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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}}{{RAK}}
+{{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 VII|VIIa]] and thereby controlling the [[coagulation cascade]].
+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==
-*[[Protein S]] was first discovered and purified in Seattle, Washington in 1979, and it was arbitrarily named [[protein S]] after 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>
+*[[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.
-*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>
+*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>
+*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>
 ==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:<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>
+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>
-*'''Type I:''' Reduced total protein S, free protein S, and protein S function
-It is the classic form of hereditary protein S deficiency. Total protein S levels drop to approximately 50% of normal values while free protein S levels collapse to almost 15% of the normal. On a genetic level, type I deficiency usually results from [[missense]] or [[nonsense mutations]]. On few occasions, [[microinsertions]], [[Deletion (genetics)|microdeletions]], and [[Splice site mutation|splice site mutations]] have occurred with this type.
-*'''Type II:''' Normal total and free protein S, reduced protein S function
-This form results from a qualitative defect and is very rare. The genetics behind this type isn't certain; however, some reports have linked it to [[missense mutations]] affecting protein S's ability to bind to the activated [[protein C]].
-*'''Type III:''' Normal total protein S, reduced free protein S and protein S function
-This is a quantitative defect.
 {| class="wikitable"
@@ Line 45: / Line 37: @@
 ! style="background:#4479BA; color: #FFFFFF;" align="center" + |Protein S Function
 ! style="background:#4479BA; color: #FFFFFF;" align="center" + |Characteristics
+! style="background:#4479BA; color: #FFFFFF;" align="center" + |Genetics
 |-
-| style="background:#DCDCDC;" align="center" + |I
+| style="background:#DCDCDC;" align="center" + |Type I
-|style="background:#F5F5F5;" align="center" + |↓
+| style="background:#F5F5F5;" align="center" + |↓
-|style="background:#F5F5F5;" align="center" + |↓
+| style="background:#F5F5F5;" align="center" + |↓
-|style="background:#F5F5F5;" align="center" + |↓
+| style="background:#F5F5F5;" align="center" + |↓
-|style="background:#F5F5F5;" align="center" + |
+| style="background:#F5F5F5;" align="center" + |Classic form
+| style="background:#F5F5F5;" align="center" + |Usually results from [[missense]] or [[nonsense mutations]]
 |-
-| style="background:#DCDCDC;" align="center" + |II
+| style="background:#DCDCDC;" align="center" + |Type II
-|style="background:#F5F5F5;" align="center" + |↔
+| style="background:#F5F5F5;" align="center" + |↔
-|style="background:#F5F5F5;" align="center" + |↔
+| style="background:#F5F5F5;" align="center" + |↔
-|style="background:#F5F5F5;" align="center" + |↓
+| style="background:#F5F5F5;" align="center" + |↓
-|style="background:#F5F5F5;" align="center" + |
+| style="background:#F5F5F5;" align="center" + |Rare qualitative defect
+| style="background:#F5F5F5;" align="center" + |Linked to [[missense mutations]]
 |-
-| style="background:#DCDCDC;" align="center" + |III
+| style="background:#DCDCDC;" align="center" + |Type III
-|style="background:#F5F5F5;" align="center" + |↔
+| style="background:#F5F5F5;" align="center" + |↔
-|style="background:#F5F5F5;" align="center" + |↓
+| style="background:#F5F5F5;" align="center" + |↓
-|style="background:#F5F5F5;" align="center" + |↓
+| style="background:#F5F5F5;" align="center" + |↓
-|style="background:#F5F5F5;" align="center" + |
+| style="background:#F5F5F5;" align="center" + |Quantitative defect
+| style="background:#F5F5F5;" align="center" + |Unknown
 |}
@@ Line 70: / Line 66: @@
 [[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>]]
 |}
 *[[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]]. <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>
+*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
+**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]].<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>
+***It is the only form that will take part in the [[coagulation cascade]].
-**[[C4b-binding protein|C4b]]-bound [[protein S]]
+**[[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. <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>
+***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  [[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>
+*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 mutations]] in the ''PROS1'' [[gene]]; however, rare cases of [[homozygous]] protein S deficiencies have been reported.
