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What is being tested?

Proteins C and S help adjust the rate of blood clot formation. When a blood vessel or tissue is injured, the body initiates the coagulation cascade - a step by step process involving the activation of up to 20 protein factors - which results in the formation of a stable blood clot. This clot prevents additional blood loss and protects the injury until it heals. Once it is no longer needed other factors break the clot down so that it can be removed.

Thrombin is a clotting factor that can accelerate or decelerate blood clot formation by promoting or inhibiting its own activation. It forms a feedback loop that uses Protein C and Protein S to slow down the coagulation cascade. Thrombin first combines with a protein called thrombomodulin, then activates Protein C. This activated Protein C (APC) then combines with Protein S (a cofactor) and together they work to degrade coagulation factors VIIIa and Va (these activated factors are required to produce thrombin). This has the net effect of slowing down the generation of new thrombin and inhibiting further clotting.

If there is not enough Protein C or Protein S, or if either one is not functioning normally, then thrombin generation goes on largely unchecked. This can lead to excessive or inappropriate clotting that may block the flow of blood in the veins (VTE - venous thromboembolism) and, more rarely, in the arteries.

Problems with Protein C and Protein S can be inherited or acquired. There are two types of Protein C deficiencies - type 1 is related to quantity and type 2 to abnormal function. Protein S exists in 2 forms, free and bound, but only the free Protein S is available to combine with Protein C. There are 3 types of Protein S deficiencies. Type 1 deficiency is due to an insufficient quantity, type 2 to abnormal function, and type 3 to a shift from free Protein S to bound Protein S.

Decreased Protein C and Protein S quantity 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, a shortage of vitamin K, or 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 throughout the body use up clotting factors, including Protein C and Protein S, at an increased rate, and so, decrease their concentrations in the blood.

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

  • a decreased level of Protein C or Protein S being produced
  • an abnormal protein that cannot bind properly to its cofactor (C or S)
  • an abnormal protein which when combined, does not degrade factors VIIIa and Va normally.


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). Changes in the gene may be heterozygous (one mutated copy of the C or S gene) or homozygous (two changed copies of C or S). A heterozygous change raises the risk of developing a VTE a moderate amount but a homozygous change in either 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.

How is it used?

Tests for Protein C and Protein S may look at their function (activity) or quantity. They are usually used to help diagnose the cause of a venous thromboembolism (VTE) – especially if the blood clot is 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 cerebral veins. While immediate treatment of the VTE does not depend on the test result, your doctor will want to determine its cause and the likelihood of recurrent clotting once your condition has stabilised.

Functional tests for Protein C and free Protein S are usually requested with other tests for excessive coagulation, to screen for sufficient, normal factor activity. Based on those results, quantities of Protein C and Protein S are often measured to look for decreased production due to an acquired or inherited condition and to classify the type of deficiency. If the shortage is due to an inherited genetic change, the quantity of Protein C or Protein S available and its degree of activity can be used to help determine whether a person is heterozygous or homozygous.

A test that shows decreased activity or quantity of Protein C or Protein S should usually be repeated on another occasion before a diagnosis is made because there are a variety of conditions that can cause temporary changes in the level and function of Proteins C and S. If an acquired deficiency is identified, Protein C or Protein S concentrations may be monitored occasionally as the underlying condition progresses – as may happen with liver disease – or, is resolved – as may happen with Vitamin K deficiency. An inherited change is usually not monitored but your doctor will keep it in mind when you are exposed to situations that increase your risk of clotting, such as surgery, chemotherapy for cancer, or oral contraceptive use.

When is it requested?

Protein C and Protein S tests are requested when you have had a thrombotic episode, especially when you are relatively young (less than 50 years old) and/or do not have any other obvious reasons for developing a blood clot. Protein C and Protein S tests should not, however, be requested for at least 10 days after the episode and they should not be used while you are on anticoagulant therapy.

Usually this means that your doctor will treat your venous thromboembolism (VTE), eliminate the immediate blood clotting threat and put you on a limited course of anticoagulant therapy (often about 3 to 6 months). During this time period, your doctor may request other tests to look for underlying diseases or conditions such as liver disease, vitamin K deficiency, or cancer that may causing inappropriate blood clotting.

When your situation is stable, your doctor will often use Protein C and free Protein S function/activity levels, along with other tests associated with excessive coagulation, to help determine the cause of the thrombus and to help evaluate your risk of recurrence.

Protein C and Protein S concentrations (quantity) may be measured with, or after, function/activity levels to determine whether a sufficient amount of each is being produced, to determine the severity of any deficiencies, and to classify the type of deficiency. When an acquired condition is identified, Protein C and/or Protein S levels may be occasionally monitored when your doctor wants to evaluate the progress or resolution of the condition (to see if the protein levels have decreased further or returned to near normal levels).

Although Protein C and Protein S tests are not recommended as routine screens, they may sometimes be measured in close relatives of someone who has 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 result mean?

Elevated levels of Protein C and Protein S are not usually a problem as long as the protein is functional and, in the case of Protein S, free. If both the activity and the concentrations of Protein C and Protein S are normal, it usually indicates adequate clotting regulation. If the activity of Protein C or Protein S is low then it is likely that that protein is not functioning normally. If the protein is dysfunctional or if the quantity of Protein C or Protein S is insufficient, due to decreased production or to increased use, the coagulation cascade will not be sufficiently regulated. This increases the risk of developing a VTE, but the severity of the risk depends on how abnormal and how deficient the protein is.

As noted above, there are three types of Protein S deficiency, which are distinguished on the basis of the laboratory test results. The three types are summarised below.


Is there anything else I should know?

If other factor deficiencies such as decreased antithrombin, or inherited conditions, such as Factor V mutation (Leiden) or Prothrombin 20210 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 measure when a patient is having a necessary surgical procedure. There is also a concentrate of Protein C available that can be used to provide temporary protection.

Common questions

  • 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, that condition must be addressed. If you have inherited Protein C or Protein S deficiencies or dysfunction your doctor will often advise you to concentrate on lowering other clotting risk factors, such as 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.


  • 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 doctor might choose to use genetic testing 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.

Last Updated: Thursday, 1st June 2023

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