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 predispose 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 frequencies vary in other well defined racial groups) but in patients with recurrent episodes of VTE the incidence of such disorders increases 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 conditions 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 development 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 widespread 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 particularly 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 contraceptive pill and to about 60 for women during pregnancy. If one assesses the rate of VTE when associated with specific thrombophilias, 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 prevented, 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 further 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 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 prevented over the entire 5-year period [11]. They concluded therefore that the decision to promote widespread thrombophilia 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 defects and the lower limit of the normal range and this can be particularly affected by the age of the individual, their contraceptive status and also during pregnancy. Some tests are affected 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 practice 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.


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  2. References
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