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When Is Testing for Thrombophilia Indicated?
Author(s)
Martina Stehlikova, MD
Paul Martin, MD, MPH
Murali Janakiram, MD
Jason Korcak, MD, MPH
Sanjay Galhotra, MD
Yelena Averbukh, MD
And William Southern, MD, MS, SFHM

Key Points

  • Thrombophilia testing does not predict anticoagulation failure and does not alter the initial treatment for VTE.

  • There is no conclusive evidence that patients with thrombophilia are more likely to suffer recurrence after anticoagulation cessation compared with those without thrombophilia.

  • The strongest predictor for recurrence is whether the initial VTE event was unprovoked.

Blood tests to work up thrombophilia are rarely indicated.
click for large version
Blood tests to work up thrombophilia are rarely indicated.

Additional Reading

  • Baglin T, Gray E, Greaves M, et al. Clinical guidelines for testing for heritable thrombophilia. Br J Haematol. 2010;149(2):209-220.

  • Middeldorp S. Evidence-based approach to thrombophilia testing. J Thromb Thrombolysis. 2011;31(3):275-81.

  • Baglin T. Unraveling the thrombophilia paradox: from hypercoagulability to the prothrombotic state. J Thromb Haemostasis. 2010;8:228-233.

  • Merriman L, Greaves M. Testing for thrombophilia: an evidence based approach. Postgrad Med J. 2006;82(973):699-704.

The Case

A healthy 42-year-old woman presents to the hospital with acute-onset pleuritic chest pain and shortness of breath. She has not had any recent surgeries, takes no medications, and is very active. A lung ventilation-perfusion scan reveals a high probability of pulmonary embolism (PE). The patient’s history is notable for two second-trimester pregnancy losses. The patient is started on low-molecular heparin and warfarin (LMHW).

Should this patient be tested for thrombophilia?

Background

Thrombophilia can now be identified in more than half of all patients presenting with VTE, and testing for underlying causes of thrombophilia has become widespread.1 Physicians believe that thrombophilia testing frequently changes management of patients with VTE.2

Thrombophilias can be classified into three major categories: deficiency of natural inhibitors of coagulation, abnormal function or elevated level of coagulation factors, and acquired thrombophilias (see Table 1).

Table 1. Classification of Thrombophilias

INHERITED THROMBOPHILIAS

Deficiency of natural inhibitors of coagulation

  • Antithrombin III deficiency

  • Protein C deficiency

  • Protein S deficiency

Abnormal functions/elevated levels of coagulation factors

  • Factor V Leiden (G1691A mutation)

  • Prothrombin gene mutation (G20210A mutation)

  • Elevated Factor VIII

  • Elevated factors IX, XI, or fibrinogen

ACQUIRED THROMBOPHILIAS

  • Antiphospholipid syndrome

  • Myeloproliferative disorders

  • Paroxysmal nocturnal hemoglobinuria

  • Nephrotic syndrome

  • Occult malignancy

The prevalence of specific thrombophilias varies widely. For example, the prevalence of activated protein C resistance (the factor V Leiden mutation) is 3% to 7%. In comparison, the prevalence of antithrombin deficiency is estimated at 0.02%. Each thrombophilia is associated with an increased VTE risk, but the level of risk associated with a given thrombophilia varies greatly.1

Before testing for thrombophilia in acute VTE, assess the risk of recurrent VTE by determining if the thrombosis was provoked or unprovoked. A VTE event is considered provoked if it occurs in the setting of pregnancy within the previous three months; estrogen therapy; immobility from acute illness for more than one week; travel lasting for more than six hours; leg trauma, fracture, or surgery within the previous three months; or active malignancy (see Table 2,).3 Unprovoked VTE has a recurrence rate of 7.4% per patient year, compared with 3.3% per patient year for a provoked VTE; the risk is even lower (0.7% per patient year) if the risk factor for the provoked VTE was surgical.4

Testing for thrombophilia is indicated if the results would add significant prognostic information beyond the clinical history, or if it would change patient management—in particular, the intensity or the duration of anticoagulation.

Classification of Provoked vs. Unprovoked Venous Thromboembolism
click for large version
Table 2. Classification of Provoked vs. Unprovoked Venous Thromboembolism
 

 

Review of the Data

Does presence of thrombophilia alter the intensity of anticoagulation for VTE?

If thrombophilia increases the risk of VTE recurrence while on anticoagulation, then a more intense level of anticoagulation might prevent future VTE. There are no studies investigating higher intensity of anticoagulation, but if standard anticoagulation were insufficient for patients with identifiable thrombophilia, one might expect to observe increased recurrence rates among patients with thrombophilia treated with standard warfarin therapy.

In a substudy of the Extended Low-Intensity Anticoagulation for Unprovoked Venous ThromboEmbolism (ELATE) trial, the risk of recurrence of VTE among treated subjects was very low overall, and the presence of thrombophilic abnormalities was not associated with significantly higher risk.5 Observational studies have found VTE recurrence rates are low in patients treated with warfarin, with or without thrombophilia.6-8

The impact of the initial level of anticoagulation on recurrence after the completion of the treatment period has been evaluated. Although one study suggested that patients with substandard levels of anticoagulation were at an increased risk of subsequent VTE, this was not confirmed in the Leiden Thrombophilia Study (LETS). 9,10

In sum, the majority of data do not suggest a significantly increased risk of recurrent VTE in patients with thrombophilia treated with standard anticoagulation. Therefore, treatment with warfarin to a goal INR of 2 to 3 is sufficient.

Does presence of thrombophilia alter duration of VTE treatment?

A major decision clinicians face when caring for VTE patients is the duration of anticoagulation treatment. The current ACCP recommendation for treatment of a provoked VTE is three months, with treatment for an unprovoked VTE three months or lifelong.11 If the presence of thrombophilia increases the risk of recurrence after cessation of anticoagulation treatment, longer duration of treatment might be indicated. One of the goals of thrombophilia testing should be to identify those patients.

Overall, the recurrence rate after first VTE is high, with a cumulative incidence of 25% at five years, 30% at eight years, and 56% at 20 years.12,13

Deficiency of natural inhibitors of coagulation.

