Genetic thrombophilia and natural anticoagulants: importance of polymorphisms within and outside the genes

We read with interest the report by Kim et al. on the unique pattern of mutations in the specific genes encoding blood coagulation inhibitors in a Korean population.1 This undoubtedly represents a large amount of data on the prevalence of deficiencies of natural anticoagulants along with the spectrum of mutations in both control and patient populations.

The basal plasma levels of the three natural protein anticoagulant proteins, i.e. protein C, protein S and antithrombin, are affected by multiple factors which include age, sex, use of oral contraceptives, lupus anticoagulants, pregnancy, liver disease and so on. One indirect way of controlling this is to look for an isolated deficiency of the natural anticoagulant, though it can be argued that there may be a differential reduction of these proteins under such circumstances. Another important factor is the high rate of laboratory test errors. As these deficiencies manifest in the heterozygous condition, even a minute variation in the test results might misclassify them as deficient or vice versa. Identification of causative mutation thus remains the most important and definitive tool in the confirmation of any underlying inherited defect. However, in a large number of patients with thrombosis and deficiencies of any of the natural anticoagulants, the causative genetic defects are not identified.2,3

Several reports now confirm that polymorphisms within or outside the genes, other genes within or outside the vitamin K cycle may affect the plasma levels of these natural anticoagulants.4,5 It remains to be seen whether these polymorphisms, either singly or in combinations, based on the strength of their association with the plasma levels of natural anticoagulants, may effectively be translated into the routine battery of thrombophilia investigations.