1. Top of page
  2. Abstract
  3. Disclosure of Conflict of Interests
  4. References

See also Mahmoodi BK, Brouwer J-LP, ten Kate MK, Lijfering WM, Veeger NJGM, Mulder AB, Kluin-Nelemans HC, van der Meer J. A prospective cohort study on the absolute risks of venous thromboembolism and predictive value of screening asymptomatic relatives of patients with hereditary deficiencies of protein S, protein C or antithrombin. This issue, pp 1193–200.

Why might one want to screen patients with venous thromboembolism (VTE) and their relatives for heritable thrombophilia? Possibly: (i) to offer long-term rather than short-term anticoagulation in the index case, or (ii) to identify asymptomatic relatives at increased risk of VTE so that an intervention not suitable for all relatives can be made to reduce the risk of a first VTE.

For the index case an increased risk of recurrence is predicted by a permanent risk factor, an idiopathic event [1], male sex [2], a raised D-dimer after completing anticoagulation [3], post-thrombotic syndrome [4] and residual vein thrombosis [5]. Prospective cohort studies have shown that heritable thrombophilia does not usefully predict recurrence [1,6]. This is certainly true for the factor (F) V Leiden and prothrombin G20210A mutations [7,8]. Deficiencies of the natural anticoagulants (antithrombin, protein C, protein S) may be higher risk thrombophilias [9]. In patients with these deficiencies the effect on the risk of recurrence is uncertain but the relative risk of recurrence appears to be less than two in patients who are not selected from thrombosis-prone families [1,6,10]. Thrombophilia screening would appear to have only a minor role in deciding on duration of anticoagulation and the recent British guideline [11] is against indiscriminate testing of patients presenting with VTE and suggests testing is only considered in selected patients, such as those with a strong family history of unprovoked recurrent thrombosis.

In this issue of the journal Mahmoodi and colleagues [12] present a prospective cohort study on the absolute risks of VTE in asymptomatic relatives of patients with VTE and hereditary deficiencies of protein S, protein C or antithrombin. The annual risk of VTE in deficient as compared with non-deficient relatives is shown in Table 1.

Table 1.   Annual risk of VTE in deficient as compared with non-deficient relatives
 Deficient (%)Non-deficient (%)RR
All VTE1.530.297.0
Unprovoked VTE0.950.0522.3
Provoked VTE0.580.242.8

As long-term treatment of asymptomatic deficient relatives is not recommended we are only concerned with the possibility of trying to prevent the provoked cases. The rate of provoked VTE in asymptomatic deficient relatives was 0.58% after screening, which was not significantly different to the rate found before screening (0.84%, P = 0.32). At this point many would say that this shows screening to be unhelpful. However, there were six events in deficient relatives undergoing 91 high-risk episodes and all six occurred in the 45 episodes when prophylaxis was not given. This could be interpreted as showing that testing would be helpful if doctors acted on the results and insisted on thromboprophylaxis in deficient relatives at times of high risk. Closer inspection shows that five of these events occurred during 60 episodes of surgery, trauma or immobilization and one event occurred in 31 pregnancies (in an antithrombin-deficient relative). So one might argue that if thromboprophylaxis for surgery, trauma or immobilization was given to all the relatives (deficient and non-deficient) as a routine then thrombophilia testing would have little to offer. Indeed if thrombophilia testing resulted in withholding thromboprophylaxis in unaffected relatives it could result in more, not less, provoked thrombosis. Finally, there were two episodes of VTE in 54 years of combined oral contraceptive use in deficient relatives. Where does this leave the poor clinician (if not screaming)? I think that in most high-risk situations thromboprophylaxis could be given to all relatives without thrombophilia testing so I would agree with the recent British guideline which states that case finding of asymptomatic relatives with high-risk thrombophilia, such as deficiency of antithrombin, protein C or protein S, should only be considered in selected thrombosis-prone families [11]. Women who have a first-degree relative with VTE should consider an alternative form of contraception rather than the combined pill though I agree that testing for heritable thrombophilia may assist counselling of selected women if a high-risk thrombophilia has been identified in the symptomatic relative. Women should be assessed for their risk of pregnancy-associated venous thrombosis in relation to clinical risk factors, and in the asymptomatic woman with a family history of VTE, testing is not required if the clinical risks alone are sufficient to result in antepartum thromboprophylaxis. If not, then testing for high-risk thrombophilias can be justified as antithrombin deficiency (or combined defects, or homozygosity for low-risk mutations) would result in antepartum thromboprophylaxis.

Disclosure of Conflict of Interests

  1. Top of page
  2. Abstract
  3. Disclosure of Conflict of Interests
  4. References

The author states that he has no conflict of interest.


  1. Top of page
  2. Abstract
  3. Disclosure of Conflict of Interests
  4. References
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