pros and cons of thrombophilia testing: cons

2
DEBATE Pros and cons of thrombophilia testing: cons S. J. MACHIN Department of Haematology, University College London, UK Thrombophilia is generally defined as an inherited disorder of the hemostatic system that results in an increased risk of venous thromboembolism (VTE). There are several well characterized and accepted inherited thrombophilia conditions that predis- pose to venous thrombosis. The most important ones are the factor (F)V Leiden mutation, the prothrombin gene mutation, protein C, protein S and antithrombin deficiency, high levels of FVIIIc and hyper-homocystinemia [1]. Generally speaking these inherited thrombophilias are present in about 10–15% of the Caucasian Western European population (their frequen- cies vary in other well defined racial groups) but in patients with recurrent episodes of VTE the incidence of such disorders in- creases to about 50%. However, there is a paucity of evidence- based medicine regarding how, if at all, the clinical management of patients with thrombophilia and VTE differs from those individuals who do not have a specific inherited thrombophilia. It is not clear whether or not these individuals should be treated differently and risk stratification of the thrombophilia condi- tions does not change clinical recommendations for specific treatment regimes [2]. So as not to be condemned as adopting a nihilistic approach in this discussion, thrombophilia testing for research projects, particularly prospective randomized clinical trials and the dev- elopment of new diagnostic laboratory methodology, is not at issue. The main argument that needs to be considered is whether indiscriminate generalized screening and the routine clinical practice of testing is necessary or helpful, particularly also focusing on cost effectiveness and the financial waste of wide- spread testing diverting scarce health care resources from other areas of clinical medicine. Widespread thrombophilia screening has been advocated in many clinical situations but particularly in women prior to starting a combined oral contraceptive pill or hormone replacement therapy and also during pregnancy. Other areas of consideration are prior to long haul air travel particu- larly in the cramped economy section, prior to high risk surgical procedures, in patients after a first proven episode of VTE for which there was no obvious predisposing condition and also to assess the risk of developing pulmonary embolism after an episode of deep vein thrombosis (DVT). The rate of VTE according to combined oral contraceptive usage is now well defined and it is useful to compare this to similar aged women who are not receiving any form of hormone preparation and also to similar aged women during pregnancy. It is generally accepted that the rate of VTE per 100 000 women per year is approximately five in women who are not pregnant or taking oral contraceptives and increases to a rate of about 15 in women taking a second generation combined oral contra- ceptive pill and to about 60 for women during pregnancy. If one assesses the rate of VTE when associated with specific throm- bophilias, there is an increase in patients on the combined pill with the heterozygous form of the FV Leiden mutation to about 25.5 per 10 000 persons per year. In patients with antithrombin deficiency, the rate has been reported to be as high as 27.5% per year compared with 12% per year with protein C deficiency and no difference in patients with protein S deficiency compared with an annual control rate of between 3.4 and 6.9% [3]. The simple question resulting from these epidemiological incidence figures is – should women receive some form of thrombophilia screening prior to starting the combined oral contraceptive pill? It has been estimated that overall, one would need to screen 2 000 000 women to prevent one death from pulmonary embolism [4]. Although 100 episodes of DVT could be pre- vented, they cause little long-term morbidity in otherwise young healthy women who receive the appropriate treatment. The downside obviously is that contraceptive failure rate by other methods is considerably higher which would reverse even fur- ther any benefits from screening. Even focused screening of patients with a proven personal or family history of VTE would require testing of between 5000 and 10 000 women to prevent one death from PE. We know that approximately 40% of European women who test thrombophilia positive will never develop a VTE event and one can always get false reassurance through inappropriate interpretation of negative laboratory tests [5]. A similar argument can be made against thrombophilia screening in pregnancy. We know that the overall incidence for VTE is about 0.67 per 1000 pregnant women with about one in 500 for the FV Leiden mutation, one in 200 for the prothrombin gene mutation and 4.6 in 100 for the combination of the FV Leiden and prothrombin gene mutation [6]. Again these figures do not support the concept of overall general screening as the potential overall predictive value is relatively low. The risks of venous thrombosis associated with long haul air travel has recently been widely recognized. A prospective randomized study has shown that symptomless calf DVT may occur in up to 10% of long haul travelers over the age of 50 and that this incidence is considerably reduced by wearing below Journal of Thrombosis and Haemostasis, 1: 412–413 # 2003 International Society on Thrombosis and Haemostasis Correspondence: S. J. Machin, Department of Haematology, University College London Hospitals, 3rd Floor A & E Building, 25 Grafton Way, London WC1E 6DB, UK. Tel.: þ44 207 3809884; fax: þ44 207 3809886; e-mail: samuel.machin@ ucl.ac.uk

