Accessibility

LabCorp and its Specialty Testing Group, a fully integrated portfolio of specialty and esoteric testing laboratories.

Patient Test Information

Protein C and Protein S

  • Why Get Tested?

    To help investigate the cause of a blood clot (thromboembolism), such as a deep vein thrombosis (DVT) or pulmonary embolism (PE); to determine whether you may have a protein C or protein S deficiency

    When To Get Tested?

    When you have had an unexplained blood clot, especially when you don't have classic risk factors, have a blood clot at a young age (younger than age 50) or in an unusual location; when your newborn has a severe clotting disorder; sometimes when a close relative has an inherited protein C or protein S deficiency

    Sample Required?

    A blood sample drawn from a vein in your arm

    Test Preparation Needed?

    You must wait until your blood clot has been treated and resolves before having this test done. You may also be instructed to discontinue anticoagulant therapy. Follow any instructions you are given by your healthcare practitioner.

  • What is being tested?

    Protein C and protein S are two proteins in the blood that help regulate blood clot formation. Two separate tests for these proteins are often performed together as part of the investigation of a possible excessive clotting disorder. The tests measure the amount of each protein (antigen tests) and evaluate whether they are performing their proper functions (activity tests).

    Normally, when a body tissue or blood vessel wall is injured, a process called hemostasis begins to form a plug at the injury site to help stop the bleeding. Small cell fragments called platelets adhere to and aggregate at the site and a coagulation cascade begins as proteins called coagulation factors are activated one after the other. Eventually, a stable clot forms, preventing additional blood loss and remaining in place until the injured area has healed. The clot is then broken down when it is no longer needed. There must be an adequate amount of platelets and sufficient clotting factors and each must function normally in order for a stable clot to form.

    Proteins S acts as a principal cofactor to protein C. The two work together to help regulate and control blood clot formation by inactivating specific coagulation factors (factors V and VIII) that are required to generate and form blood clots. This has the net effect of slowing down clot formation, much like brakes slow a speeding car. Therefore, if there is not enough protein C or S or they are not functioning normally, clot formation can go unchecked, possibly leading to excessive clotting. These conditions can range from mild to severe.

    Deficient or dysfunctional protein C or protein S may be due to an underlying condition (acquired), such as liver disease, kidney disease, severe infections or cancer, or can be inherited, passed from parent to child. Both protein C deficiency and protein S deficiency are inherited in an autosomal dominant pattern. About 1 out of every 200-500 people has one normal gene and one abnormal gene (heterozygous), causing protein C deficiency. About 1 in 500 people have protein S deficiency due to heterozygous gene mutation.

    There are two types of inherited protein C deficiencies:

    • Type 1 is related to insufficient quantity.
    • Type 2 is related to abnormal function and is less common than Type 1.

    Protein S exists in two forms in the blood: free and bound to another protein, but only the free protein S is available to be a cofactor for protein C. There are three types of inherited protein S deficiencies:

    • Type 1 deficiency is due to an insufficient quantity.
    • Type 2 is due to abnormal function.
    • Type 3 is due to decreased free protein S levels, though total protein S levels are normal.
  • How is it used?

    Tests for protein C and protein S are two separate tests that are often performed together to help diagnose the cause of an inappropriate blood clot such as deep venous thrombosis (DVT) or pulmonary embolism (PE) (venous thromboembolism or VTE). Testing may be used to help investigate a possible excessive clotting disorder and determine the risk of having another blood clot, especially if you have no obvious risk factors or a family history of blood clots.

    Tests for protein C and protein S measure their function (activity) or quantity (antigen):

    • Protein C and protein S functional (activity) tests are usually ordered, along with other tests for excessive clotting, to measure their activity and evaluate their ability to regulate and slowdown blood clotting. Decreased activity may be due to a decreased amount of protein C or S or, more rarely, due to dysfunctional protein C or S
    • Depending on the functional test results, the amount of protein C antigen and free, or sometimes total, protein S antigen may be measured to determine if decrease in activity is due to decreased production or abnormal function and to help classify the type of deficiency. If the protein S or C deficiency is due to an inherited genetic change, the quantity of protein C or protein S available and the degree of activity can be used to help determine whether you have one copy (heterozygous) or two copies (homozygous) of the mutation. A homozygous mutation in protein C or protein S is rare.

    When is it ordered?