Deficiency of a natural inhibitor of coagulation has been associated with a risk of recurrence of VTE of as much as 10% per year, according to some studies.6,14 However, the estimates are based on studies that include individuals from thrombosis-prone families, and selection bias might have contributed to the high recurrence rates.1 In the unselected population represented in the LETS study, only a modest elevation was seen in the estimated risk of recurrence for patients with inhibitor deficiencies.15

Testing for deficiency of inhibitors offers little prognostic information beyond that obtained when determining whether a VTE event is provoked or unprovoked. In studies that have separately examined subjects with provoked vs. unprovoked VTE, deficiency of an inhibitor is not associated with increased risk of recurrence.15,16

Abnormal function or level of anticoagulation factors.

Factor V Leiden (FVL) is the most common cause of inherited thrombophilia and is associated with as much as a sixfold increase in VTE risk, while the prothrombin gene mutation is associated with a twofold increase.17,18

In contrast, the evidence associating these mutations with recurrent VTE risk is not as consistent. Although a study conducted at a referral center in Italy found an increased risk of recurrence with either Factor V Leiden or prothrombin gene mutation, a large meta-analysis of 23 studies found increased risk only with Factor V Leiden.19,20 Another meta-analysis demonstrated only a modest increased risk of recurrence in subjects with Factor V Leiden or prothrombin gene mutation, and a prospective study from Austria found no increased risk of recurrence with Factor V Leiden two years after discontinuation of anticoagulation.18,21 Additionally, when using patients with unprovoked VTE as reference, there was no increased risk of recurrence among patients homozygous for Factor V Leiden or the prothrombin gene mutation.22

 

 

In summary, although Factor V Leiden and prothrombin gene defects are associated with increased risk of recurrent VTE, the magnitude of the risk increase is modest and, therefore, should not alter duration of therapy.

Acquired thrombophilia.

It appears that the only thrombophilic state that might have a significant impact on the risk of recurrence is the antiphospholipid syndrome. The cessation of warfarin therapy in patients with thrombosis associated with antiphospholipid antibodies carries a 69% risk of recurrent thrombosis within a year.23 Some studies have suggested that the presence of specific antibodies (i.e. anticardiolipin antibodies) is associated with increased risk in patients with antiphospholipid syndrome.24

However, at present, all patients with VTE and antiphospholipid syndrome should be candidates for lifelong anticoagulation. Antiphospholipid antibody testing should be performed in patients with a suggestive history, including those with recurrent fetal loss or a single fetal loss after 10 weeks, or known collagen vascular disease.25

Indications for Thrombophilia Testing
click for large version
Table 3. Indications for Thrombophilia Testing

The role of provoked vs. unprovoked VTE.

Identifying whether a VTE is provoked or unprovoked has been shown to be an important predictor of recurrence. For example, one prospective, cohort study found two-year recurrence rates of zero in patients with a surgery or pregnancy-related VTE, 9% with other provoked VTE, and 19% with unprovoked VTE.26 In the same study, thrombophilia testing failed to reliably predict recurrence risk. Patients with unprovoked VTE who were tested and found to not have a defect were at equally high risk of recurrent VTE as those found to have a thrombophilia.27

The most significant predictor for VTE recurrence is whether the first event was provoked, and thrombophilia testing offers little additional prognostic information.28

VTE as a multifactorial disorder.

It is becoming increasingly clear that VTE is multifactorial disorder, caused by the interactions of genotypic, phenotypic, and environmental factors. In the case of an unprovoked VTE, the patient already carries a significantly elevated risk for recurrence, and further testing for known causes of thrombophilia appears to add very little additional information. The optimal duration of anticoagulation for unprovoked VTE is unclear, but current guidelines suggest at least three months—and clinicians should consider lifelong treatment.

In the vast majority of cases, testing for thrombophilia has no impact on the management of VTE and is not warranted. In patients with antiphospholipid-antibody syndrome, given the high risk of recurrence, long-term anticoagulation after a first VTE might be indicated. In select patients with a clinical picture suggestive of antiphospholipid-antibody syndrome, or a strong family history, testing should be considered.

Back to the Case

Our patient appears to have an unprovoked VTE. She should receive regular anticoagulation with warfarin, with a goal INR of 2 to 3, for at least three months. Lifelong anticoagulation therapy should be considered. Testing for heritable thrombophilia will not change the current management or treatment duration and, hence, is not indicated. However, the patient’s history is suggestive of antiphospholipid-antibody syndrome, so she should be tested. If the diagnosis of antiphospholipid syndrome is made, lifelong anticoagulation should be considered.

Bottom Line

Unprovoked VTE provides the strongest predictor for recurrence. Thrombophilia testing adds little in predicting recurrence and rarely is indicated.

Dr. Stehlikova is a clinical hospitalist in the division of hospital medicine, department of medicine, at Albert Einstein College of Medicine and Montefiore Medical Center in Bronx, N.Y. Dr. Martin is director of the Einstein Hospitalist Service. Dr. Janakiram is a fellow in the department of hematology at Einstein, and Dr. Korcak is an instructor at Einstein in the department of medicine and director of the Weiler Medical Service. Dr. Galhotra is associate director for inpatient quality in the department of medicine at Einstein; Dr. Averbukh is an academic hospitalist; and Dr. Southern is chief of the division of hospital medicine at Einstein.

 

 

References

  1. Middeldorp S, van Hylckama Vlieg A. Does thrombophilia testing help in the clinical management of patients? Br J Haematol. 2008;143:321-335.

  2. Coppens M, van Mourik JA, Eckmann CM, Büller HR, Middeldorp S. Current practise of testing for inherited thrombophilia. J Thromb Haemost. 2007;5:1979-1981.

  3. Prandoni P, Noventa F, Ghirarduzzi A, et al. 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. Haematologica. 2007;92:199-205.

  4. Iorio A, Kearon C, Filippucci E, et al. Risk of recurrence after a first episode of symptomatic venous thromboembolism provoked by a transient risk factor: a systematic review. Arch Intern Med. 2010;170:1710-1716.

  5. Kearon C, Julian JA, Kovacs MJ, et al. Influence of thrombophilia on risk of recurrent venous thromboembolism while on warfarin: results from a randomized trial. Blood. 2008;112:4432-4436.

