Free Protein S

Discovered in Seattle in 1979, Protein S is a vital anticoagulant that aids activated protein C (APC) in regulating blood clot formation by inactivating factors Va and VIIIa. 

Primarily synthesized in the liver, and also in megakaryocytes and endothelial cells, Protein S is vitamin K-dependent and crucial for maintaining hemostasis. 

It exists in two forms in the plasma: free (unbound) and bound to complement C4b-binding protein (C4BP). The free form, making up 40% of total Protein S, is biologically active and essential for its anticoagulant function. 

Deficiency in Protein S, which can be hereditary due to mutations in the PROS1 gene or acquired through conditions like liver disease or vitamin K deficiency, leads to an increased risk of venous thromboembolism (VTE). 

Proper diagnosis involves measuring both free and total Protein S levels, with free Protein S assays being the most reliable indicator of functional Protein S activity.

What is Protein S? [6., 8.] 

Discovered in Seattle in 1979 and then named for the city, protein S is an anticoagulant that aids activated protein C (APC) in regulating blood clot formation by inactivating factors Va and VIIIa. 

The glycoprotein Protein S is primarily synthesized in the liver, but also in megakaryocytes and endothelial cells. [1.] As a vitamin K-dependent protein, it is essential for maintaining physiological hemostasis.

Deficiency in protein S impairs this regulatory function, leading to an increased risk of excessive blood clotting, known as thrombophilia, and venous thromboembolism (VTE). 

Protein S deficiency seems to manifest specifically in venous thrombosis; evidence is lacking that points to it as a causal factor for arterial thrombosis.  

The condition can be hereditary, due to mutations in the PROS1 gene, or acquired, often associated with liver disease, nephrotic syndrome, or vitamin K deficiency. 

Hereditary Protein S deficiency is autosomal dominant, so both heterozygous and homozygous individuals will develop thrombosis.  [10.] 

Protein S deficiency typically manifests as VTE, and management involves anticoagulation therapy. Proper care coordination among the interprofessional healthcare team is essential for effective management and improved patient outcomes.

Very high levels of protein S have paradoxically been linked to increased risk of thrombosis; it has also been associated with obesity and chronic inflammation. [9.] 

Interestingly, Protein S has also been identified as a stimulator of phagocytosis of apoptotic cells; by binding to the phosphatidylserine portions on the surface of apoptotic cells, it stimulates phagocytosis of those cells by macrophages. [2.] 

What is Free Protein S? [3., 4.] 

Free Protein S is the free, or unbound, form of Protein S. Because it is not bound to any other proteins in the bloodstream, it is able to bind to activated protein C, making it biologically active.  

In contrast, bound Protein S is also found in the blood; bound Protein S is the Protein S molecule complexed with complement regulatory protein, complement C4b-binding protein (C4BP).  

Approximately 50-60% of the protein S in human plasma exists in a noncovalent complex with C4BP. [5.] This binding suggests a potential regulatory role in the complement system, although the exact function of this interaction is not fully understood. 

Importantly, when protein S is bound to C4BP, it loses its ability to act as a cofactor for APC, thereby diminishing its anticoagulant activity. 

Protein S Deficiency [8.] 

Deficiency in protein S, whether inherited or acquired, disrupts the balance of coagulation factors, leading to an increased risk of thromboembolic events such as deep vein thrombosis (DVT) and pulmonary embolism (PE). 

Thrombosis can occur when protein S function drops below 50% of normal. [1.] 

There are 3 recognized types of inherited protein S deficiency.

Causes of Protein S Deficiency

Inherited protein S deficiency is typically an autosomal dominant disorder linked to mutations in the PROS1 gene on chromosome 3q11.1. 

Acquired protein S deficiency can result from liver disease, infection, inflammation, nephrotic syndrome, chemotherapy, pregnancy, and the use of oral contraceptives or vitamin K antagonists like warfarin. 

Proper diagnosis involves measuring total and free protein S levels, and managing the condition requires anticoagulation therapy, often involving a coordinated interprofessional healthcare approach to ensure optimal patient outcomes.

Three Types of Inherited Protein S Deficiency [1., 8.] 

The three types of protein S deficiency are: 

• Type I (low total and free protein S levels): this is the most common type of inherited Protein S deficiency.

• Type II (normal levels but low activity)

• Type III (normal total protein S but low free protein S and activity)

Laboratory Testing for Free Protein S

Diagnosing protein S (PS) deficiency involves assessing its activity and antigen levels in plasma, which is crucial for understanding a patient's thrombotic risk. 

Three main assays are used: the protein S activity assay, free protein S antigen assay, and total protein S antigen assay, each with specific advantages and limitations.

Protein S Activity Assay [7., 10.]

This clot-based test measures the functional capacity of Free Protein S.  Specifically, it assesses the ability of protein S to act as a cofactor for activated protein C (APC) to inactivate coagulation factors Va and VIIIa,  

It is difficult to perform, has high sensitivity but moderate specificity.  It can also be influenced by various preanalytical and biological factors, such as lupus anticoagulants and factor V Leiden mutations, leading to potential false low values.

Antigen Assays [7., 10.] 

Free Protein S Antigen Assay

Considered the most reliable test, this immunological assay uses enzyme-linked immunosorbent assay (ELISA) technology to measure the unbound, functionally active form of protein S. 

It is less affected by external factors and has a lower rate of false results compared to the activity assay. 

Free protein S antigen can serve as a surrogate marker for PS activity, accurately identifying most PS deficiencies.