    Protein C and protein S tests may be ordered when:

    • You have had a blood clot, especially when you are relatively young (younger than 50 years old)
    • You have had a clot in an unusual location, such as the veins coming from the liver or kidney or the blood vessels of the brain
    • You have had multiple clotting episodes
    • You do not have any other obvious reasons for developing a blood clot


    Protein C and protein S levels are affected by an existing blood clot and by treatment for blood clots. Therefore, in order to determine the baseline levels, testing should be performed after your blood clot has been treated and resolves and after you have discontinued anticoagulant therapy. Usually this means that your healthcare practitioner will treat your DVT or VTE to eliminate the immediate health risk from the blood clot and then order the tests several weeks or months later to help determine the cause of your blood clot.

    Testing is typically repeated on another occasion when a test that shows decreased activity or quantity of protein C or protein S. If an acquired deficiency is identified, protein C or protein S levels may be re-checked occasionally as the underlying condition progresses or is resolved.

    Protein C and S tests may be ordered when a newborn has a severe clotting disorder, such as disseminated intravascular coagulation (DIC) or purpura fulminans.

    Protein C and protein S tests may sometimes be ordered when you have a close relative with an inherited protein C or protein S deficiency, especially if your relative has a severe form or had their first VTE at a young age.

    What does the test result mean?

    Normal activity and level of protein C and protein S usually indicate adequate clotting regulation.

    Low protein C or protein S level or activity indicates blood clotting is not sufficiently regulated and there is an increased risk of developing a clot that blocks the flow of blood in the veins.

    • The degree of blood clotting risk depends on the extent of the deficiency and/or dysfunction of the protein.
    • Low levels may result from the body not producing enough or using up too much of the proteins or producing proteins that do not function properly.
    • Low amounts or dysfunctional proteins may be cause by underlying acquired conditions or, less commonly, inherited (genetic) disorders.


    Acquired deficiencies

    Conditions causing low protein C and protein S that develop later in life (you are not born with them) may be mild and temporary or have variable severity and be acute, chronic, or progressive. The following are some examples:

    • Both proteins are produced in the liver and production depends on vitamin K. Therefore low levels may be due to:
      • Liver disease
      • Vitamin K deficiency
      • Warfarin (Coumadin®) anticoagulant therapy (a vitamin K antagonist)
    • Conditions such as disseminated intravascular coagulation (DIC) that cause clotting and bleeding simultaneously throughout the body use up clotting factors, including protein C and protein S, at an increased rate.
    • Severe infections
    • Conditions that cause inflammation
    • Kidney disease
    • Cancers and certain chemotherapy
    • HIV
    • Pregnancy


    Inherited deficiencies

    Inherited mutations in the genes that code for the production of protein C and protein S are relatively uncommon. They can result in:

    • Decreased production of protein C or protein S
    • Abnormal protein C or S that cannot function normally
    • Abnormal protein S that is cleared more rapidly by the body (Type 3 deficiency)


    When these mutations occur, they are independent of each other and the mutation is in one or the other gene (protein C or protein S). Mutations in the gene may occur in one gene copy (heterozygous) or two gene copies (homozygous). A mutation in one gene copy raises the risk of developing a DVT and/or VTE a moderate amount, but a mutation in two gene copies can cause severe clotting and may cause life-threatening purpura fulminans or DIC in the newborn. This requires a lifetime of vigilance against recurrent blood clots. Homozygous mutations in protein C or protein S are rare.

    Once an inherited deficiency is confirmed, your healthcare practitioner will manage accordingly when you are in situations that increase your risk of clotting, such as surgery, chemotherapy for cancer, or oral contraceptive use.

    There are three types of inherited protein S deficiencies associated with being heterozygous for protein S deficiency. People who are heterozygous for protein S deficiency have a significantly increased risk for VTE. Results that may be seen with the three types of deficiency are summarized below. The most common types are 1 and 3.

    Type of
    Deficiency
    Free protein S Total protein S antigen Total protein S Activity
    1 Decreased Decreased Decreased
    2 Normal Normal Decreased
    3 Decreased Normal Decreased

    Elevated protein C and/or elevated protein S are not usually associated with medical problems and are not considered clinically significant.

    What other tests might be ordered?

    A healthcare practitioner will also likely order other tests to look for underlying diseases or conditions, such as liver disease, vitamin K deficiency, or cancer, that may cause inappropriate blood clotting (bleeding or thrombosis). Examples of other tests that may be used to investigate excessive clotting include:

    Is there anything else I should know?

    If other factor deficiencies, such as decreased antithrombin, or inherited conditions such as Factor V Leiden or prothrombin 20210 mutation are concomitantly present, the risk of blood clots is increased.

    How is a protein C or protein S deficiency treated?

    If you have not experienced a blood clot, you may not need treatment. Standard anticoagulation therapy may be prescribed if you do experience a blood clot. It stops a blood clot from growing bigger while the body slowly reabsorbs it and also helps prevent new clots from forming. Treating and/or resolving underlying conditions and avoiding other risk factors, such as smoking, can decrease risk of blood clots.

