eMedicine Specialties > Hematology > Coagulation, Hemostasis, and Disorders

Protein S Deficiency

Author: 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
Contributor Information and Disclosures

Updated: Aug 27, 2009

Introduction

Background

In 1979, researchers in Seattle, Wash, first discovered protein S and arbitrarily named it after the city of its discovery. Protein S is a vitamin K–dependent anticoagulant protein. Its major function 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 diseases or a vitamin K deficiency. Protein S deficiency usually manifests clinically as venous thromboembolism (VTE). The 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 deficiency manifests as an autosomal dominant trait; manifestations of thrombosis are observed in both heterozygous and homozygous genetic deficiencies of protein S.

Pathophysiology

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.1 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.

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. Image 1 shows a simplified outline of the function of protein S in the protein C system.

A simplified outline of the protein C system.

A simplified outline of the protein C system.

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A simplified outline of the protein C system.

A simplified outline of 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.

Furthermore, protein S interacts with the complement system and may play a role in phagocytosis of apoptotic cells. It has been recently observed that protein S binds to phosphatidyl serine on apoptotic cells and stimulates macrophage phagocytosis of early apoptotic cells. 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.

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.

A recent study by Heeb et al reported protein S has APC-independent anticoagulant activity, termed PS-direct, that directly inhibits thrombin generated by the factor Xa/factor Va prothrombinase complex,2 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.2

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.2

Researchers have identified 2 genes for human protein S and both are linked closely on chromosome 3p11.1-3q11.2. One gene is the active gene, PROS -b (ie, PROS1), and the other, PROS- a, is an evolutionarily duplicated nonfunctional gene, which is classified as a pseudogene because it contains multiple coding errors (eg, frameshifts, stop codons). The expressed (alpha) PROS1 gene is more than 80 kb long and contains 15 exons and 14 introns. The protein S pseudogene (beta) has 97% homology to the PROS -a gene.

Molecular studies into the genetic causes of protein S deficiency are complicated by the presence of the pseudogene, PROS- b, and phenotypic variation. Deletions of large portions of the PROS- a gene are associated with protein S deficiency and thrombophilia.3 Researchers located the first such deletion in the central portion of the PROS- a gene. The second deletion described (5.3 kb) was a deletion of coding exon XIII, which resulted in a truncated protein product.

Family members with either deletion exhibit protein S deficiency and thrombophilia; however, subsequent studies indicate that the most common genetic defects in the protein S gene are point mutations rather than gene deletions. Phenotypic variation has been observed in protein S deficiency. The coexistence of type I deficiency and type III deficiency in families with the same protein S mutation has been shown at least in one family to be due to an age-related increase in total protein S level. In this family, the apparent type III variant with only low free S blood levels, was explained by the age increase in total protein S. Younger persons in the family when tested for blood levels still had low total and free protein S.

Frequency

United States

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

Protein S deficiency is rare in the healthy population without abnormalities. Frequency is approximately 1 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%.4

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.5

International

Data for European studies indicated the same frequencies for protein S deficiency as in the United States. Recent 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%. However, Japanese patients with VTE have reported a frequency of approximately 12.7% protein S deficiency and similarly elevated population frequencies of approximately 0.63%.

Mortality/Morbidity

  • 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.
  • 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

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.

Sex

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

Age

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.

Clinical

History

  • Symptoms related to protein S deficiency are those associated with deep venous thrombosis (DVT), thrombophlebitis, or pulmonary embolus. As noted in Deterrence/Prevention, some women may have fetal loss as their only manifestation of a thrombophilic disorder (eg, protein S deficiency).
  • Venous thrombosis of the lower limbs: Lower limb swelling and discomfort are the usual symptoms. Occasionally, redness or discoloration also is present, with or without associated cellulitis.
  • A family history of thrombosis is an important finding, which suggests inherited thrombophilia.
  • Thrombosis at an early age (eg, usually <55 y) or recurrent thrombosis is also frequently indicative of an inherited thrombophilic state (eg, protein S deficiency).

