Protein S deficiency
Synonyms and keywords: Protein S deficiency disease

# Overview
Protein S deficiency is an autosomal dominant thrombophilia, which leads to an increased risk of thromboembolic events. Protein S is a vitamin K-dependent glycoprotein and plays a role in anticoagulation. It is mainly a cofactor to the activated protein C (APC), which inactivates coagulation factors Va and VIIIa and thereby controlling the coagulation cascade.

# Historical Perspective
- Protein S was first discovered and purified in Seattle, Washington in 1979, and it was arbitrarily named protein S after the initial of the city it was discovered in.
- The function of this protein was still unknown; however, it was hypothesized that protein S plays a role in activating protein C.
- Protein S deficiency was first discovered in 1984 when two related individuals with recurrent thromboembolic events and normal coagulation tests were studied. At the time, protein C deficiency was usually associated with recurrent familial thrombosis. These individuals were found to have diminished anticoagulation activity with normal coagulation tests (including a normal protein C level), and when purified human protein S was added to their plasma, effective anticoagulation was restored.

# Classification
Protein S deficiency can be subdivided into three types depending on whether the abnormality affects total protein S level, free protein S level, and/or protein S function:

# Pathophysiology
- Protein S is a natural anticoagulant that works with other proteins to regulate coagulation in the body.
- After it gets produced by the hepatocytes, endothelial cells, and megakaryocytes, protein S undergoes activation via vitamin K-dependent gamma-carboxylation.
The vitamin K-dependent gamma-carboxyalse enzyme acts by modifying the glutamic acid residues in protein S to gamma-carboxyglutamic acid residues.
These gamma-carboxyglutamic acid residues are needed to ensure calcium-dependent binding to membrane surfaces.
- The vitamin K-dependent gamma-carboxyalse enzyme acts by modifying the glutamic acid residues in protein S to gamma-carboxyglutamic acid residues.
- These gamma-carboxyglutamic acid residues are needed to ensure calcium-dependent binding to membrane surfaces.
- The now mature and activated protein S will circulate in the blood in two states:
Free protein S:
This form constitutes 30 to 40 percent of the total protein S in the body.
It is the only form that will take part in the coagulation cascade.
C4b-bound protein S: 
There is a high affinity interaction between protein S and C4b-binding protein.
C4b-binding protein is a complement regulator; hence, it is responsible for controlling the activity of protein S.
Around 70 percent of circulating protein S is in the bound form.
- Free protein S:
This form constitutes 30 to 40 percent of the total protein S in the body.
It is the only form that will take part in the coagulation cascade.
- This form constitutes 30 to 40 percent of the total protein S in the body.
- It is the only form that will take part in the coagulation cascade.
- C4b-bound protein S: 
There is a high affinity interaction between protein S and C4b-binding protein.
C4b-binding protein is a complement regulator; hence, it is responsible for controlling the activity of protein S.
Around 70 percent of circulating protein S is in the bound form.
- There is a high affinity interaction between protein S and C4b-binding protein.
- C4b-binding protein is a complement regulator; hence, it is responsible for controlling the activity of protein S.
- Around 70 percent of circulating protein S is in the bound form.
- The activated free protein S acts as a cofactor to activated protein C, and with the help of phospholipids and Ca2+, it inactivates procoagulant factor Va and factor VIIIa thereby reducing thrombin formation.
- Protein S deficiency is a hereditary disease that results from mutations in the PROS1 gene, located on chromosome 3.
- This disease usually occurs due to heterozygous gene mutations in the PROS1 gene; however, rare cases of homozygous protein S deficiencies have been reported.
- Although another gene, PROS2, has been isolated on the same chromosome 3, it does not seem to have any relevance and has since been classified as a pseudogene.

