Using the laboratory to predict recurrent venous thrombosis

Abstract

Characterisation of heritable thrombophilic defects has facilitated an understanding of the complex mechanisms influencing risk of venous thromboembolism. In parallel with this, the importance of gene-environment interaction in the development of this disease has become apparent. However, testing for a limited number of heritable thrombophilic defects (first generation thrombophilia testing) has not been shown to predict likelihood of recurrent venous thrombosis to any useful degree. This paradox whereby thrombophilia testing identifies defects associated with an increased risk of a first venous thrombosis but not of a particularly high risk of recurrence is likely the result of limitations imposed by a limited dichotomous testing strategy compounded by test inaccuracy and imprecision. Consequently, the observed intermediate phenotype (defined by limited dichotomous testing) is not concordant with the risk of recurrent venous thrombosis. Whilst a simple dichotomous testing strategy for a limited number of heritable thrombophilic defects has not been shown to have useful clinical predictive value, proof-of-principle is emerging for testing of multiple genetic factors in predicting the likelihood of recurrent thrombosis. In addition, recent studies indicate that measurement of the global activity of the coagulation system using either biomarkers or measuring the thrombin generating potential (second generation thrombophilia testing) may have useful clinical predictive value for recurrent thrombosis. The assessment of the intermediate phenotype by global coagulation tests and genome-wide mutation and SNP (single nucleotide polymorphisms) detection may provide complimentary approaches to the quantification of risk of recurrence and enable a move towards more patient-focussed rather than disease-focussed care.