Physical

Direct the examination to identify signs of venous thrombosis or pulmonary embolism. The results of the physical examination are nonspecific and often misleadingly indicate the diagnosis of DVT.

  • Deep vein thrombosis
    • The most common manifestation is venous thrombosis of the lower extremities, and this accounts for approximately 90% of all events.
    • Superficial veins that are obviously thrombosed usually appear distended, firm, and noncompressible (cords), with or without associated redness or pain.
    • Superficial thrombophlebitis can be observed in some cases, with or without DVT.
    • Suspect DVT if identifying signs of venous obstruction and local inflammation are present on examination.
    • The classic presentation of DVT is a triad of calf pain, edema, and pain on dorsiflexion of the foot (ie, Homans sign). However, less than a third of DVT cases exhibit these 3 findings. Physicians observe unilateral leg or calf swelling with mild or moderate pain more often, which suggests DVT. Rarely, calf discomfort without swelling is the only sign of DVT.
    • Differential diagnoses for DVT include muscle strains and tears, passive swelling of a paralyzed or immobilized limb, Baker cyst, cellulitis, knee trauma or derangement, lymphatic obstruction, and postphlebitic syndrome.
  • In postphlebitic syndrome, chronic swelling and pain are present in the limb, and the occurrence of a new venous thrombosis is often impossible to assess without Doppler or venography.
  • Pulmonary embolism
    • Some patients may have associated or isolated pulmonary embolism and may experience dyspnea, chest pain, syncope, or cardiac palpitations. Dyspnea is the most frequent symptom of pulmonary embolism, and tachypnea is the most frequent sign.
    • Some patients with massive pulmonary embolism can present with syncope or cyanosis.
    • Classic pleuritic chest pain, cough, or hemoptysis suggests an embolism with pleural involvement.
    • Acute right-sided heart failure occurs rarely and is associated with massive embolus.
    • Findings of right ventricular dysfunction include bulging neck veins, a left parasternal lift, and an accentuated pulmonic component of the second heart sound. These findings in the chest are also not specific for pulmonary embolism.
  • Unusual sites of thrombosis (eg, mesenteric vein,6 cerebral sinuses) are rare (<5%) but, when observed, characteristically suggest one of the inherited thrombophilias (eg, protein S deficiency).

Causes

  • The causes of protein S deficiency are due to genetic defects (hereditary) as described above in detail in the Pathophysiology section.
  • Acquired protein S deficiency
    • Rarely, an acquired disorder causes protein S deficiency. Acquired deficiencies of protein S occur with liver disease, vitamin K deficiency, or as a result of antagonism with oral warfarin anticoagulants.
    • Protein S levels decrease in pregnancy and can fall into the abnormal-low laboratory range. These low levels of protein S in pregnancy do not cause thrombosis by themselves.
    • Another seldom recognized cause for acquired protein S deficiency is sickle cell anemia; however, this condition alone does not produce a thrombophilic state.
    • 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. Type I deficiency is a reduction in both total and free protein S. Type III deficiency is isolated reduction in free protein S. When families with the same genetic type I defect are surveyed, older individuals even with deficiency in protein S have an increase in total S and now appear to have type III deficiency.

More on Protein S Deficiency

Overview: Protein S Deficiency
Differential Diagnoses & Workup: Protein S Deficiency
Treatment & Medication: Protein S Deficiency
Follow-up: Protein S Deficiency
Multimedia: Protein S Deficiency
References
Further Reading
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References

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  2. 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. Jul 2009;23(7):2244-53. [Medline].

  3. 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. May 21 2009;113(21):5314-22. [Medline].

  4. 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. Jan 2009;101(1):93-9. [Medline].

  5. 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].

  6. 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. Jun 2009;7(3):210-3. [Medline].

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  9. Baker ME, French FS, Joseph DR. Vitamin K-dependent protein S is similar to rat androgen-binding protein. Biochem J. Apr 1 1987;243(1):293-6. [Medline].

  10. Brill-Edwards P, Ginsberg JS, Johnston M, Hirsh J. Establishing a therapeutic range for heparin therapy. Ann Intern Med. Jul 15 1993;119(2):104-9. [Medline].