  6. Vossen CY, Walker ID, Svensson P, et al. Recurrence rate after a first venous thrombosis in patients with familial thrombophilia. Arterioscler Thromb Vasc Biol. 2005;25:1992-1997.

  7. Brown K, Luddington R, Williamson D, Baker P, Baglin T. Risk of venous thromboembolism associated with a G to A transition at position 20210 in the 3'-untranslated region of the prothrombin gene. Br J Haematol. 1997;98:907-909.

  8. Schulman S, Tengborn L. Treatment of venous thromboembolism in patients with congenital deficiency of antithrombin III. Thromb Haemost. 1992;68:634-636.

  9. Palareti G, Legnani C, Cosmi B, Guazzaloca G, Cini M, Mattarozzi S. Poor anticoagulation quality in the first 3 months after unprovoked venous thromboembolism is a risk factor for long-term recurrence. J Thromb Haemost. 2005;3:955-961.

  10. Gadisseur AP, Christiansen SC, van der Meer FJ, Rosendaal FR. The quality of oral anticoagulant therapy and recurrent venous thrombotic events in the Leiden Thrombophilia Study. J Thromb Haemost. 2007;5:931-936.

  11. Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133:454S-545S.

  12. Prandoni P, Lensing AW, Cogo A, et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med. 1996;125:1-7.

  13. Laczkovics C, Grafenhofer H, Kaider A, et al. Risk of recurrence after a first venous thromboembolic event in young women. Haematologica. 2007;92:1201-1207.

  14. Brouwer JL, Lijfering WM, Ten Kate MK, Kluin-Nelemans HC, Veeger NJ, van der Meer J. High long-term absolute risk of recurrent venous thromboembolism in patients with hereditary deficiencies of protein S, protein C or antithrombin. Thromb Haemost. 2009;101:93-99.

  15. Christiansen SC, Cannegieter SC, Koster T, Vandenbroucke JP, Rosendaal FR. Thrombophilia, clinical factors, and recurrent venous thrombotic events. JAMA. 2005;293:2352-2361.

  16. De Stefano V, Simioni P, Rossi E, et al. The risk of recurrent venous thromboembolism in patients with inherited deficiency of natural anticoagulants antithrombin, protein C and protein S. Haematologica. 2006;91:695-698.

  17. Price DT, Ridker PM. Factor V Leiden mutation and the risks for thromboembolic disease: a clinical perspective. Ann Intern Med. 1997;127:895-903.

  18. Ho WK, Hankey GJ, Quinlan DJ, Eikelboom JW. Risk of recurrent venous thromboembolism in patients with common thrombophilia: a systematic review. Arch Intern Med. 2006;166:729-736.

  19. Simioni P, Prandoni P, Lensing AW, et al. 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. 2000;96:3329-3333.

  20. Segal JB, Brotman DJ, Necochea AJ, et al. Predictive value of factor V Leiden and prothrombin G20210A in adults with venous thromboembolism and in family members of those with a mutation: a systematic review. JAMA. 2009;301:2472-2485.

  21. 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.

  22. Lijfering WM, Middeldorp S, Veeger NJ, et al. Risk of recurrent venous thrombosis in homozygous carriers and double heterozygous carriers of factor V Leiden and prothrombin G20210A. Circulation. 2010;121(15):1706-1712.

  23. Khamashta MA, Cuadrado MJ, Mujic F, Taub NA, Hunt BJ, Hughes GR. The management of thrombosis in the antiphospholipid-antibody syndrome. N Engl J Med. 1995;332:993-997.

  24. Schulman S, Svenungsson E, Granqvist S. Anticardiolipin antibodies predict early recurrence of thromboembolism and death among patients with venous thromboembolism following anticoagulant therapy. Duration of Anticoagulation Study Group. Am J Med. 1998;104:332-338.

  25. Pengo V, Tripodi A, Reber G, et al. Update of the guidelines for lupus anticoagulant detection. Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. J Thromb Haemost. 2009;7:1737-1740.

  26. 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;362:523-526.

  27. Rosendaal FR. Once and only once. Circulation. 2010;121:1688-1690.

  28. Dalen JE. Should patients with venous thromboembolism be screened for thrombophilia? Am J Med. 2008;121:458-463.

Issue
The Hospitalist - 2012(10)
Publications
The Hospitalist
Sections
Patient Care
Clinical Care Conundrums
Clinical
All Content
Author(s)
Martina Stehlikova, MD
Paul Martin, MD, MPH
Murali Janakiram, MD
Jason Korcak, MD, MPH
Sanjay Galhotra, MD
Yelena Averbukh, MD
And William Southern, MD, MS, SFHM
Author(s)
Martina Stehlikova, MD
Paul Martin, MD, MPH
Murali Janakiram, MD
Jason Korcak, MD, MPH
Sanjay Galhotra, MD
Yelena Averbukh, MD
And William Southern, MD, MS, SFHM

Key Points

  • Thrombophilia testing does not predict anticoagulation failure and does not alter the initial treatment for VTE.

  • There is no conclusive evidence that patients with thrombophilia are more likely to suffer recurrence after anticoagulation cessation compared with those without thrombophilia.

  • The strongest predictor for recurrence is whether the initial VTE event was unprovoked.

Blood tests to work up thrombophilia are rarely indicated.
click for large version
Blood tests to work up thrombophilia are rarely indicated.

Additional Reading

  • Baglin T, Gray E, Greaves M, et al. Clinical guidelines for testing for heritable thrombophilia. Br J Haematol. 2010;149(2):209-220.

  • Middeldorp S. Evidence-based approach to thrombophilia testing. J Thromb Thrombolysis. 2011;31(3):275-81.

  • Baglin T. Unraveling the thrombophilia paradox: from hypercoagulability to the prothrombotic state. J Thromb Haemostasis. 2010;8:228-233.

  • Merriman L, Greaves M. Testing for thrombophilia: an evidence based approach. Postgrad Med J. 2006;82(973):699-704.

The Case

A healthy 42-year-old woman presents to the hospital with acute-onset pleuritic chest pain and shortness of breath. She has not had any recent surgeries, takes no medications, and is very active. A lung ventilation-perfusion scan reveals a high probability of pulmonary embolism (PE). The patient’s history is notable for two second-trimester pregnancy losses. The patient is started on low-molecular heparin and warfarin (LMHW).