    When necessary, fresh frozen plasma, which contains protein C and protein S, can be given as a short-term preventive measure (for instance, before a surgical procedure), but this is not a treatment that can be used on a daily basis.

    A protein C concentrate was approved by the FDA in 2007 for use in patients with protein C deficiency, and it is used immediately for treatment in infants who suffer from severe protein C deficiency and develop purpura fulminans. However, its use in other populations remains controversial.

    I am on anticoagulant therapy. Can I still have this test done?

    If you are on anticoagulation therapy, your healthcare provider may need to consult an expert on coagulation testing and decide if the protein C and/or protein S activity assay can be reliably performed and interpreted. Anticoagulant drugs may either alter protein C and protein S levels or interfere with the protein C and protein S activity assays; therefore, the treatment may have to be stopped for a period of time before blood samples are collected for the tests.

    Is there anything I can do to increase protein C and protein S levels?

    Not directly. If you have deficiencies that are due to a temporary condition (such as pregnancy or an infection), they should return to normal levels by themselves. If they are due to an underlying condition, like liver disease or vitamin K deficiency, then that condition must be addressed. If you have inherited protein C or protein S deficiencies or dysfunction, your healthcare provider will often advise you to concentrate on lowering other clotting risk factors. This may include not smoking and avoiding oral contraceptive use.

    Should relatives of someone with an inherited protein C or protein S deficiency be tested?

    Not necessarily. Routine screening has not been recommended because the penetrance of the genes is low. This means that even if you have the genetic change, you may or may not ever have a clotting problem. Your healthcare provider may want to order this testing, however, if you have a strong family history of a severe protein C or protein S deficiency or a history of developing a thrombosis at an early age.

  • View Sources

    Sources Used in Current Review

    (14 August 2018) Protein C and Protein S Tests. MedlinePlus. Available online at https://medlineplus.gov/lab-tests/protein-c-and-protein-s-tests/. Accessed on April 18, 2019.

    (Jan. 4, 2019) Protein C Deficiency. Medscape. Available online at https://emedicine.medscape.com/article/205470-overview. Accessed on April 18, 2019.

    (©2019) Protein S Deficiency. Indiana Hemophilia & Thrombosis Center. Available online at https://www.ihtc.org/protein-s-deficiency/. Accessed on April 21, 2019.

    Blood Clots. American Society of Hematology. Available online at https://www.hematology.org/Patients/Clots/. Accessed on April 21, 2019.

    (©2019) Protein C (Blood). University of Rochester Medical Center. Available online at https://www.urmc.rochester.edu/encyclopedia/content.aspx?contenttypeid=167&contentid=protein_c_blood. Accessed on April 21, 2019.

    (©2019) Protein C Activity, Plasma. Mayo Clinic Laboratories. Available online at https://hematology.testcatalog.org/show/CFX. Accessed on April 22, 2019.

    (©2019) Protein S Activity, Plasma. Mayo Clinic Laboratories. Available online at https://hematology.testcatalog.org/show/S_FX. Accessed on April 22, 2019.

    (2016) Protein C Deficiency. National Organization for Rare Disorders. Available online at https://rarediseases.org/rare-diseases/protein-c-deficiency/. Accessed on April 22, 2019.

    (October 2009) Protein C Deficiency. Genetics Home Reference. Available online at https://ghr.nlm.nih.gov/condition/protein-c-deficiency#statistics. Accessed on April 22, 2019.

    (October 18 2018) Congenital Protein C or S Deficiency. MedlinePlus. Available online at https://medlineplus.gov/ency/article/000559.htm. Accessed on April 22, 2019.

    Sources Used in Previous Reviews

    Thomas, Clayton L., Editor (1997). Taber's Cyclopedic Medical Dictionary. F.A. Davis Company, Philadelphia, PA [18th Edition].

    Pagana, Kathleen D. & Pagana, Timothy J. (2001). Mosby's Diagnostic and Laboratory Test Reference 5th Edition: Mosby, Inc., Saint Louis, MO.

    Gardner, B. (2001 April 3). Protein C Deficiency. Medscape Primary Care, Pediatrics Ask the Expert [Online information]. Available online at http://www.medscape.com/viewarticle/413850_print.

    Coagulation Test Panels. Florida Hospital Cancer Institute, Clinical and Research Laboratories [Online information]. Available online at http://www.fhci-labs.com/researchlabs/clinicallabs/hemostasisandthrombosis/panels.htm.

