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	Protein S deficiency;
ICD-9	289.81
OMIM	176880
DiseasesDB	10814
MedlinePlus	000559
MeSH	D018455

VisualWikitext

Latest revision as of 19:16, 12 October 2020

For patient information click here

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Roukoz A. Karam, M.D.[2]

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.^[1]
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.^[2]

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:^[3]^[4]^[5]^[6]

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

Pathophysiology

Coagulation cascade - Source: Wikipedia ^[7]

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.^[8]
- 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:^[9]
  - 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: ^[10]
  - 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.^[8]
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.^[11]^[12]

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:^[13]
- Protein S consumption:
  - Disseminated intravascular coagulation^[14]
  - Surgery
- Decreased synthesis of protein S:
  - Liver disease^[15]
  - Vitamin K deficiency^[16]
- Redistribution of complexed protein S:

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:

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. ^[20]

Age

Patients of all age groups may be diagnosed with protein S deficiency.^[20]
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.^[20]

Race

Protein S deficiency usually affects the individuals of the Asian race.^[20]
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.^[21]

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.^[22]
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.^[23]^[24]
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:^[13]^[25]
1. 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
2. Total protein S antigen:
  - Determines both free and bound protein S
  - ELISA technique
3. Protein S activity assay:^[26]
  - 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.^[21] 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.^[27]^[28]

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.^[29]
- 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.
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

References

↑ Di Scipio RG, Hermodson MA, Yates SG, Davie EW (1977). "A comparison of human prothrombin, factor IX (Christmas factor), factor X (Stuart factor), and protein S." Biochemistry. 16 (4): 698–706. PMID 836809.
↑ Comp PC, Nixon RR, Cooper MR, Esmon CT (1984). "Familial protein S deficiency is associated with recurrent thrombosis". J Clin Invest. 74 (6): 2082–8. doi:10.1172/JCI111632. PMC 425398. PMID 6239877.
↑ Gandrille S, Borgel D, Sala N, Espinosa-Parrilla Y, Simmonds R, Rezende S; et al. (2000). "Protein S deficiency: a database of mutations--summary of the first update". Thromb Haemost. 84 (5): 918. PMID 11127877.
↑ Schwarz HP, Fischer M, Hopmeier P, Batard MA, Griffin JH (1984). "Plasma protein S deficiency in familial thrombotic disease". Blood. 64 (6): 1297–300. PMID 6238642.
↑ Simmonds RE, Ireland H, Kunz G, Lane DA (1996). "Identification of 19 protein S gene mutations in patients with phenotypic protein S deficiency and thrombosis. Protein S Study Group". Blood. 88 (11): 4195–204. PMID 8943854.
↑ Gandrille S, Borgel D, Eschwege-Gufflet V, Aillaud M, Dreyfus M, Matheron C; et al. (1995). "Identification of 15 different candidate causal point mutations and three polymorphisms in 19 patients with protein S deficiency using a scanning method for the analysis of the protein S active gene". Blood. 85 (1): 130–8. PMID 7803790.
↑ "Protein C - Wikipedia".
↑ ^8.0 ^8.1 Esmon CT (1992). "Protein S and protein C Biochemistry, physiology, and clinical manifestation of deficiencies". Trends Cardiovasc Med. 2 (6): 214–9. doi:10.1016/1050-1738(92)90027-P. PMID 21239244.
↑ Rezende SM, Simmonds RE, Lane DA (2004). "Coagulation, inflammation, and apoptosis: different roles for protein S and the protein S-C4b binding protein complex". Blood. 103 (4): 1192–201. doi:10.1182/blood-2003-05-1551. PMID 12907438.
↑ Dahlbäck B (2011). "C4b-binding protein: a forgotten factor in thrombosis and hemostasis". Semin Thromb Hemost. 37 (4): 355–61. doi:10.1055/s-0031-1276584. PMID 21805441.
↑ Ploos van Amstel JK, van der Zanden AL, Bakker E, Reitsma PH, Bertina RM (1987). "Two genes homologous with human protein S cDNA are located on chromosome 3". Thromb Haemost. 58 (4): 982–7. PMID 2895503.
↑ Schmidel DK, Tatro AV, Phelps LG, Tomczak JA, Long GL (1990). "Organization of the human protein S genes". Biochemistry. 29 (34): 7845–52. PMID 2148110.
↑ ^13.0 ^13.1 Marlar RA, Gausman JN (2011). "Protein S abnormalities: a diagnostic nightmare". Am J Hematol. 86 (5): 418–21. doi:10.1002/ajh.21992. PMID 21523802.
↑ Heeb MJ, Mosher D, Griffin JH (1989). "Activation and complexation of protein C and cleavage and decrease of protein S in plasma of patients with intravascular coagulation". Blood. 73 (2): 455–61. PMID 2521800.
↑ Comp PC, Doray D, Patton D, Esmon CT (1986). "An abnormal plasma distribution of protein S occurs in functional protein S deficiency". Blood. 67 (2): 504–8. PMID 2935211.
↑ Matsuzaka T, Tanaka H, Fukuda M, Aoki M, Tsuji Y, Kondoh H (1993). "Relationship between vitamin K dependent coagulation factors and anticoagulants (protein C and protein S) in neonatal vitamin K deficiency". Arch Dis Child. 68 (3 Spec No): 297–302. PMC 1590375. PMID 8466266.
↑ Comp PC, Thurnau GR, Welsh J, Esmon CT (1986). "Functional and immunologic protein S levels are decreased during pregnancy". Blood. 68 (4): 881–5. PMID 2944555.
↑ Gilabert J, Fernandez JA, España F, Aznar J, Estelles A (1988). "Physiological coagulation inhibitors (protein S, protein C and antithrombin III) in severe preeclamptic states and in users of oral contraceptives". Thromb Res. 49 (3): 319–29. PMID 2966452.
↑ Vigano-D'Angelo S, D'Angelo A, Kaufman CE, Sholer C, Esmon CT, Comp PC (1987). "Protein S deficiency occurs in the nephrotic syndrome". Ann Intern Med. 107 (1): 42–7. PMID 2954500.
↑ ^20.0 ^20.1 ^20.2 ^20.3 Pintao MC, Ribeiro DD, Bezemer ID, Garcia AA, de Visser MC, Doggen CJ; et al. (2013). "Protein S levels and the risk of venous thrombosis: results from the MEGA case-control study". Blood. 122 (18): 3210–9. doi:10.1182/blood-2013-04-499335. PMID 24014240.
↑ ^21.0 ^21.1 Engesser L, Broekmans AW, Briët E, Brommer EJ, Bertina RM (1987). "Hereditary protein S deficiency: clinical manifestations". Ann Intern Med. 106 (5): 677–82. PMID 2952034.
↑ Wu O, Robertson L, Twaddle S, Lowe G, Clark P, Walker I; et al. (2005). "Screening for thrombophilia in high-risk situations: a meta-analysis and cost-effectiveness analysis". Br J Haematol. 131 (1): 80–90. doi:10.1111/j.1365-2141.2005.05715.x. PMID 16173967.
↑ Wu O, Robertson L, Langhorne P, Twaddle S, Lowe GD, Clark P; et al. (2005). "Oral contraceptives, hormone replacement therapy, thrombophilias and risk of venous thromboembolism: a systematic review. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) Study". Thromb Haemost. 94 (1): 17–25. doi:10.1160/TH04-11-0759. PMID 16113779.
↑ Dalen JE (2008). "Should patients with venous thromboembolism be screened for thrombophilia?". Am J Med. 121 (6): 458–63. doi:10.1016/j.amjmed.2007.10.042. PMID 18501222.
↑ Alshaikh NA, Rosing J, Thomassen MCLGD, Castoldi E, Simioni P, Hackeng TM (2017). "New functional assays to selectively quantify the activated protein C- and tissue factor pathway inhibitor-cofactor activities of protein S in plasma". J Thromb Haemost. 15 (5): 950–960. doi:10.1111/jth.13657. PMID 28211163.
↑ Faioni EM, Franchi F, Asti D, Sacchi E, Bernardi F, Mannucci PM (1993). "Resistance to activated protein C in nine thrombophilic families: interference in a protein S functional assay". Thromb Haemost. 70 (6): 1067–71. PMID 8165605.
↑ Hwang ET, Kang WS, Park JW, Lee JH, Han HJ, Shin SY; et al. (2014). "[Portal-splenic-mesenteric venous thrombosis in a patients with protein S deficiency due to novel PROS1 gene mutation]". Korean J Gastroenterol. 64 (2): 110–4. PMID 25168054.
↑ Simioni P, Zanardi S, Prandoni P, Girolami A (1992). "Combined inherited protein S and heparin co-factor II deficiency in a patient with upper limb thrombosis: a family study". Thromb Res. 67 (1): 23–30. PMID 1440513.
↑ Lijfering WM, Mulder R, ten Kate MK, Veeger NJ, Mulder AB, van der Meer J (2009). "Clinical relevance of decreased free protein S levels: results from a retrospective family cohort study involving 1143 relatives". Blood. 113 (6): 1225–30. doi:10.1182/blood-2008-08-174128. PMID 18945960.

