Protein S Deficiency Profile

CPT: 85305; 85306(x2)
Print Share

Test Details

Test Includes

Protein S, free; protein S, functional; protein S, total

Use

Confirmation and characterization of protein S (PS) congenital deficiency

Limitations

The presence of heparin or lupus anticoagulants leads to overestimation of PS. aPC resistance due to factor V Leiden mutation or some other cause can falsely lower measured PS activity levels.6

Methodology

Total PS and free PS antigen: Total PS and free PS antigens are measured by latex immunoassay (IA). PS activity: The patient plasma is added to PS-depleted normal plasma with normal levels of all factors but PS. The mixture is supplemented with excess aPC, and factor V is then added. The extent of prolongation of the time to clot formation after calcium chloride is added is proportional to plasma PS activity.

Additional Information

Protein S (PS) is produced by the liver, megakaryocytes, and endothelial cells.6-8 PS is synthesized as an inactive precursor that is activated by carboxylation of several glutamic acid residues by a vitamin K-dependent carboxylase. PS serves as an essential cofactor of activated protein C (aPC). In the presence of calcium, PS binds tightly to the phospholipid surfaces of endothelial cells and activated platelets. This serves to concentrate the PS/aPC complex at the site of thrombus formation where it regulates the coagulation process by enzymatically neutralizing activated factors Va and VIIIa. PS greatly potentiates the anticoagulant function of aPC. PS is enzymatically neutralized by thrombin. After thrombin proteolysis, PS retains its affinity for phospholipids, but loses its anticoagulant function as the cofactor for aPC.

A portion of the PS in blood is bound to the protein, which binds the C4b region of complement (ie, the C4b-binding protein [C4b-BP]).7 This C4b-BP forms a 1:1 complex with PS. In plasma, a dynamic equilibrium is reached between C4b-BP-bound and free PS. The free PS form represents about 40% of total PS in normal individuals. Only the free form can act as the cofactor for aPC and accelerate its anticoagulant activity. The PS that is bound to C4b-BP does not possess any anticoagulant activity because in cannot interact with aPC.

A deficiency in PS, either congenital or acquired, increases the risk of thromboembolism because of a decrease in the anticoagulant capacity of the blood. Thrombotic episodes can occur when PS activity drops to <50% of normal.6

Congenital protein S deficiency: The prevalence of congenital PS deficiency in the general population experiencing their first venous thrombosis is approximately 1%.7 In patients with a family history of thrombophilia, the likelihood of congenital PS deficiency being the cause reaches as high as 10%.7 This autosomal dominant defect occurs in the general population in approximately 1 in 700 individuals.6 Nearly 50% of individuals with congenital PS deficiency will experience a thrombotic event before the age of 45.6 Thrombosis can sometimes occur at unusual sites, including mesenteric and axillary veins. Recurrent thrombotic events are common.6

Congenital PS deficiency can be further classified based on the measured levels of total and free PS antigen along with functional PS activity.7

• Type I PS deficiency is the most common type, representing approximately 90% of cases.6 This condition is characterized by a reduction in overall PS antigen levels. Levels of total PS in patients with type I deficiency are typically around 50% of normal while free PS and PS activity are often even lower.

• Type II PS deficiency is characterized by a reduced PS activity but with normal antigen levels of both total and free PS.

• Type III PS deficiency is characterized by a disproportionately reduced PS activity and free antigen levels in individuals with normal total PS levels.

Acquired protein S deficiency: Acquired PS deficiency occurs more frequently than congenital deficiency.6-8 Acquired deficiency can occur as the result of decreased PS synthesis or increased consumption. PS synthesis can be diminished in a number of conditions including oral anticoagulant therapy, vitamin K deficiency, liver disease, chemotherapy, and L-asparaginase therapy. PS consumption can occur during disseminated intravascular coagulation (DIC), acute thrombosis, polycythemia vera, sickle cell disease, and essential thrombocythemia. Protein S levels are also dependent, in part, on age, sex, and hormonal status, tending to be lower in the young and lower in women than in men. Levels may be further decreased in premenopausal women on oral contraceptive agents. Protein S values decrease with increasing gestational age. Free PS antigen and PS activities are also often diminished in nephrotic syndrome.7

Warfarin-induced skin necrosis has been reported in some cases of PS deficiency.8 Infants born with homozygous or doubly heterozygous PS deficiency are usually born with purpura fulminans of the newborn, a devastating condition requiring immediate treatment.8

Specimen Requirements

Specimen

Plasma, frozen

Volume

3 mL

Minimum Volume

2 mL

Container

Blue-top (sodium citrate) tube

Patient Preparation

Avoid warfarin (Coumadin®) therapy for two weeks and heparin therapy for two days prior to the test. Do not draw from an arm with a heparin lock or heparinized catheter.

