Protein S Deficiency

Protein S Deficiency

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Protein S is a vitamin K–dependent anticoagulant protein that was first discovered in Seattle, Washington in 1979 and arbitrarily named after that city. The major function of protein S is as a cofactor to facilitate the action of activated protein C (APC) on its substrates, activated factor V (FVa) and activated factor VIII (FVIIIa). Protein S deficiencies are associated with thrombosis.

Protein S deficiency may be hereditary or acquired; the latter is usually due to hepatic disease or a vitamin K deficiency. Protein S deficiency usually manifests clinically as venous thromboembolism (VTE).

Any association of protein S deficiency with arterial thrombosis appears coincidental or weak at best. Arterial thrombosis is not evident with other hereditary anticoagulant abnormalities (eg, protein C or antithrombin III deficiency, factor V Leiden gene mutation).

Protein S and C levels are lower in sickle cell anemia and they decrease further significantly during crisis. [1]

Hereditary protein S deficiency is an autosomal dominant trait. Thrombosis is observed in both heterozygous and homozygous genetic deficiencies of protein S.

Protein S deficiency is diagnosed using laboratory tests for the protein S antigen and by using other tests for functional protein S activity (based on clotting assays); see Workup. Management takes place in the event of acute VTE. Prophylaxis may be used in selected patients with asymptomatic carrier states without a thrombotic event. (See Treatment and Medication.)

For patient education information, see Deep Vein Thrombosis.

To understand how thrombosis occurs in protein S deficiency, its physiological function should be briefly reviewed. Protein S is part of a system of anticoagulant proteins that regulate normal coagulation mechanisms in the body. [2] Under most normal circumstances, the anticoagulant proteins prevail and blood remains in a liquid nonthrombotic state. Whenever procoagulant forces are locally activated to form a physiologic or pathologic clot, protein S participates as part of one mechanism of controlling clot formation. [3, 4, 5]

Protein S functions predominantly as a nonenzymatic cofactor for the action of another anticoagulant protein, activated protein C (APC). This activity occurs via a coordinated system of proteins, termed the protein C system. The image below shows a simplified outline of the function of protein S in the protein C system.

During the process of clotting, multimolecular complexes are formed on membrane surfaces. These membranes are usually negatively charged phospholipids and/or activated platelets. These multimolecular complexes are referred to as the tenase and prothrombinase complexes for their key activities of activation of factor X and prothrombin, respectively. Anchoring these two complexes are the activated form of factor VIII (FVIIa) used for the tenase complex and the activated form of factor V (FVa) for the prothrombinase complex. These two large proteins are homologous in structure and are cofactors, not enzymes, in the clotting process.

In one of many examples of nature’s efficiency, the same enzyme that clots blood, thrombin, is converted from clotting to an anticoagulant mechanism on the surface of the endothelium and it then activates protein C to its active enzymatic form, APC. APC requires protein S as a cofactor in its enzymatic action on its 2 substrates, FVa and FVIIIa. Thus, this process is designed to dampen and shut off clotting by switching off the key cofactor proteins FVa and FVIIIa. Protein S and APC are sufficient to inactivate FVa. However, for the inactivation of FVIIIa, APC and protein S require the help of the nonactivated clotting protein, factor V. This is another example of dual use of a protein in this same process.

Factor Va as noted above is cleaved by APC to an inactive form. However, in assisting protein S to inactivate FVIIIa, it is the inactive FV that is cleaved by APC. An important consequence of this dual procoagulant and anticoagulant property of factor V, is that the mutant factor V Leiden, which resists APC cleavage, cannot be switched off but also cannot function here at this step as an anticoagulant protein (see factor V Leiden gene mutation in Race). In addition to its cofactor role in the protein C system, protein S functions independently of protein C to directly inhibit the factor X clotting factor–activating complex and the prothrombin-activating complex. [6, 7]

Furthermore, protein S interacts with the complement system and may play a role in phagocytosis of apoptotic cells. Protein S binds to phosphatidyl serine on apoptotic cells and stimulates macrophage phagocytosis of early apoptotic cells. [8] The physiological impact of protein S deficiencies on these nonanticoagulant roles of protein S is not yet known.

