Tests for Protein C and Protein S are usually ordered 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, the doctor will want to determine its cause and the likelihood of recurrent clotting once the affected patient's condition has stabilized.

Functional tests for Protein C and free Protein S are usually ordered, along with other tests for hypercoagulability, 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 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 the doctor 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.

Protein C and Protein S tests are ordered when a person has had a thrombotic episode or thromboembolism, especially when the affected patient 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 anticoagulant therapy. Usually this means that the doctor will treat his patient's venous thromboembolism (VTE), eliminate the immediate blood clotting threat, and put them on a limited course of anticoagulant therapy (often about 3 to 6 months). During this time period, the doctor may 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 the patient’s situation has stabilized, the doctor will often order Protein C and free Protein S function/activity levels, along with other tests associated with hypercoagulability, to help determine the cause of the thrombus and to help evaluate the 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. Typically, measurements that determine the amount of protein S include determinations of free and total Protein S levels. When an acquired condition is identified, Protein C and/or Protein S levels may be occasionally monitored when the 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 ordered on 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.

Elevated levels of Protein C and Protein S are not usually associated with medical problems. If both the activity and the concentrations of Protein C and Protein S are normal, it usually indicates adequate clotting regulation. Low levels of Protein C or Protein S can result in excessive formation of blood clots. If the protein is dysfunctional (normal levels of protein but they do 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.

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 summarized below.

Type of deficiency	Functional protein S	Free protein S antigen	Total protein S antigen
1	decreased	decreased	decreased
2	decreased	normal	normal
3	decreased	decreased	normal

Decreased concentrations of Protein C and Protein S may be seen with vitamin K deficiency, liver disease, severe infections (inflammatory conditions), renal disease, cancers, disseminated intravascular coagulation (DIC), HIV, during pregnancy, immediately following a thrombotic episode, and with warfarin or heparin 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.

If other factor deficiencies such as decreased Antithrombin, or inherited conditions, such as Factor V 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 when a patient is having a necessary surgical procedure.

Activated Protein C is being investigated as suitable therapy for the treatment of patients with sepsis, but this agent has generally not been used in patients with Protein C deficiency. Recently, a protein C concentrate was approved by the FDA for use in patients with Protein C deficiency.