A prothrombin mutation. NEJM;1999:341:801-06.
    
    
19. Ho W, Hankey G, Quinlan D, Eikelboom J. Risk of recurrent venous thromboembolism in patients with common thrombophilia. Arch Intern Med 2006;166:729-36.
    
    
20. Kyrle P, Minar E, Hirschl M, Bialonczyk C, et al. High plasma levels of factor VIII and the risk of recurrent venous thromboembolism. NEJM 2000;343:457-62.
    
    
21. Lensing A, Prins M. Recurrent deep vein thrombosis and two coagulation factor gene mutations: quo vadis? Thromb Haemost 1999;82:1564-66.
    
    
22. Eichinger S, Minar E, Hirschl M, Bialonczyk C. 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.
    
    
23. Eichinger S, Pabinger I, Stumpflen A, Hirschl M. The risk of recurrent venous thromboembolism in patients with and without Factor V Leiden. Thromb Haemost 1997;77:624-28.
    
    
24. Lindmarker P, Schulman S, Sten-Linder M, Wiman B. 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;81:684-89.
    
    
25. Prandoni P, Lensing A, Cogo A, Cuppini S, et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med 1996;125:1-7.
    
    
26. Miles J, Miletich J, Goldhaber S, Hennekens C, et al. G20210A mutation in the prothrombin gene and the risk of recurrent venous thromboembolism. JACC 2001;37:215-18.
    
    
27. Simioni P, Prandoni P, Lensing A, Manfrin D, et al. Risk for subsequent venous thromboembolic complications in carriers of the prothrombin or factor V gene mutation with a first episode of deep-vein thrombosis. Blood 2000;96:3329-33.
    
    
28. Kearon C, Gent M, Hirsh J, Weitz J, et al. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. NEJM 1999;340: 901-07.
    
    
29. Schulman S, Svenungsson E, Granqvist S. Anticardiolipin antibodies predict early recurrence of thromboembolism and death among patients with venous thromboembolism following anticoagulant therapy. Am J Med 1998;104:332-38.