Protein S is a single-chain glycoprotein, and it is dependent on vitamin K action for posttranslational modification of the protein to a normal functional state. Vitamin K–dependent proteins are synthesized with a unique recognition propeptide piece. The propeptide sequence serves as a recognition site for the vitamin K–dependent gamma-carboxylase enzyme that modifies the nearby glutamic acid residues to gamma-carboxyglutamic acid (Gla) residues. Gla residues are responsible for calcium-dependent binding to membrane surfaces. Structural studies indicate that protein S contains 10-12 Gla residues, a loop region sensitive to thrombin (ie, thrombin-sensitive region [TSR]), 4 epidermal growth factor (EGF)–like modules, and a carboxy-terminal portion that is homologous to a sex hormone-binding globulin (SHBG)–like region.

In blood plasma, protein S exists in both a bound and a free state. A portion of protein S is noncovalently bound with high affinity to the complement regulatory protein C4b-binding protein (C4BP). The C4BP molecule consists of 7 alpha chains that bind to the complement protein, C4b, and one beta chain. The beta chain of the C4bBP molecules contains the binding sites for protein S. The role of protein S in complement regulation by C4BP is not completely understood.

In healthy individuals, approximately 30-40% of total protein S is in the free state. Only free protein S is capable of acting as a cofactor in the protein C system. This distinction between free and total protein S levels is important and gives rise to the current terminology regarding the deficiency states. Type I protein S deficiency is a reduction in the level of free and total protein S. Type III deficiency is a reduction in the level of free protein S only. Type II deficiency is a reduction in the cofactor activity of protein S, with normal antigenic levels.

Age affects total protein S but not free protein S levels. Generally, the total protein S level increases in persons older than 50 years. This rise is in association with total increases in the complement binding protein, C4BP. Free protein S levels do not increase with age. These factors may explain the observation that families with the same recognized genetic defect in protein S can have both type I and type III deficiencies. When families with the same genetic type I defect are surveyed, older individuals even with deficiency in protein S have an increase in total protein S and now appear to have type III deficiency.

APC and protein S require negatively charged phospholipids (PL) and Ca2+ for normal anticoagulant activity. Studies of the structure and function relationships of protein S demonstrate that the APC interaction sites are located in the Gla, TSR, and first EGF-like modules of protein S. The binding site for C4BP is located in the SHBG-like region, which is also important for full anticoagulant activity.

Heeb et al reported that protein S has APC-independent anticoagulant activity, termed PS-direct, that directly inhibits thrombin generated by the factor Xa/factor Va prothrombinase complex, a process made possible by the presence of zinc (Zn2+) content in protein S. The investigators found Zn2+ content positively correlated with PS-direct in prothrombinase and clotting assays, but the APC-cofactor activity of protein S was independent of Zn2+ content. In addition, protein S that contained Zn2+ bound factor Xa more efficiently than protein S without Zn2+, and, independent of Zn2+ content, protein S also efficiently bound tissue factor pathway inhibitor. [9]

Heeb et al suggested that conformation differences at or near the interface of 2 laminin G-like domains near the protein S C terminus may indicate that Zn2+ is necessary for PS-direct and efficient factor Xa binding and could have a role in stabilizing protein S conformation. [9]

United States

Congenital protein S deficiency is an autosomal dominant disease, and the heterozygous state occurs in approximately 2% of unselected patients with venous thromboembolism (VTE).

Protein S deficiency is rare in the healthy population without abnormalities. Frequency is approximately one out of 700 based on extrapolations from a study of over 9000 blood donors who were tested for protein C deficiency. When looking at a selected group of patients with recurrent thrombosis or family history of thrombosis, the frequency of protein S deficiency increases to 3-6%. [10]

Very rarely, protein S deficiency occurs as a homozygous state, and these individuals have a characteristic thrombotic disorder, purpura fulminans. Purpura fulminans is characterized by small-vessel thrombosis with cutaneous and subcutaneous necrosis, and it appears early in life, usually during the neonatal period or within the first year of life. [11]

International

Data for European studies indicated the same frequencies for protein S deficiency as in the United States. Studies have indicated that the prevalence of protein S deficiency is particularly high in the Japanese population. In several reported series of patients with VTE in the United States, protein S deficiency was seen in 1-7% of patients. The deficiency is rare in population surveys of Caucasians, at approximately 0.03%.