Should this patient be tested for thrombophilia?

Background

Thrombophilia can now be identified in more than half of all patients presenting with VTE, and testing for underlying causes of thrombophilia has become widespread.1 Physicians believe that thrombophilia testing frequently changes management of patients with VTE.2

Thrombophilias can be classified into three major categories: deficiency of natural inhibitors of coagulation, abnormal function or elevated level of coagulation factors, and acquired thrombophilias (see Table 1).

Table 1. Classification of Thrombophilias

INHERITED THROMBOPHILIAS

Deficiency of natural inhibitors of coagulation

  • Antithrombin III deficiency

  • Protein C deficiency

  • Protein S deficiency

Abnormal functions/elevated levels of coagulation factors

  • Factor V Leiden (G1691A mutation)

  • Prothrombin gene mutation (G20210A mutation)

  • Elevated Factor VIII

  • Elevated factors IX, XI, or fibrinogen

ACQUIRED THROMBOPHILIAS

  • Antiphospholipid syndrome

  • Myeloproliferative disorders

  • Paroxysmal nocturnal hemoglobinuria

  • Nephrotic syndrome

  • Occult malignancy

The prevalence of specific thrombophilias varies widely. For example, the prevalence of activated protein C resistance (the factor V Leiden mutation) is 3% to 7%. In comparison, the prevalence of antithrombin deficiency is estimated at 0.02%. Each thrombophilia is associated with an increased VTE risk, but the level of risk associated with a given thrombophilia varies greatly.1

Before testing for thrombophilia in acute VTE, assess the risk of recurrent VTE by determining if the thrombosis was provoked or unprovoked. A VTE event is considered provoked if it occurs in the setting of pregnancy within the previous three months; estrogen therapy; immobility from acute illness for more than one week; travel lasting for more than six hours; leg trauma, fracture, or surgery within the previous three months; or active malignancy (see Table 2,).3 Unprovoked VTE has a recurrence rate of 7.4% per patient year, compared with 3.3% per patient year for a provoked VTE; the risk is even lower (0.7% per patient year) if the risk factor for the provoked VTE was surgical.4

Testing for thrombophilia is indicated if the results would add significant prognostic information beyond the clinical history, or if it would change patient management—in particular, the intensity or the duration of anticoagulation.

Classification of Provoked vs. Unprovoked Venous Thromboembolism
click for large version
Table 2. Classification of Provoked vs. Unprovoked Venous Thromboembolism
 

 

Review of the Data

Does presence of thrombophilia alter the intensity of anticoagulation for VTE?

If thrombophilia increases the risk of VTE recurrence while on anticoagulation, then a more intense level of anticoagulation might prevent future VTE. There are no studies investigating higher intensity of anticoagulation, but if standard anticoagulation were insufficient for patients with identifiable thrombophilia, one might expect to observe increased recurrence rates among patients with thrombophilia treated with standard warfarin therapy.

In a substudy of the Extended Low-Intensity Anticoagulation for Unprovoked Venous ThromboEmbolism (ELATE) trial, the risk of recurrence of VTE among treated subjects was very low overall, and the presence of thrombophilic abnormalities was not associated with significantly higher risk.5 Observational studies have found VTE recurrence rates are low in patients treated with warfarin, with or without thrombophilia.6-8

The impact of the initial level of anticoagulation on recurrence after the completion of the treatment period has been evaluated. Although one study suggested that patients with substandard levels of anticoagulation were at an increased risk of subsequent VTE, this was not confirmed in the Leiden Thrombophilia Study (LETS). 9,10

In sum, the majority of data do not suggest a significantly increased risk of recurrent VTE in patients with thrombophilia treated with standard anticoagulation. Therefore, treatment with warfarin to a goal INR of 2 to 3 is sufficient.

Does presence of thrombophilia alter duration of VTE treatment?

A major decision clinicians face when caring for VTE patients is the duration of anticoagulation treatment. The current ACCP recommendation for treatment of a provoked VTE is three months, with treatment for an unprovoked VTE three months or lifelong.11 If the presence of thrombophilia increases the risk of recurrence after cessation of anticoagulation treatment, longer duration of treatment might be indicated. One of the goals of thrombophilia testing should be to identify those patients.

Overall, the recurrence rate after first VTE is high, with a cumulative incidence of 25% at five years, 30% at eight years, and 56% at 20 years.12,13

Deficiency of natural inhibitors of coagulation.

Deficiency of a natural inhibitor of coagulation has been associated with a risk of recurrence of VTE of as much as 10% per year, according to some studies.6,14 However, the estimates are based on studies that include individuals from thrombosis-prone families, and selection bias might have contributed to the high recurrence rates.1 In the unselected population represented in the LETS study, only a modest elevation was seen in the estimated risk of recurrence for patients with inhibitor deficiencies.15

Testing for deficiency of inhibitors offers little prognostic information beyond that obtained when determining whether a VTE event is provoked or unprovoked. In studies that have separately examined subjects with provoked vs. unprovoked VTE, deficiency of an inhibitor is not associated with increased risk of recurrence.15,16

Abnormal function or level of anticoagulation factors.

Factor V Leiden (FVL) is the most common cause of inherited thrombophilia and is associated with as much as a sixfold increase in VTE risk, while the prothrombin gene mutation is associated with a twofold increase.17,18

In contrast, the evidence associating these mutations with recurrent VTE risk is not as consistent. Although a study conducted at a referral center in Italy found an increased risk of recurrence with either Factor V Leiden or prothrombin gene mutation, a large meta-analysis of 23 studies found increased risk only with Factor V Leiden.19,20 Another meta-analysis demonstrated only a modest increased risk of recurrence in subjects with Factor V Leiden or prothrombin gene mutation, and a prospective study from Austria found no increased risk of recurrence with Factor V Leiden two years after discontinuation of anticoagulation.18,21 Additionally, when using patients with unprovoked VTE as reference, there was no increased risk of recurrence among patients homozygous for Factor V Leiden or the prothrombin gene mutation.22

 

 

In summary, although Factor V Leiden and prothrombin gene defects are associated with increased risk of recurrent VTE, the magnitude of the risk increase is modest and, therefore, should not alter duration of therapy.

