Patient Test Information

Protein C and Protein S

Also known as:

Protein C Activity; Protein C Level; Protein S Activity; Protein S Level

Formal name:

Protein C, Functional or Antigen; Protein S, Functional or Antigen (Free or Total)

Related tests:

Factor V Leiden Mutation and PT 20210 Mutation; Homocysteine; Lupus Anticoagulant Testing; Antithrombin

Board approvedAll content on Lab Tests Online has been reviewed and approved by our Editorial Review Board.

Why Get Tested?

To help evaluate inappropriate blood clot formation (thrombotic episode or thromboembolism); 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; 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 at least 10 days after a thrombotic episode and be off oral warfarin (Coumadin®) anticoagulant therapy for 2 weeks before having this test done. (See also Common Questions #1.)

How is it used?

Tests for protein C and protein S are two separate tests that are often performed together to help investigate a possible excessive clotting (hypercoagulable) disorder and/or to help diagnose the cause of an inappropriate blood clot such as deep venous thrombosis (DVT) or a venous thromboembolism (VTE).

Normally, protein S combines with protein C and together they help control blood clot formation. However, if there is not enough protein C or S or they are not functioning normally, clot formation can go unchecked, possibly leading to an excessive clotting disorder.

Testing is used to evaluate people who have unexplained blood clots or a family history of blood clots, especially if the blood clot occurs in a relatively young person (less than 50 years old) or has formed in an unusual location, such as the veins leading to the liver or kidney or the blood vessels of the brain. It may also be used when someone has had multiple miscarriages. While immediate treatment of the VTE does not depend on the test result, a health practitioner will want to determine the cause and the likelihood of recurrent clotting once the affected person's condition has stabilized.

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

  • Functional tests for protein C and protein S are usually ordered, along with other tests for excessive clotting, to screen for normal factor activity.
  • Based on the functional test results, quantities of protein C antigen and free, or sometimes total, protein S antigen may be measured to look for decreased production due to an acquired or inherited condition, to determine the severity, and to classify the type of deficiency. For protein S, the free protein antigen test is recommended rather than an activity test for initial detection of an inherited deficiency because there are other conditions that can interfere with functional testing. If the protein S or C shortage is due to a rare inherited genetic change, the quantity of protein C or protein S available and the degree of activity can be used to help determine whether a person has one copy (heterozygous) or two copies (homozygous) of the mutation.

A health 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).

When is it ordered?

Protein C and protein S tests are ordered when a person has had a thrombotic episode or thromboembolism, especially when the affected person is relatively young (less than 50 years old) and/or does not have any other obvious reasons for developing a blood clot.

Protein C and protein S tests should not, however, be ordered for at least 10 days after the episode, and they should not be ordered while a person is on oral warfarin (Coumadin®) anticoagulant therapy (see Common Questions #1). Usually this means that the health practitioner will treat a person's DVT or VTE, eliminate the immediate blood clotting threat, and put the person on a limited course of anticoagulant therapy (often about 3 to 6 months).

When the person's situation has stabilized, the health practitioner will often order protein C and free protein S function/activity tests, along with other tests associated with excessive clotting, to help determine the cause of the blood clot and to help evaluate the risk of recurrence.

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.

A test that shows decreased activity or quantity of protein C or protein S should be repeated on another occasion before a diagnosis can be made. 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. Once an inherited deficiency is confirmed, the health practitioner will keep it in mind when the patient is exposed to situations that increase his or her risk of clotting, such as surgery, chemotherapy for cancer, or oral contraceptive use.

Although protein C and protein S tests are not recommended as routine screens, they may sometimes be ordered when someone has a close relative with an inherited protein C or protein S deficiency, especially if the person affected has a severe form or had their first VTE at a young age.

What does the test result mean?

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

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

Low protein C or protein S level or activity can result in excessive or inappropriate blood clotting. If the protein is dysfunctional (normal levels of protein, but it does not work correctly), the coagulation process will not be sufficiently regulated. Either situation can lead to an increased risk of developing a clot that blocks the flow of blood in the veins, but the severity of the risk depends on the magnitude of the deficiency and/or the degree of dysfunction of the protein.