Template:WikiDoc Sources

[pmid836809-1] Di Scipio RG, Hermodson MA, Yates SG, Davie EW (1977). "A comparison of human prothrombin, factor IX (Christmas factor), factor X (Stuart factor), and protein S." Biochemistry. 16 (4): 698–706. PMID 836809.

[pmid6239877-2] Comp PC, Nixon RR, Cooper MR, Esmon CT (1984). "Familial protein S deficiency is associated with recurrent thrombosis". J Clin Invest. 74 (6): 2082–8. doi:10.1172/JCI111632. PMC 425398. PMID 6239877.

[pmid11127877-3] Gandrille S, Borgel D, Sala N, Espinosa-Parrilla Y, Simmonds R, Rezende S; et al. (2000). "Protein S deficiency: a database of mutations--summary of the first update". Thromb Haemost. 84 (5): 918. PMID 11127877.

[pmid6238642-4] Schwarz HP, Fischer M, Hopmeier P, Batard MA, Griffin JH (1984). "Plasma protein S deficiency in familial thrombotic disease". Blood. 64 (6): 1297–300. PMID 6238642.

[pmid8943854-5] Simmonds RE, Ireland H, Kunz G, Lane DA (1996). "Identification of 19 protein S gene mutations in patients with phenotypic protein S deficiency and thrombosis. Protein S Study Group". Blood. 88 (11): 4195–204. PMID 8943854.

[pmid7803790-6] Gandrille S, Borgel D, Eschwege-Gufflet V, Aillaud M, Dreyfus M, Matheron C; et al. (1995). "Identification of 15 different candidate causal point mutations and three polymorphisms in 19 patients with protein S deficiency using a scanning method for the analysis of the protein S active gene". Blood. 85 (1): 130–8. PMID 7803790.

[urlProtein_C_-_Wikipedia-7] "Protein C - Wikipedia".

[pmid21239244-8] 8.0 ^8.1 Esmon CT (1992). "Protein S and protein C Biochemistry, physiology, and clinical manifestation of deficiencies". Trends Cardiovasc Med. 2 (6): 214–9. doi:10.1016/1050-1738(92)90027-P. PMID 21239244.

[pmid12907438-9] Rezende SM, Simmonds RE, Lane DA (2004). "Coagulation, inflammation, and apoptosis: different roles for protein S and the protein S-C4b binding protein complex". Blood. 103 (4): 1192–201. doi:10.1182/blood-2003-05-1551. PMID 12907438.

[pmid21805441-10] Dahlbäck B (2011). "C4b-binding protein: a forgotten factor in thrombosis and hemostasis". Semin Thromb Hemost. 37 (4): 355–61. doi:10.1055/s-0031-1276584. PMID 21805441.

[pmid2895503-11] Ploos van Amstel JK, van der Zanden AL, Bakker E, Reitsma PH, Bertina RM (1987). "Two genes homologous with human protein S cDNA are located on chromosome 3". Thromb Haemost. 58 (4): 982–7. PMID 2895503.

[pmid2148110-12] Schmidel DK, Tatro AV, Phelps LG, Tomczak JA, Long GL (1990). "Organization of the human protein S genes". Biochemistry. 29 (34): 7845–52. PMID 2148110.

[pmid21523802-13] 13.0 ^13.1 Marlar RA, Gausman JN (2011). "Protein S abnormalities: a diagnostic nightmare". Am J Hematol. 86 (5): 418–21. doi:10.1002/ajh.21992. PMID 21523802.

[pmid2521800-14] Heeb MJ, Mosher D, Griffin JH (1989). "Activation and complexation of protein C and cleavage and decrease of protein S in plasma of patients with intravascular coagulation". Blood. 73 (2): 455–61. PMID 2521800.

[pmid2935211-15] Comp PC, Doray D, Patton D, Esmon CT (1986). "An abnormal plasma distribution of protein S occurs in functional protein S deficiency". Blood. 67 (2): 504–8. PMID 2935211.

