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Coagulation laboratory tests

Protein S assays

Reviewer: Jeremy Parsons, M.D. (see Reviewers page)
Revised: 10 February 2013, last major update November 2012
Copyright: (c) 2002-2013, PathologyOutlines.com, Inc.


● Deficiencies are either quantitative (type I - reduced normal protein) or qualitative (type II - normal amount of defective protein)
● Assays are either functional (measure protein activity) or antigenic (immunoassays that measure quantity, not function)
● Gold standard to measure free protein S or APC cofactor activity of protein S is considered the polyclonal ELISA with or without polyethylene glycol precipitation, although this procedure has poor reproducibility
● Perform functional assay first (detects all types of deficiencies)
● Functional assays are clot-based, cannot be performed in patients taking hirudin or argatroban
● Antigenic assays measure free protein S (functionally active form) or total (bound plus free) protein S - usually 60% of protein S is bound to C4b-binding protein
● Free protein S levels in protein S deficient patients are very sensitive to timing, temperature and dilutional conditions of assays compared to normal individuals

Reference ranges (nmol/liter)

● Each lab should establish its own, values in acute phase plasma are higher:
● Total protein S:- 65% of value in pooled normal human plasma (289-397)
● Free protein S: 71-115
● C4 binding protein beta+: 228-310
● Total C4 binding protein: 257-423

Acquired causes

● More common than hereditary deficiencies - clot formation, surgery, liver disease, warfarin (should be discontinued at least 10 days prior to testing), nephrotic syndrome, DIC, L-asparaginase therapy, any stimulus to acute phase response (increases C4b binding protein, decreases free protein S), newborns (12-60% of adult levels, rise to adult levels by 6 months), women (lower than men before menopause, while taking oral contraceptives, during pregnancy or with hormone replacement therapy), vitamin K antagonist drugs, vitamin K deficiency, elevated factor VIII levels (> 200%) in PTT based functional assays or thrombosis; also nephrotic syndrome, varicella infection and HIV infection
Classification of deficiencies: all have low functional protein S; I - also low free and total protein S; II / IIb - also normal free and total protein S; III / IIa - low free, but normal total protein S


● Clot based protein S method is based on the addition of activated protein C, which in the presence of protein S, accelerates the inhibition of thrombin-activated factors VIII and V
● The prolongation of clotting time is proportional to the amount of factor S activity
● Interference may occur with elevated factor VIII (acute phase reactions or otherwise, Thromb Res 1995;77:375)
● Values falsely increased by bivalirudin, lepirudin, argatroban and fondaparinux (Arch Pathol Lab Med 2004;128:1142), lupus anticoagulants

End of Coagulation > Coagulation laboratory tests > Protein S assays

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