Use of a functional assay to diagnose protein S deficiency; inappropriate testing yields equivocal results

Abstract

Inherited deficiency of protein S (PS) is a rare but accepted risk factor for venous thromboembolism. There is accumulating evidence that inherited PS deficiency may be associated with a variety of adverse obstetric events. Acquired PS deficiency may be caused by a variety of clinical states including normal pregnancy. We conducted a retrospective audit of the results of screening for PS deficiency through our reference laboratory. The majority of patients in this audit with significantly reduced (<50%) free functional PS levels had a major confounding factor likely to cause acquired PS deficiency, most frequently pregnancy. Recommendations for PS testing for the diagnosis of hereditary PS deficiency include deferring testing until at least 40 days post-partum. It appears that these recommendations are not being adhered to leading to difficulty in the interpretation of results.

Protein S abnormalities: A diagnostic nightmare

“…Interestingly, in some genetic studies, DNA mutations have not always been found in patients with a plasma‐based phenotype of heterozygous PS deficiency [2, 8]. The complexity of PS in plasma makes it imperative that PS assays be reliable and reproducible to diagnose a plasma phenotype for true genetic abnormalities [7, 9, 10]. Three plasma phenotypes of PS deficiency are recognized based on laboratory values (Table I), however no differences in clinical presentation and severity have been observed [5, 7, 9, 11].…”

“…The complexity of PS in plasma makes it imperative that PS assays be reliable and reproducible to diagnose a plasma phenotype for true genetic abnormalities [7, 9, 10]. Three plasma phenotypes of PS deficiency are recognized based on laboratory values (Table I), however no differences in clinical presentation and severity have been observed [5, 7, 9, 11]. Types I and III PS deficiencies (both quantitative defects) are most common [3, 5, 11].…”

“…Three basic assay types are utilized for assessing PS in plasma [7, 9]. The “activity” assay is based on the ability of PS to function as a cofactor for APC, however it is fraught with the most problems [9, 10].…”

“…Three basic assay types are utilized for assessing PS in plasma [7, 9]. The “activity” assay is based on the ability of PS to function as a cofactor for APC, however it is fraught with the most problems [9, 10]. Free PS antigen assay is an immunologic measure of the unbound PS fraction and in most cases can be used as a surrogate marker for PS activity [9, 10].…”

“…The “activity” assay is based on the ability of PS to function as a cofactor for APC, however it is fraught with the most problems [9, 10]. Free PS antigen assay is an immunologic measure of the unbound PS fraction and in most cases can be used as a surrogate marker for PS activity [9, 10]. Finally, the Total PS antigen assay determines both free and bound fractions of PS in plasma [7, 9].…”