Molecular diagnosis of inherited bleeding disorders and thrombophilia

Molecular genetic characterization of the hemostatic system began more than 15 years ago, and, as a result, our knowledge of the genetic pathology of inherited bleeding disorders is well advanced. However, molecular testing for hemophilia and von Willebrand disease (vWD) has been impeded by the large size and complex genomic organization of the genes involved, and by the heterogeneity of the mutations underlying these disorders. Such limitations have significantly reduced the ability to provide diagnostic testing for these conditions through direct mutation detection. Many diagnostic laboratories continue to utilize linkage analysis with highly informative intragenic polymorphisms for the investigation of hemophilia. The one important exception to this trend has been the factor VIII inversion mutation, which provides a definitive test for the mutant allele in approximately 45% of severe hemophilia A patients. In contrast to patients with bleeding disorders, characterization of the factor V Leiden and prothrombin 20,210 variants has dramatically improved the diagnostic yield for patients with inherited thrombophilia. One of these two genotypes is now found in greater than 60% of patients with a clinical history of familial thrombophilia. Finally, recent studies indicate that molecular genetic analysis is beginning to permit preliminary progress in the identification of arterial thrombotic risk. Further advances in characterizing the multigenic basis of thrombotic disease and the application of new technologies to aid in the assessment of genetic variability predict an increasingly important role for molecular diagnostic approaches to the evaluation of disorders of hemostasis.