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Page 1: Pros and cons of thrombophilia testing: cons

DEBATE

Pros and cons of thrombophilia testing: cons

S . J . M A C H I N

Department of Haematology, University College London, UK

Thrombophilia is generally defined as an inherited disorder of

the hemostatic system that results in an increased risk of venous

thromboembolism (VTE). There are several well characterized

and accepted inherited thrombophilia conditions that predis-

pose to venous thrombosis. The most important ones are the

factor (F)V Leiden mutation, the prothrombin gene mutation,

protein C, protein S and antithrombin deficiency, high levels of

FVIIIc and hyper-homocystinemia [1]. Generally speaking

these inherited thrombophilias are present in about 10–15%

of the Caucasian Western European population (their frequen-

cies vary in other well defined racial groups) but in patients with

recurrent episodes of VTE the incidence of such disorders in-

creases to about 50%. However, there is a paucity of evidence-

based medicine regarding how, if at all, the clinical management

of patients with thrombophilia and VTE differs from those

individuals who do not have a specific inherited thrombophilia.

It is not clear whether or not these individuals should be treated

differently and risk stratification of the thrombophilia condi-

tions does not change clinical recommendations for specific

treatment regimes [2].

So as not to be condemned as adopting a nihilistic approach

in this discussion, thrombophilia testing for research projects,

particularly prospective randomized clinical trials and the dev-

elopment of new diagnostic laboratory methodology, is not at

issue. The main argument that needs to be considered is whether

indiscriminate generalized screening and the routine clinical

practice of testing is necessary or helpful, particularly also

focusing on cost effectiveness and the financial waste of wide-

spread testing diverting scarce health care resources from other

areas of clinical medicine. Widespread thrombophilia screening

has been advocated in many clinical situations but particularly

in women prior to starting a combined oral contraceptive pill or

hormone replacement therapy and also during pregnancy. Other

areas of consideration are prior to long haul air travel particu-

larly in the cramped economy section, prior to high risk surgical

procedures, in patients after a first proven episode of VTE for

which there was no obvious predisposing condition and also to

assess the risk of developing pulmonary embolism after an

episode of deep vein thrombosis (DVT).

