Thrombotic Risks: A Clarification

Spectra Laboratories, 48818 Kato Rd., Freemont, CA 94538, Fax 510-770-1516

To the Editor:

Rogier M. Bertina has written a clear, timely, and authoritative review of factor V Leiden and other coagulation factor mutations affecting thrombotic risk (1).

I was confused by the fact that the sum of genetic defects in inherited thrombophilia plus the cases with unknown cause add up to 109.7% (Table 1 of reference 1). This could occur due to multiple defects in individual patients. However, it might just be a typographical error, where the unknown cases are 20% rather than 30%.

I would appreciate clarification, as the answer either reduces the number of residual unclassified cases or possibly suggests frequent overlap of thrombophilic states, which would seem to be new area of inquiry.

References

1. Bertina RM. Factor V Leiden and other coagulation factor mutations affecting thrombotic risk. Clin Chem 1997;43:1678-1683.[Abstract/Free Full Text]

Dr. Bertina responds:

Hemostasis & Thrombosis Res. Center, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands
^a Address correspondence to: fax 31-526-6755; e-mail Bertina{at}rullf2.leidenuniv.nl.

To the Editor:

In my review of factor V Leiden and other coagulation factor mutations affecting thrombotic risk (1), Table 1 summarized the prevalences of different genetic defects among symptomatic pro-bands from families with inherited thrombophilia. Burdick is right that by adding up these prevalences one arrives at 109.7%. This is not due to typographical error but reflects the situation that 9.7% of these pro-bands have two different genetic defects. In fact, the present model for familial thrombophilia is that of a multigene disorder (2). Although such a model was already proposed in 1987 (3), it was only after the identification of common genetic risk factors for thrombosis, such as the factor V Leiden mutation (4) and the prothrombin 20210 A allele (5), that experimental support for this model was obtained. Koeleman et al. (6) reported for the first time that factor V Leiden is an additional risk factor for thrombosis in families where both protein C deficiency and the factor V Leiden mutation segregate. Therefore, in these families, individuals that carry two mutations develop thrombosis earlier in life and more frequently than those carrying only one mutation. In the meantime, similar observations have been made by other groups and on other combinations of risk factors (e.g., protein S deficiency and factor V Leiden, antithrombin deficiency and factor V Leiden, and more recently, factor V Leiden and the prothrombin 20210 A allele).

Returning to Table 1 in reference 1, we might expect that, when all the individual genetic risk factors become known, the sum of the various prevalences will approach 200% (each pro-band has at least two different gene defects).

Of course, the concept of familial thrombophilia as a multigenetic disease has important implications for the laboratory analysis of patients who come from thrombophilia families and underlines the need for identification of those genetic risk factors that thus far remain unnoticed.

References

1. Bertina RM. Factor V Leiden and other coagulation factor mutations affecting thrombotic risk. Clin Chem 1996;43:1678-1683.
2. Koeleman BPC, Reitsma PH, Bertina RM. Familial thrombophilia: a complex genetic disorder. Sem Haemat 1997;34:256-264.
3. Miletich JP, Sherman L, Broze G. Absence of thrombosis in subjects with heterozygous protein C deficiency. N Engl J Med 1987;317:991-996.[Abstract]
4. Bertina RM, Koeleman BP, Kester T, Rosendaal FR, Dirven RJ, de Ronde H, et al. Mutation in blood coagulation factor V associated with resistance to actuated protein C. Nature 1994;369:64-67.[Medline] [Order article via Infotrieve]
5. Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3' untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996;88:3698-3703.[Abstract/Free Full Text]
6. Koeleman BPC, Reitsma PH, Allaart CF, Bertina RM. Activated protein C resistance as an additional risk factor for thrombosis in protein C deficient families. Blood 1994;84:1031-1035.[Abstract/Free Full Text]