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Electronic Letters to:
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Electronic letters published:
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Thrombophilia testing lacks specificity and clinical utility
Rebuttal: Laboratory investigation of thrombophilia
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Ian Morison, Haematologist Southern Community Laboratories, Dunedin, New Zealand
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ian.morison{at}sclabs.co.nz Ian Morison
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Subsequent to recent discoveries of new risk factors for venous thrombophilia, several authors including Tripodi and Mannucci (1) have recommended vigorous testing regimens for affected patients. While others might share their views on testing (for example, see reference 2), the specificity of their recommended testing protocol is unacceptably poor. Given that factor V Leiden, the prothrombin gene polymorphism (G20210A), hyperhomocysteinemia and increased factor VIII have been recorded in 5%, 3%, 5% and 11% of the normal population respectively (2, 3), the specificity of this battery of tests can be no better than 76%. In addition, the biological and analytical pitfalls associated with homocysteine and factor VIII testing may result in test results with even lower specificity if testing is widely implemented. Furthermore, apart from antithrombin, protein C and protein S deficiencies, there is no consensus as to how the other thrombophilic polymorphisms should influence patient management, if at all. Although Tripodi and Mannucci offer some reasons to justify why we should test, the appropriate paragraph contains statements such as “Even if no conclusive evidence has to date come from clinical studies…” and “… at a time when there are no accepted guidelines”. Such facts might be cited by others as evidence against testing but, at present, the field of thrombophilia testing appears to be in the optimistic phase of the champions, and is yet to be subjected to the level of critical appraisal that we expect for other areas of laboratory testing, although it is reassuring to see a change on the horizon. For example, in contrast to the prevailing recommendations (1,2), Middeldorp et al (4) have recently reported data which suggest that the routine screening of the families of symptomatic patients with factor V Leiden is not justified. 1. Tripodi A and Munnucci PM. Laboratory investigation of thrombophilia. Clin Chem 2001; 47: 1597-1606. 2. Seligsohn U and Lubetsky A. Genetic susceptibility to venous thrombosis. New Engl J Med 2001; 344: 1222-1231. 3. Federman DG and Kirsner RS. An update on hypercoagulable disorders. Arch Intern Med 2001; 161: 1051-1056. 4. Middeldorp S, Meinardi JR, Koopman MM, van Pampus EC, Hamulyak K, van Der Meer J, Prins MH, Buller HR. A prospective study of asymptomatic carriers of the factor V Leiden mutation to determine the incidence of venous thromboembolism. Ann Intern Med 2001; 135: 322-327 |
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Armando Tripodi, established investigator University of Milan, Italy
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armando.tripodi{at}unimi.it Armando Tripodi
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Rebuttal: Laboratory investigation of thrombophilia We appreciate the point of view expressed by Dr. Morison (1), but wish to point out the following. We did not suggest vigorous testing regimens. Rather, we suggested to select carefully the patients in order to increase the diagnostic efficacy. Thus, we maintain that no screening should be performed in the general population, including women before oral contraceptive intake unless they have a personal or family history of thrombosis. Screening should be performed in patients with a history of venous thromboembolism and then offered to first-degree family members of index patients. The reasons for this choice have been discussed in our review (2) and reiterated more recently by one of us (3). Dr Morison contends that the biological and analytical pitfalls associated with homocysteine and factor VIII testing may further weaken the diagnostic efficacy. This may be true, but should also apply to protein C and protein S measurement where, according to national external quality assessment surveys carried out in different countries, there is need for standardization. Furthermore, we all know that searching for lupus anticoagulants and anticardiolipin antibodies is problematic. However, very few (if any) question the usefulness of performing such screening in thrombophilic patients. In more general terms, standardization and reliability of testing is an issue for many assays widely used in the clinical laboratory. Perhaps we should devote more effort to improve assays, when this is deemed necessary. Whether or not laboratory testing influences patients management is the most important point and has been discussed thoroughly in our review. We are certainly aware of the need for clinical studies to validate the strategy for laboratory testing. However, such studies are unlikely to be performed because of their complexity and of the large numbers of patients needed to draw conclusions. Perhaps, until these studies become available, a pragmatic approach based on good sense is probably more appropriate than doing nothing at all. Armando Tripodi References 1. Morison IM. Thrombophilia testing lacks specificity and clinical utility. Clin Chem. 2001. In press 2. Tripodi A, Mannucci PM. Laboratory investigation of thrombophilia. Clin Chem 2001; 47: 1597-1606. 3. Mannucci PM. Genetic hypercoagulability: prevention suggests testing family members. Blood 2001; 98: 21-22. |
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