Protein S Deficiency Profile
| Protein S Deficiency Profile | | | |
| Number | | 117754 |
| CPT | | 85305; 85306 (x2) |
| Related Information | | Hemostasis and Thrombosis Appendix Protein S Antigen Protein S:Factor VII Antigen Ratio |
| Test Includes | | Protein S, free; protein S, functional; protein S, total |
| 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. |
| Specimen | | Plasma, frozen |
| Volume | | 3 mL |
| Minimum Volume | | 2 mL |
| Container | | Blue-top (sodium citrate) tube |
Collection | | 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.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 and carefully remove the plasma
using a plastic transfer pipette, being careful not to
disturb the cells. Transfer the plasma into a LabCorp PP
transpak frozen purple tube with screw cap (LabCorp
No 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 Specimen
Collection Bulletin as a tube-filling guide. |
| Storage Instructions | | Freeze |
| Patient Preparation | | Avoid warfarin (Coumadin®) therapy for 2 weeks and heparin therapy for 2 days prior to the test. Do not draw from an arm with a heparin lock or heparinized catheter. |
| Causes for Rejection | | Gross hemolysis; clotted specimen; frozen specimen thawed in transit; improper labeling |
| Reference Interval | | Total: 58% to 150%; free: 56% to 124%; functional: 60% to 145%. In newborns, total PS levels are lower than in adults (12% to 60%). Levels gradually reach to adult ranges by 6 months of age.6 |
| 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 VLeiden mutation or some other cause can falsely lower measured PS activity levels.7 |
| Methodology | | Total PS and free PS antigen assays: Total PS is measured directly by enzyme immunoassay (EIA). The free PS is measured by EIA after C4b-BP complexed PS is precipitated out with polyethylene glycol. 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 extend 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.7,8,9 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]).8 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.7 Congenital protein S deficiency: The prevalence of congenital PS deficiency in the general population experiencing their first venous thrombosis is approximately 1%.8 In patients with a family history of thrombophilia, the likelihood of congenital PS deficiency being the cause reaches as high as 10%.8 This autosomal dominant defect occurs in the general population in approximately 1 in 700 individuals.7 Nearly 50% of individuals with congenital PS deficiency will experience a thrombotic event before the age of 45.7 Thrombosis can sometimes occur at unusual sites, including mesenteric and axillary veins. Recurrent thrombotic events are common.7 Congenital PS deficiency can be further classified based on the measured levels of total and free PS antigen along with functional PS activity.8 - Type I PS deficiency is the most common type, representing approximately 90% of cases.7 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.7,8,9 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. C4b-BP is an acute phase reactant whose concentration increases rapidly due to inflammatory conditions. This serves to increase bound PS antigen and produces a relative decrease in free PS antigen and PS activity. Conditions that can cause an increase in C4b-BP levels include pregnancy, oral contraceptive use, diabetes mellitus, systemic lupus erythematosus, AIDS, and renal allograph rejection. Free PS antigen and PS activities are also often diminished in nephrotic syndrome.8 Warfarin-induced skin necrosis has been reported in some cases of PS deficiency.9 Infants born with homozygous or doubly heterozygous PS deficiency are usually born with purpura fulminans of the newborn, a devastating condition requiring immediate treatment.9 |
| Footnotes | | - Adcock DM, Kressin DC, and Marlar RA, “Effect of 3.2% vs 3.8% Sodium Citrate Concentration on Routine Coagulation Testing,” Am J Clin Pathol, 1997, 107(1):105-10.
- Reneke J, Etzell J, Leslie S, et al, “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, 109(6):754-7.
- “National Committee for Clinical Laboratory Standardization: Collection, Transport, and Processing of Blood Specimens for Coagulation Testing and General Performance of Coagulation Assays; Approved Guideline,” Third Edition, Villanova: NCCLS Document H21-A3:11(23), 1999.
- Gottfried EL and Adachi MM, “Prothrombin Time and Activated Partial Thromboplastin Time Can Be Performed on the First Tube,” Am J Clin Pathol, 1997, 107(6):681-3.
- McGlasson DL, More L, Best HA, et al, “Drawing Specimens for Coagulation Testing: Is a Second Tube Necessary?” Clin Lab Sci, 1999, 12(3):137-9.
- Van Cott EM and Laposata M, “Coagulation,” Laboratory Test Handbook With Key Word Index, Jacobs DS, DeMott WR, and Oxley DK eds, Hudson, OH: Lexi-Comp, 2001, 327-58.
- Adcock DM, Jensen R, Johns CS, et al, Coagulation Handbook, Esoterix Coagulation, 2002.
- Zwicker J and Bauer KA, “Thrombophilia,” Consultative Hemostasis and Thrombosis, Kitchens CS, Alving BM, and Kessler CM, eds, Philadelphia, PA: WB Saunders Co, 2002, 181-96.
- Triplett DA, “Thrombophilia,” Clinical Laboratory Medicine, 2nd ed, McClatchey KD, ed, Philadelphia, PA: Lippincott Williams and Wilkins, 2002, 1050-6
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