Japanese patients with VTE have reported a frequency of approximately 12.7% protein S deficiency and similarly elevated population frequencies of approximately 0.48%-0.63%. [12] In a Japanese study that evaluated patients with VTE for congenital thrombophilia, Ikejiri et al diagnosed congenital protein S deficiency in eight of 130 patients (6.2%). [13]

VTE develops in 60-80% of patients who are heterozygous for protein S deficiency. The remaining patients are asymptomatic, and some heterozygous individuals never develop VTE.

Though it is controversial, no clear association exists between protein S deficiency and arterial thrombosis. Many case reports and small case series describe protein S deficiency as one factor found in patients with arterial thrombosis, most commonly stroke. However, prospective and cohort studies have not shown convincing increased risk for arterial thrombosis.

Protein S deficiency is also associated with fetal loss in women, in the absence of VTE. Some authors suggest that as many as 40% of women with obstetric complications other than VTE may carry some form of thrombophilia. Protein S deficiency is one of these factors along with several other more common genetic thrombophilic states.

Cases of warfarin-induced skin necrosis have been reported in patients with protein S deficiency. [14]

Mortality is from pulmonary embolism. In several studies, the 3-month mortality rate of pulmonary embolism ranged from 10.0-17.5%. In a study of Medicare recipients with pulmonary embolism, men had a 13.7% mortality rate compared to 12.8% in women; the mortality rate was 16.1% in blacks, compared to 12.9% in whites.

Race-related variations exist in thrombophilic disorders, as one may expect from genetic-based population traits. In general, a significant difference exists in the frequency of thrombophilic disorders in whites compared with thrombophilic disorders in Japanese (Asian) and black African persons. Current research indicates that protein S deficiency is 5-10 times higher in Japanese populations compared with Caucasians. Protein C deficiency is estimated to be 3 times higher in Japanese populations.

The factor V Leiden mutation is common in white populations and is now known to be the result of a founder effect estimated to be 30,000 years old. This mutation is rare and almost never found in Japanese or Asian populations. In general, black Africans and African Americans with VTE have a lower detection of any of the currently recognized thrombophilic disorders, especially factor V Leiden.

No difference exists in the male-to-female rate of occurrence.

Protein S deficiency is a hereditary disorder, but the age of onset of thrombosis varies by heterozygous versus homozygous state. Most VTE events in heterozygous protein S deficiency occur in persons younger than 40-45 years. The rare homozygous patients have neonatal purpura fulminans, as described above; onset occurs in early infancy. As noted above in the discussion on genetics, age does affect total protein S antigen levels, but not free protein S levels. Older patients deficient in protein S have low free S levels, even if their total protein S level rises into the normal range.

Piccin A, Murphy C, Eakins E, Kinsella A, McMahon C, Smith OP, et al. Protein C and free protein S in children with sickle cell anemia. Ann Hematol. 2012 Oct. 91 (10):1669-71. [Medline].

Castoldi E, Hackeng TM. Regulation of coagulation by protein S. Curr Opin Hematol. 2008 Sep. 15(5):529-36. [Medline].

Soare AM, Popa C. Deficiencies of proteins C, S and antithrombin and activated protein C resistance–their involvement in the occurrence of Arterial thromboses. J Med Life. 2010 Oct-Dec. 3(4):412-5. [Medline]. [Full Text].

Castoldi E, Maurissen LF, Tormene D, Spiezia L, Gavasso S, Radu C, et al. Similar hypercoagulable state and thrombosis risk in type I and type III protein S-deficient individuals from families with mixed type I/III protein S deficiency. Haematologica. 2010 Sep. 95(9):1563-71. [Medline]. [Full Text].

Marlar RA, Gausman JN. Protein S abnormalities: a diagnostic nightmare. Am J Hematol. 2011 May. 86(5):418-21. [Medline].