[pmid8466266-16] Matsuzaka T, Tanaka H, Fukuda M, Aoki M, Tsuji Y, Kondoh H (1993). "Relationship between vitamin K dependent coagulation factors and anticoagulants (protein C and protein S) in neonatal vitamin K deficiency". Arch Dis Child. 68 (3 Spec No): 297–302. PMC 1590375. PMID 8466266.

[pmid2944555-17] Comp PC, Thurnau GR, Welsh J, Esmon CT (1986). "Functional and immunologic protein S levels are decreased during pregnancy". Blood. 68 (4): 881–5. PMID 2944555.

[pmid2966452-18] Gilabert J, Fernandez JA, España F, Aznar J, Estelles A (1988). "Physiological coagulation inhibitors (protein S, protein C and antithrombin III) in severe preeclamptic states and in users of oral contraceptives". Thromb Res. 49 (3): 319–29. PMID 2966452.

[pmid2954500-19] Vigano-D'Angelo S, D'Angelo A, Kaufman CE, Sholer C, Esmon CT, Comp PC (1987). "Protein S deficiency occurs in the nephrotic syndrome". Ann Intern Med. 107 (1): 42–7. PMID 2954500.

[pmid24014240-20] 20.0 ^20.1 ^20.2 ^20.3 Pintao MC, Ribeiro DD, Bezemer ID, Garcia AA, de Visser MC, Doggen CJ; et al. (2013). "Protein S levels and the risk of venous thrombosis: results from the MEGA case-control study". Blood. 122 (18): 3210–9. doi:10.1182/blood-2013-04-499335. PMID 24014240.

[pmid2952034-21] 21.0 ^21.1 Engesser L, Broekmans AW, Briët E, Brommer EJ, Bertina RM (1987). "Hereditary protein S deficiency: clinical manifestations". Ann Intern Med. 106 (5): 677–82. PMID 2952034.

[pmid16173967-22] Wu O, Robertson L, Twaddle S, Lowe G, Clark P, Walker I; et al. (2005). "Screening for thrombophilia in high-risk situations: a meta-analysis and cost-effectiveness analysis". Br J Haematol. 131 (1): 80–90. doi:10.1111/j.1365-2141.2005.05715.x. PMID 16173967.

[pmid16113779-23] Wu O, Robertson L, Langhorne P, Twaddle S, Lowe GD, Clark P; et al. (2005). "Oral contraceptives, hormone replacement therapy, thrombophilias and risk of venous thromboembolism: a systematic review. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) Study". Thromb Haemost. 94 (1): 17–25. doi:10.1160/TH04-11-0759. PMID 16113779.

[pmid18501222-24] Dalen JE (2008). "Should patients with venous thromboembolism be screened for thrombophilia?". Am J Med. 121 (6): 458–63. doi:10.1016/j.amjmed.2007.10.042. PMID 18501222.

[pmid28211163-25] Alshaikh NA, Rosing J, Thomassen MCLGD, Castoldi E, Simioni P, Hackeng TM (2017). "New functional assays to selectively quantify the activated protein C- and tissue factor pathway inhibitor-cofactor activities of protein S in plasma". J Thromb Haemost. 15 (5): 950–960. doi:10.1111/jth.13657. PMID 28211163.

[pmid8165605-26] Faioni EM, Franchi F, Asti D, Sacchi E, Bernardi F, Mannucci PM (1993). "Resistance to activated protein C in nine thrombophilic families: interference in a protein S functional assay". Thromb Haemost. 70 (6): 1067–71. PMID 8165605.

[pmid25168054-27] Hwang ET, Kang WS, Park JW, Lee JH, Han HJ, Shin SY; et al. (2014). "[Portal-splenic-mesenteric venous thrombosis in a patients with protein S deficiency due to novel PROS1 gene mutation]". Korean J Gastroenterol. 64 (2): 110–4. PMID 25168054.

[pmid1440513-28] Simioni P, Zanardi S, Prandoni P, Girolami A (1992). "Combined inherited protein S and heparin co-factor II deficiency in a patient with upper limb thrombosis: a family study". Thromb Res. 67 (1): 23–30. PMID 1440513.

[pmid18945960-29] Lijfering WM, Mulder R, ten Kate MK, Veeger NJ, Mulder AB, van der Meer J (2009). "Clinical relevance of decreased free protein S levels: results from a retrospective family cohort study involving 1143 relatives". Blood. 113 (6): 1225–30. doi:10.1182/blood-2008-08-174128. PMID 18945960.

