- Blue top (sodium citrate) tube
- 5 mL venous blood
Additional information
- Avoid warfarin 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
- Avoid venous stasis due to placement of tourniquet for longer than 1 minute
- Draw the blood sample avoiding excessive probing of site
- Completely fill collection tube and invert it several times to mix sample, gently
- Cap the specimen and place on ice slurry
- Send sample to lab immediately
- Protein S is one of the body’s natural anticoagulant proteins
- Synthesized in the liver, megakaryocytes, endothelial cells
- Vitamin K dependent
- Occurs in 2 forms in circulation:
- Free form (active)
- Complex form bound to complement protein C4b (inactive, 60%)
- Protein S test is an estimation of Protein S concentration in the blood
- The free form of Protein S functions as a cofactor for activated Protein C (APC) in the inhibition of factors Va and VIIIa, thus preventing extension of intravascular thrombi
- In addition to its antithrombotic activity, Protein S interacts with the complement system and plays a role in phagocytosis of apoptotic cells
- Deficiency of Protein S, either hereditary or acquired, reduces the anticoagulant effect and can result in a hypercoagulable state
- The Protein S assay is indicated in the following conditions:
- To evaluate unexplained venous thrombosis or thromboembolism, especially at younger ages (<50 yrs)
- To aid in the diagnosis of inherited or acquired deficiency of Protein S
- To evaluate clotting disorders in newborns such as disseminated intravascular coagulation or purpura fulminans
- To evaluate women with recurrent midtrimester fetal loss or other adverse pregnancy outcomes
- To evaluate persons at increased risk or having a family history of thrombosis
- To evaluate laboratory abnormalities associated with thrombosis
- Deficiency of Protein S may be caused by inherited (congenital) or acquired conditions. Inherited Protein S deficiency is an autosomal dominant disorder
- There are 3 types of congenital Protein S deficiency:
- Type I: Decreased Protein S activity, reduced synthesis of active/free Protein S, normal levels of bound Protein S
- Type II: Decreased Protein S activity, low levels of free Protein S, low levels of bound Protein S
- Type III: Decreased Protein S activity, normal levels with defective synthesis of free Protein S, normal levels of bound Protein S
- Protein S deficiency may clinically present as:
- Most common presentation is deep vein thrombosis (DVT), thrombophlebitis, and/or pulmonary embolism
- Recurrent venous thromboembolism (VTE) of lower limbs or thrombosis at other unusual sites
- DVT may present as:
- Calf pain
- Edema
- Pain on dorsiflexion of the foot (Homan’s sign)
- Swelling
- Discomfort
- Redness or discoloration at the site
- Cellulitis (uncommon)
- Pulmonary embolism (PE) may present as:
- Dyspnea
- Chest pain
- Syncope
- Cardiac palpitations
- Tachypnea
- Cyanosis
- 60-80% of heterozygous individuals present with VTE, most of the remaining persons are asymptomatic, and some never develop VTE
- Arterial thrombotic events are very rare
- Homozygous persons are characterized by rapidly fatal thrombosis in perinatal period, a condition known as purpura fulminans neonatalis
- When treating patients with symptomatic protein S deficiency, heparin or heparinoid therapy is typically indicated while warfarin (Coumadin®) therapy is initiated as warfarin may induce a hypercoagulable state when initiated and result in additional thrombosis and sometimes skin necrosis (characterized by skin and fat necrosis) which can be life threatening
- Thrombosis may be precipitated by:
- Pregnancy
- Surgery
- Trauma
- Use of oral contraceptives
- Neonatal purpura fulminans
- Commonly seen in homozygotes or double heterozygotes for protein S deficiency
- The neonate develops tender ecchymoses (subcutaneous thrombosis) on the head, trunk and extremities. These skin lesions coalesce and then slowly ulcerate leading to necrosis, often accompanied with cerebral infarction and DIC
- It rapidly progresses to gangrene and shock followed by coma and death
Additional information
- The prevalence of Protein S deficiency is 0.7% in the general population
- Protein S deficiency is 5-10 times higher in Japanese populations compared with Caucasians
- Acquired Protein S deficiency is more frequent than congenital forms. Acquired deficiency of protein S can be seen in various autoimmune disorders and inflammatory states owing to elevation of C4-binding protein
- C4b is an acute phase reactant whose concentration increases rapidly due to inflammatory conditions. Increases in bound PS antigen produces a relative decrease in free PS antigen and PS activity
- For screening purposes, estimation of free protein S antigen or APC-cofactor anticoagulant activity is better than determining total protein S antigen (free and complex form)
- Interpretation of an abnormally low protein S must be correlated with the clinical setting, anticoagulant therapy, DIC, and liver disease
- Factors interfering with test results include:
- Recent acute thrombotic event or administration of warfarin or heparin anticoagulant therapy within 2 weeks of test
- Use of oral contraceptives
- Hemolysis due to excessive probing at venipuncture site or rough handling of sample
- Vascular injury during phlebotomy (activates platelets and coagulation factors)
- Venous stasis
- Lipemic or icteric serum
- First month of life
- Incompletely filled tubes, contamination with heparin, or clotted specimens
- Related laboratory tests include
- Anticardiolipin antibody
- Antithrombin III
- Complete blood count
- Fibrinogen
- Homocysteine
- Lupus anticoagulant
- Protein C
- Protein C resistance test
- Prothrombin 20210
- DNA techniques (useful within a family with a previously established mutation)
Consult your laboratory for their normal ranges as these may vary somewhat from the ones listed below.