Hackeng TM, Rosing J. Protein S as cofactor for TFPI. Arterioscler Thromb Vasc Biol. 2009 Aug 6. epub ahead of print. [Medline].

Heeb MJ, Rosing J, Bakker HM, Fernandez JA, Tans G, Griffin JH. Protein S binds to and inhibits factor Xa. Proc Natl Acad Sci U S A. 1994 Mar 29. 91(7):2728-32. [Medline].

Anderson HA, Maylock CA, Williams JA, Paweletz CP, Shu H, Shacter E. Serum-derived protein S binds to phosphatidylserine and stimulates the phagocytosis of apoptotic cells. Nat Immunol. 2003 Jan. 4 (1):87-91. [Medline].

Heeb MJ, Prashun D, Griffin JH, Bouma BN. Plasma protein S contains zinc essential for efficient activated protein C-independent anticoagulant activity and binding to factor Xa, but not for efficient binding to tissue factor pathway inhibitor. FASEB J. 2009 Jul. 23(7):2244-53. [Medline]. [Full Text].

Brouwer JL, Lijfering WM, Ten Kate MK, Kluin-Nelemans HC, Veeger NJ, van der Meer J. High long-term absolute risk of recurrent venous thromboembolism in patients with hereditary deficiencies of protein S, protein C or antithrombin. Thromb Haemost. 2009 Jan. 101(1):93-9. [Medline].

Edlich RF, Cross CL, Dahlstrom JJ, Long WB 3rd. Modern concepts of the diagnosis and treatment of purpura fulminans. J Environ Pathol Toxicol Oncol. 2008. 27(3):191-6. [Medline].

Adachi T. Protein S and congenital protein S deficiency: the most frequent congenital thrombophilia in Japanese. Curr Drug Targets. 2005 Aug. 6(5):585-92. [Medline].

Ikejiri M, Wada H, Yamada N, Nakamura M, Fujimoto N, Nakatani K, et al. High prevalence of congenital thrombophilia in patients with pregnancy-related or idiopathic venous thromboembolism/pulmonary embolism. Int J Hematol. 2017 Mar. 105 (3):272-279. [Medline].

Fraga R, Diniz LM, Lucas EA, Emerich PS. Warfarin-induced skin necrosis in a patient with protein S deficiency. An Bras Dermatol. 2018 Jul-Aug. 93 (4):612-613. [Medline]. [Full Text].

Alvi AR, Khan S, Niazi SK, Ghulam M, Bibi S. Acute mesenteric venous thrombosis: improved outcome with early diagnosis and prompt anticoagulation therapy. Int J Surg. 2009 Jun. 7(3):210-3. [Medline].

Watkins PC, Eddy R, Fukushima Y, Byers MG, Cohen EH, Dackowski WR, et al. The gene for protein S maps near the centromere of human chromosome 3. Blood. 1988 Jan. 71(1):238-41. [Medline].

Ploos van Amstel HK, Reitsma PH, van der Logt CP, Bertina RM. Intron-exon organization of the active human protein S gene PS alpha and its pseudogene PS beta: duplication and silencing during primate evolution. Biochemistry. 1990 Aug 28. 29(34):7853-61. [Medline].

Schmidel DK, Tatro AV, Phelps LG, Tomczak JA, Long GL. Organization of the human protein S genes. Biochemistry. 1990 Aug 28. 29(34):7845-52. [Medline].

Gomez E, Poort SR, Bertina RM, Reitsma PH. Identification of eight point mutations in protein S deficiency type I–analysis of 15 pedigrees. Thromb Haemost. 1995 May. 73(5):750-5. [Medline].

Jang MA, Kim SH, Kim DK, Kim HJ. A novel nonsense mutation Tyr301* of PROS1 causing protein S deficiency. Blood Coagul Fibrinolysis. 2015 Mar. 26 (2):223-4. [Medline].

