Thrombophilia testing

Abstract

Until recently the most common laboratory testing for thrombophilia encompassed assays for detecting reduced levels of the antithrombotic proteins antithrombin III, protein C and protein S. These assays were initially based on immunologic, subsequently chromogenic and most recendy on functional methods. The rate of abnormality detection was exceedingly low. A variety of genetic abnormalities were found underlying such defects in cases where they were congenital. The field of thrombophilia testing has recently been revolutionised through the discovery of the APC resistance phenomenon ascribable in most cases to the factor V(Leiden) mutation. The frequency of this single point mutation, its high risk significance made DNA analysis an attractive testing proposition. However functional tests such as the original APTT-based method which originally gave poor discrimination of FVL carriers from normals, have been improved through more specific clotting tests and the use of mixes of specimen with factor V deficient plasma. Careful analysis of risk factors among thrombotic patients as well as control groups now reveals that individual defects in protein C and S may not be as important as originally believed. Also that combinations of prothrombotic defects are more significant. These defects may include acquired as well as genetic abnormalities. Thus contraceptive use, acute phase reactants and smoking may contribute to the thrombotic risk due to primary defects such as factor V(Leiden). New thrombotic risks are continuously being identified. Prothrombin 20210 is a upregulating defect in the prothrombin promotor gene which is almost as common as FVL. Factor V(Cambridge), Arg306>Thr has been recognised as another mutation causing APC resistance, as has FV: Arg306>Gly in Hong Kong patients, though both of these are rare. Recognition that several of these thrombotic risk factors function together, for example in the protein C pathway has allowed the development of thrombophilia screening tests. At least 3 types are currently available, based on APTT dilute PT and DRWT tests. These are carried out after activation of endogenous protein C by PROTAC. Use of these tests has potential to save resources in and rationalise requests for thrombophilia testing.