| Conv. (% activity) | SI units (U/mL) | |
|---|---|---|
| Adult male* | 60-150 | 0.6-1.5 |
| Adult female* | 55-140 | 0.55-1.4 |
| Pediatric* | 50-150 | 0.5-1.5 |
| Neonate* | 15-55 | 0.15-0.55 |
*Units are in % or U/mL as compared to "normal activity"
-Normals for pediatrics increase progressively with age
No clinically significant conditions are associated with an elevated protein S level.
Conditions associated with decreased Protein S levels include:
- Acquired
- Acute inflammation
- Cerebral venous thrombosis
- Chronic renal failure
- Diabetic nephropathy
- Disseminated intravascular coagulation (DIC)
- Essential thrombocythemia
- Liver disease
- Nephrotic syndrome
- Polycythemia vera
- Pregnancy
- Sickle cell disease
- Thrombotic thrombocytopenia purpura (TTP)
- Vitamin K deficiency
- Drugs
- Heparin
- L-Asparaginase therapy
- Oral contraceptives
- Warfarin
- Congenital
Conditions with an increased C4b level, which then results in a relative decrease in free Protein S antigen and Protein S activity include:
- AIDS
- Diabetes mellitus
- Use of oral contraceptives
- Pregnancy
- Renal allograph rejection
- Systemic lupus erythematosus (SLE)
- Archer KA et al. Protein s deficiency and lower-extremity arterial thrombosis: complicating a common presentation. J Am Podiatr Med Assoc. 2007 Mar-Apr;97(2):151-5.
- ARUP's Laboratories®. Protein C & S Panel, Functional. [Homepage on the Internet] ©2007. Last accessed on March 28, 2007. Available at URL: http://www.aruplab.com/guides/ug/tests/0030182.jsp
- ARUP's Laboratories®. Protein S, Total Antigen. [Homepage on the Internet] ©2007. Last accessed on March 28, 2007. Available at URL: http://www.aruplab.com/guides/ug/tests/0030112.jsp
- Dixit A et al. Roles of protein C, protein S, and antithrombin III in acute leukemia. Am J Hematol. 2006 Mar;81(3):171-4.
- eMedicine from WebMD®. Protein S Deficiency. [Homepage on the Internet] ©1996-2006. Last updated on March 31, 2006. Last accessed on March 28, 2007. Available at URL: http://www.emedicine.com/med/topic1924.htm
- Folkeringa N et al. Reduction of high fetal loss rate by anticoagulant treatment during pregnancy in antithrombin, protein C or protein S deficient women. Br J Haematol. 2007 Feb;136(4):656-61.
- Laboratory Corporation of America. Protein S Deficiency Profile. [Homepage on the internet]©2007. Last accessed on March 28, 2007. Available at URL: http://www.labcorp.com/datasets/labcorp/html/chapter/mono/cf004700.htm
- LabTestsOnline®. Protein C and Protein S. [Homepage on the Internet]©2001-2007. Last reviewed on July 18, 2005. Last accessed on March 28, 2007. Available at URL: http://www.labtestsonline.org/understanding/analytes/protein_c_and_s/glance.html
- Makris M et al. Genetic analysis, phenotypic diagnosis, and risk of venous thrombosis in families with inherited deficiencies of protein S. Blood, Vol. 95 No. 6 (March 15), 2000: pp. 1935-1941. Available at URL: http://bloodjournal.hematologylibrary.org/cgi/content/full/95/6/1935?ijkey=9MbnT/FxZrdB.