Acquired thrombophilia.

It appears that the only thrombophilic state that might have a significant impact on the risk of recurrence is the antiphospholipid syndrome. The cessation of warfarin therapy in patients with thrombosis associated with antiphospholipid antibodies carries a 69% risk of recurrent thrombosis within a year.23 Some studies have suggested that the presence of specific antibodies (i.e. anticardiolipin antibodies) is associated with increased risk in patients with antiphospholipid syndrome.24

However, at present, all patients with VTE and antiphospholipid syndrome should be candidates for lifelong anticoagulation. Antiphospholipid antibody testing should be performed in patients with a suggestive history, including those with recurrent fetal loss or a single fetal loss after 10 weeks, or known collagen vascular disease.25

Indications for Thrombophilia Testing
click for large version
Table 3. Indications for Thrombophilia Testing

The role of provoked vs. unprovoked VTE.

Identifying whether a VTE is provoked or unprovoked has been shown to be an important predictor of recurrence. For example, one prospective, cohort study found two-year recurrence rates of zero in patients with a surgery or pregnancy-related VTE, 9% with other provoked VTE, and 19% with unprovoked VTE.26 In the same study, thrombophilia testing failed to reliably predict recurrence risk. Patients with unprovoked VTE who were tested and found to not have a defect were at equally high risk of recurrent VTE as those found to have a thrombophilia.27

The most significant predictor for VTE recurrence is whether the first event was provoked, and thrombophilia testing offers little additional prognostic information.28

VTE as a multifactorial disorder.

It is becoming increasingly clear that VTE is multifactorial disorder, caused by the interactions of genotypic, phenotypic, and environmental factors. In the case of an unprovoked VTE, the patient already carries a significantly elevated risk for recurrence, and further testing for known causes of thrombophilia appears to add very little additional information. The optimal duration of anticoagulation for unprovoked VTE is unclear, but current guidelines suggest at least three months—and clinicians should consider lifelong treatment.

In the vast majority of cases, testing for thrombophilia has no impact on the management of VTE and is not warranted. In patients with antiphospholipid-antibody syndrome, given the high risk of recurrence, long-term anticoagulation after a first VTE might be indicated. In select patients with a clinical picture suggestive of antiphospholipid-antibody syndrome, or a strong family history, testing should be considered.

Back to the Case

Our patient appears to have an unprovoked VTE. She should receive regular anticoagulation with warfarin, with a goal INR of 2 to 3, for at least three months. Lifelong anticoagulation therapy should be considered. Testing for heritable thrombophilia will not change the current management or treatment duration and, hence, is not indicated. However, the patient’s history is suggestive of antiphospholipid-antibody syndrome, so she should be tested. If the diagnosis of antiphospholipid syndrome is made, lifelong anticoagulation should be considered.

Bottom Line

Unprovoked VTE provides the strongest predictor for recurrence. Thrombophilia testing adds little in predicting recurrence and rarely is indicated.

Dr. Stehlikova is a clinical hospitalist in the division of hospital medicine, department of medicine, at Albert Einstein College of Medicine and Montefiore Medical Center in Bronx, N.Y. Dr. Martin is director of the Einstein Hospitalist Service. Dr. Janakiram is a fellow in the department of hematology at Einstein, and Dr. Korcak is an instructor at Einstein in the department of medicine and director of the Weiler Medical Service. Dr. Galhotra is associate director for inpatient quality in the department of medicine at Einstein; Dr. Averbukh is an academic hospitalist; and Dr. Southern is chief of the division of hospital medicine at Einstein.

 

 

References

  1. Middeldorp S, van Hylckama Vlieg A. Does thrombophilia testing help in the clinical management of patients? Br J Haematol. 2008;143:321-335.

  2. Coppens M, van Mourik JA, Eckmann CM, Büller HR, Middeldorp S. Current practise of testing for inherited thrombophilia. J Thromb Haemost. 2007;5:1979-1981.

  3. Prandoni P, Noventa F, Ghirarduzzi A, et al. 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. Haematologica. 2007;92:199-205.

  4. Iorio A, Kearon C, Filippucci E, et al. Risk of recurrence after a first episode of symptomatic venous thromboembolism provoked by a transient risk factor: a systematic review. Arch Intern Med. 2010;170:1710-1716.

  5. Kearon C, Julian JA, Kovacs MJ, et al. Influence of thrombophilia on risk of recurrent venous thromboembolism while on warfarin: results from a randomized trial. Blood. 2008;112:4432-4436.

  6. Vossen CY, Walker ID, Svensson P, et al. Recurrence rate after a first venous thrombosis in patients with familial thrombophilia. Arterioscler Thromb Vasc Biol. 2005;25:1992-1997.

  7. Brown K, Luddington R, Williamson D, Baker P, Baglin T. Risk of venous thromboembolism associated with a G to A transition at position 20210 in the 3'-untranslated region of the prothrombin gene. Br J Haematol. 1997;98:907-909.

  8. Schulman S, Tengborn L. Treatment of venous thromboembolism in patients with congenital deficiency of antithrombin III. Thromb Haemost. 1992;68:634-636.

  9. Palareti G, Legnani C, Cosmi B, Guazzaloca G, Cini M, Mattarozzi S. Poor anticoagulation quality in the first 3 months after unprovoked venous thromboembolism is a risk factor for long-term recurrence. J Thromb Haemost. 2005;3:955-961.

  10. Gadisseur AP, Christiansen SC, van der Meer FJ, Rosendaal FR. The quality of oral anticoagulant therapy and recurrent venous thrombotic events in the Leiden Thrombophilia Study. J Thromb Haemost. 2007;5:931-936.

  11. Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133:454S-545S.

  12. Prandoni P, Lensing AW, Cogo A, et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med. 1996;125:1-7.

  13. Laczkovics C, Grafenhofer H, Kaider A, et al. Risk of recurrence after a first venous thromboembolic event in young women. Haematologica. 2007;92:1201-1207.

  14. Brouwer JL, Lijfering WM, Ten Kate MK, Kluin-Nelemans HC, Veeger NJ, van der Meer J. High long-term absolute risk of recurrent venous thromboembolism in patients with hereditary deficiencies of protein S, protein C or antithrombin. Thromb Haemost. 2009;101:93-99.