Total Protein S Antigen Assay

This assay measures both free and bound protein S levels in plasma, using the enzyme-linked immunosorbent assay (ELISA) method. 

While it can help differentiate types of PS deficiency, it is less useful as a primary diagnostic tool because total PS levels can remain normal in some hereditary deficiencies and acquired conditions.

Test Information, Sample Collection, and Preparation

Protein S testing is a blood test that requires a venipuncture.  

Typically, no special preparation is required, although individuals taking certain medications or supplements should consult with the ordering provider prior to sample collection.

Interpretation of Test Results

Optimal Levels of Free Protein S

Optimal levels of free Protein S should be determined within the context of an individual’s family and personal medical history, genetic information, and any other relevant information.  

One lab reports the following ranges for free protein S: 61-136% [1.] 

The same laboratory reports the following reference ranges for additional protein S testing: [1.] 

Total protein S: 60-150%

Functional protein S: 63-140%

Clinical Significance of Elevated Free Protein S [9.] 

High free protein S levels may or may not be clinically significant; results should be interpreted in the context of an individual’s health history.  

High free protein S levels above the 97.5th percentile have demonstrated an increased risk of venous thrombosis. [9.] 

Higher protein S levels have been observed in overweight/obese individuals, who are at an increased risk of venous thrombosis due to chronic inflammation.

Clinical Significance of Decreased Free Protein S 

Low free protein S levels may indicate an inherited or acquired protein S deficiency.  Low levels can also be  seen in conditions of extreme coagulation such as disseminated intravascular coagulation.  

Free Protein S Related Biomarkers

In addition to Free Protein S, several other biomarkers play crucial roles in the coagulation cascade and are closely associated with thrombotic disorders. Understanding these related biomarkers is essential for a comprehensive evaluation of thrombotic risk and the diagnosis of underlying conditions.

Total Protein S and Protein S Activity

Protein S (PS) Activity Assay measures PS's cofactor function for APC; however, it is prone to technical issues.

The total PS Antigen Assay measures both free and bound PS; less commonly used due to cost and limited additional information, although it can provide additional information regarding protein S deficiency.  

Protein C [8.] 

Protein C is a vitamin K-dependent glycoprotein that acts as a natural anticoagulant. It is activated by thrombin in the presence of its cofactor, Protein S, and subsequently inactivates coagulation factors Va and VIIIa, thereby inhibiting thrombin formation. 

Deficiencies in Protein C can lead to an increased risk of thrombotic events, and testing for Protein C levels is often performed in conjunction with Free Protein S testing.

FAQ: Free Protein S

What is Free Protein S?

Free Protein S is a form of Protein S that is not bound to other proteins in the blood. Protein S is a vitamin K-dependent plasma protein that plays a crucial role in regulating blood clotting by acting as a cofactor to activated Protein C.

What is the Function of Free Protein S in the Body?

Free Protein S functions as a natural anticoagulant. It works with Protein C to inactivate factors Va and VIIIa, preventing excessive blood clotting and maintaining the balance between clot formation and dissolution.

How is Free Protein S Measured?

Free Protein S is measured through a blood test. The test specifically quantifies the levels of Protein S that are not bound to other proteins (such as C4b-binding protein) in the blood, providing an accurate assessment of the anticoagulant activity.

What is a Normal Free Protein S Level?

Normal levels of free Protein S can vary based on age, sex, and specific laboratory standards. 

Generally, normal ranges for adults are approximately 60-150% of the normal control value.

What Do Low Levels of Free Protein S Indicate?

Low levels of free Protein S can indicate:

• Hereditary Protein S deficiency: A genetic disorder that increases the risk of developing abnormal blood clots (thrombosis).

• Acquired Protein S deficiency: Can be due to various conditions, such as liver disease, vitamin K deficiency, pregnancy, use of oral contraceptives, or certain medications.

• Disseminated intravascular coagulation (DIC): A condition characterized by widespread clotting and bleeding in the body.

What Do high Levels of Free Protein S Indicate?

High levels of free Protein S are rare and usually not clinically significant. They might occur in certain conditions but typically do not pose health risks.

How are Abnormal Free Protein S Levels Managed?

Management of abnormal free Protein S levels depends on the underlying cause:

• Low levels:some text
  • Thrombosis prevention: Use of anticoagulant medications to prevent blood clots.

• Address underlying conditions: Treating liver disease, adjusting medications, or managing vitamin K deficiency.

• Genetic counseling: For hereditary Protein S deficiency, genetic counseling may be recommended.

• High levels: Typically, no specific treatment is needed unless associated with an underlying condition.

Can Lifestyle Changes Affect Free Protein S Levels?

Lifestyle changes can help support overall health by reducing coagulation tendency through the following measures: 

• Diet: eating a balanced diet rich in vitamins and minerals, including vitamin K can help balance coagulation 

• Regular exercise: physical activity can help maintain overall cardiovascular health and may reduce the risk of thrombotic effects

• Avoiding smoking and excessive alcohol: both can affect blood clotting mechanisms

• Regular medical check-ups: Monitoring health conditions that could impact Protein S levels.

Where Can I Find More Information About Free Protein S and Related Conditions?

For more information about free Protein S and related conditions, consider consulting:

• Healthcare providers: Medical professionals can provide personalized advice and diagnosis.

• Scientific literature: Research articles and reviews on Protein S and its role in blood clotting.

• Reputable health organizations: Websites of organizations such as the National Institutes of Health (NIH), American Heart Association (AHA), and American Society of Hematology (ASH).

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