# Causes
- In addition to the common hereditary form of protein S deficiency, there are rare circumstances in which acquired causes can result in diminished protein S levels. These situations arise due to different mechanisms:
Protein S consumption:
Disseminated intravascular coagulation
Surgery
Decreased synthesis of protein S:
Liver disease
Vitamin K deficiency
Redistribution of complexed protein S:
Pregnancy
Oral hormonal contraceptives
Nephrotic syndrome
- Protein S consumption:
Disseminated intravascular coagulation
Surgery
- Disseminated intravascular coagulation
- Surgery
- Decreased synthesis of protein S:
Liver disease
Vitamin K deficiency
- Liver disease
- Vitamin K deficiency
- Redistribution of complexed protein S:
Pregnancy
Oral hormonal contraceptives
Nephrotic syndrome
- Pregnancy
- Oral hormonal contraceptives
- Nephrotic syndrome

# Differentiating Protein S Deficiency From Other Diseases
Protein S deficiency must be differentiated from other diseases that cause symptoms of DVT and pulmonary embolism such as:
- Factor V Leiden mutation
- Antithrombin III deficiency
- Protein C deficiency
- Prothrombin gene mutation
- Disseminated intravascular coagulation (DIC)
- Antiphospholipid antibody syndrome
For more information on differentiating protein S deficiency, click here.

# Epidemiology and Demographics
- The prevalence of protein S deficiency in the general population is unknown.
- However, its prevalence in individuals with a history of venous thromboembolism is approximately 900 per 100,000 individuals worldwide. 

## Age
- Patients of all age groups may be diagnosed with protein S deficiency.
- It is, however, more commonly observed among patients younger than 40 to 50 years old.

## Gender
- There is no difference in the prevalence of the disease between men and women.

## Race
- Protein S deficiency usually affects the individuals of the Asian race.
- Caucasian individuals are less likely to develop protein S deficiency.

# Risk Factors
- There are no established risk factors for protein S deficiency.
- Family history of thrombosis poses increased risk for a mutation.

# Screening
- There is insufficient evidence to recommend routine screening for protein S deficiency in the general population.
- A simple positive family history incident of thrombosis is not enough to recommend screening in an asymptomatic low risk individual.
- High risk patients with a positive family history (first degree relative with protein S deficiency or first degree relative with multiple venous thromboembolic events at an age younger than 50), warrant a screening preferably prior to initiation of the high risk events including taking oral contraceptives or pregnancy.
- The free protein S antigen assay is the best screening test.

# Natural History, Complications, and Prognosis
- If left untreated, patients with protein S deficiency are at high risk to develop life-threatening venous thromboembolic events.
- For specific complications and prognosis associated with pulmonary embolism, click here.
- For specific complications and prognosis associated with deep vein thrombosis, click here.

# Diagnosis

## Diagnostic Study of Choice
- There is no established criteria for a definitive diagnosis of protein S deficiency.
- The diagnosis of protein S deficiency is the toughest out of all the hereditary thrombophilias due to the interaction of protein S with other proteins, its complex genetic regulation, and its biologic variation.
- The diagnosis is made even more strenuous due to the relatively high prevalence of acquired protein S deficiency causes including pregnancy, liver disease, and DIC.
- Three tests are used to assess protein S in plasma:
Free protein S antigen:
Determines free protein S level in plasma
Most reliable of the three tests
Evaluates the function of protein S indirectly
ELISA technique
Total protein S antigen:
Determines both free and bound protein S
ELISA technique
Protein S activity assay:
Assesses the function of protein S as a cofactor for activated protein C
Indirectly measured based on a coagulation assay and the time to clot
Not very reliable due to inability to differentiate from factor V Leiden mutation (resistance to activated protein C)
- Free protein S antigen:
Determines free protein S level in plasma
Most reliable of the three tests
Evaluates the function of protein S indirectly
ELISA technique
- Determines free protein S level in plasma
- Most reliable of the three tests
- Evaluates the function of protein S indirectly
- ELISA technique
- Total protein S antigen:
Determines both free and bound protein S
ELISA technique
- Determines both free and bound protein S
- ELISA technique
- Protein S activity assay:
Assesses the function of protein S as a cofactor for activated protein C
Indirectly measured based on a coagulation assay and the time to clot
Not very reliable due to inability to differentiate from factor V Leiden mutation (resistance to activated protein C)
- Assesses the function of protein S as a cofactor for activated protein C
- Indirectly measured based on a coagulation assay and the time to clot
- Not very reliable due to inability to differentiate from factor V Leiden mutation (resistance to activated protein C)