  15. Christiansen SC, Cannegieter SC, Koster T, Vandenbroucke JP, Rosendaal FR. Thrombophilia, clinical factors, and recurrent venous thrombotic events. JAMA. 2005;293:2352-2361.

  16. De Stefano V, Simioni P, Rossi E, et al. The risk of recurrent venous thromboembolism in patients with inherited deficiency of natural anticoagulants antithrombin, protein C and protein S. Haematologica. 2006;91:695-698.

  17. Price DT, Ridker PM. Factor V Leiden mutation and the risks for thromboembolic disease: a clinical perspective. Ann Intern Med. 1997;127:895-903.

  18. Ho WK, Hankey GJ, Quinlan DJ, Eikelboom JW. Risk of recurrent venous thromboembolism in patients with common thrombophilia: a systematic review. Arch Intern Med. 2006;166:729-736.

  19. Simioni P, Prandoni P, Lensing AW, et al. 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. 2000;96:3329-3333.

  20. Segal JB, Brotman DJ, Necochea AJ, et al. Predictive value of factor V Leiden and prothrombin G20210A in adults with venous thromboembolism and in family members of those with a mutation: a systematic review. JAMA. 2009;301:2472-2485.

  21. 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.

  22. Lijfering WM, Middeldorp S, Veeger NJ, et al. Risk of recurrent venous thrombosis in homozygous carriers and double heterozygous carriers of factor V Leiden and prothrombin G20210A. Circulation. 2010;121(15):1706-1712.

  23. Khamashta MA, Cuadrado MJ, Mujic F, Taub NA, Hunt BJ, Hughes GR. The management of thrombosis in the antiphospholipid-antibody syndrome. N Engl J Med. 1995;332:993-997.

  24. Schulman S, Svenungsson E, Granqvist S. Anticardiolipin antibodies predict early recurrence of thromboembolism and death among patients with venous thromboembolism following anticoagulant therapy. Duration of Anticoagulation Study Group. Am J Med. 1998;104:332-338.

  25. Pengo V, Tripodi A, Reber G, et al. Update of the guidelines for lupus anticoagulant detection. Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. J Thromb Haemost. 2009;7:1737-1740.

  26. 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;362:523-526.

  27. Rosendaal FR. Once and only once. Circulation. 2010;121:1688-1690.

  28. Dalen JE. Should patients with venous thromboembolism be screened for thrombophilia? Am J Med. 2008;121:458-463.

Key Points

  • Thrombophilia testing does not predict anticoagulation failure and does not alter the initial treatment for VTE.

  • There is no conclusive evidence that patients with thrombophilia are more likely to suffer recurrence after anticoagulation cessation compared with those without thrombophilia.

  • The strongest predictor for recurrence is whether the initial VTE event was unprovoked.

Blood tests to work up thrombophilia are rarely indicated.
click for large version
Blood tests to work up thrombophilia are rarely indicated.

Additional Reading

  • Baglin T, Gray E, Greaves M, et al. Clinical guidelines for testing for heritable thrombophilia. Br J Haematol. 2010;149(2):209-220.

  • Middeldorp S. Evidence-based approach to thrombophilia testing. J Thromb Thrombolysis. 2011;31(3):275-81.

  • Baglin T. Unraveling the thrombophilia paradox: from hypercoagulability to the prothrombotic state. J Thromb Haemostasis. 2010;8:228-233.

  • Merriman L, Greaves M. Testing for thrombophilia: an evidence based approach. Postgrad Med J. 2006;82(973):699-704.

The Case

A healthy 42-year-old woman presents to the hospital with acute-onset pleuritic chest pain and shortness of breath. She has not had any recent surgeries, takes no medications, and is very active. A lung ventilation-perfusion scan reveals a high probability of pulmonary embolism (PE). The patient’s history is notable for two second-trimester pregnancy losses. The patient is started on low-molecular heparin and warfarin (LMHW).

Should this patient be tested for thrombophilia?

Background

Thrombophilia can now be identified in more than half of all patients presenting with VTE, and testing for underlying causes of thrombophilia has become widespread.1 Physicians believe that thrombophilia testing frequently changes management of patients with VTE.2

Thrombophilias can be classified into three major categories: deficiency of natural inhibitors of coagulation, abnormal function or elevated level of coagulation factors, and acquired thrombophilias (see Table 1).

Table 1. Classification of Thrombophilias

INHERITED THROMBOPHILIAS

Deficiency of natural inhibitors of coagulation

  • Antithrombin III deficiency

  • Protein C deficiency

  • Protein S deficiency

Abnormal functions/elevated levels of coagulation factors

  • Factor V Leiden (G1691A mutation)

  • Prothrombin gene mutation (G20210A mutation)

  • Elevated Factor VIII

  • Elevated factors IX, XI, or fibrinogen

ACQUIRED THROMBOPHILIAS

  • Antiphospholipid syndrome

  • Myeloproliferative disorders

  • Paroxysmal nocturnal hemoglobinuria

  • Nephrotic syndrome

  • Occult malignancy

The prevalence of specific thrombophilias varies widely. For example, the prevalence of activated protein C resistance (the factor V Leiden mutation) is 3% to 7%. In comparison, the prevalence of antithrombin deficiency is estimated at 0.02%. Each thrombophilia is associated with an increased VTE risk, but the level of risk associated with a given thrombophilia varies greatly.1

Before testing for thrombophilia in acute VTE, assess the risk of recurrent VTE by determining if the thrombosis was provoked or unprovoked. A VTE event is considered provoked if it occurs in the setting of pregnancy within the previous three months; estrogen therapy; immobility from acute illness for more than one week; travel lasting for more than six hours; leg trauma, fracture, or surgery within the previous three months; or active malignancy (see Table 2,).3 Unprovoked VTE has a recurrence rate of 7.4% per patient year, compared with 3.3% per patient year for a provoked VTE; the risk is even lower (0.7% per patient year) if the risk factor for the provoked VTE was surgical.4

Testing for thrombophilia is indicated if the results would add significant prognostic information beyond the clinical history, or if it would change patient management—in particular, the intensity or the duration of anticoagulation.

