Protein S deficiency
|Protein S deficiency|
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Synonyms and Keywords: Protein S deficiency disease
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.
- 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.
|Type||Total Protein S||Free Protein S||Protein S Function||Characteristics||Genetics|
|Type I||↓||↓||↓||Classic form||Usually results from missense or nonsense mutations|
|Type II||↔||↔||↓||Rare qualitative defect||Linked to missense mutations|
|Type III||↔||↓||↓||Quantitative defect||Unknown|
- 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 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: 
- Free protein S:
- 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.
- 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:
Differentiating Protein S Deficiency From Other Diseases
- 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. 
- 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.
- Protein S deficiency usually affects the individuals of the Asian race.
- Caucasian individuals are less likely to develop protein S deficiency.
- There are no established risk factors for protein S deficiency.
- Family history of thrombosis poses increased risk for a mutation.
- 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.
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:
- Total protein S antigen:
- Determines both free and bound protein S
- ELISA technique
- Protein S activity assay:
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 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.
- 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.
- 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.
- There are no specific ECG findings associated with protein S deficiency.
- For ECG findings related to pulmonary embolism, click here.
- 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.
- There are no specific CT scan findings associated with protein S deficiency.
- For CT scan findings related to pulmonary embolism, click here.
- 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.
- 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.
- 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).
- Surgical intervention is not recommended for the management of protein S deficiency.
- There are no established measures for the primary prevention of protein S deficiency.
- Effective measures for the secondary prevention of protein S deficiency include:
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