## History and Symptoms
- The hallmark of protein S deficiency is venous thromboembolism.
- A positive history of a venous thromboembolic event prior to age 50, a strong family history of venous thromboembolic events, and/or a known protein S deficient family member is suggestive of a protein S deficiency.
- The most common sites of venous thromboembolism include deep vein thrombosis and pulmonary embolism. For detailed symptoms associated with protein S deficiency refer to deep vein thrombosis history and symptoms and pulmonary embolism history and symptoms.
- Less common sites of venous thromboembolism include cerebral, axillary, and mesenteric veins.

## Physical Examination
- Physical examination of patients with protein S deficiency is usually remarkable for signs of deep vein thrombosis or pulmonary embolism.
- For detailed findings associated with protein S deficiency refer to deep vein thrombosis physical examination and pulmonary embolism physical examination.

## Laboratory Findings
- A reduced concentration of serum free protein S is diagnostic of protein S deficiency; however, there is no standard cutoffs for diagnosis.
- The exact levels used to differentiate patients with protein S deficiency from those without this deficiency depends on the patient's risk factors.
Free protein S levels < 65 IU/dL are diagnostic of protein S deficiency in patients with a history of thromboembolic events or a strong family history of these events.
Lower levels of free protein S are required to diagnose patients who are asymptomatic or have no strong family history.
- Free protein S levels < 65 IU/dL are diagnostic of protein S deficiency in patients with a history of thromboembolic events or a strong family history of these events.
- Lower levels of free protein S are required to diagnose patients who are asymptomatic or have no strong family history.
- For specific laboratory findings in patients with associated pulmonary embolism, click here
- For specific laboratory findings in patients with associated deep vein thrombosis, click here.

## Electrocardiogram
- There are no specific ECG findings associated with protein S deficiency.
- For ECG findings related to pulmonary embolism, click here.

## X-ray
- There are no specific x-ray findings associated with protein S deficiency.
- For specific x-ray findings seen with pulmonary embolism, click here.

## Echocardiography or Ultrasound
- There are no specific echocardiography/ultrasound  findings associated with protein S deficiency.
- For ultrasound findings related to deep vein thrombosis, click here.
- For echocardiography findings associated with pulmonary embolism, click here.

## CT scan
- There are no specific CT scan findings associated with protein S deficiency.
- For CT scan findings related to pulmonary embolism, click here.

## MRI
- There are no MRI findings associated with protein S deficiency.

## Other Imaging Findings
- There are no other imaging findings associated with protein S deficiency.

## Other Diagnostic Studies
- There are no other diagnostic studies associated with protein S deficiency.

# Treatment

## Medical Therapy
- Patients with protein S deficiency that remain asymptomatic and have no history of venous thromboembolic events do not require medical therapy.
- Patients with an acute event of venous thrombosis require same initial medical therapy regardless of whether the cause was hereditary or not.
For management of patients suffering from pulmonary embolism, click here.
For management of patient suffering from deep venous thrombosis, click here.
- For management of patients suffering from pulmonary embolism, click here.
- For management of patient suffering from deep venous thrombosis, click here.
- Patients with protein S deficiency that suffer from a venous thromboembolic event are advised to continue anticoagulation indefinitely especially if the event was unprovoked (occurred without a preceding major risk event like surgery, trauma, oral contraceptives, and immobility).

## Surgery
- Surgical intervention is not recommended for the management of protein S deficiency.

## Primary Prevention
- There are no established measures for the primary prevention of protein S deficiency.

## Secondary Prevention
- Effective measures for the secondary prevention of protein S deficiency include:
Avoiding oral contraceptives in women
Prophylactic anticoagulation postoperatively
Considering anticoagulation during pregnancy
Education concerning signs and symptoms of venous thromboembolic events
- Avoiding oral contraceptives in women
- Prophylactic anticoagulation postoperatively
- Considering anticoagulation during pregnancy
- Education concerning signs and symptoms of venous thromboembolic events