Laboratory identification of familial thrombophilia: do the pitfalls exceed the benefits? A reassessment of ABO-blood group, gender, age, and other laboratory parameters on the potential influence on a diagnosis of protein C, protein S, and antithrombin deficiency and the potential high risk of a false positive diagnosis

Laboratory testing for familial thrombophilia defines a large proportion of the modern hemostasis laboratory workload. As part of an ongoing assessment of our activities, we have re-evaluated our laboratory procedures for antithrombin (AT), Protein C (PC), and Protein S (PS), inclusive of normal reference ranges (NRR), the potential influence of ABO-blood group, gender and age, as well as other laboratory parameters, in order to help assess the effectiveness of testing as an aid to clinical diagnosis. We did not observe a significant influence of ABO-blood group on AT, PC, or PS. However, there were gender-related effects for PS (lower in females) and AT (higher in females), but not for PC. There were also age-related effects for AT, PC, and PS. Data is compared with literature findings. We also audited the positive detection rate for PC and/or PS deficiencies. In a 6-month period of testing, we identified that 18.9% of tested samples yielded low or near-low PC and/or PS levels. However, 33.3% of such samples were potentially derived from patients on oral anticoagulant therapy (ie, potential false positives). Additional pre-analytical variables, intra-assay, inter-assay, and inter-laboratory variability also contribute to the possibility of false positive detection. Thus, whilst NRR can be developed for test parameters, the likelihood of a false-positive test result can still be shown to exceed the likelihood of a true positive result, and this casts a shadow over the clinical value of such testing in some cases. In conclusion, laboratory testing for these markers of familial thrombophilia may or may not assist in the clinical diagnosis of this condition and clinical specialists should be made aware of laboratory test limitations, and consult with laboratories prior to making a definitive diagnosis of AT, PC, or PS deficiency.