Acquired deficiencies

Low protein C and protein S may be related to insufficient production or to increased use. Since both proteins are produced in the liver and are vitamin K-dependent, liver disease, vitamin K deficiency, or warfarin (Coumadin®) anticoagulant therapy that opposes vitamin K may result in reduced protein C and/or protein S levels. 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 and so decrease their levels in the blood.

Low protein C and low protein S may be seen with severe infections, inflammatory conditions, kidney disease, cancers, treatment with certain chemotherapeutic agents, HIV, during pregnancy, immediately following a thrombotic episode, and with warfarin (Coumadin®) anticoagulant therapy. These conditions reflect the decreased production or increased use of protein C and/or protein S. They may be mild and temporary (as with pregnancy) or have variable severity and be acute, chronic, or progressive.

Inherited deficiencies

Although inherited mutations in the genes that produce protein C and protein S are relatively rare, they can result in:

  • Decreased production of protein C or protein S
  • Abnormal protein C or S that cannot bind properly to the other to form a functional activated protein C complex
  • Abnormal protein that can bind and form a protein C complex, but the complex is not capable of inactivating specific coagulation factors VIII and V as it normally does
  • Abnormal protein S that is cleared more rapidly by the body, as seen in Type 3 deficiency

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

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 10 fold 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
Free protein STotal protein S antigenTotal protein S Activity
1 Decreased Decreased Decreased
2 Normal Normal Decreased
3 Decreased Normal Decreased

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 also present, the effects of a protein C or protein S deficiency can be exacerbated.

Fresh frozen plasma contains protein C and protein S, and it can be used as a short-term preventative when a patient is having a surgical procedure.

Activated protein C is being investigated as therapy for the treatment of patients with sepsis, but this agent has generally not been used in patients with protein C deficiency. A protein C concentrate was approved by the FDA for use in patients with protein C deficiency. However, its use remains controversial.

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 and evaluate whether they are performing their proper functions.

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 clotting factors and each must function normally in order for a stable clot to form.

Proteins C and protein S work together to help control blood clot formation. They inactivate 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. However, 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. About 1 out of every 300 people has one normal gene and one abnormal gene (heterozygous) for protein C deficiency and about 1 in 20,000 people have protein S or C deficiencies that lead to symptoms.

There are two types of inherited protein C deficiencies:

  • Type 1 is related to 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 combine with 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 low free protein S levels, though total protein S levels are normal.

Two types of tests may be used to evaluate protein C and protein S:

  • Functional tests for protein C and protein S measure their activity and evaluate their ability to regulate and slow 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.
  • Protein C and protein S antigen tests measure the amount of the protein present. Protein S antigen tests measure either free protein S or total protein S or both.

How is the sample collected for testing?

A blood sample is obtained by inserting a needle into a vein in the arm.

NOTE: If undergoing medical tests makes you or someone you care for anxious, embarrassed, or even difficult to manage, you might consider reading one or more of the following articles: Coping with Test Pain, Discomfort, and Anxiety, Tips on Blood Testing, Tips to Help Children through Their Medical Tests, and Tips to Help the Elderly through Their Medical Tests.

Another article, Follow That Sample, provides a glimpse at the collection and processing of a blood sample and throat culture.

Is any test preparation needed to ensure the quality of the sample?

You must wait at least 10 days after a thrombotic episode and be off oral warfarin (Coumadin®) anticoagulant therapy for 2 weeks before having this test done. (See also Common Questions #1.)

  1. 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.

  2. 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 lowering elevated homocysteine levels, not smoking, and avoiding oral contraceptive use. When necessary, fresh frozen plasma, which contains protein C and protein S, can be given as a short-term preventative measure (for instance, before a surgical procedure), but this is not a treatment that can be used on a daily basis.

  3. 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.