+*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>
 ==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:<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
+**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]]
+**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
+**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>
-==Differentiating Protein S deficiency from Other Diseases==
+==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 112: / Line 111: @@
 '''For more information on differentiating protein S deficiency, [[Thrombophilia differential diagnosis|click here.]]'''
 ==Epidemiology and Demographics==
@@ Line 119: / Line 119: @@
 ===Age===
-*Patients of all age groups may be diagnosed with protein S deficiency.
+*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.
+*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.
+*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===
-*Protein S deficiency usually affects individuals of the Asian race.
+*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.
 ==Risk Factors==
 *There are no established risk factors for protein S deficiency.
-*Family history of [[thrombosis]] poses increased risk for a mutation.
+*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 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 event such as 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>
+*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, patients with protein S deficiency are at high risk to develop life-threatening [[Venous thromboembolism|venous thromboembolic events]].
-*Specific complications and prognosis associated with [[pulmonary embolism]] can be found [[Pulmonary embolism natural history, complications and prognosis|here]] and for those related to [[deep vein thrombosis]], [[Deep vein thrombosis natural history, complications and prognosis|click here]].
+*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===
 *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 protein S's interaction with other [[proteins]], its complex genetic regulation, and its biologic variation.
+*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.
-*The diagnosis is made even more strenuous due to the the [[prevalence]] of acquired protein S deficiency causes ([[pregnancy]], [[liver disease]], [[DIC]]...).
+*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>
-*#Free protein S [[antigen]]
+*#Free protein S [[antigen]]:
 *#*Determines free [[protein S]] level in [[plasma]]
 *#*Most reliable of the three tests
 *#*Evaluates the function of protein S indirectly
 *#*[[Enzyme linked immunosorbent assay (ELISA)|ELISA technique]]
-*#Total protein S antigen
+*#Total protein S antigen:
 *#*Determines both free and bound protein S
 *#*[[Enzyme linked immunosorbent assay (ELISA)|ELISA technique]]
-*#Protein S activity [[assay]]
+*#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 protein S's function as a [[cofactor]] for 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|factor V Leiden mutation]] ([[resistance]] to activated protein C)<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>
+*#*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 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 thromboembolic events, and/or a known protein S deficient family member is suggestive of a protein S deficiency.
+*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 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]].
+*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>.
+*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===
 *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]]
+*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 cutoff for [[diagnosis]].
-*The exact levels used to differentiate patients with protein S deficiency from those without this deficiency depends on the patient's associated [[risk factors]] in addition to the [[hospital]] and [[laboratory]].
+*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>
 **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]].<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>
+**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]] [[Pulmonary embolism laboratory findings|click here]] or [[deep vein thrombosis]] [[Deep vein thrombosis laboratory tests|click here]].
+*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 specific [[ECG]] findings associated with protein S deficiency.
-*For ECG findings related to [[pulmonary embolism]] [[Pulmonary embolism electrocardiogram|click here]].
+*For ECG findings related to [[pulmonary embolism]], [[Pulmonary embolism electrocardiogram|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]] [[Pulmonary embolism chest x ray|click here]].
+*For specific x-ray findings seen with [[pulmonary embolism]], [[Pulmonary embolism chest x ray|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]] [[Deep vein thrombosis ultrasound|click here]].
+*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]].
+*For echocardiography findings associated with [[pulmonary embolism]], [[Pulmonary embolism echocardiography|click here]].
 ===CT scan===
 *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]]
+*For CT scan findings related to [[pulmonary embolism]], [[Pulmonary embolism CT|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.
+*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 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.
-**For management of patients suffering from [[pulmonary embolism]] [[Pulmonary embolism treatment approach|click here]].
+**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]].
+**For management of patient suffering from [[deep venous thrombosis]], [[Deep vein thrombosis treatment approach|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]], [[birth control|oral contraceptives]], [[immobility]]...).
+*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]]).
 *
 ===Surgery===
-* Surgical intervention is not recommended for the management of protein S deficiency.
+*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 [[birth control|oral contraceptives]] in women

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