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| __NOTOC__ | | __NOTOC__ |
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| {{CMG}}; {{AE}}{{RAK}}
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| ==Overview==
| | Cardiac surgery<ref name="pmid23447502">{{cite journal| author=Aya HD, Cecconi M, Hamilton M, Rhodes A| title=Goal-directed therapy in cardiac surgery: a systematic review and meta-analysis. | journal=Br J Anaesth | year= 2013 | volume= 110 | issue= 4 | pages= 510-7 | pmid=23447502 | doi=10.1093/bja/aet020 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23447502 }} </ref> |
| 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 VIIa and thereby controlling the coagulation cascade.
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| ==Historical Perspective==
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| *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.
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| *The function of this protein was still unknown; however, it was hypothesized that protein S plays a role in activating protein C.
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| *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. <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>
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| ==Classification==
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| 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:
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| *'''Type I:''' Reduced total protein S, free protein S, and protein S function
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| 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, microdeletions, and splice site mutations have occurred with this type. <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>
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| *'''Type II:''' Normal total and free protein S, reduced protein S function
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| 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 the protein S's ability to bind to the activated protein C. <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>
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| *'''Type III:''' Normal total protein S, reduced free protein S and protein S function
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| This is a quantitative defect.
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| {| class="wikitable sortable"
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| !Type
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| !Total Protein S
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| !Free Protein S
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| !Protein S Function
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| |-
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| |I
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| |↓
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| |↓
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| |↓
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| |-
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| |II
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| |↔
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| |↔
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| |↓
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| |-
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| |III
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| |↔
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| |↓
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| |↓
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| |}
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| ==Pathophysiology==
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| {| align="right"
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| [[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>]]
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| |}
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| *Protein S is a natural anticoagulant that works with other proteins to regulate coagulation in the body.
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| *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>
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| **The vitamin K-dependent gamma-carboxyalse enzyme acts by modifying the glutamic acid residues in protein S to gamma-carboxyglutamic acid residues.
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| **These gamma-carboxyglutamic acid residues are needed to ensure calcium-dependent binding to membrane surfaces.
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| *The now mature and activated protein S will circulate in the blood in two states:
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| **Free protein S
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| ***This form constitutes 30 to 40 percent of the total protein S in the body.
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| ***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>
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| **C4b-bound protein S
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| ***There is a high affinity interaction between protein S and C4b-binding protein.
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| ***C4b-binding protein is a complement regulator; hence, it is responsible for controlling the activity of protein S.
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| ***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>
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| *The activated free protein S acts as a cofactor to activated protein C, and with the help of phospholipids and Ca<sup>2+</sup>, inactivates factor Va and 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>
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| *
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| ==Clinical Features==
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| ==Differentiating [disease name] from other Diseases==
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| ==Epidemiology and Demographics==
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| *The prevalence of protein S deficiency is approximately 90 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>
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| ===Age===
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| *The age of onset of thromboembolic events varies by heterozygous vs homozygous.
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| **The thromboembolic events seen in heterozygous protein S deficiency usually occurs in individuals younger that 40-50 years of age.
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| **The homozygous patients have neonatal purpura fulminans at birth.
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| ===Gender===
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| *There is no difference in the prevalence of the disease between men and women.
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| ===Race===
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| *Current data shows that protein S deficiency affects Asians 5 to 10 times more than caucasians.
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| ==Risk Factors==
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| == Natural History, Complications and Prognosis==
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| == Diagnosis ==
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| ===Diagnostic Criteria===
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| === Symptoms ===
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| === Physical Examination ===
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| === Laboratory Findings ===
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| ===Imaging Findings===
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| === Other Diagnostic Studies ===
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| == Treatment ==
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| === Medical Therapy ===
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| === Surgery ===
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| === Prevention ===
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| ==References==
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| {{Reflist|2}}
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