Diagnosing protein S deficiency - Navigating challenges

Describe challenges in diagnosing protein S deficiency.

A women in her late 20 s and pregnant in third trimester (G1P0) suffered non-hemorrhagic adrenal infarction. Thrombophilia testing was performed five months post-partum and included analyses for the factor V Leiden (FVL; NM_000130:c.1601G > A; rs6025) and prothrombin c.20210G > A (NM_000506:c.*97G > A; rs1799963) variants, and measurement of antiphospholipid antibodies, protein C (PC) activity and antigen, protein S (PS) activity and antigen, and antithrombin. Initial testing suggested PS deficiency of unknown type. Therefore, targeted genetic screening of the PROS1 gene was performed using Sanger sequencing and multiplex ligation-dependent probe amplification to rule out large structural DNA rearrangements, along with repeated thrombophilia testing.

The first round of thrombophilia testing found low PS and PC, and heterozygosity for the FVL variant. FVL is known to falsely reduce PS activity up to 15 %, but not influence antigen assays (free and total PS levels). A PROS1 variant was identified (c.698G > A; p.(Arg233Lys)), but as this is relatively common, we classified the variant as likely benign. The final round of thrombophilia testing was performed 8 months after the first, and showed normal PC activity, normal PS total, PS free at the lower normal threshold and low PS activity.

The patient does not meet the criteria for PS deficiency based on either coagulation assays or PROS1 gene genotyping. This case highlights the necessity for clear guidelines to define the role of PROS1 genetic testing in routine clinical practice.