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@@ Line 15: / Line 15: @@
 '''For patient information click [[Congenital protein C or S deficiency (patient information)|here]]'''
-{{CMG}} {{AE}}
+{{CMG}}; {{AE}} {{RAK}}
-{{SK}}
+{{SK}} Protein S deficiency disease
 ==Overview==
+Protein S deficiency is an [[autosomal dominant]] [[thrombophilia]], which leads to an increased risk of [[thrombosis|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 [[factor V|factors Va]] and [[Factor VIII|VIIIa]] and thereby controlling the [[coagulation cascade]].
 ==Historical Perspective==
-[Disease name] was first discovered by [name of scientist], a [nationality + occupation], in [year]/during/following [event].
-The association between [important risk factor/cause] and [disease name] was made in/during [year/event].
+*[[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]].<ref name="pmid836809">{{cite journal| author=Di Scipio RG, Hermodson MA, Yates SG, Davie EW| title=A comparison of human prothrombin, factor IX (Christmas factor), factor X (Stuart factor), and protein S. | journal=Biochemistry | year= 1977 | volume= 16 | issue= 4 | pages= 698-706 | pmid=836809 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=836809  }} </ref>
-In [year], [scientist] was the first to discover the association between [risk factor] and the development of [disease name].
+*Protein S deficiency was first discovered in 1984 when two related individuals with recurrent [[thrombosis|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.<ref name="pmid6239877">{{cite journal| author=Comp PC, Nixon RR, Cooper MR, Esmon CT| title=Familial protein S deficiency is associated with recurrent thrombosis. | journal=J Clin Invest | year= 1984 | volume= 74 | issue= 6 | pages= 2082-8 | pmid=6239877 | doi=10.1172/JCI111632 | pmc=425398 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6239877  }} </ref>
-In [year], [gene] mutations were first implicated in the pathogenesis of [disease name].
-There have been several outbreaks of [disease name], including -----.
-In [year], [diagnostic test/therapy] was developed by [scientist] to treat/diagnose [disease name].
 ==Classification==
-There is no established system for the classification of [disease name].
+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:<ref name="pmid11127877">{{cite journal| author=Gandrille S, Borgel D, Sala N, Espinosa-Parrilla Y, Simmonds R, Rezende S et al.| title=Protein S deficiency: a database of mutations--summary of the first update. | journal=Thromb Haemost | year= 2000 | volume= 84 | issue= 5 | pages= 918 | pmid=11127877 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11127877  }} </ref><ref name="pmid6238642">{{cite journal| author=Schwarz HP, Fischer M, Hopmeier P, Batard MA, Griffin JH| title=Plasma protein S deficiency in familial thrombotic disease. | journal=Blood | year= 1984 | volume= 64 | issue= 6 | pages= 1297-300 | pmid=6238642 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6238642  }} </ref><ref name="pmid8943854">{{cite journal| author=Simmonds RE, Ireland H, Kunz G, Lane DA| title=Identification of 19 protein S gene mutations in patients with phenotypic protein S deficiency and thrombosis. Protein S Study Group. | journal=Blood | year= 1996 | volume= 88 | issue= 11 | pages= 4195-204 | pmid=8943854 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8943854  }} </ref><ref name="pmid7803790">{{cite journal| author=Gandrille S, Borgel D, Eschwege-Gufflet V, Aillaud M, Dreyfus M, Matheron C et al.| title=Identification of 15 different candidate causal point mutations and three polymorphisms in 19 patients with protein S deficiency using a scanning method for the analysis of the protein S active gene. | journal=Blood | year= 1995 | volume= 85 | issue= 1 | pages= 130-8 | pmid=7803790 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7803790  }} </ref>
-OR
+{| class="wikitable"
+! style="background:#4479BA; color: #FFFFFF;" align="center" + |Type
-[Disease name] may be classified according to [classification method] into [number] subtypes/groups: [group1], [group2], [group3], and [group4].
+! style="background:#4479BA; color: #FFFFFF;" align="center" + |Total Protein S
+! style="background:#4479BA; color: #FFFFFF;" align="center" + |Free Protein S
-OR
+! style="background:#4479BA; color: #FFFFFF;" align="center" + |Protein S Function
+! style="background:#4479BA; color: #FFFFFF;" align="center" + |Characteristics
-[Disease name] may be classified into [large number > 6] subtypes based on [classification method 1], [classification method 2], and [classification method 3].
+! style="background:#4479BA; color: #FFFFFF;" align="center" + |Genetics
-[Disease name] may be classified into several subtypes based on [classification method 1], [classification method 2], and [classification method 3].
+|-
+| style="background:#DCDCDC;" align="center" + |Type I
-OR
+| style="background:#F5F5F5;" align="center" + |↓
+| style="background:#F5F5F5;" align="center" + |↓
-Based on the duration of symptoms, [disease name] may be classified as either acute or chronic.
+| style="background:#F5F5F5;" align="center" + |↓
+| style="background:#F5F5F5;" align="center" + |Classic form
-OR
+| style="background:#F5F5F5;" align="center" + |Usually results from [[missense]] or [[nonsense mutations]]
+|-
-If the staging system involves specific and characteristic findings and features:
+| style="background:#DCDCDC;" align="center" + |Type II
-According to the [staging system + reference], there are [number] stages of [malignancy name] based on the [finding1], [finding2], and [finding3]. Each stage is assigned a [letter/number1] and a [letter/number2] that designate the [feature1] and [feature2].
+| style="background:#F5F5F5;" align="center" + |↔
+| style="background:#F5F5F5;" align="center" + |↔
-OR
+| style="background:#F5F5F5;" align="center" + |↓
+| style="background:#F5F5F5;" align="center" + |Rare qualitative defect
-The staging of [malignancy name] is based on the [staging system].
+| style="background:#F5F5F5;" align="center" + |Linked to [[missense mutations]]
+|-
-OR
+| style="background:#DCDCDC;" align="center" + |Type III
+| style="background:#F5F5F5;" align="center" + |↔
-There is no established system for the staging of [malignancy name].
+| style="background:#F5F5F5;" align="center" + |↓
+| style="background:#F5F5F5;" align="center" + |↓
+| style="background:#F5F5F5;" align="center" + |Quantitative defect
+| style="background:#F5F5F5;" align="center" + |Unknown
+|}
 ==Pathophysiology==
-The exact pathogenesis of [disease name] is not fully understood.
+{| align="right"
+|
+[[File:Coagulation cascade.png|thumb|600px|Coagulation cascade - Source: Wikipedia <ref name="urlProtein C - Wikipedia">{{cite web |url=https://en.wikipedia.org/wiki/Protein_C |title=Protein C - Wikipedia |format= |work= |accessdate=}}</ref>]]
+|}
-OR
+*[[Protein S]] is a natural [[anticoagulant]] that works with other [[proteins]] to regulate [[coagulation]] in the [[body]].
-It is thought that [disease name] is the result of / is mediated by / is produced by / is caused by either [hypothesis 1], [hypothesis 2], or [hypothesis 3].
