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)

This article was last modified on September 22, 2020

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D-dimer

At a Glance

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 health care practitioner.

Looking For Test Results?

Looking For Reference Ranges?

You may be able to find your test results on your laboratory’s website or patient portal. However, you are currently at Testing.com. You may have been directed here by your lab’s website in order to provide you with background information about the test(s) you had performed. You will need to return to your lab’s website or portal, or contact your healthcare practitioner in order to obtain your test results.

Testing.com is an award-winning patient education website offering information on laboratory tests. The content on the site, which has been reviewed by laboratory scientists and other medical professionals, provides general explanations of what results might mean for each test listed on the site, such as what a high or low value might suggest to your healthcare practitioner about your health or medical condition.

The reference ranges for your tests can be found on your laboratory report. They are typically found to the right of your results.

If you do not have your lab report, consult your healthcare provider or the laboratory that performed the test(s) to obtain the reference range.

Laboratory test results are not meaningful by themselves. Their meaning comes from comparison to reference ranges. Reference ranges are the values expected for a healthy person. They are sometimes called “normal” values. By comparing your test results with reference values, you and your healthcare provider can see if any of your test results fall outside the range of expected values. Values that are outside expected ranges can provide clues to help identify possible conditions or diseases.

While accuracy of laboratory testing has significantly evolved over the past few decades, some lab-to-lab variability can occur due to differences in testing equipment, chemical reagents, and techniques. This is a reason why so few reference ranges are provided on this site. It is important to know that you must use the range supplied by the laboratory that performed your test to evaluate whether your results are “within normal limits.”

For more information, please read the article Reference Ranges and What They Mean.

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.

Common Questions

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:

Antithrombin
Lupus anticoagulant and other antiphospholipid antibodies—to help diagnose antiphospholipid syndrome (APS)
Factor V Leiden and prothrombin (factor II) 20210 mutation—to detect inherited risk factors (may not be done with the first DVT but may be used if you have a recurrent blood clot)

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 health care 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 health care 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

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Protein C and Protein S