Classification of Provoked vs. Unprovoked Venous Thromboembolism
click for large version
Table 2. Classification of Provoked vs. Unprovoked Venous Thromboembolism
 

 

Review of the Data

Does presence of thrombophilia alter the intensity of anticoagulation for VTE?

If thrombophilia increases the risk of VTE recurrence while on anticoagulation, then a more intense level of anticoagulation might prevent future VTE. There are no studies investigating higher intensity of anticoagulation, but if standard anticoagulation were insufficient for patients with identifiable thrombophilia, one might expect to observe increased recurrence rates among patients with thrombophilia treated with standard warfarin therapy.

In a substudy of the Extended Low-Intensity Anticoagulation for Unprovoked Venous ThromboEmbolism (ELATE) trial, the risk of recurrence of VTE among treated subjects was very low overall, and the presence of thrombophilic abnormalities was not associated with significantly higher risk.5 Observational studies have found VTE recurrence rates are low in patients treated with warfarin, with or without thrombophilia.6-8

The impact of the initial level of anticoagulation on recurrence after the completion of the treatment period has been evaluated. Although one study suggested that patients with substandard levels of anticoagulation were at an increased risk of subsequent VTE, this was not confirmed in the Leiden Thrombophilia Study (LETS). 9,10

In sum, the majority of data do not suggest a significantly increased risk of recurrent VTE in patients with thrombophilia treated with standard anticoagulation. Therefore, treatment with warfarin to a goal INR of 2 to 3 is sufficient.

Does presence of thrombophilia alter duration of VTE treatment?

A major decision clinicians face when caring for VTE patients is the duration of anticoagulation treatment. The current ACCP recommendation for treatment of a provoked VTE is three months, with treatment for an unprovoked VTE three months or lifelong.11 If the presence of thrombophilia increases the risk of recurrence after cessation of anticoagulation treatment, longer duration of treatment might be indicated. One of the goals of thrombophilia testing should be to identify those patients.

Overall, the recurrence rate after first VTE is high, with a cumulative incidence of 25% at five years, 30% at eight years, and 56% at 20 years.12,13

Deficiency of natural inhibitors of coagulation.

Deficiency of a natural inhibitor of coagulation has been associated with a risk of recurrence of VTE of as much as 10% per year, according to some studies.6,14 However, the estimates are based on studies that include individuals from thrombosis-prone families, and selection bias might have contributed to the high recurrence rates.1 In the unselected population represented in the LETS study, only a modest elevation was seen in the estimated risk of recurrence for patients with inhibitor deficiencies.15

Testing for deficiency of inhibitors offers little prognostic information beyond that obtained when determining whether a VTE event is provoked or unprovoked. In studies that have separately examined subjects with provoked vs. unprovoked VTE, deficiency of an inhibitor is not associated with increased risk of recurrence.15,16

Abnormal function or level of anticoagulation factors.

Factor V Leiden (FVL) is the most common cause of inherited thrombophilia and is associated with as much as a sixfold increase in VTE risk, while the prothrombin gene mutation is associated with a twofold increase.17,18

In contrast, the evidence associating these mutations with recurrent VTE risk is not as consistent. Although a study conducted at a referral center in Italy found an increased risk of recurrence with either Factor V Leiden or prothrombin gene mutation, a large meta-analysis of 23 studies found increased risk only with Factor V Leiden.19,20 Another meta-analysis demonstrated only a modest increased risk of recurrence in subjects with Factor V Leiden or prothrombin gene mutation, and a prospective study from Austria found no increased risk of recurrence with Factor V Leiden two years after discontinuation of anticoagulation.18,21 Additionally, when using patients with unprovoked VTE as reference, there was no increased risk of recurrence among patients homozygous for Factor V Leiden or the prothrombin gene mutation.22

 

 

In summary, although Factor V Leiden and prothrombin gene defects are associated with increased risk of recurrent VTE, the magnitude of the risk increase is modest and, therefore, should not alter duration of therapy.

Acquired thrombophilia.

It appears that the only thrombophilic state that might have a significant impact on the risk of recurrence is the antiphospholipid syndrome. The cessation of warfarin therapy in patients with thrombosis associated with antiphospholipid antibodies carries a 69% risk of recurrent thrombosis within a year.23 Some studies have suggested that the presence of specific antibodies (i.e. anticardiolipin antibodies) is associated with increased risk in patients with antiphospholipid syndrome.24

However, at present, all patients with VTE and antiphospholipid syndrome should be candidates for lifelong anticoagulation. Antiphospholipid antibody testing should be performed in patients with a suggestive history, including those with recurrent fetal loss or a single fetal loss after 10 weeks, or known collagen vascular disease.25

Indications for Thrombophilia Testing
click for large version
Table 3. Indications for Thrombophilia Testing

The role of provoked vs. unprovoked VTE.

Identifying whether a VTE is provoked or unprovoked has been shown to be an important predictor of recurrence. For example, one prospective, cohort study found two-year recurrence rates of zero in patients with a surgery or pregnancy-related VTE, 9% with other provoked VTE, and 19% with unprovoked VTE.26 In the same study, thrombophilia testing failed to reliably predict recurrence risk. Patients with unprovoked VTE who were tested and found to not have a defect were at equally high risk of recurrent VTE as those found to have a thrombophilia.27

The most significant predictor for VTE recurrence is whether the first event was provoked, and thrombophilia testing offers little additional prognostic information.28

VTE as a multifactorial disorder.

It is becoming increasingly clear that VTE is multifactorial disorder, caused by the interactions of genotypic, phenotypic, and environmental factors. In the case of an unprovoked VTE, the patient already carries a significantly elevated risk for recurrence, and further testing for known causes of thrombophilia appears to add very little additional information. The optimal duration of anticoagulation for unprovoked VTE is unclear, but current guidelines suggest at least three months—and clinicians should consider lifelong treatment.

In the vast majority of cases, testing for thrombophilia has no impact on the management of VTE and is not warranted. In patients with antiphospholipid-antibody syndrome, given the high risk of recurrence, long-term anticoagulation after a first VTE might be indicated. In select patients with a clinical picture suggestive of antiphospholipid-antibody syndrome, or a strong family history, testing should be considered.