+*After it gets produced by the [[hepatocytes]], [[endothelial cells]], and [[megakaryocytes]], protein S undergoes activation via [[vitamin K]]-dependent [[gamma-carboxylation]].<ref name="pmid21239244">{{cite journal| author=Esmon CT| title=Protein S and protein C Biochemistry, physiology, and clinical manifestation of deficiencies. | journal=Trends Cardiovasc Med | year= 1992 | volume= 2 | issue= 6 | pages= 214-9 | pmid=21239244 | doi=10.1016/1050-1738(92)90027-P | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21239244  }} </ref>
+**The [[vitamin K]]-dependent [[Gamma-glutamyl carboxylase|gamma-carboxyalse enzyme]] acts by modifying the [[glutamic acid]] residues in protein S to [[Carboxyglutamate|gamma-carboxyglutamic acid]] residues.
+**These [[Carboxyglutamate|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:<ref name="pmid12907438">{{cite journal| author=Rezende SM, Simmonds RE, Lane DA| title=Coagulation, inflammation, and apoptosis: different roles for protein S and the protein S-C4b binding protein complex. | journal=Blood | year= 2004 | volume= 103 | issue= 4 | pages= 1192-201 | pmid=12907438 | doi=10.1182/blood-2003-05-1551 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12907438  }} </ref>
+***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-binding protein|C4b]]-bound [[protein S]]: <ref name="pmid21805441">{{cite journal| author=Dahlbäck B| title=C4b-binding protein: a forgotten factor in thrombosis and hemostasis. | journal=Semin Thromb Hemost | year= 2011 | volume= 37 | issue= 4 | pages= 355-61 | pmid=21805441 | doi=10.1055/s-0031-1276584 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21805441  }} </ref>
+***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.
-OR
+*The activated free protein S acts as a [[cofactor]] to activated [[protein C]], and with the help of [[phospholipids]] and [[calcium|Ca<sup>2+</sup>]], it inactivates procoagulant [[factor V|factor Va]] and [[factor VIII|factor VIIIa]] thereby reducing [[thrombin]] formation.<ref name="pmid21239244">{{cite journal| author=Esmon CT| title=Protein S and protein C Biochemistry, physiology, and clinical manifestation of deficiencies. | journal=Trends Cardiovasc Med | year= 1992 | volume= 2 | issue= 6 | pages= 214-9 | pmid=21239244 | doi=10.1016/1050-1738(92)90027-P | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21239244  }} </ref>
+*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 mutation|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]].<ref name="pmid2895503">{{cite journal| author=Ploos van Amstel JK, van der Zanden AL, Bakker E, Reitsma PH, Bertina RM| title=Two genes homologous with human protein S cDNA are located on chromosome 3. | journal=Thromb Haemost | year= 1987 | volume= 58 | issue= 4 | pages= 982-7 | pmid=2895503 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2895503  }} </ref><ref name="pmid2148110">{{cite journal| author=Schmidel DK, Tatro AV, Phelps LG, Tomczak JA, Long GL| title=Organization of the human protein S genes. | journal=Biochemistry | year= 1990 | volume= 29 | issue= 34 | pages= 7845-52 | pmid=2148110 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2148110  }} </ref>
-[Pathogen name] is usually transmitted via the [transmission route] route to the human host.
+==Causes==
-OR
+*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:<ref name="pmid21523802">{{cite journal| author=Marlar RA, Gausman JN| title=Protein S abnormalities: a diagnostic nightmare. | journal=Am J Hematol | year= 2011 | volume= 86 | issue= 5 | pages= 418-21 | pmid=21523802 | doi=10.1002/ajh.21992 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21523802  }} </ref>
+**Protein S consumption:
+***[[Disseminated intravascular coagulation]]<ref name="pmid2521800">{{cite journal| author=Heeb MJ, Mosher D, Griffin JH| title=Activation and complexation of protein C and cleavage and decrease of protein S in plasma of patients with intravascular coagulation. | journal=Blood | year= 1989 | volume= 73 | issue= 2 | pages= 455-61 | pmid=2521800 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2521800  }} </ref>
+***[[Surgery]]
+**Decreased synthesis of [[protein S]]:
+***[[Liver disease]]<ref name="pmid2935211">{{cite journal| author=Comp PC, Doray D, Patton D, Esmon CT| title=An abnormal plasma distribution of protein S occurs in functional protein S deficiency. | journal=Blood | year= 1986 | volume= 67 | issue= 2 | pages= 504-8 | pmid=2935211 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2935211  }} </ref>
+***[[Vitamin K deficiency]]<ref name="pmid8466266">{{cite journal| author=Matsuzaka T, Tanaka H, Fukuda M, Aoki M, Tsuji Y, Kondoh H| title=Relationship between vitamin K dependent coagulation factors and anticoagulants (protein C and protein S) in neonatal vitamin K deficiency. | journal=Arch Dis Child | year= 1993 | volume= 68 | issue= 3 Spec No | pages= 297-302 | pmid=8466266 | doi= | pmc=1590375 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8466266  }} </ref>
+**Redistribution of complexed protein S:
+***[[Pregnancy]]<ref name="pmid2944555">{{cite journal| author=Comp PC, Thurnau GR, Welsh J, Esmon CT| title=Functional and immunologic protein S levels are decreased during pregnancy. | journal=Blood | year= 1986 | volume= 68 | issue= 4 | pages= 881-5 | pmid=2944555 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2944555  }} </ref>
+***[[Birth control|Oral hormonal contraceptives]]<ref name="pmid2966452">{{cite journal| author=Gilabert J, Fernandez JA, España F, Aznar J, Estelles A| title=Physiological coagulation inhibitors (protein S, protein C and antithrombin III) in severe preeclamptic states and in users of oral contraceptives. | journal=Thromb Res | year= 1988 | volume= 49 | issue= 3 | pages= 319-29 | pmid=2966452 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2966452  }} </ref>
+***[[Nephrotic syndrome]]<ref name="pmid2954500">{{cite journal| author=Vigano-D'Angelo S, D'Angelo A, Kaufman CE, Sholer C, Esmon CT, Comp PC| title=Protein S deficiency occurs in the nephrotic syndrome. | journal=Ann Intern Med | year= 1987 | volume= 107 | issue= 1 | pages= 42-7 | pmid=2954500 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2954500  }} </ref>
-Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell.
+==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:
-OR
-[Disease or malignancy name] arises from [cell name]s, which are [cell type] cells that are normally involved in [function of cells].
-OR
-The progression to [disease name] usually involves the [molecular pathway].
-OR
-The pathophysiology of [disease/malignancy] depends on the histological subtype.
-==Causes==
-Disease name] may be caused by [cause1], [cause2], or [cause3].
-OR
-Common causes of [disease] include [cause1], [cause2], and [cause3].
-OR
-The most common cause of [disease name] is [cause 1]. Less common causes of [disease name] include [cause 2], [cause 3], and [cause 4].
-OR
-The cause of [disease name] has not been identified. To review risk factors for the development of [disease name], click [[Pericarditis causes#Overview|here]].
-==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]]
@@ Line 118: / Line 113: @@
 ==Epidemiology and Demographics==
-The incidence/prevalence of [disease name] is approximately [number range] per 100,000 individuals worldwide.
-OR