Collection

Citrated plasma samples should be collected by double centrifugation. Blood should be collected in a blue-top tube containing 3.2% buffered sodium citrate.1 Evacuated collection tubes must be filled to completion to ensure a proper blood to anticoagulant ratio.2,3 The sample should be mixed immediately by gentle inversion at least six times to ensure adequate mixing of the anticoagulant with the blood. A discard tube is not required prior to collection of coagulation samples, except when using a winged blood collection device (ie, "butterfly"), in which case a discard tube should be used.4,5 When noncitrate tubes are collected for other tests, collect sterile and nonadditive (red-top) tubes prior to citrate (blue-top) tubes. Any tube containing an alternate anticoagulant should be collected after the blue-top tube. Gel-barrier tubes and serum tubes with clot initiators should also be collected after the citrate tubes. Centrifuge for 10 minutes and carefully remove 2/3 of the plasma using a plastic transfer pipette, being careful not to disturb the cells. Deliver to a plastic transport tube, cap, and recentrifuge for 10 minutes. Use a second plastic pipette to remove the plasma, staying clear of the platelets at the bottom of the tube. Transfer the plasma into a LabCorp PP transpak frozen purple tube with screw cap (LabCorp N° 49482). Freeze immediately and maintain frozen until tested. To avoid delays in turnaround time when requesting multiple tests on frozen samples, please submit separate frozen specimens for each test requested.

Please print and use the Volume Guide for Coagulation Testing to ensure proper draw volume.

Storage Instructions

Freeze.

Causes for Rejection

Gross hemolysis; clotted specimen; frozen specimen thawed in transit; improper labeling

Clinical Information

Special Instructions

If the patient's hematocrit exceeds 55%, the volume of citrate in the collection tube must be adjusted. Refer to Coagulation Collection Procedures for directions.

Footnotes

1. Adcock DM, Kressin DC, Marlar RA. Effect of 3.2% vs 3.8% sodium citrate concentration on routine coagulation testing. Am J Clin Pathol. 1997 Jan; 107(1):105-110. 8980376
2. Reneke J, Etzell J, Leslie S, NG VL, Gottfried EL. Prolonged prothrombin time and activated partial thromboplastin time due to underfilled specimen tubes with 109 mmol/L (3.2%) citrate anticoagulant. Am J Clin Pathol. 1998 Jun; 109(6):754-757. 9620035
3. National Committee for Clinical Laboratory Standardization. Collection, Transport, and Processing of Blood Specimens for Coagulation Testing and General Performance of Coagulation Assays; Approved Guideline. 5th ed. Villanova, Pa: NCCLS; 2008. Document H21-A5:28(5).
4. Gottfried EL, Adachi MM. Prothrombin time and activated partial thromboplastin time can be performed on the first tube. Am J Clin Pathol. 1997 Jun; 107(6):681-683. 9169665
5. McGlasson DL, More L, Best HA, Norris WL, Doe RH, Ray H. Drawing specimens for coagulation testing: Is a second tube necessary? Clin Lab Sci. 1999 May-Jun; 12(3):137-139. 10539100
6. Adcock DM, Bethel MA, Macy PA. Coagulation Handbook. Aurora, Colo: Esoterix−Colorado Coagulation; 2006.
7. Zwicker J, Bauer KA. Thrombophilia. In: Kitchens CS, Alving BM, Kessler CM, eds.Consultative Hemostasis and Thrombosis. Philadelphia, Pa: WB Saunders Co; 2002:181-196.
8. Triplett DA. Thrombophilia. In: McClatchey KD, ed. Clinical Laboratory Medicine 2nd ed. Philadelphia, Pa: Lippincott Williams and Wilkins; 2002:1050-1056.

LOINC® Map

Order Code Order Code Name Order Loinc Result Code Result Code Name UofM Result LOINC
117754 Protein S Panel 164518 Protein S, Total % 27823-4
117754 Protein S Panel 164519 Protein S, Free % 27821-8
117754 Protein S Panel 164526 Protein S-Functional % 27822-6

For Providers

Please login to order a test.

 

© 2017  Laboratory Corporation of America® Holdings and Lexi-Comp Inc. All Rights Reserved.

CPT Statement/Profile Statement

The LOINC® codes are copyright © 1994-2017, Regenstrief Institute, Inc. and the Logical Observation Identifiers Names and Codes (LOINC) Committee. Permission is granted in perpetuity, without payment of license fees or royalties, to use, copy, or distribute the LOINC® codes for any commercial or non-commercial purpose, subject to the terms under the license agreement found at https://loinc.org/license/. Additional information regarding LOINC® codes can be found at LOINC.org, including the LOINC Manual, which can be downloaded at LOINC.org/downloads/files/LOINCManual.pdf