    Confusing Coagulation Test Names. UAB Coagulation Service, Univ of Alabama at Birmingham [Online information]. Available online at http://peir.path.uab.edu/coag/article_187.shtml and Protein C Activity, Activated Protein C Resistance (Screen for Factor V Leiden) at http://peir.path.uab.edu/coag/cat_index_14.shtml#191.

    Schlesinger, K. and Ragni, M. (2002). DIC, Inflammation, Sepsis And Activated Protein C (APC). Transfusion Medicine Update, Issue #3 [On-line information]. Available online at http://www.annals.org/issues/v135n5/full/200109040-00013.html.

    Chapter 132 Thrombotic Disorders, General. The Merck Manual of Diagnosis and Therapy, Section 11. Hematology And Oncology [Online information]. Available online at http://www.merck.com/pubs/mmanual/section11/chapter132/132a.htm.

    Protein C Deficiency. University of Illinois - Urbana/Champaign, Carle Cancer Center, Hematology Resource Page, Patient Resources [On-line information]. Available online at http://www-admin.med.uiuc.edu/hematology/PtProtC.htm.

    Protein S Deficiency. University of Illinois - Urbana/Champaign, Carle Cancer Center, Hematology Resource Page, Patient Resources [On-line information]. Available online at http://www-admin.med.uiuc.edu/hematology/PtProtS.htm.

    Bardi, J. (2002). Mysteries of a Therapy Unveiled. The Scripps Research Institute, News & Views [On-line Newsletter]. Available online at http://www.scripps.edu/newsandviews/e_20020617/print-ruf.html.

    Elstrom, R. (2001 October 28, Updated). Protein C. MedlinePlus Health Information, Medical Encyclopedia [On-line information]. Available online at http://www.nlm.nih.gov/medlineplus/ency/article/003659.htm.

    Elstrom, R. (2001 October 28, Updated). Protein S. MedlinePlus Health Information, Medical Encyclopedia [On-line information]. Available online at http://www.nlm.nih.gov/medlineplus/ency/article/003660.htm.

    Coagulation Test Panels. Clinical and Research Laboratories, Florida Hospital Cancer Institute [On-line information]. Available online at http://www.fhci-labs.com/researchlabs/clinicallabs/hemostasisandthrombosis/panels.htm.

    Laposata, M. & Vancott, E. (2000 January). How to work up hypercoagulability. CAP In the News [On-line Coagulation Case Study]. Available online at http://www.cap.org/CAPToday/casestudy/coag5.html.

    Venomous Bites and Stings. The Merck Manual of Medical Information-Home Edition, Section 24. Accidents and Injuries, Chapter 287 [On-line information]. Available online at http://www.merck.com/mrkshared/mmanual_home/sec24/287.jsp.

    Menta, S. (1999 Spring). The Coagulation Cascade. Physiology Disorders Evaluation, College of Medicine, Univ of Florida [On-line information]. Available online at http://www.medinfo.ufl.edu/year2/coag/title.html.

    Bauer, K. (2001). The Thrombophilias: Well-Defined Risk Factors with Uncertain Therapeutic Implications. Ann Intern Med. 2001;135:367-373 [Journal]. Available online through http://www.annals.org.

    DeLoughery, T. (1999 March 15). Tests of Hemostasis and Thrombosis. OHSU [Online student handout]. Available online at http://www.ohsu.edu/som-hemonc/handouts/deloughery/printtest.html.

    (2001 January 10, Modified). Coagulation Test Descriptions. Clinical Coagulation Laboratory, A division of Duke University Regional Referral Laboratory Services [Online information]. Available online at http://pathology.mc.duke.edu/coag/TestDes.htm.

    Pagana, Kathleen D. & Pagana, Timothy J. (© 2007). Mosby's Diagnostic and Laboratory Test Reference 8th Edition: Mosby, Inc., Saint Louis, MO. P 781-782.

    Nanda, R. (2005 April 15). Congenital protein C or S deficiency. MedlinePlus [On-line information]. Available online at http://www.nlm.nih.gov/medlineplus/ency/article/000559.htm. Accessed on 3/25/07.

    Nanda, R. (2005 April 15). Protein C. MedlinePlus [On-line information]. Available online at http://www.nlm.nih.gov/medlineplus/ency/article/003659.htm. Accessed on 3/25/07.

    Nanda, R. (2005 April 15). Protein S. MedlinePlus [On-line information]. Available online at http://www.nlm.nih.gov/medlineplus/ency/article/003660.htm. Accessed on 3/25/07.

    (© 2007). Laboratory Issues in Diagnosing Abnormalities of Protein C, Thrombomodulin, and Endothelial Cell Protein C Receptor. CAP [On-line information]. Available online through http://www.cap.org. Accessed on 3/25/07.