The rate of VTE according to combined oral contraceptive

usage is now well defined and it is useful to compare this to

similar aged women who are not receiving any form of hormone

preparation and also to similar aged women during pregnancy. It

is generally accepted that the rate of VTE per 100 000 women

per year is approximately five in women who are not pregnant

or taking oral contraceptives and increases to a rate of about 15

in women taking a second generation combined oral contra-

ceptive pill and to about 60 for women during pregnancy. If one

assesses the rate of VTE when associated with specific throm-

bophilias, there is an increase in patients on the combined pill

with the heterozygous form of the FV Leiden mutation to about

25.5 per 10 000 persons per year. In patients with antithrombin

deficiency, the rate has been reported to be as high as 27.5% per

year compared with 12% per year with protein C deficiency and

no difference in patients with protein S deficiency compared

with an annual control rate of between 3.4 and 6.9% [3]. The

simple question resulting from these epidemiological incidence

figures is – should women receive some form of thrombophilia

screening prior to starting the combined oral contraceptive

pill? It has been estimated that overall, one would need to

screen 2 000 000 women to prevent one death from pulmonary

embolism [4]. Although 100 episodes of DVT could be pre-

vented, they cause little long-term morbidity in otherwise young

healthy women who receive the appropriate treatment. The

downside obviously is that contraceptive failure rate by other

methods is considerably higher which would reverse even fur-

ther any benefits from screening. Even focused screening of

patients with a proven personal or family history of VTE would

require testing of between 5000 and 10 000 women to prevent

one death from PE. We know that approximately 40% of

European women who test thrombophilia positive will never

develop a VTE event and one can always get false reassurance

through inappropriate interpretation of negative laboratory tests

[5]. A similar argument can be made against thrombophilia

screening in pregnancy. We know that the overall incidence for

VTE is about 0.67 per 1000 pregnant women with about one in

500 for the FV Leiden mutation, one in 200 for the prothrombin

gene mutation and 4.6 in 100 for the combination of the FV

Leiden and prothrombin gene mutation [6]. Again these figures

do not support the concept of overall general screening as the

potential overall predictive value is relatively low.

The risks of venous thrombosis associated with long haul air

travel has recently been widely recognized. A prospective

randomized study has shown that symptomless calf DVT may

occur in up to 10% of long haul travelers over the age of 50 and

that this incidence is considerably reduced by wearing below

Journal of Thrombosis and Haemostasis, 1: 412–413

# 2003 International Society on Thrombosis and Haemostasis

Correspondence: S. J. Machin, Department of Haematology, University

College London Hospitals, 3rd Floor A & E Building, 25 Grafton Way,

London WC1E 6DB, UK.

Tel.: þ44 207 3809884; fax: þ44 207 3809886; e-mail: samuel.machin@

ucl.ac.uk

Page 2: Pros and cons of thrombophilia testing: cons

knee fitted compression stockings [7]. Although 7% of travelers

had either the FV Leiden or prothrombin gene mutation, these

defects were of no predictive value for the development of

symptomless DVT in the group of travelers who were not

wearing prophylactic compression hosiery.

Recently it has been claimed that a DVT associated with the

FV Leiden mutation is more stable and adherent to the vessel

wall. This is presumed to be due to the fact that the FV Leiden

mutation enhances local thrombin generation, intensifies the

local inflammatory process and impairs the pro-fibrinolytic

response to activated protein C [8]. A phlebography study of

the location and extension of acute DVT has shown that in the

presence of the FV Leiden mutation a DVT is less likely to

extend into the ileo-femoral veins compared with a group of

patients with acute DVT who do not have the FV Leiden

mutation [9]. They reported an odds ratio of 0.5 (0.06–3.9)

for extension of a DVT into the ileo-femoral veins when the FV

Leiden was present compared with control subjects. Indeed the

prevalence of the FV Leiden mutation in patients with isolated

pulmonary embolus without DVT seems to be about half of that

in patients with isolated DVT alone [10].

The standard approach to the anti-thrombotic regime after a

first DVT is to continue oral anticoagulation for the first

6 months. A frequent question is, if thrombophilia screening

of such individuals after their first proven episode of VTE is

positive, would extension of warfarin therapy for say a 1–5-year

further period reduce the recurrence rate of further VTEs after

this initial 6 months treatment period for those individuals with

an inherited thrombophilia? Using a Markov decision analysis

model, which takes into account the yearly risk of major

bleeding, the high rate of clinical PE and a maximum efficiency

of warfarin of approximately 90%, they concluded that the

number of major hemorrhages induced would significantly

exceed the number of clinical pulmonary embolic events pre-

vented over the entire 5-year period [11]. They concluded

therefore that the decision to promote widespread thrombophi-

lia screening after a first episode of VTE was not justified and

the decision to extend oral anticoagulant therapy in such

individuals did not lead to any improved clinical outcome.

