As part of an investigation of patients with a history of thrombosis
If free protein S is below normal range, then total protein S will be performed at an additional charge.
Only orderable as part of a profile, see PSTF / Protein S Antigen, Plasma.
Latex Immunoassay
TEST
If free protein S is below normal range, then total protein S will be performed at an additional charge.
Plasma Na Cit
Only orderable as part of a profile, see PSTF / Protein S Antigen, Plasma.
Specimen Type: Platelet-poor plasma
Patient Preparation: Patient must not be receiving heparin or Coumadin. If the patient is being treated with Coumadin, this should be noted. Coumadin will lower protein S.
Collection Container/Tube: Light-blue top (3.2% sodium citrate)
Submission Container/Tube: Plastic vials
Specimen Volume: 1 mL in 2 plastic vials each containing 0.5 mL
Collection Instructions:
1. For complete instructions, see Coagulation Guidelines for Specimen Handling and Processing.
2. Centrifuge, transfer all plasma into a plastic vial, and centrifuge plasma again.
3. Aliquot plasma into separate plastic vial leaving 0.25 mL in the bottom of centrifuged vial.
4. Freeze plasma immediately (no longer than 4 hours after collection) at -20 degrees C or, ideally -40 degrees C or below.
5. Send specimens in the same shipping container.
Additional Information:
1. Double-centrifuged specimen is critical for accurate results as platelet contamination may cause spurious results.
2. Each coagulation assay requested should have its own vial.
0.5 mL
| Gross hemolysis | Reject |
| Gross lipemia | Reject |
| Gross icterus | Reject |
| Specimen Type | Temperature | Time | Special Container |
|---|---|---|---|
| Plasma Na Cit | Frozen | 14 days |
As part of an investigation of patients with a history of thrombosis
If free protein S is below normal range, then total protein S will be performed at an additional charge.
Protein S is a vitamin K-dependent glycoprotein present in platelets and synthesized within the liver and endothelial cells. Protein S works as part of the natural anticoagulant system by acting as a cofactor to activated protein C (APC) in the proteolytic inactivation of procoagulant factors Va and VIIIa. In addition, protein S has direct APC-independent anticoagulant activity by inhibiting formation of the prothrombin and tenase complexes, possibly due to its high affinity for anionic phospholipid membranes. In human plasma, protein S forms a complex with the compliment regulatory protein, C4b-binding protein (C4bBP). Of the total plasma protein S, approximately 60% circulates bound to C4bBP while the remaining 40% circulates as "free" protein S. Only free protein S has anticoagulant function. C4bBP is composed of 6 or 7 alpha-chains and 1 or no beta-chain (C4bBP-beta). Different C4bBP isoforms are present in plasma, but only C4bBP-beta binds protein S.
Congenital protein S deficiency is an autosomal dominant disorder that is present in 2% to 6% of patients with venous thrombosis. Patients with protein S deficiency have an approximately 10-fold increased risk of venous thrombosis. In addition, they may also experience recurrent miscarriage, complications of pregnancy (preeclampsia, abruptio placentae, intrauterine growth restriction, and stillbirth) and possibly arterial thrombosis.
Three types of protein S deficiency have been described according to the levels of total protein S antigen, free protein S antigen, and protein S activity in plasma. Types I and III protein S deficiency are much more common than type II (dysfunctional) protein S deficiency. Type III protein S deficiency appears to be partly due to mutations within the protein S binding region for C4bBP-beta.
Homozygous protein S deficiency is rare but can present as neonatal purpura fulminans, reflecting severe disseminated intravascular coagulation/intravascular coagulation and fibrinolysis (DIC/ICF) caused by the absence of plasma protein S.
Acquired deficiency of protein S has causes that are generally of unknown hemostatic significance (ie, uncertain thrombosis risk), and is much more common than hereditary protein S deficiency. Acquired protein S deficiency can present through vitamin K deficiency, oral anticoagulant therapy, liver disease, DIC/ICF, thrombotic thrombocytopenia purpura, pregnancy or estrogen therapy, nephritic syndrome, and sickle cell anemia. As an acute-phase reactant, plasma C4bBP levels increase with acute illness and may cause acquired free protein S deficiency.
Measurement of plasma free protein S antigen is performed as the initial testing for protein S deficiency. When the free protein S antigen level is below the age- and sex-adjusted normal range, reflexive testing will be performed for total plasma protein S antigen.
Only orderable as part of a profile, see PSTF / Protein S Antigen, Plasma.
Males: 65-160%
Females:
<50 years: 50-160%
> or =50 years: 65-160%
Normal, full-term newborn infants or healthy premature infants may have decreased levels of total protein S (15%-50%), but because of low levels of C4bBP, free protein S may be normal or near the normal adult level (> or =50%). Total protein S reaches adult levels by 90-180 days postnatal.*
*See Pediatric Hemostasis References section in Coagulation Guidelines for Specimen Handling and Processing
Protein S values vary widely in the normal population and are age- and sex-dependent.
Table. Types of Heterozygous Protein S Deficiency
|
| Protein S antigen free | Protein S antigen total | Protein S activity |
| I | Low | Low | Low |
| II | Normal | Normal | Low |
| III | Low | Normal | Low |
Protein S and C4b-binding protein (C4bBP) are coordinately regulated, and an increased total protein S antigen and low free protein S antigen most commonly reflect acute or chronic inflammation or illness with an associated increase in plasma C4bBP.