-In [year], the incidence/prevalence of [disease name] was estimated to be [number range] cases per 100,000 individuals worldwide.
-OR
-In [year], the incidence of [disease name] is approximately [number range] per 100,000 individuals with a case-fatality rate of [number range]%.
+*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. <ref name="pmid24014240">{{cite journal| author=Pintao MC, Ribeiro DD, Bezemer ID, Garcia AA, de Visser MC, Doggen CJ et al.| title=Protein S levels and the risk of venous thrombosis: results from the MEGA case-control study. | journal=Blood | year= 2013 | volume= 122 | issue= 18 | pages= 3210-9 | pmid=24014240 | doi=10.1182/blood-2013-04-499335 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24014240  }} </ref>
+===Age===
+*Patients of all age groups may be diagnosed with protein S deficiency.<ref name="pmid24014240">{{cite journal| author=Pintao MC, Ribeiro DD, Bezemer ID, Garcia AA, de Visser MC, Doggen CJ et al.| title=Protein S levels and the risk of venous thrombosis: results from the MEGA case-control study. | journal=Blood | year= 2013 | volume= 122 | issue= 18 | pages= 3210-9 | pmid=24014240 | doi=10.1182/blood-2013-04-499335 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24014240  }} </ref>
+*It is, however, more commonly observed among patients younger than 40 to 50 years old.
-Patients of all age groups may develop [disease name].
+===Gender===
-OR
+*There is no difference in the [[prevalence]] of the [[disease]] between men and women.<ref name="pmid24014240">{{cite journal| author=Pintao MC, Ribeiro DD, Bezemer ID, Garcia AA, de Visser MC, Doggen CJ et al.| title=Protein S levels and the risk of venous thrombosis: results from the MEGA case-control study. | journal=Blood | year= 2013 | volume= 122 | issue= 18 | pages= 3210-9 | pmid=24014240 | doi=10.1182/blood-2013-04-499335 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24014240  }} </ref>
+===Race===
-The incidence of [disease name] increases with age; the median age at diagnosis is [#] years.
+*Protein S deficiency usually affects the individuals of the Asian race.<ref name="pmid24014240">{{cite journal| author=Pintao MC, Ribeiro DD, Bezemer ID, Garcia AA, de Visser MC, Doggen CJ et al.| title=Protein S levels and the risk of venous thrombosis: results from the MEGA case-control study. | journal=Blood | year= 2013 | volume= 122 | issue= 18 | pages= 3210-9 | pmid=24014240 | doi=10.1182/blood-2013-04-499335 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24014240  }} </ref>
+*Caucasian individuals are less likely to develop protein S deficiency.
-OR
-[Disease name] commonly affects individuals younger than/older than [number of years] years of age.
-OR
-[Chronic disease name] is usually first diagnosed among [age group].
-OR
-[Acute disease name] commonly affects [age group].
-There is no racial predilection to [disease name].
-OR
-[Disease name] usually affects individuals of the [race 1] race. [Race 2] individuals are less likely to develop [disease name].
-[Disease name] affects men and women equally.
-OR
-[Gender 1] are more commonly affected by [disease name] than [gender 2]. The [gender 1] to [gender 2] ratio is approximately [number > 1] to 1.
-The majority of [disease name] cases are reported in [geographical region].
-OR
-[Disease name] is a common/rare disease that tends to affect [patient population 1] and [patient population 2].
 ==Risk Factors==
-There are no established risk factors for [disease name].
-OR
-The most potent risk factor in the development of [disease name] is [risk factor 1]. Other risk factors include [risk factor 2], [risk factor 3], and [risk factor 4].
-OR
-Common risk factors in the development of [disease name] include [risk factor 1], [risk factor 2], [risk factor 3], and [risk factor 4].
-OR
-Common risk factors in the development of [disease name] may be occupational, environmental, genetic, and viral.
+*There are no established risk factors for protein S deficiency.
+*Family history of [[thrombosis]] poses increased risk for a mutation.<ref name="pmid2952034">{{cite journal| author=Engesser L, Broekmans AW, Briët E, Brommer EJ, Bertina RM| title=Hereditary protein S deficiency: clinical manifestations. | journal=Ann Intern Med | year= 1987 | volume= 106 | issue= 5 | pages= 677-82 | pmid=2952034 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2952034  }} </ref>
 ==Screening==
-There is insufficient evidence to recommend routine screening for [disease/malignancy].
-OR
-According to the [guideline name], screening for [disease name] is not recommended.
-OR
-According to the [guideline name], screening for [disease name] by [test 1] is recommended every [duration] among patients with [condition 1], [condition 2], and [condition 3].
+*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.<ref name="pmid16173967">{{cite journal| author=Wu O, Robertson L, Twaddle S, Lowe G, Clark P, Walker I et al.| title=Screening for thrombophilia in high-risk situations: a meta-analysis and cost-effectiveness analysis. | journal=Br J Haematol | year= 2005 | volume= 131 | issue= 1 | pages= 80-90 | pmid=16173967 | doi=10.1111/j.1365-2141.2005.05715.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16173967  }} </ref>
+*High risk patients with a positive family history ([[first degree relative]] with protein S deficiency or first degree relative with multiple [[Venous thromboembolism|venous thromboembolic events]] at an age younger than 50), warrant a [[screening]] preferably prior to initiation of the high risk events including taking [[birth control|oral contraceptives]] or [[pregnancy]].<ref name="pmid16113779">{{cite journal| author=Wu O, Robertson L, Langhorne P, Twaddle S, Lowe GD, Clark P et al.| title=Oral contraceptives, hormone replacement therapy, thrombophilias and risk of venous thromboembolism: a systematic review. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) Study. | journal=Thromb Haemost | year= 2005 | volume= 94 | issue= 1 | pages= 17-25 | pmid=16113779 | doi=10.1160/TH04-11-0759 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16113779  }} </ref><ref name="pmid18501222">{{cite journal| author=Dalen JE| title=Should patients with venous thromboembolism be screened for thrombophilia? | journal=Am J Med | year= 2008 | volume= 121 | issue= 6 | pages= 458-63 | pmid=18501222 | doi=10.1016/j.amjmed.2007.10.042 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18501222  }} </ref>
+*The free protein S [[antigen]] [[assay]] is the best [[screening test]].
 ==Natural History, Complications, and Prognosis==
-If left untreated, [#]% of patients with [disease name] may progress to develop [manifestation 1], [manifestation 2], and [manifestation 3].
-OR
-Common complications of [disease name] include [complication 1], [complication 2], and [complication 3].
-OR
-Prognosis is generally excellent/good/poor, and the 1/5/10-year mortality/survival rate of patients with [disease name] is approximately [#]%.
+*If left untreated, patients with protein S deficiency are at high risk to develop life-threatening [[Venous thromboembolism|venous thromboembolic events]].
+*For specific complications and prognosis associated with [[pulmonary embolism]], [[Pulmonary embolism natural history, complications and prognosis|click here]].