    (© 2007). A Review of the Technical, Diagnostic, and Epidemiological Considerations for Protein S Assays. CAP [On-line information]. Available online through http://www.cap.org. Accessed on 3/25/07.

    Dugdale, D. et. al. (Updated 2009 March 2). Protein C. MedlinePlus Medical Encyclopedia [On-line information]. Available online at http://www.nlm.nih.gov/medlineplus/ency/article/003659.htm. Accessed September 2010.

    Dugdale, D. et. al. (Updated 2010 March 28). Congenital protein C or S deficiency. MedlinePlus Medical Encyclopedia [On-line information]. Available online at http://www.nlm.nih.gov/medlineplus/ency/article/000559.htm. Accessed September 2010.

    Cuker, A. and Pollak, E. (Updated 2009 June 11). Protein C Deficiency. eMedicine [On-line information]. Available online at http://emedicine.medscape.com/article/205470-overview. Accessed September 2010.

    (Reviewed 2009 October). Protein C deficiency. Genetics Home Reference [On-line information]. Available online at http://ghr.nlm.nih.gov/condition/protein-c-deficiency. Accessed September 2010.

    (Reviewed 2009 October). Protein S deficiency. Genetics Home Reference [On-line information]. Available online at http://ghr.nlm.nih.gov/condition/protein-s-deficiency. Accessed September 2010.

    Spence, R. et. al. (Updated 2010 January 12). Hemostatic Disorders, Nonplatelet eMedicine. [On-line information]. Available online at http://emedicine.medscape.com/article/210467-overview. Accessed September 2010.

    Godwin, J. (Updated 2009 August 27). Protein S Deficiency. eMedicine [On-line information]. Available online at http://emedicine.medscape.com/article/205582-overview. Accessed September 2010.

    Pagana, K. D. & Pagana, T. J. (© 2007). Mosby's Diagnostic and Laboratory Test Reference 8th Edition: Mosby, Inc., Saint Louis, MO. Pp 781-782.

    Wu, A. (© 2006). Tietz Clinical Guide to Laboratory Tests, 4th Edition: Saunders Elsevier, St. Louis, MO. Pp 922-923, 926-927.

    National Blood Clot Alliance. Protein C deficiency. Available online at http://www.stoptheclot.org/News/article136.htm. Accessed September 2010.

    National Blood Clot Alliance. Protein S deficiency: a clinical perspective. Available online at http://www.stoptheclot.org/News/article137.htm. Accessed September 2010.

    Chen, Yi-Ben. et. al. (Updated 2013 March 3). Protein C. MedlinePlus Medical Encyclopedia. Available online at http://www.nlm.nih.gov/medlineplus/ency/article/003659.htm. Accessed October 2014.

    Gersten, T. et. al. (Updated 2012 February 8). Congenital protein C or S deficiency. MedlinePlus Medical Encyclopedia. Available online at http://www.nlm.nih.gov/medlineplus/ency/article/000559.htm. Accessed October 2014.

    Cuker, A. and Pollak, E. (Updated 2013 March 5). Protein C Deficiency. eMedicine. Available online at http://emedicine.medscape.com/article/205470-overview. Accessed October 2014.

    (Reviewed 2013 May). Protein C deficiency. Genetics Home Reference. Available online at http://ghr.nlm.nih.gov/condition/protein-c-deficiency. Accessed October 2014.

    (Reviewed 2009 October). Protein S deficiency. Genetics Home Reference.Available online at http://ghr.nlm.nih.gov/condition/protein-s-deficiency. Accessed October 2014.

    (© 1995-2014) Protein S Activity, Plasma. Mayo Medical Laboratories. http://www.mayomedicallaboratories.com/test-catalog/Clinical+and+Interpretive/80775. Accessed October 2014.

    Sadaka, F. et al. Activated protein C in septic shock: a propensity matched analysis. Critical Care 2011, 15: R89. doi:10.1186/cc10089. Available online at http://ccforum.com/content/15/2/R89. Accessed October 2014.

    Godwin, J. (Updated 2012 January 10). Protein S Deficiency. eMedicine. Available online at http://emedicine.medscape.com/article/205582-overview. Accessed October 2014.

    Pagana, K. D. & Pagana, T. J. (© 2012). Mosby's Diagnostic and Laboratory Test Reference 11th Edition: Mosby, Inc., Saint Louis, MO. Pp 767-768.

    National Blood Clot Alliance. Protein C deficiency. Available online at http://www.stoptheclot.org/News/article136.htm. Accessed October 2014.