Whenever one is considering thrombophilia screening, one

has to take into account the local availability of laboratory

methodology. For each thrombotic condition, each laboratory

must establish its own age, sex and racial group reference

ranges. In some conditions, particularly protein S deficiency,

there is considerable overlap between some heterozygous de-

fects and the lower limit of the normal range and this can be

particularly affected by the age of the individual, their contra-

ceptive status and also during pregnancy. Some tests are affect-

ed by the acute post thrombotic state, any acute phase response

and also obviously by anticoagulant use. The individual level of

any heterozygous specific inherited thrombophilic defect does

not affect the management of any acute or indeed long-term

thrombotic event. In the United Kingdom, with a population of

about 55 million, one can estimate from national quality control

exercises that there are about 30 000 inherited thrombophilia

screens performed per year. Using in-house University College

Hospital prices, a complete thrombophilia screen in real terms

costs approximately 500 Euros with an estimated total UK cost

to the National Health Service budget of about 15 000 000 Euros

per year. Thrombophilia testing is therefore a very expensive

exercise, inappropriate laboratory testing is poor clinical prac-

tice and diverts scarce resources from other areas of healthcare.

To conclude, identification of a non-modifiable contributory

factor (i.e. an inherited thrombophilic condition) is not a

worthwhile end in its own right [12]. Testing of any patient

or their relatives generates needless anxiety or indeed promotes

false reassurance in those who are reported as being negative

for the various tests performed. Indiscriminate thrombophilia

screening cannot be justified. There is no evidence, particularly

in the areas discussed above, that thrombophilia testing affects

the overall standard clinical management of patients.

References

1 British Committee for Standards in Haematology. Investigation and

management of heritable thrombophilia. Br J Haematol 2001; 114:

512–28.

2 Martinelli I. Risk factors in venous thromboembolism. Thromb Haemost

2001; 86: 395–403.

3 Pabinger I, Schneider B. Thrombotic risk of women with hereditary

antithrombin III, protein C and protein S deficiency taking oral contra-

ceptive medication: the GTH Study Group on Natural Inhibitors.

Thromb Haemost 1994; 71: 548–52.

4 Rosendaal FR. Oral contraceptives and screening for factor V Leiden.

Thromb Haemost 1996; 75: 524–5.

5 Bloemenkamp KWM, Rosendaal FR, Helmerhorst FM, Vandenbroucke

JP. Higher risk of venous thrombosis during early use of oral contra-

ceptives in women with inherited clotting defects. Arch Intern Med

2000; 160: 49–52.

6 Gerhardt A, Scharf RE, Beckmann MQ, Struve S, Bender HG, Pillny M,

Sandmann W, Zotz RB. Prothrombin and factor V Leiden mutations in

women with a history of thrombosis during pregnancy and the puerper-

ium. N Engl J Med 2000; 342: 374–80.

7 Scurr JH, Machin SJ, Bailey-King S, Mackie IJ, McDonald S, Coleridge

Smith PD. Frequency and prevention of symptomless deep vein

thrombosis in long haul flights: a randomised trial. Lancet 2001;

357: 1485–9.

8 Bounameaux H. Factor V Leiden paradox: risk of deep-vein thrombosis

but not of pulmonary embolism. Lancet 2000; 356: 182–3.

9 Bjorgell O, Nilsson PE, Nilsson JA, Svensson PJ. Location and extent of

deep vein thrombosis in patients with and without FV-R 506Q mutation.

Thromb Haemost 2000; 83: 648–51.

10 Turkstra F, Karemaker R, Kiujer PMM, Prins MH, Buller HR. Is the

prevalence of the factor V Leiden mutation in patients with pulmonary

embolus and deep vein thrombosis really different? Thromb Haemost

1999; 81: 345–8.

11 Sarasin FP, Bounameaux H. Decision analysis model of prolonged oral

anticoagulant treatment in factor V Leiden carriers with first episode of

deep vein thrombosis. Br Med J 1998; 316: 95–9.

12 Greaves M, Baglin T. Laboratory testing for heritable thrombophilia:

impact on clinical management of thrombotic disease. Br J Haematol

2000; 109: 699–703.

# 2003 International Society on Thrombosis and Haemostasis

Debate 413