Back to the Case

Our patient appears to have an unprovoked VTE. She should receive regular anticoagulation with warfarin, with a goal INR of 2 to 3, for at least three months. Lifelong anticoagulation therapy should be considered. Testing for heritable thrombophilia will not change the current management or treatment duration and, hence, is not indicated. However, the patient’s history is suggestive of antiphospholipid-antibody syndrome, so she should be tested. If the diagnosis of antiphospholipid syndrome is made, lifelong anticoagulation should be considered.

Bottom Line

Unprovoked VTE provides the strongest predictor for recurrence. Thrombophilia testing adds little in predicting recurrence and rarely is indicated.

Dr. Stehlikova is a clinical hospitalist in the division of hospital medicine, department of medicine, at Albert Einstein College of Medicine and Montefiore Medical Center in Bronx, N.Y. Dr. Martin is director of the Einstein Hospitalist Service. Dr. Janakiram is a fellow in the department of hematology at Einstein, and Dr. Korcak is an instructor at Einstein in the department of medicine and director of the Weiler Medical Service. Dr. Galhotra is associate director for inpatient quality in the department of medicine at Einstein; Dr. Averbukh is an academic hospitalist; and Dr. Southern is chief of the division of hospital medicine at Einstein.

 

 

References

  1. Middeldorp S, van Hylckama Vlieg A. Does thrombophilia testing help in the clinical management of patients? Br J Haematol. 2008;143:321-335.

  2. Coppens M, van Mourik JA, Eckmann CM, Büller HR, Middeldorp S. Current practise of testing for inherited thrombophilia. J Thromb Haemost. 2007;5:1979-1981.

  3. Prandoni P, Noventa F, Ghirarduzzi A, et al. 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. Haematologica. 2007;92:199-205.

  4. Iorio A, Kearon C, Filippucci E, et al. Risk of recurrence after a first episode of symptomatic venous thromboembolism provoked by a transient risk factor: a systematic review. Arch Intern Med. 2010;170:1710-1716.

  5. Kearon C, Julian JA, Kovacs MJ, et al. Influence of thrombophilia on risk of recurrent venous thromboembolism while on warfarin: results from a randomized trial. Blood. 2008;112:4432-4436.

  6. Vossen CY, Walker ID, Svensson P, et al. Recurrence rate after a first venous thrombosis in patients with familial thrombophilia. Arterioscler Thromb Vasc Biol. 2005;25:1992-1997.

  7. Brown K, Luddington R, Williamson D, Baker P, Baglin T. Risk of venous thromboembolism associated with a G to A transition at position 20210 in the 3'-untranslated region of the prothrombin gene. Br J Haematol. 1997;98:907-909.

  8. Schulman S, Tengborn L. Treatment of venous thromboembolism in patients with congenital deficiency of antithrombin III. Thromb Haemost. 1992;68:634-636.

  9. Palareti G, Legnani C, Cosmi B, Guazzaloca G, Cini M, Mattarozzi S. Poor anticoagulation quality in the first 3 months after unprovoked venous thromboembolism is a risk factor for long-term recurrence. J Thromb Haemost. 2005;3:955-961.

  10. Gadisseur AP, Christiansen SC, van der Meer FJ, Rosendaal FR. The quality of oral anticoagulant therapy and recurrent venous thrombotic events in the Leiden Thrombophilia Study. J Thromb Haemost. 2007;5:931-936.

  11. Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133:454S-545S.

  12. Prandoni P, Lensing AW, Cogo A, et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med. 1996;125:1-7.

  13. Laczkovics C, Grafenhofer H, Kaider A, et al. Risk of recurrence after a first venous thromboembolic event in young women. Haematologica. 2007;92:1201-1207.

  14. Brouwer JL, Lijfering WM, Ten Kate MK, Kluin-Nelemans HC, Veeger NJ, van der Meer J. High long-term absolute risk of recurrent venous thromboembolism in patients with hereditary deficiencies of protein S, protein C or antithrombin. Thromb Haemost. 2009;101:93-99.

  15. Christiansen SC, Cannegieter SC, Koster T, Vandenbroucke JP, Rosendaal FR. Thrombophilia, clinical factors, and recurrent venous thrombotic events. JAMA. 2005;293:2352-2361.

  16. De Stefano V, Simioni P, Rossi E, et al. The risk of recurrent venous thromboembolism in patients with inherited deficiency of natural anticoagulants antithrombin, protein C and protein S. Haematologica. 2006;91:695-698.

  17. Price DT, Ridker PM. Factor V Leiden mutation and the risks for thromboembolic disease: a clinical perspective. Ann Intern Med. 1997;127:895-903.

  18. Ho WK, Hankey GJ, Quinlan DJ, Eikelboom JW. Risk of recurrent venous thromboembolism in patients with common thrombophilia: a systematic review. Arch Intern Med. 2006;166:729-736.

  19. Simioni P, Prandoni P, Lensing AW, et al. 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. 2000;96:3329-3333.

  20. Segal JB, Brotman DJ, Necochea AJ, et al. Predictive value of factor V Leiden and prothrombin G20210A in adults with venous thromboembolism and in family members of those with a mutation: a systematic review. JAMA. 2009;301:2472-2485.

  21. 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.

  22. Lijfering WM, Middeldorp S, Veeger NJ, et al. Risk of recurrent venous thrombosis in homozygous carriers and double heterozygous carriers of factor V Leiden and prothrombin G20210A. Circulation. 2010;121(15):1706-1712.

  23. Khamashta MA, Cuadrado MJ, Mujic F, Taub NA, Hunt BJ, Hughes GR. The management of thrombosis in the antiphospholipid-antibody syndrome. N Engl J Med. 1995;332:993-997.

  24. Schulman S, Svenungsson E, Granqvist S. Anticardiolipin antibodies predict early recurrence of thromboembolism and death among patients with venous thromboembolism following anticoagulant therapy. Duration of Anticoagulation Study Group. Am J Med. 1998;104:332-338.

  25. Pengo V, Tripodi A, Reber G, et al. Update of the guidelines for lupus anticoagulant detection. Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. J Thromb Haemost. 2009;7:1737-1740.

  26. 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;362:523-526.

  27. Rosendaal FR. Once and only once. Circulation. 2010;121:1688-1690.

  28. Dalen JE. Should patients with venous thromboembolism be screened for thrombophilia? Am J Med. 2008;121:458-463.

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