Huang X, Xu F, Assa CR, Shen L, Chen B, Liu Z. Recurrent pulmonary embolism associated with deep venous thrombosis diagnosed as protein s deficiency owing to a novel mutation in PROS1: A case report. Medicine (Baltimore). 2018 May. 97 (19):e0714. [Medline]. [Full Text].

Lijfering WM, Brouwer JL, Veeger NJ, Bank I, Coppens M, Middeldorp S, et al. Selective testing for thrombophilia in patients with first venous thrombosis: results from a retrospective family cohort study on absolute thrombotic risk for currently known thrombophilic defects in 2479 relatives. Blood. 2009 May 21. 113(21):5314-22. [Medline].

Ploos van Amstel HK, Huisman MV, Reitsma PH, Wouter ten Cate J, Bertina RM. Partial protein S gene deletion in a family with hereditary thrombophilia. Blood. 1989 Feb. 73(2):479-83. [Medline].

Schmidel DK, Nelson RM, Broxson EH Jr, Comp PC, Marlar RA, Long GL. A 5.3-kb deletion including exon XIII of the protein S alpha gene occurs in two protein S-deficient families. Blood. 1991 Feb 1. 77(3):551-9. [Medline].

Castoldi E, Simioni P, Tormene D, Rosing J, Hackeng TM. Hereditary and acquired protein S deficiencies are associated with low TFPI levels in plasma. J Thromb Haemost. 2010 Feb. 8 (2):294-300. [Medline]. [Full Text].

Yilmaz S, Gunaydin S. Inherited risk factors in low-risk venous thromboembolism in patients under 45 years. Interact Cardiovasc Thorac Surg. 2014 Oct 17. [Medline].

Klostermeier UC, Limperger V, Kenet G, Kurnik K, Alhenc Gelas M, Finckh U, et al. Role of protein S deficiency in children with venous thromboembolism. An observational international cohort study. Thromb Haemost. 2014 Oct 2. 113(1):[Medline].

Tripodi A, Asti D, Chantarangkul V, Biguzzi E, Mannucci PM. Interference of factor V Leiden on protein S activity: evaluation of a new prothrombin time-based assay. Blood Coagul Fibrinolysis. 2007 Sep. 18(6):543-6. [Medline].

Alshaikh NA, Rosing J, Thomassen MCLGD, Castoldi E, Simioni P, Hackeng TM. 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. 2017 May. 15 (5):950-960. [Medline].

Ameku K, Higa M. Rivaroxaban Treatment for Warfarin-Refractory Thrombosis in a Patient with Hereditary Protein S Deficiency. Case Rep Hematol. 2018. 2018:5217301. [Medline]. [Full Text].

Mohammad Muhsin Chisti, MD, FACP Assistant Professor of Hematology and Oncology, Medical Director of Research, Karmanos Cancer Institute, Wayne State University School of Medicine

Mohammad Muhsin Chisti, MD, FACP is a member of the following medical societies: American College of Physicians, American Medical Association, American Society of Clinical Oncology, American Society of Hematology, Medical Society of the State of New York

Disclosure: Nothing to disclose.

Suma Chinta, MD, MBBS Resident Physician, Department of Internal Medicine, St Joseph Mercy Oakland Hospital

Suma Chinta, MD, MBBS is a member of the following medical societies: American College of Physicians, Medical Council of India

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Perumal Thiagarajan, MD Professor, Department of Pathology and Medicine, Baylor College of Medicine; Director, Transfusion Medicine and Hematology Laboratory, Michael E DeBakey Veterans Affairs Medical Center

Perumal Thiagarajan, MD is a member of the following medical societies: American College of Physicians, American Heart Association, American Society for Biochemistry and Molecular Biology, American Society for Clinical Investigation, American Society of Hematology, Association of American Physicians, Royal College of Physicians

Disclosure: Nothing to disclose.

John E Godwin, MD, MS Professor of Medicine, Chief Division of Hematology/Oncology, Associate Director, Simmons Cooper Cancer Institute, Southern Illinois University School of Medicine

John E Godwin, MD, MS is a member of the following medical societies: American Association for the Advancement of Science, American Heart Association, and American Society of Hematology

Disclosure: Nothing to disclose.

Protein S Deficiency

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