For patients in whom hereditary protein S deficiency is strongly suspected and the free plasma protein S antigen level is normal, consideration should be given to testing of free protein S activity, SFX / Protein S Activity, Plasma, for detecting type II protein S deficiency (which is rare).
An increased total protein S antigen is of uncertain clinical significance because free protein S antigen levels are usually normal, in such situations. However, the total protein S antigen level may be helpful in distinguishing acquired versus congenital protein S deficiency. High normal or increased total protein S antigen and reduced free protein S antigen suggests acquired protein S deficiency, as may be seen in pregnancy or inflammation. In contrast, low normal or decreased total protein S antigen and reduced free protein S antigen suggests vitamin K deficiency or a warfarin effect, but also could reflect congenital protein S deficiency (type I or III).
Vitamin K deficiency, oral anticoagulant therapy, presence of liver disease, or disseminated intravascular coagulation/intravascular coagulation and fibrinolysis (DIC/ICF) are common acquired causes of protein S deficiency, which is of uncertain significance when such conditions are present. Concomitant assay of coagulation factor II activity may be helpful in differentiating congenital protein S deficiency from oral anticoagulation effects, but supportive data are currently suboptimal.
Differentiation of congenital and acquired protein S deficiency requires clinical correlation and may require repeated laboratory study of the patient and selected family members in some instances. DNA-based testing may be helpful; see GNPRS / Protein S Deficiency, PROS1 Gene, Next-Generation Sequencing, Varies.
Free protein S antigen results are potentially affected by:
-Heparin (unfractionated or low-molecular-weight) >4 U/mL
-Hemoglobin >200 mg/dL
-Bilirubin >25 mg/dL
-Triglycerides >1,500 mg/dL
-Platelets >10(10)/L
-Rheumatoid factor >900 IU/mL
-Factor V Leiden mutation (activated protein C resistance; APC-R)
1. Borgel D, Gandrille S, Aiach M. Protein S deficiency. Thromb Haemost. 1997;78(1):351-356
2. De Stefano V, Finazzi G, Mannucci PM. Inherited thrombophilia: pathogenesis, clinical syndromes, and management. Blood. 1996;87(9):3531-3544
3. Zoller B, Garcia de Frutos P, Dahlback B. Evaluation of the relationship between protein S and C4b-binding protein isoforms in hereditary protein S deficiency demonstrating type I and type III deficiencies to be phenotypic variants of the same genetic disease. Blood. 1995;85(12):3524-3531
4. Grandrille S, Borgel D, Ireland H, et al. Protein S deficiency: a database of mutations. For the Plasma Coagulation Inhibitors Subcommittee for the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost. 1997;77(6):1201-1214
5. Wolf M, Boyer-Neumann C, Peynaud-Debayle E, Marfaing-Koka A, Amiral J, Meyer D. Clinical applications of a direct assay of free protein S antigen using monoclonal antibodies. A study of 59 cases. Blood Coagul Fibrinolysis. 1994;5(2):187-192
6. Goodwin AJ, Rosendaal FR, Kottke-Marchant K, Bovill EG. A review of the technical, diagnostic, and epidemiologic considerations for protein S assays. Arch Pathol Lab Med. 2002;126(11):1349-1366
7. Serra J, Sales M, Chitolie A, et al: Multicentre evaluation of IL Test Free PS: a fully automated assay to quantify free protein S. Thromb Haemost. 2002;88(6):975-983
8. Marlar RA, Gausman JN, Tsuda H, Rollins-Raval MA, Brinkman HJM. Recommendations for clinical laboratory testing for S deficiency: Communication from the SCC committee plasma coagulation inhibitors of the ISTH. J Thromb Haemost. 2021;19(1):68-74
This assay is performed using the HemosIL Free Protein S kit on the Instrumentation Laboratory ACL TOP. The assay uses latex immunoassay methodology to determine the presence of free protein S. It consists of 2 latex reagents, one being latex particles coated with purified human C4b-binding protein (C4BP) and the other is latex particles coated with a monoclonal antibody directed against human protein S. Patient plasma is combined with the purified C4BP that reacts with a high affinity for free protein S in the patient plasma. The free protein S adsorbed on the C4BP latex triggers the agglutination reaction with the second latex reagent. The aggregates form diameters greater than the wavelength of the light (405 nm) passing through, causing absorption of the light. This change in absorption is measured over time and reported as delta optical density. The increase in absorption is proportional to the concentration of free protein S antigen present in the patient plasma.(Package insert: HemosIL Free Protein S. Instrumentation Laboratory Company; 04/2019)
Monday through Friday
This test has been modified from the manufacturer's instructions. Its performance characteristics were determined by Mayo Clinic in a manner consistent with CLIA requirements. This test has not been cleared or approved by the US Food and Drug Administration.
85306
| Test Id | Test Order Name | Order LOINC Value |
|---|---|---|
| PSF | Protein S Ag, Free, P | 27821-8 |
| Result Id | Test Result Name |
Result LOINC Value
Applies only to results expressed in units of measure originally reported by the performing laboratory. These values do not apply to results that are converted to other units of measure.
|
|---|---|---|
| PSF | Protein S Ag, Free, P | 27821-8 |