+*For specific complications and prognosis associated with [[deep vein thrombosis]], [[Deep vein thrombosis natural history, complications and prognosis|click here]].
 ==Diagnosis==
 ===Diagnostic Study of Choice===
-The diagnosis of [disease name] is made when at least [number] of the following [number] diagnostic criteria are met: [criterion 1], [criterion 2], [criterion 3], and [criterion 4].
-OR
-The diagnosis of [disease name] is based on the [criteria name] criteria, which include [criterion 1], [criterion 2], and [criterion 3].
+*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 [[thrombophilia|hereditary thrombophilias]] due to the interaction of protein S with other [[proteins]], its complex genetic regulation, and its biologic variation.
-OR
+*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]]:<ref name="pmid21523802">{{cite journal| author=Marlar RA, Gausman JN| title=Protein S abnormalities: a diagnostic nightmare. | journal=Am J Hematol | year= 2011 | volume= 86 | issue= 5 | pages= 418-21 | pmid=21523802 | doi=10.1002/ajh.21992 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21523802  }} </ref><ref name="pmid28211163">{{cite journal| author=Alshaikh NA, Rosing J, Thomassen MCLGD, Castoldi E, Simioni P, Hackeng TM| title=New functional assays to selectively quantify the activated protein C- and tissue factor pathway inhibitor-cofactor activities of protein S in plasma. | journal=J Thromb Haemost | year= 2017 | volume= 15 | issue= 5 | pages= 950-960 | pmid=28211163 | doi=10.1111/jth.13657 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28211163  }} </ref>
-The diagnosis of [disease name] is based on the [definition name] definition, which includes [criterion 1], [criterion 2], and [criterion 3].
+*#Free protein S [[antigen]]:
+*#*Determines free [[protein S]] level in [[plasma]]
-OR
+*#*Most reliable of the three tests
+*#*Evaluates the function of protein S indirectly
-There are no established criteria for the diagnosis of [disease name].
+*#*[[Enzyme linked immunosorbent assay (ELISA)|ELISA technique]]
+*#Total protein S antigen:
+*#*Determines both free and bound protein S
+*#*[[Enzyme linked immunosorbent assay (ELISA)|ELISA technique]]
+*#Protein S activity [[assay]]:<ref name="pmid8165605">{{cite journal| author=Faioni EM, Franchi F, Asti D, Sacchi E, Bernardi F, Mannucci PM| title=Resistance to activated protein C in nine thrombophilic families: interference in a protein S functional assay. | journal=Thromb Haemost | year= 1993 | volume= 70 | issue= 6 | pages= 1067-71 | pmid=8165605 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8165605  }} </ref>
+*#*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|factor V Leiden mutation]] ([[resistance]] to activated protein C)
 ===History and Symptoms===
-The majority of patients with [disease name] are asymptomatic.
-OR
+*The hallmark of protein S deficiency is [[venous thromboembolism]].
+*A positive history of a [[venous thromboembolism|venous thromboembolic event]] prior to age 50, a strong [[family history]] of [[Venous thromboembolism|venous thromboembolic events]], and/or a known protein S deficient family member is suggestive of a protein S deficiency.
-The hallmark of [disease name] is [finding]. A positive history of [finding 1] and [finding 2] is suggestive of [disease name]. The most common symptoms of [disease name] include [symptom 1], [symptom 2], and [symptom 3]. Common symptoms of [disease] include [symptom 1], [symptom 2], and [symptom 3]. Less common symptoms of [disease name] include [symptom 1], [symptom 2], and [symptom 3].
+*The most common sites of [[venous thromboembolism]] include [[deep vein thrombosis]] and [[pulmonary embolism]].<ref name="pmid2952034">{{cite journal| author=Engesser L, Broekmans AW, Briët E, Brommer EJ, Bertina RM| title=Hereditary protein S deficiency: clinical manifestations. | journal=Ann Intern Med | year= 1987 | volume= 106 | issue= 5 | pages= 677-82 | pmid=2952034 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2952034  }} </ref> 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 veins|cerebral]], [[axillary vein|axillary]], and [[Mesenteric vein thrombosis|mesenteric veins]].<ref name="pmid25168054">{{cite journal| author=Hwang ET, Kang WS, Park JW, Lee JH, Han HJ, Shin SY et al.| title=[Portal-splenic-mesenteric venous thrombosis in a patients with protein S deficiency due to novel PROS1 gene mutation]. | journal=Korean J Gastroenterol | year= 2014 | volume= 64 | issue= 2 | pages= 110-4 | pmid=25168054 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25168054  }} </ref><ref name="pmid1440513">{{cite journal| author=Simioni P, Zanardi S, Prandoni P, Girolami A| title=Combined inherited protein S and heparin co-factor II deficiency in a patient with upper limb thrombosis: a family study. | journal=Thromb Res | year= 1992 | volume= 67 | issue= 1 | pages= 23-30 | pmid=1440513 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1440513  }} </ref>
 ===Physical Examination===
-Patients with [disease name] usually appear [general appearance]. Physical examination of patients with [disease name] is usually remarkable for [finding 1], [finding 2], and [finding 3].
-OR
-Common physical examination findings of [disease name] include [finding 1], [finding 2], and [finding 3].
-OR
+*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]].
-The presence of [finding(s)] on physical examination is diagnostic of [disease name].
-OR
-The presence of [finding(s)] on physical examination is highly suggestive of [disease name].
 ===Laboratory Findings===
-An elevated/reduced concentration of serum/blood/urinary/CSF/other [lab test] is diagnostic of [disease name].
-OR
-Laboratory findings consistent with the diagnosis of [disease name] include [abnormal test 1], [abnormal test 2], and [abnormal test 3].
-OR
-[Test] is usually normal among patients with [disease name].
-OR
-Some patients with [disease name] may have elevated/reduced concentration of [test], which is usually suggestive of [progression/complication].
+*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]].<ref name="pmid18945960">{{cite journal| author=Lijfering WM, Mulder R, ten Kate MK, Veeger NJ, Mulder AB, van der Meer J| title=Clinical relevance of decreased free protein S levels: results from a retrospective family cohort study involving 1143 relatives. | journal=Blood | year= 2009 | volume= 113 | issue= 6 | pages= 1225-30 | pmid=18945960 | doi=10.1182/blood-2008-08-174128 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18945960  }} </ref>
-OR
+**Free protein S levels < 65 IU/dL are diagnostic of protein S deficiency in patients with a history of [[thrombosis|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]].
-There are no diagnostic laboratory findings associated with [disease name].
+*For specific laboratory findings in patients with associated [[pulmonary embolism]], [[Pulmonary embolism laboratory findings|click here]]
+*For specific laboratory findings in patients with associated [[deep vein thrombosis]], [[Deep vein thrombosis laboratory tests|click here]].
 ===Electrocardiogram===
-There are no ECG findings associated with [disease name].
-OR