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  12. Dahlbäck B, Stenflo J. High molecular weight complex in human plasma between vitamin K-dependent protein S and complement component C4b-binding protein. Proc Natl Acad Sci U S A. Apr 1981;78(4):2512-6. [Medline].

  13. Di Scipio RG, Hermodson MA, Yates SG, Davie EW. A comparison of human prothrombin, factor IX (Christmas factor), factor X (Stuart factor), and protein S. Biochemistry. Feb 22 1977;16(4):698-706. [Medline].

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  15. Giri TK, Villoutreix BO, Wallqvist A, Dahlbäck B, de Frutos PG. Topological studies of the amino terminal modules of vitamin K-dependent protein S using monoclonal antibody epitope mapping and molecular modeling. Thromb Haemost. Nov 1998;80(5):798-804. [Medline].

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  22. 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. Aug 28 1990;29(34):7853-61. [Medline].

  23. Ridker PM, Hennekens CH, Lindpaintner K, Stampfer MJ, Eisenberg PR, Miletich JP. Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men. N Engl J Med. Apr 6 1995;332(14):912-7. [Medline].

  24. 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. Feb 1 1991;77(3):551-9. [Medline].

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

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  27. Simmonds RE, Zöller B, Ireland H, Thompson E, de Frutos PG, Dahlbäck B, et al. Genetic and phenotypic analysis of a large (122-member) protein S-deficient kindred provides an explanation for the familial coexistence of type I and type III plasma phenotypes. Blood. Jun 15 1997;89(12):4364-70. [Medline].

  28. Tait RC, Walker ID, Reitsma PH, Islam SI, McCall F, Poort SR, et al. Prevalence of protein C deficiency in the healthy population. Thromb Haemost. Jan 1995;73(1):87-93. [Medline].

  29. Walker MC, Garner PR, Keely EJ, Rock GA, Reis MD. Changes in activated protein C resistance during normal pregnancy. Am J Obstet Gynecol. Jul 1997;177(1):162-9. [Medline].

  30. 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. Jan 1988;71(1):238-41. [Medline].

  31. Zhang D, Hao J, Yang N. Protein C and D-dimer are related to portal vein thrombosis in patients with liver cirrhosis. J Gastroenterol Hepatol. Aug 3 2009;epub ahead of print. [Medline].

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Keywords

protein S deficiency, purpura fulminans, thrombosis, venous thromboembolism, VTE, arterial thrombosis, anticoagulants, blood clots, protein S and pregnancy, vitamin K–dependent anticoagulant protein, protein S, activated protein C, APC, activated factor V, FVa, activated factor VIII, FVIIIa, blood coagulation factor inhibitors

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Contributor Information and Disclosures

Author

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.

Medical Editor

Rodger L Bick, MD, PhD, FACP, Clinical Professor of Medicine, University of Texas Southwestern Medical Center; Director, Dallas and Pacific Thrombosis Hemostasis and Vascular Medicine Clinical Center
Rodger L Bick, MD, PhD, FACP is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Association of Blood Banks, American Cancer Society, American College of Angiology, American College of Physicians, American Geriatrics Society, American Heart Association, American Medical Association, American Society for Clinical Pathology, American Society of Hematology, Association of Clinical Scientists, California Medical Association, California Thoracic Society, International College of Angiology, International Society of Hematology, International Society on Thrombosis and Haemostasis, New York Academy of Sciences, and Southwest Oncology Group
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Troy H Guthrie, Jr, MD, Director of Cancer Institute, Baptist Medical Center
Troy H Guthrie, Jr, MD is a member of the following medical societies: American Federation for Medical Research, American Medical Association, American Society of Hematology, Florida Medical Association, Medical Association of Georgia, and Southern Medical Association
Disclosure: Nothing to disclose.

CME Editor

Rajalaxmi McKenna, MD, FACP, Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Thomas Jefferson University
Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Clinical Oncology, American Society of Hematology, and New York Academy of Sciences
Disclosure: Nothing to disclose.

 
 
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