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{{CMG}}; {{AE}}{{RAK}}


==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 [[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]].
 
==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]].
*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>
 
*'''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. <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>
 
*'''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]]. <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 III:''' Normal total protein S, reduced free protein S and protein S function
This is a quantitative defect.
 
{| class="wikitable sortable"
|+
!Type
!Total Protein S
!Free Protein S
!Protein S Function
|-
|I
|↓
|↓
|↓
|-
|II
|↔
|↔
|↓
|-
|III
|↔
|↓
|↓
|}
 
==Pathophysiology==
{| 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>]]
|}
*[[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>
**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
***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>
**[[C4b-binding protein|C4b]]-bound [[protein S]]
***There is a high [[affinity]] interaction between [[protein S]] and [[C4b-binding protein]].
***[[C4b-binding protein]] is a [[complement]] regulator; hence, it is responsible for controlling the activity of protein S.
***Around 70 percent of circulating protein S is in the bound form. <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>
 
*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.
*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
***[[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>
 
==Differentiating Protein S deficiency from Other Diseases==
Protein S deficiency must be differentiated from other diseases that cause symptoms of [[DVT]] and [[pulmonary embolism]] such as:
*[[Factor V Leiden mutation]]
*[[Antithrombin III deficiency]]
*[[Protein C deficiency]]
*[[Prothrombin gene mutation G20210A|Prothrombin gene mutation]]
*[[Disseminated intravascular coagulation|Disseminated intravascular coagulation (DIC)]]
*[[Antiphospholipid antibody syndrome]]
 
'''For more information on differentiating protein S deficiency, [[Thrombophilia differential diagnosis|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. <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.
*It is; however, more commonly observed among patients younger than 40 to 50 years old.
 
===Gender===
 
*There is no difference in the [[prevalence]] of the [[disease]] between men and women.
===Race===
 
*Protein S deficiency usually affects individuals of the Asian race.
*Caucasian individuals are less likely to develop protein S deficiency.
 
==Risk Factors==
*There are no established risk factors for protein S deficiency.
*Family history of [[thrombosis]] poses increased risk for a mutation.
 
==Screening==
*There is insufficient evidence to recommend routine [[screening]] for protein S deficiency in the general population.
*A simple positive family history incident of [[thrombosis]] is not enough to recommend [[screening]] in an [[asymptomatic]] low risk individual.<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>
*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]].
 
==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 is made even more strenuous due to the the [[prevalence]] of acquired protein S deficiency causes ([[pregnancy]], [[liver disease]], [[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]]
*#*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
*#*Determines both free and bound protein S
*#*[[Enzyme linked immunosorbent assay (ELISA)|ELISA technique]]
*#Protein S activity [[assay]]
*#*Assesses protein S's function 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>
 
===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.
*The most common sites of venous thromboembolism include [[deep vein thrombosis]] and [[pulmonary embolism]]. For detailed symptoms associated with protein S deficiency refer to [[deep vein thrombosis history and symptoms]] and [[pulmonary embolism history and symptoms]].
*Less common sites of venous thromboembolism include [[cerebral 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]]
 
===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]].
**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>
*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]].
 
===Electrocardiogram===
*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 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 protein S deficiency.
 
===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]]
 
===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 [[Pulmonary embolism 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, oral contraceptives, 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==
{{Reflist|2}}

Latest revision as of 15:09, 26 March 2021


Cardiac surgery[1]

  1. ↑ Aya HD, Cecconi M, Hamilton M, Rhodes A (2013). "Goal-directed therapy in cardiac surgery: a systematic review and meta-analysis". Br J Anaesth. 110 (4): 510–7. doi:10.1093/bja/aet020. PMID 23447502.
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