-An ECG may be helpful in the diagnosis of [disease name]. Findings on an ECG suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].
+*There are no specific [[ECG]] findings associated with protein S deficiency.
+*For ECG findings related to [[pulmonary embolism]], [[Pulmonary embolism electrocardiogram|click here]].
 ===X-ray===
-There are no x-ray findings associated with [disease name].
-OR
-An x-ray may be helpful in the diagnosis of [disease name]. Findings on an x-ray suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].
-OR
-There are no x-ray findings associated with [disease name]. However, an x-ray may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].
+*There are no specific [[x-ray]] findings associated with protein S deficiency.
+*For specific x-ray findings seen with [[pulmonary embolism]], [[Pulmonary embolism chest x ray|click here]].
 ===Echocardiography or Ultrasound===
-There are no echocardiography/ultrasound  findings associated with [disease name].
-OR
-Echocardiography/ultrasound  may be helpful in the diagnosis of [disease name]. Findings on an echocardiography/ultrasound suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].
-OR
-There are no echocardiography/ultrasound  findings associated with [disease name]. However, an echocardiography/ultrasound  may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].
+*There are no specific [[echocardiography]]/[[ultrasound]]  findings associated with protein S deficiency.
+*For ultrasound findings related to [[deep vein thrombosis]], [[Deep vein thrombosis ultrasound|click here]].
+*For echocardiography findings associated with [[pulmonary embolism]], [[Pulmonary embolism echocardiography|click here]].
 ===CT scan===
-There are no CT scan findings associated with [disease name].
-OR
-[Location] CT scan may be helpful in the diagnosis of [disease name]. Findings on CT scan suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].
-OR
-There are no CT scan findings associated with [disease name]. However, a CT scan may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].
+*There are no specific [[CT scan]] findings associated with protein S deficiency.
+*For CT scan findings related to [[pulmonary embolism]], [[Pulmonary embolism CT|click here]].
 ===MRI===
-There are no MRI findings associated with [disease name].
-OR
-[Location] MRI may be helpful in the diagnosis of [disease name]. Findings on MRI suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].
-OR
-There are no MRI findings associated with [disease name]. However, a MRI may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].
+*There are no [[MRI]] findings associated with protein S deficiency.
 ===Other Imaging Findings===
-There are no other imaging findings associated with [disease name].
-OR
-[Imaging modality] may be helpful in the diagnosis of [disease name]. Findings on an [imaging modality] suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].
+*There are no other imaging findings associated with protein S deficiency.
 ===Other Diagnostic Studies===
-There are no other diagnostic studies associated with [disease name].
-OR
-[Diagnostic study] may be helpful in the diagnosis of [disease name]. Findings suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].
-OR
+*There are no other diagnostic studies associated with protein S deficiency.
-Other diagnostic studies for [disease name] include [diagnostic study 1], which demonstrates [finding 1], [finding 2], and [finding 3], and [diagnostic study 2], which demonstrates [finding 1], [finding 2], and [finding 3].
 ==Treatment==
 ===Medical Therapy===
-There is no treatment for [disease name]; the mainstay of therapy is supportive care.
-OR
+*Patients with protein S deficiency that remain [[asymptomatic]] and have no history of [[venous thromboembolism|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.
-Supportive therapy for [disease name] includes [therapy 1], [therapy 2], and [therapy 3].
+**For management of patients suffering from [[pulmonary embolism]], [[Pulmonary embolism treatment approach|click here]].
+**For management of patient suffering from [[deep venous thrombosis]], [[Deep vein thrombosis treatment approach|click here]].
-OR
+*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]], [[birth control|oral contraceptives]], and [[immobility]]).
+*
-The majority of cases of [disease name] are self-limited and require only supportive care.
-OR
-[Disease name] is a medical emergency and requires prompt treatment.
-OR
-The mainstay of treatment for [disease name] is [therapy].
-OR
-The optimal therapy for [malignancy name] depends on the stage at diagnosis.
-OR
-[Therapy] is recommended among all patients who develop [disease name].
-OR
-Pharmacologic medical therapy is recommended among patients with [disease subclass 1], [disease subclass 2], and [disease subclass 3].
-OR
-Pharmacologic medical therapies for [disease name] include (either) [therapy 1], [therapy 2], and/or [therapy 3].
-OR
-Empiric therapy for [disease name] depends on [disease factor 1] and [disease factor 2].
-OR
-Patients with [disease subclass 1] are treated with [therapy 1], whereas patients with [disease subclass 2] are treated with [therapy 2].
 ===Surgery===
-Surgical intervention is not recommended for the management of [disease name].
-OR
-Surgery is not the first-line treatment option for patients with [disease name]. Surgery is usually reserved for patients with either [indication 1], [indication 2], and [indication 3]
-OR
-The mainstay of treatment for [disease name] is medical therapy. Surgery is usually reserved for patients with either [indication 1], [indication 2], and/or [indication 3].
-OR
-The feasibility of surgery depends on the stage of [malignancy] at diagnosis.
-OR
-Surgery is the mainstay of treatment for [disease or malignancy].
+*Surgical intervention is not recommended for the management of protein S deficiency.
 ===Primary Prevention===
-There are no established measures for the primary prevention of [disease name].
-OR
-There are no available vaccines against [disease name].
-OR
-Effective measures for the primary prevention of [disease name] include [measure1], [measure2], and [measure3].
-OR
-[Vaccine name] vaccine is recommended for [patient population] to prevent [disease name]. Other primary prevention strategies include [strategy 1], [strategy 2], and [strategy 3].
+*There are no established measures for the primary prevention of protein S deficiency.
 ===Secondary Prevention===
-There are no established measures for the secondary prevention of [disease name].
-OR
-Effective measures for the secondary prevention of [disease name] include [strategy 1], [strategy 2], and [strategy 3].
+*Effective measures for the secondary prevention of protein S deficiency include:
+**Avoiding [[birth control|oral contraceptives]] in women
+**[[prophylaxis|Prophylactic]] [[anticoagulation]] postoperatively
+**Considering [[anticoagulation]] during [[pregnancy]]
+**Education concerning signs and symptoms of [[venous thrombosis|venous thromboembolic events]]
 ==References==
-{{reflist|2}}
+{{Reflist|2}}
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Protein S deficiency
ICD-9	289.81
OMIM	176880
DiseasesDB	10814
MedlinePlus	000559
MeSH	D018455